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40e70249b62230389ec7faecd6dd881a *tests/test.methods.haplo.glm.Rout.save haplo.stats/man/0000755000176000001440000000000012075615022013315 5ustar ripleyusershaplo.stats/man/seqhap.dat.Rd0000644000176000001440000000410211551405165015634 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2009/04/27 21:22:07 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/seqhap.dat.Rd,v 1.8 2009/04/27 21:22:07 sinnwell Exp $ % $Locker: $ % $Log: seqhap.dat.Rd,v $ % Revision 1.8 2009/04/27 21:22:07 sinnwell % em to emph % % Revision 1.7 2009/04/09 20:25:06 sinnwell % add log keyword for RCS % \name{seqhap.dat} \alias{seqhap.dat} \alias{seqhap.pos} \title{ Simulated data for seqhap examples } \description{ Simulated data set for the demonstration of seqhap functionality. Contains one column for disease status and columns representing 10 SNP loci with a known association. seqhap.pos contains a column for chromosome position, as required by seqhap. } \usage{ data(seqhap.dat) data(seqhap.pos) } \format{ A data frame with 1000 observations on the following 21 variables. \describe{ \item{\code{disease}}{numeric, indicator of disease status 0=no, 1=yes} \item{\code{m1.1}}{first allele of genotype} \item{\code{m1.2}}{second allele of genotype} \item{\code{m2.1}}{first allele of genotype} \item{\code{m2.2}}{second allele of genotype} \item{\code{m3.1}}{first allele of genotype} \item{\code{m3.2}}{second allele of genotype} \item{\code{m4.1}}{first allele of genotype} \item{\code{m4.2}}{second allele of genotype} \item{\code{m5.1}}{first allele of genotype} \item{\code{m5.2}}{second allele of genotype} \item{\code{m6.1}}{first allele of genotype} \item{\code{m6.2}}{second allele of genotype} \item{\code{m7.1}}{first allele of genotype} \item{\code{m7.2}}{second allele of genotype} \item{\code{m8.1}}{first allele of genotype} \item{\code{m8.2}}{second allele of genotype} \item{\code{m9.1}}{first allele of genotype} \item{\code{m9.2}}{second allele of genotype} \item{\code{m10.1}}{first allele of genotype} \item{\code{m10.2}}{second allele of genotype} } } \references{ Yu Z, Schaid DJ (2007) Sequantial haplotype scan methods for association analysis. \emph{Gen Epi}, in print. } \examples{ data(seqhap.dat) } \keyword{datasets} haplo.stats/man/haplo.design.Rd0000644000176000001440000000447211656766745016215 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.design.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: \name{haplo.design} \alias{haplo.design} \title{ Build a design matrix for haplotypes } \description{ Build a design matrix for haplotypes estimated from a haplo.em object. } \usage{ haplo.design(obj, haplo.effect="additive", hapcodes=NA, min.count=5, haplo.base=NA) } \arguments{ \item{obj}{ an object created from haplo.em } \item{haplo.effect }{ The "effect" pattern of haplotypes on the response. This parameter determines the coding for scoring the haplotypes. Valid coding options for heterozygous and homozygous carriers of a haplotype are "additive" (1, 2, respectively), "dominant" (1,1, respectively), and "recessive" (0, 1, respectively). } \item{hapcodes}{ codes assigned in haplo.em, corresponding to the row numbers in the obj\$haplotypes matrix } \item{min.count }{ The minimum number of estimated counts of the haplotype in the sample in order for a haplotype to be included in the design matrix. } \item{haplo.base }{ code for which haplotype will be the reference group, or to be considered the baseline of a model. The code is the row number of the obj\$haplotypes matrix. This haplotype is removed from the design matrix. } } \value{ Matrix of columns for haplotype effects. Column names are "hap.k" where k is the row number of the unique haplotypes within the haplo.em object's "haplotypes" item. } \details{ First a matrix is made for the possible haplotypes for each person, coded for the haplo.effect, weighted by the posterior probability of those possible haplotypes per person, and then collapsed back to a single row per person. } \seealso{ \code{\link{haplo.em}} } \examples{ ###------------------------------------------------ ### See the user manual for more complete examples ###------------------------------------------------ data(hla.demo) attach(hla.demo) geno <- hla.demo[,c(17,18,21:24)] label <-c("DQB","DRB","B") keep <- !apply(is.na(geno) | geno==0, 1, any) save.em.keep <- haplo.em(geno=geno[keep,], locus.label=label) save.df <- haplo.design(save.em.keep, min.count=10) dim(save.df) names(save.df) save.df[1:10,] } \keyword{models} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/f.power.Rd0000644000176000001440000000177611650343656015210 0ustar ripleyusers\name{f.power} \alias{f.power} \alias{f.power.dif} \alias{f.sample.size} \title{ Power and sample size for the F distribution } \description{ Power and sample size for the F distribution given non-centrality, degrees of freedom, alpha, N (for f.power), and power (for f.sample.size) } \usage{ f.power(n, nc, df1, alpha) f.power.dif(n, nc, df1, alpha, power) f.sample.size(nc, df1, alpha, power, lower=20, upper=10000) } \arguments{ \item{n}{ sample size } \item{nc}{ non-centrality parameter } \item{df1}{ degrees of freedom for numerator of f distribution } \item{alpha}{ type-I error } \item{power}{ desired power (for sample size) } \item{lower}{ lower limit for search space for sample size solution } \item{upper}{ upper limit for search space for sample size solution } } \value{ power, the difference in power from target power, and sample size, respectively for the three functions, assuming an F distribution for the test statistic } \keyword{power} % docclass is function % Converted by Sd2Rd version 43268. haplo.stats/man/haplo.power.cc.Rd0000644000176000001440000001352411551405165016436 0ustar ripleyusers\name{haplo.power.cc} \alias{haplo.power.cc} \alias{haplo.power.cc.ncp} \alias{find.intercept.logistic} \title{ Compute either power or sample size for haplotype associations in a case-control study. } \description{ For a given set of haplotypes, their population frequencies, and assumed logistic regression coefficients (log-odds-ratios per haplotype, assuming a log-additive model of haplotype effects), determine either the sample size (total number of subjects) to achieve a stated power or the power for a stated sample size. } \usage{ haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac, prevalence, alpha, sample.size=NULL, power=NULL) } \arguments{ \item{haplo}{ matrix of haplotypes, with rows the different haplotypes and columns the alleles of the haplotypes. For H haplotypes of L loci, haplo has dimension H x L. } \item{haplo.freq }{ vector of length H for the population haplotype frequencies (corresponding to the rows of haplo) } \item{base.index }{ integer index of the haplotype considered to be the base-line for logistic regression (index between 1 and H); often, the most common haplotype is chosen for the base-line. } \item{haplo.beta }{ vector of length H for the haplotype effects: each beta is the log-odds-ratio for the corresponding haplotype effect. The base-line hapoltype should have a beta=0, as this base-line beta coefficient will be automatically calculated according to the haplotype frequencies, the other haplo.beta's, and the disease prevalence. } \item{case.frac }{ fraction of cases in the total sample size (e.g., case.frac = .5 for typical case-control studies with equal numbers of cases and controls) } \item{prevalence}{ popultaion disease prevalence (used to calculate the base-line intercept beta) } \item{alpha}{ type-I error rate } \item{sample.size }{ total sample size (if power is to be calcualted). Either sample.size or power must be specified, but not both. } \item{power}{ desired power (if sample.size is to be calculated). Either sample.size or power must be specified, but not both. } } \value{ list with components: \item{ss.phased.haplo}{ sample size for phased haplotypes } \item{ss.unphased.haplo}{ sample size for unphased haplotypes } \item{power.phased.haplo}{ power for phased haplotypes } \item{power.unphased.haplo}{ power for unphased haplotypes } } \details{ Asympotic power calcuations are based on the non-centrality parameter of a non-central chi-square distribution. This non-centrality parameter is determined by the specified regression coefficients ( values in haplo.beta), as well as the distribution of haplotypes (determined by haplo.freq). To account for haplotypes with unknown phase, all possible haplotype pairs are enumerated, and the EM algorithm is used to determine the posterior probabilities of pairs of haplotypes, conditional on unphased genotype data. Because this function uses the function haplo.em, the number of possible haplotypes can be large when there is a large number of loci (i.e., large number of columns in the haplo matrix). If too large, the function haplo.em will run out of memory, making this function (haplo.power.cc) fail. If this occurs, then consider reducing the "size" of the haplotypes, by reducing the number of columns of haplo, and adjusting the corresponding vectors (e.g., haplo.freq, haplo.beta). } \references{ Schaid, DJ. Power and sample size for testing associations of haplotypes with complex traits. Ann Hum Genet (2005) 70:116-130. } \seealso{ \code{\link{haplo.em}} \code{\link{haplo.power.qt}} } \examples{ haplo <- rbind( c( 1, 2, 2, 1, 2), c( 1, 2, 2, 1, 1), c( 1, 1, 2, 1, 1), c( 1, 2, 1, 1, 2), c( 1, 2, 2, 2, 1), c( 1, 2, 1, 1, 1), c( 1, 1, 2, 2, 1), c( 1, 1, 1, 1, 2), c( 1, 2, 1, 2, 1), c( 1, 1, 1, 2, 1), c( 2, 2, 1, 1, 2), c( 1, 1, 2, 1, 2), c( 1, 1, 2, 2, 2), c( 1, 2, 2, 2, 2), c( 2, 2, 2, 1, 2), c( 1, 1, 1, 1, 1), c( 2, 1, 1, 1, 1), c( 2, 1, 2, 1, 1), c( 2, 2, 1, 1, 1), c( 2, 2, 1, 2, 1), c( 2, 2, 2, 1, 1)) dimnames(haplo)[[2]] <- paste("loc", 1:ncol(haplo), sep=".") haplo <- data.frame(haplo) haplo.freq <- c(0.170020121, 0.162977867, 0.123742455, 0.117706237, 0.097585513, 0.084507042, 0.045271630, 0.039235412, 0.032193159, 0.019114688, 0.019114688, 0.013078471, 0.013078471, 0.013078471, 0.013078471, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217) # define index for risk haplotypes (having alleles 1-1 at loci 2 and 3) haplo.risk <- (1:nrow(haplo))[haplo$loc.2==1 & haplo$loc.3==1] # define index for baseline haplotype base.index <- 1 # specify OR for risk haplotypes or <- 1.25 # determine beta regression coefficients for risk haplotypes haplo.beta <- numeric(length(haplo.freq)) haplo.beta[haplo.risk] <- log(or) # Note that non-risk haplotypes have beta=0, as does the intercept # (haplotype with base.index value). # Compute total sample size for given power haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac=.5, prevalence=.1, alpha=.05, power=.8) # Compute power for given sample size haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac=.5, prevalence=.1, alpha=.05, sample.size=11978) } \keyword{design} % docclass is function % Converted by Sd2Rd version 43268. haplo.stats/man/print.haplo.group.Rd0000644000176000001440000000410311656766745017222 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.group.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % %$Log: print.haplo.group.Rd,v $ %Revision 1.3 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.2 2008/01/08 20:38:37 sinnwell %add log % %Revision 1.7 2004/06/09 19:01:37 sinnwell %haplo.group class, not haplo.score % %Revision 1.6 2004/04/06 21:30:30 sinnwell %add nlines parm % %Revision 1.5 2004/03/02 15:05:30 sinnwell %take out example, already shown in haplo.group.sgml % %Revision 1.4 2004/02/27 15:33:19 sinnwell %add entry for '...' arg % %Revision 1.3 2003/03/19 16:17:02 sinnwell %remove spaces after keywords for Rd conversion % %Revision 1.2 2002/09/16 14:59:07 sinnwell %Fix RCs keywords \name{print.haplo.group} \alias{print.haplo.group} \title{ Print a haplo.group object } \description{ Method function to print a class of type haplo.group } \usage{ \method{print}{haplo.group}(x, digits=max(options()$digits-2, 5), nlines=NULL, ...) } \arguments{ \item{x}{ The object returned from haplo.group (which has old class haplo.group). } \item{digits}{ Set the number of significant digits to print for haplotype probabilities. } \item{nlines}{ For shorter output, print first 1:nlines rows of the large data frame } \item{\dots}{ Optional arguments for the print method } } \value{ Nothing is returned. } \details{ This is a print method function used to print information from the haplo.group class, with haplotype-specific information given in a table. Because haplo.group is a class, the generic print function can be used, which in turn calls this print.haplo.group function. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Expected haplotype frequencies for association of traits with haplotypes when linkage phase is ambiguous. Submitted to Amer J Hum Genet. } \seealso{ haplo.score, haplo.group, haplo.em } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/get.hapPair.Rd0000644000176000001440000000636711551405165015765 0ustar ripleyusers%$Author: sinnwell $ %$Date: 2009/09/30 20:05:38 $ %$Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/get.hapPair.Rd,v 1.3 2009/09/30 20:05:38 sinnwell Exp $ %$Locker: $ %$Log: get.hapPair.Rd,v $ %Revision 1.3 2009/09/30 20:05:38 sinnwell %rm keywords, or leave one with one from /doc/KEYWORDS % %Revision 1.2 2009/09/30 19:21:50 sinnwell %remove empty sections % %Revision 1.1 2008/03/10 18:59:33 sinnwell %Initial revision % % \name{get.hapPair} \alias{get.hapPair} \title{ Get a list of objects for haplotype pairs } \description{ Get a list of objects for modeling haplotype pairs from a set of unique haplotypes and their frequencies, given the baseline haplotype } \usage{ get.hapPair(haplo, haplo.freq, base.index) } \arguments{ \item{haplo}{ matrix of haplotypes, with rows the different haplotypes and columns the alleles of the haplotypes. For H haplotypes of L loci, haplo has dimension H x L. } \item{haplo.freq }{ vector of length H for the population haplotype frequencies (corresponding to the rows of haplo) } \item{base.index }{ integer index of the haplotype considered to be the base-line for logistic regression (index between 1 and H); often, the most common haplotype is chosen for the base-line. } } \value{ list with components: \item{p.g}{ Genotype probability under Hardy-Weinberg Equilibrium, where the genotype is the haplotype pair } \item{x.haplo}{ Design matrix for all pairs of haplotypes, excluding the baseline haplotype. Effects are coded to an additive effect for the haplotypes. } \item{haplo.indx}{ two-column matrix containing the indices for the haplotypes in x.haplo. The indices are the row of the haplotype in haplo. } } \examples{ haplo <- rbind( c( 1, 2, 2, 1, 2), c( 1, 2, 2, 1, 1), c( 1, 1, 2, 1, 1), c( 1, 2, 1, 1, 2), c( 1, 2, 2, 2, 1), c( 1, 2, 1, 1, 1), c( 1, 1, 2, 2, 1), c( 1, 1, 1, 1, 2), c( 1, 2, 1, 2, 1), c( 1, 1, 1, 2, 1), c( 2, 2, 1, 1, 2), c( 1, 1, 2, 1, 2), c( 1, 1, 2, 2, 2), c( 1, 2, 2, 2, 2), c( 2, 2, 2, 1, 2), c( 1, 1, 1, 1, 1), c( 2, 1, 1, 1, 1), c( 2, 1, 2, 1, 1), c( 2, 2, 1, 1, 1), c( 2, 2, 1, 2, 1), c( 2, 2, 2, 1, 1)) dimnames(haplo)[[2]] <- paste("loc", 1:ncol(haplo), sep=".") haplo <- data.frame(haplo) haplo.freq <- c(0.170020121, 0.162977867, 0.123742455, 0.117706237, 0.097585513, 0.084507042, 0.045271630, 0.039235412, 0.032193159, 0.019114688, 0.019114688, 0.013078471, 0.013078471, 0.013078471, 0.013078471, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217) hPair <- get.hapPair(haplo, haplo.freq, base.index=1) names(hPair) dim(hPair$x.haplo) } % docclass is function haplo.stats/man/seqhap.Rd0000644000176000001440000001527311656766745015124 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/seqhap.Rd,v 1.5 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: seqhap.Rd,v $ % Revision 1.5 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.4 2008/10/06 15:26:39 sinnwell % *** empty log message *** % % Revision 1.3 2008/10/03 20:21:28 sinnwell % *** empty log message *** % % Revision 1.2 2008/09/26 20:12:20 sinnwell % remove n.sim, add sim.control % % Revision 1.1 2008/01/09 19:49:38 sinnwell % Initial revision % %Revision 1.8 2007/05/23 18:02:43 sinnwell %add pos and n.sim to result, add locus.label to input % %Revision 1.7 2007/04/27 21:28:22 sinnwell %minor updates % %Revision 1.6 2007/04/24 16:53:26 sinnwell %r2 to r-squared, not liked in Rd conversion to latex % %Revision 1.5 2007/04/24 16:36:14 sinnwell %changes recommended by Dan % %Revision 1.4 2007/04/16 20:11:44 sinnwell %fix example to run % %Revision 1.3 2007/04/13 18:49:58 sinnwell %*** empty log message *** % %Revision 1.2 2007/04/13 18:37:04 sinnwell %change some parameter descriptions to match haplo.score % %Revision 1.1 2007/04/06 19:31:18 sinnwell %Initial revision \name{seqhap} \alias{seqhap} \alias{print.seqhap} \title{ Sequential Haplotype Scan Association Analysis for Case-Control Data } \description{ Seqhap implements sequential haplotype scan methods to perform association analyses for case-control data. When evaluating each locus, loci that contribute additional information to haplotype associations with disease status will be added sequentially. This conditional evaluation is based on the Mantel-Haenszel (MH) test. Two sequential methods are provided, a sequential haplotype method and a sequential summary method, as well as results based on the traditional single-locus method. Currently, seqhap only works with bialleleic loci (single nucleotide polymorphisms, or SNPs) and binary traits. } \usage{ seqhap(y, geno, pos, locus.label=NA, weight=NULL, mh.threshold=3.84, r2.threshold=0.95, haplo.freq.min=0.005, miss.val=c(0, NA), sim.control=score.sim.control(), control=haplo.em.control()) \method{print}{seqhap}(x, digits=max(options()$digits-2, 5), ...) } \arguments{ \item{y}{ vector of binary response (1=case, 0=control). The length is equal to the number of rows in geno. } \item{geno}{ matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno)=2*K. Rows represent the alleles for each subject. Currently, only bi-allelic loci (SNPs) are allowed. } \item{pos}{ vector of physical positions (or relative physical positions) for loci. If there are K loci, length(pos)=K. The scale (in kb, bp, or etc.) doesn't affect the results. } \item{locus.label }{ vector of labels for the set of loci } \item{weight}{ weights for observations (rows of geno matrix). } \item{mh.threshold }{ threshold for the Mantel-Haenszel statistic that evaluates whether a locus contributes additional information of haplotype association to disease, conditional on current haplotypes. The default is 3.84, which is the 95th percentile of the chi-square distribution with 1 degree of freedom. } \item{r2.threshold }{ threshold for a locus to be skipped. When scanning locus k, loci with correlations r-squared (the square of the Pearson's correlation) greater than r2.threshold with locus k will be ignored, so that the haplotype growing process continues for markers that are further away from locus k. } \item{haplo.freq.min }{ the minimum haplotype frequency for a haplotype to be included in the association tests. The haplotype frequency is based on the EM algorithm that estimates haplotype frequencies independent of trait. } \item{miss.val }{ vector of values that represent missing alleles. } \item{sim.control}{ A list of control parameters to determine how simulations are performed for permutation p-values, similar to the strategy in haplo.score. The list is created by the function score.sim.control and the default values of this function can be changed as desired. Permutations are performed until a p.threshold accuracy rate is met for the three region-based p-values calculated in seqhap. See score.sim.control for details. } \item{control}{ A list of parameters that control the EM algorithm for estimating haplotype frequencies when phase is unknown. The list is created by the function haplo.em.control - see this function for more details. } \item{x}{ a seqhap object to print } \item{digits}{ Number of significant digits to print for numeric values } \item{\dots }{ Additional parameters for the print method } } \value{ list with components: \item{converge}{ indicator of convergence of the EM algorithm (see haplo.em); 1 = converge, 0=failed } \item{locus.label}{ vector of labels for loci } \item{pos}{ chromosome positions for loci, same as input. } \item{n.sim}{ number of permutations performed for emperical p-values } \item{inlist}{ matrix that shows which loci are combined for association analysis in the sequential scan. The non-zero values of the kth row of inlist are the indices of the loci combined when scanning locus k. } \item{chi.stat}{ chi-square statistics of single-locus analysis. } \item{chi.p.point}{ permuted pointwise p-values of single-locus analysis. } \item{chi.p.region}{ permuted regional p-value of single-locus analysis. } \item{hap.stat}{ chi-square statistics of sequential haplotype analysis. } \item{hap.df}{ degrees of freedom of sequential haplotype analysis. } \item{hap.p.point}{ permuted pointwise p-values of sequential haplotype analysis. } \item{hap.p.region}{ permuted region p-value of sequential haplotype analysis. } \item{sum.stat}{ chi-square statistics of sequential summary analysis. } \item{sum.df}{ degrees of freedom of sequential summary analysis. } \item{sum.p.point}{ permuted pointwise p-values of sequential summary analysis. } \item{sum.p.region}{ permuted regional p-value of sequential summary analysis. } } \details{ No further details } \section{References}{ Yu Z, Schaid DJ. (2007) Sequential haplotype scan methods for association analysis. Genet Epidemiol, in print. } \seealso{ \code{\link{haplo.em}}, \code{\link{print.seqhap}}, \code{\link{plot.seqhap}}, \code{\link{score.sim.control}} } \examples{ # load example data with response and genotypes. data(seqhap.dat) mydata.y <- seqhap.dat[,1] mydata.x <- seqhap.dat[,-1] # load positions data(seqhap.pos) pos=seqhap.pos$pos # run seqhap with default settings myobj <- seqhap(y=mydata.y, geno=mydata.x, pos=pos) print.seqhap(myobj) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/find.haplo.beta.qt.Rd0000644000176000001440000000311511650350140017156 0ustar ripleyusers\name{find.haplo.beta.qt} \alias{find.haplo.beta.qt} \alias{find.beta.qt.phase.known} \alias{find.intercept.qt.phase.known} \title{ Find beta coefficients for risk haplotypes, for specified r2 } \description{ Find betas for risk haplotypes and intercept (beta for base.index haplotype) with a given r2 } \usage{ find.haplo.beta.qt(haplo, haplo.freq, base.index, haplo.risk, r2, y.mu=0, y.var=1) find.beta.qt.phase.known(beta.size, haplo.risk, base.index, haplo, haplo.freq, r2, y.mu, y.var) find.intercept.qt.phase.known(beta.no.intercept, base.index, haplo, haplo.freq, y.mu) } \arguments{ \item{haplo}{ matrix of haplotypes, with rows the different haplotypes and columns the alleles of the haplotypes. For H haplotypes of L loci, haplo has dimension H x L. } \item{haplo.freq }{ vector of length H for the population haplotype frequencies (corresponding to the rows of haplo) } \item{base.index }{ integer index of the haplotype considered to be the base-line for logistic regression (index between 1 and H); often, the most common haplotype is chosen for the base-line. } \item{haplo.risk }{ vector of relative risks for haplotypes } \item{r2}{ correlation coefficient } \item{y.mu }{ mean of y, a quantitative trait } \item{y.var }{ variance of y, a quantitative trait } \item{beta.size}{ beta values for risk haplotypes in find.beta.qt.phase.known } \item{beta.no.intercept}{ beta vector for haplotypes for quantitative trait, excluding the beta for intercept } } \value{ beta estimates for haplotypes or intercept } \keyword{power} % docclass is function % Converted by Sd2Rd version 43268. haplo.stats/man/haplo.score.Rd0000644000176000001440000002442511656766745016057 0ustar ripleyusers%$Author: sinnwell $ %$Date: 2011/11/10 15:29:41 $ %$Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.score.Rd,v 1.6 2011/11/10 15:29:41 sinnwell Exp $ %$Locker: $ %$Log: haplo.score.Rd,v $ %Revision 1.6 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.5 2008/04/14 21:38:51 sinnwell %fix syntax error % %Revision 1.4 2008/04/14 20:00:33 sinnwell %change eps.svd comment % %Revision 1.3 2008/04/08 20:26:42 sinnwell %add svd.eps, undo control parameter change % %Revision 1.2 2008/04/08 14:18:21 sinnwell %move haplo.effect, sim.control, em.control to haplo.score.control with eps.svd % %Revision 1.1 2008/01/09 19:34:34 sinnwell %Initial revision % %Revision 1.20 2007/01/23 22:09:39 sinnwell %added parameters min.count and haplo.effect %Revision 1.19 2005/01/28 21:40:27 sinnwell %warn to not discard missings under standard usage %Revision 1.18 2004/12/29 18:51:13 sinnwell %update for skip.haplo default change %Revision 1.17 2004/03/22 20:00:05 sinnwell %limit simulations in example %Revision 1.16 2004/03/03 15:52:59 sinnwell %add labels in examples %Revision 1.15 2004/03/02 17:15:59 sinnwell %change sex to male of hla.demo %Revision 1.14 2004/03/01 21:47:26 sinnwell %fix examples %Revision 1.13 2004/02/16 17:28:07 sinnwell %change F to FALSE in call %Revision 1.12 2003/08/27 21:04:55 schaid %*** empty log message *** %Revision 1.11 2003/08/22 20:10:36 sinnwell %update for haplo.score version 1.2.0 with PIN and simulations updated %Revision 1.10 2003/08/13 21:52:00 sinnwell %update source cited %Revision 1.9 2003/01/17 16:57:06 sinnwell %revision for haplo.score version 1.2 %Revision 1.8 2002/09/13 21:04:14 sinnwell %More commenting revisions %Revision 1.7 2002/09/13 19:44:16 sinnwell %Fix sgml commenting scheme %Revision 1.6 2002/09/13 17:00:55 sinnwell %Fixed RCS keywords to meet sgml rules %Revision 1.5 2002/09/13 14:26:10 sinnwell %Fix RCS keywords and comments. %Revision 1.4 2002/09/12 21:20:24 det01 %Added RCS keywords Author, Date, Header, Id, Locker, Log \name{haplo.score} \alias{haplo.score} \title{ Score Statistics for Association of Traits with Haplotypes } \description{ Compute score statistics to evaluate the association of a trait with haplotypes, when linkage phase is unknown and diploid marker phenotypes are observed among unrelated subjects. For now, only autosomal loci are considered. } \usage{ haplo.score(y, geno, trait.type="gaussian", offset = NA, x.adj = NA, min.count=5, skip.haplo=min.count/(2*nrow(geno)), locus.label=NA, miss.val=c(0,NA), haplo.effect="additive", eps.svd=1e-5, simulate=FALSE, sim.control=score.sim.control(), em.control=haplo.em.control()) } \arguments{ \item{y}{ Vector of trait values. For trait.type = "binomial", y must have values of 1 for event, 0 for no event. } \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent alleles for each subject. } \item{trait.type }{ Character string defining type of trait, with values of "gaussian", "binomial", "poisson", "ordinal". } \item{offset}{ Vector of offset when trait.type = "poisson" } \item{x.adj }{ Matrix of non-genetic covariates used to adjust the score statistics. Note that intercept should not be included, as it will be added in this function. } \item{min.count }{ The minimum number of counts for a haplotype to be included in the model. First, the haplotypes selected to score are chosen by minimum frequency greater than skip.haplo (based on min.count, by default). It is also used when haplo.effect is either dominant or recessive. This is explained best in the recessive instance, where only subjects who are homozygous for a haplotype will contribute information to the score for that haplotype. If fewer than min.count subjects are estimated to be affected by that haplotype, it is not scored. A warning is issued if no haplotypes can be scored. } \item{skip.haplo }{ Minimum haplotype frequency for which haplotypes are scored in the model. By default, the frequency is based on "min.count" divided by the 2*N total haplotype occurrences in the sample. } \item{locus.label }{ Vector of labels for loci, of length K (see definition of geno matrix) } \item{miss.val }{ Vector of codes for missing values of alleles } \item{haplo.effect }{ the "effect" of a haplotypes, which determines the covariate (x) coding of haplotypes. Valid options are "additive" (causing x = 0, 1, or 2, the count of a particular haplotype), "dominant" (causing x = 1 if heterozygous or homozygous carrier of a particular haplotype; x = 0 otherwise), and "recessive" (causing x = 1 if homozygous for a particular haplotype; x = 0 otherwise). } \item{eps.svd}{ epsilon value for singular value cutoff; to be used in the generalized inverse calculation on the variance matrix of the score vector (see help(Ginv) for details). } \item{simulate}{ Logical: if FALSE, no empirical p-values are computed; if TRUE, simulations are performed. Specific simulation parameters can be controlled in the sim.control parameter list. } \item{sim.control }{ A list of control parameters to determine how simulations are performed for simulated p-values. The list is created by the function score.sim.control and the default values of this function can be changed as desired. See score.sim.control for details. } \item{em.control }{ A list of control parameters to determine how to perform the EM algorithm for estimating haplotype frequencies when phase is unknown. The list is created by the function haplo.em.control - see this function for more details. } } \value{ List with the following components: \item{score.global}{ Global statistic to test association of trait with haplotypes that have frequencies >= skip.haplo. } \item{df}{ Degrees of freedom for score.global. } \item{score.global.p}{ P-value of score.global based on chi-square distribution, with degrees of freedom equal to df. } \item{score.global.p.sim}{ P-value of score.global based on simulations (set equal to NA when simulate=F). } \item{score.haplo}{ Vector of score statistics for individual haplotypes that have frequencies >= skip.haplo. } \item{score.haplo.p}{ Vector of p-values for score.haplo, based on a chi-square distribution with 1 df. } \item{score.haplo.p.sim}{ Vector of p-values for score.haplo, based on simulations (set equal to NA when simulate=F). } \item{score.max.p.sim}{ Simulated p-value indicating for simulations the number of times a maximum score.haplo value exceeds the maximum score.haplo from the original data (equal to NA when simulate=F). } \item{haplotype}{ Matrix of hapoltypes analyzed. The ith row of haplotype corresponds to the ith item of score.haplo, score.haplo.p, and score.haplo.p.sim. } \item{hap.prob}{ Vector of haplotype probabilies, corresponding to the haplotypes in the matrix haplotype. } \item{locus.label}{ Vector of labels for loci, of length K (same as input argument). } \item{call}{ The call to the haplo.score function; useful for recalling what parameters were used. } \item{haplo.effect}{ The haplotype effect model parameter that was selected for haplo.score. } \item{simulate}{ Same as function input parameter. If [T]rue, simulation results are included in the haplo.score object. } \item{n.val.global}{ Vector containing the number of valid simulations used in the global score statistic simulation. The number of valid simulations can be less than the number of simulations requested (by sim.control) if simulated data sets produce unstable variances of the score statistics. } \item{n.val.haplo}{ Vector containing the number of valid simulations used in the p-value simulations for maximum-score statistic and scores for the individual haplotypes. } } \details{ Compute the maximum likelihood estimates of the haplotype frequencies and the posterior probabilities of the pairs of haplotypes for each subject using an EM algorithm. The algorithm begins with haplotypes from a subset of the loci and progressively discards those with low frequency before inserting more loci. The process is repeated until haplotypes for all loci are established. The posterior probabilities are used to compute the score statistics for the association of (ambiguous) haplotypes with traits. The glm function is used to compute residuals of the regression of the trait on the non-genetic covariates. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434. } \seealso{ \code{\link{haplo.em}}, \code{\link{plot.haplo.score}}, \code{\link{print.haplo.score}}, \code{\link{haplo.em.control}}, \code{\link{score.sim.control}} } \examples{ # establish all hla.demo data, # remove genotypes with missing alleles just so haplo.score runs faster # with missing values included, this example takes 2-4 minutes # FOR REGULAR USAGE, DO NOT DISCARD GENOTYPES WITH MISSING VALUES data(hla.demo) geno <- as.matrix(hla.demo[,c(17,18,21:24)]) keep <- !apply(is.na(geno) | geno==0, 1, any) hla.demo <- hla.demo[keep,] geno <- geno[keep,] attach(hla.demo) label <- c("DQB","DRB","B") # For quantitative, normally distributed trait: score.gaus <- haplo.score(resp, geno, locus.label=label, trait.type = "gaussian") print(score.gaus) # For ordinal trait: y.ord <- as.numeric(resp.cat) score.ord <- haplo.score(y.ord, geno, locus.label=label, trait.type="ordinal") print(score.ord) # For a binary trait and simulations, # limit simulations to 500 in score.sim.control, default is 20000 y.bin <-ifelse(y.ord==1,1,0) score.bin.sim <- haplo.score(y.bin, geno, trait.type = "binomial", locus.label=label, simulate=TRUE, sim.control=score.sim.control(min.sim=200,max.sim=500)) print(score.bin.sim) # For a binary trait, adjusted for sex and age: x <- cbind(male, age) score.bin.adj <- haplo.score(y.bin, geno, trait.type = "binomial", locus.label=label, x.adj=x) print(score.bin.adj) } \keyword{scores} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/score.sim.control.Rd0000644000176000001440000000700611656766745017217 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/score.sim.control.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: score.sim.control.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 19:47:30 sinnwell % Initial revision % % Revision 1.5 2004/03/02 15:15:13 sinnwell % comment in example % % Revision 1.4 2004/02/16 17:41:03 sinnwell % change F to FALSE for verbose % % Revision 1.3 2003/09/12 20:23:12 sinnwell % remove pval.choice stuff % % Revision 1.2 2003/08/27 20:44:32 schaid % *** empty log message *** % % Revision 1.1 2003/08/22 20:29:23 sinnwell % Initial revision \name{score.sim.control} \alias{score.sim.control} \title{ Create the list of control parameters for simulations in haplo.score } \description{ In the call to haplo.score, the sim.control parameter is a list of parameters that control the simulations. This list is created by this function, score.sim.control, making it easy to change the default values. } \usage{ score.sim.control(p.threshold=0.25, min.sim=1000, max.sim=20000.,verbose=FALSE) } \arguments{ \item{p.threshold }{ A paremeter used to determine p-value precision from Besag and Clifford (1991). For a p-value calculated after min.sim simulations, continue doing simulations until the p-value's sample standard error is less than p.threshold * p-value. The dafault value for p.threshold = 1/4 corresponds approximately to having a two-sided 95\% confidence interval for the p-value with a width as wide as the p-value itself. Therefore, simulations are more precise for smaller p-values. Additionally, since simulations are stopped as soon as this criteria is met, p-values may be biased high. } \item{min.sim }{ The minimum number of simulations to run. To run exactly min.sim simulations, set max.sim = min.sim. Also, if run-time is an issue, a lower minimum (e.g. 500) may be useful, especially when doing simulations in haplo.score.slide. } \item{max.sim }{ The upper limit of simulations allowed. When the number of simulations reaches max.sim, p-values are approximated based on simulation results at that time. } \item{verbose}{ Logical, if (T)rue, print updates from every simulation to the screen. If (F)alse, do not print these details. } } \value{ A list of the control parameters: \item{p.threshold}{ As described above } \item{min.sim}{ As described above. } \item{max.sim}{ As described above } \item{verbose}{ As described above } } \details{ In simulations for haplo.score, employ the simulation p-value precision criteria of Besag and Clifford (1991). The criteria ensures both the global and the maximum score statistic simulated p-values be precise for small p-values. First, perform min.sim simulations to guarantee sufficient precision for the score statistics on individual haplotypes. Then continue simulations as needed until simulated p-values for both the global and max score statistics meet precision requirements set by p.threshold. } \section{References}{ Besag, J and Clifford, P. "Sequential Monte Carlo p-values." Biometrika. 78, no. 2 (1991): 301-304. } \seealso{ \code{\link{haplo.score}} } \examples{ # it would be used in haplo.score as appears below # # score.sim.500 <- haplo.score(y, geno, trait.type="gaussian", simulate=T, # sim.control=score.sim.control(min.sim=500, max.sim=2000) } \keyword{scores} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/louis.info.Rd0000644000176000001440000000175711656766745015732 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/louis.info.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: louis.info.Rd,v $ % Revision 1.4 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.3 2009/09/30 20:05:38 sinnwell % rm keywords, or leave one with one from /doc/KEYWORDS % % Revision 1.2 2009/09/30 19:32:08 sinnwell % remove empty sections % % Revision 1.1 2008/01/09 19:44:30 sinnwell % Initial revision % \name{louis.info} \alias{louis.info} \title{ Louis Information for haplo.glm } \description{ For internal use within the haplo.stats library's haplo.glm function } \usage{ louis.info(fit, epsilon=1e-8) } \arguments{ \item{fit}{ glm fitted object } \item{epsilon}{ cut-off for singular values in the generalized inverse of the information matrix } } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/plot.haplo.score.slide.Rd0000644000176000001440000001124411656766745020126 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/plot.haplo.score.slide.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % % $Log: plot.haplo.score.slide.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1.1.1 2011/04/13 15:48:54 sinnwell % bring in haplo.stats, uses functions from rlocal and mgenet % % Revision 1.2 2008/01/08 20:28:31 sinnwell % fix comment % % Revision 1.1 2008/01/08 17:12:10 sinnwell % Initial revision % % Revision 1.14 2007/05/29 15:53:50 sinnwell % leave cex.axis and las/srt to be given by user % % Revision 1.13 2007/05/22 21:22:25 sinnwell % cex to cex.axis and srt to las % % Revision 1.12 2007/04/12 21:08:05 sinnwell % add comments about near-zero p-values. % % Revision 1.11 2005/03/31 19:23:24 sinnwell % *** empty log message *** % % Revision 1.10 2004/03/16 22:26:38 sinnwell % comment example, point to haplo.score.slide % % Revision 1.9 2004/03/03 17:33:43 sinnwell % T to TRUE % % Revision 1.8 2004/03/03 15:47:05 sinnwell % examples update % % Revision 1.7 2004/03/02 15:03:23 sinnwell % fix example % % Revision 1.6 2004/02/06 19:30:30 sinnwell % *** empty log message *** % % Revision 1.5 2004/02/06 17:44:37 sinnwell % add cex,srt,... documentation % % Revision 1.4 2004/01/27 21:26:26 sinnwell % update for marker distance option % % Revision 1.3 2003/09/16 21:09:33 sinnwell % edit pval explanations % % Revision 1.2 2003/08/27 21:17:13 schaid % *** empty log message *** % % Revision 1.1 2003/08/22 20:37:14 sinnwell % Initial revision \name{plot.haplo.score.slide} \alias{plot.haplo.score.slide} \title{ Plot a haplo.score.slide Object } \description{ Method function to plot an object of class haplo.score.slide. The p-values from haplo.score.slide are for sub-haplotypes of a larger chromosomal region, and these are plotted to visualize the change in p-values as the sub-haplotype "slides" over a chromosome. Plot -log10(p-value) on the y-axis vs. the loci over which it was computed on the x-axis. } \usage{ \method{plot}{haplo.score.slide}(x, pval="global", dist.vec=1:x$n.loci, ...) } \arguments{ \item{x}{ The object returned from haplo.score.slide } \item{pval}{ Character string for the choice of p-value to plot. Options are: "global" (the global score statistic p-value based on an asymptotic chi-square distribution), "global.sim" (the global score statistic simulated p-value), and "max.sim" (the simulated p-value for the maximum score statistic). } \item{dist.vec }{ Numeric vector for position (i.e., in cM) of the loci along a chromosome. Distances on x-axis will correspond to these positions. } \item{\dots }{ Dynamic parameter for the values of additional parameters for the plot method. Some useful options for manageing the x-axis labels are cex.axis, las, and srt. } } \value{ Nothing is returned. } \details{ The x-axis has tick marks for all loci. The y-axis is the -log10() of the selected p-value. For each haplo.score result, plot a horizontal line at the height of -log10(p-value) drawn across the loci over which it was calculated. Therefore a p-value of 0.001 for the first 3 loci will plot as a horizontal line plotted at y=3 covering the first three tick marks. If the p-value for a set of loci is zero or very near zero, it is set to a minimum. Global asymptotic p-values of zero are set to the minimum of an epsilon or the lowest non-zero p-value in the region. Simulated p-values equal to zero are set to 0.5 divided by the total number of simulations performed. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434. } \seealso{ \code{\link{haplo.score.slide}} } \examples{ # This example has a long run-time, therefore it is commented # data(hla.demo) # attach(hla.demo) # geno.11 <- hla.demo[,-c(1:4)] # label.11 <- c("DPB","DPA","DMA","DMB","TAP1","TAP2","DQB","DQA","DRB","B","A") #For an ordinal trait, slide by 3 loci, and simulate p-values: # y.ord <- as.numeric(resp.cat) # slide.ord.sim <- haplo.score.slide(y.ord, geno.11, trait.type = "ordinal", # n.slide=3, locus.label=label.11, simulate=TRUE, # sim.control=score.sim.control(min.sim=500)) # print(slide.ord.sim) # plot(slide.ord.sim) # plot(slide.ord.sim, pval="global.sim", las=2, cex.axis=.8) # plot(slide.ord.sim, pval="max.sim", srt=90, cex.axis=.8) } \keyword{scores} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/internalHaploStats.Rd0000644000176000001440000000223712075056023017427 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2013/01/14 19:27:15 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/internalHaploStats.Rd,v 1.5 2013/01/14 19:27:15 sinnwell Exp $ % $Locker: $ % $Log: internalHaploStats.Rd,v $ % Revision 1.5 2013/01/14 19:27:15 sinnwell % add haplo.binomial % % Revision 1.4 2011/11/23 20:34:02 sinnwell % release 1.4.81, updates with test scripts % % Revision 1.3 2009/09/30 20:05:38 sinnwell % rm keywords, or leave one with one from /doc/KEYWORDS % % Revision 1.2 2009/09/30 19:30:06 sinnwell % remove empty sections % % Revision 1.1 2008/01/09 21:26:12 sinnwell % Initial revision % \name{dglm.fit} \alias{dglm.fit} \alias{haplo.chistat} \alias{haplo.enum} \alias{haplo.score.glm} \alias{haplo.score.podds} \alias{mf.gindx} \alias{haplo.binomial} \alias{residScaledGlmFit} \alias{sr.class} \alias{sr.class<-} \alias{varfunc.glm.fit} \title{ Internal functions for the HaploStats package. See the help file for the main functions (haplo.em, haplo.score, haplo.glm) for details on some of these functions. } \description{ Internal function for the HaploStats package } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/summary.haplo.glm.Rd0000644000176000001440000000372411656766745017216 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/summary.haplo.glm.Rd,v 1.1 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % $Log: summary.haplo.glm.Rd,v $ % Revision 1.1 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.4 2008/04/04 16:12:33 sinnwell % add note about returned value by invisible() % % Revision 1.3 2008/03/24 21:14:44 sinnwell % add show.missing argument % % Revision 1.2 2008/01/09 21:32:16 sinnwell % change comments to % % % Revision 1.1 2007/11/07 21:46:59 sinnwell % Initial revision % % Revision 1.2 2004/03/16 17:02:24 sinnwell % add return char to usage \name{summary.haplo.glm} \alias{summary.haplo.glm} \alias{print.summary.haplo.glm} \title{ Print and summary of a haplo.glm object } \description{ Do print and summary as in regular glm, then display extra information on haplotypes used in the model fit } \usage{ \method{summary}{haplo.glm}(object, show.all.haplo=FALSE, show.missing=FALSE, ...) \method{print}{summary.haplo.glm}(x, digits = max(getOption("digits")-3,3), ...) } \arguments{ \item{x}{ A haplo.glm object } \item{object}{ A haplo.glm object } \item{show.all.haplo }{ Logical. If TRUE, print all haplotypes considered in the model. } \item{show.missing }{ Logical. If TRUE, print number of rows removed because of missing values (NA) in y or x-covariates, or all alleles missing in geno } \item{digits}{ Number of numeric digits to print. } \item{\dots }{ Optional arguments for summary method } } \value{ If print is assigned, the object contains a list with the coefficient and haplotype data.frames which are printed by the method. } \details{ Uses print.glm for the first section, then prints information on the haplotypes. } \seealso{ \code{\link{haplo.glm}} } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/summary.haplo.em.Rd0000644000176000001440000000361111656766745017033 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/summary.haplo.em.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ % $Log: summary.haplo.em.Rd,v $ % Revision 1.3 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.2 2008/01/08 22:23:35 sinnwell % change comments % % Revision 1.1 2007/11/07 21:33:46 sinnwell % Initial revision % % Revision 1.2 2004/04/06 20:46:27 sinnwell % add nlines % % Revision 1.1 2004/02/26 22:36:18 sinnwell % Initial revision \name{summary.haplo.em} \alias{summary.haplo.em} \title{ Summarize contents of a haplo.em object } \description{ Display haplotype pairs and their posterior probabilities by subject. Also display a table with number of max haplotype pairs for a subject versus how many were kept (max vs. used). } \usage{ \method{summary}{haplo.em}(object, show.haplo=FALSE, digits=max(options()$digits-2, 5), nlines=NULL, ...) } \arguments{ \item{object}{ A haplo.em object } \item{show.haplo }{ Logical. If TRUE, show the alleles of the haplotype pairs, otherwise show only the recoded values. } \item{digits}{ number of significant digits to be printed for numeric values } \item{nlines}{ To shorten output, print the first 1:nlines rows of the large data frame. } \item{\dots }{ Optional arguments for the summary method } } \value{ A data.frame with a row for every subject's possible haplotype pairs and the posterior probabilities of that pair given their genotypes. } \seealso{ \code{\link{haplo.em}} } \examples{ data(hla.demo) geno <- hla.demo[,c(17,18,21:24)] label <-c("DQB","DRB","B") keep <- !apply(is.na(geno) | geno==0, 1, any) save.em.keep <- haplo.em(geno=geno[keep,], locus.label=label) save.df <- summary(save.em.keep) save.df[1:10,] } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/plot.seqhap.Rd0000644000176000001440000000701312075062533016046 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/plot.seqhap.Rd,v 1.6 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: plot.seqhap.Rd,v $ % Revision 1.6 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.5 2008/10/06 15:16:40 sinnwell % rm n.sim from example % % Revision 1.4 2008/05/16 18:38:02 sinnwell % fix details about 0 perm pval % % Revision 1.3 2008/05/09 20:59:41 sinnwell % add minp parameter, more comments about ... % % Revision 1.2 2008/01/08 20:27:11 sinnwell % fix comments % % Revision 1.1 2008/01/08 17:14:28 sinnwell % Initial revision % % Revision 1.5 2007/05/30 19:00:57 sinnwell % *** empty log message *** % % Revision 1.4 2007/05/30 18:29:47 sinnwell % fix example to use data % % Revision 1.3 2007/05/25 18:17:45 sinnwell % rm par optoins cex.axis and las, reserved for users in ... % % Revision 1.2 2007/05/24 19:08:17 sinnwell % add detail about cex.axis % % Revision 1.1 2007/05/23 17:41:56 sinnwell % Initial revision \name{plot.seqhap} \alias{plot.seqhap} \title{ Plot a seqhap object } \description{ Method to plot an object of class seqhap. The p-values at each locus are based on sequentially combined loci, and they are plotted to visualize the p-values when scanning each locus using seqhap methods. Plots -log10(p-value) on the y-axis vs. the loci over which it was computed on the x-axis. } \usage{ \method{plot}{seqhap}(x, pval="hap", single=TRUE, minp=.Machine$double.eps, ...) } \arguments{ \item{x}{ The object returned from seqhap } \item{pval}{ Character string for the choice of p-value to plot. Options are: "hap" (sequential haplotype asymptotic p-value), "hap.sim" (sequential haplotype simulated p-value), "sum" (sequential summary asymptotic p-value), and "sum.sim" (sequential summary simulated p-value). } \item{single}{ Logical, indicating whether to plot p-values for single-locus association tests. If TRUE, the pointwise p-values from the single-locus will be plotted using a dotted line. } \item{minp}{ Smallest "allowable" p-value; any p-value smaller will be set to log10(minp). The default is the value closest to zero that can be represented in Splus/R. } \item{\dots }{ Dynamic parameter for the values of additional parameters for the plot method. Accept the ylim parameter for plot() and other parameters for lines(), points(), and axis(). Recommended values to make locus labels vertical on the x-axis: for R: las=2, cex.axis=1.2 for S+: srt=90, cex.axis=1.2, adj=1 } } \value{ Nothing is returned. } \details{ The x-axis has tick marks for all loci. The y-axis is the -log10() of the selected p-value. For the sequential result for each locus, a horizontal line at the height of -log10(p-value) is drawn across the loci combined. The start locus is indicated by a filled triangle and other loci combined with the start locus are indicated by an asterisk or circle. If the permutation p-value is zero, for plotting purposes it is set to 1/(n.sim+1). } \section{References}{ Yu Z, Schaid DJ. (2007) Sequential haplotype scan methods for association analysis. Genet Epidemiol, in print. } \seealso{ \code{\link{seqhap}}, \code{\link{print.seqhap}} } \examples{ \dontrun{ data(seqhap.dat) mydata.y <- seqhap.dat[,1] mydata.x <- seqhap.dat[,-1] data(seqhap.pos) myobj <- seqhap(y=mydata.y, geno=mydata.x, pos=seqhap.pos$pos) plot(myobj) } } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.group.Rd0000644000176000001440000001014311656766745016070 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.group.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: haplo.group.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 17:35:35 sinnwell % Initial revision % %Revision 1.12 2004/03/22 19:52:53 sinnwell %speed up example, use keep % %Revision 1.11 2004/03/01 21:31:51 sinnwell %fix example % %Revision 1.10 2004/02/06 20:58:36 sinnwell %fix syntax for n.loci % %Revision 1.9 2003/10/27 19:24:51 sinnwell %fixed syntax error % %Revision 1.8 2003/10/15 16:16:12 schaid %*** empty log message *** % %Revision 1.7 2003/08/27 21:08:53 sinnwell %update for PIN, mostly for em.control parameter list % %Revision 1.6 2003/03/24 19:13:47 sinnwell %fix group.count description % %Revision 1.5 2003/03/24 16:38:38 sinnwell %add haplo.em to % %Revision 1.4 2003/03/11 21:45:43 sinnwell %update for haplo.group returned as list % %Revision 1.3 2003/01/17 16:56:39 sinnwell %revision for haplo.score version 1.2 % %Revision 1.2 2002/09/16 14:46:42 sinnwell %Fix RCS keywords \name{haplo.group} \alias{haplo.group} \title{ Frequencies for Haplotypes by Grouping Variable } \description{ Calculate maximum likelihood estimates of haplotype probabilities for the entire dataset and separately for each subset defined by the levels of a group variable. Only autosomal loci are considered. } \usage{ haplo.group(group, geno, locus.label=NA, miss.val=0, weight=NULL, control=haplo.em.control()) } \arguments{ \item{group}{ Group can be of logical, numeric, character, or factor class type. } \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then geno has 2*K columns. Rows represent all observed alleles for each subject. } \item{locus.label }{ Vector of labels for loci, of length K (see definition of geno matrix). } \item{miss.val }{ Vector of codes for allele missing values. } \item{weight}{ weights for observations (rows of geno matrix). One reason to use is to adjust for disproportionate sample of sub-groups. Weights only used in the frequency calculation for the pooled subject. } \item{control}{ list of control parameters for haplo.em (see haplo.em.control). } } \value{ \item{ }{ A list as an object of the haplo.group class. The three elements of the list are described below. } \item{group.df}{ A data frame with the columns described as follows. -haplotype: Names for the K columns for the K alleles in the haplotypes. -total: Estimated frequencies for haplotypes from the total sample. -group.name.i: Estimated haplotype frequencies for the haplotype if it occurs in the group referenced by 'i'. Frequency is NA if it doesn't occur for the group. The column name is the actual variable name joined with the ith level of that variable. } \item{group.count}{ Vector containing the number of subjects for each level of the grouping variable. } \item{n.loci}{ Number of loci occuring in the geno matrix. } } \details{ Haplo.em is used to compute the maximum likelihood estimates of the haplotype frequencies for the total sample, then for each of the groups separately. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434. } \seealso{ print.haplo.group, haplo.em } \examples{ data(hla.demo) geno <- as.matrix(hla.demo[,c(17,18,21:24)]) # remove any subjects with missing alleles for faster examples, # but you may keep them in practice keep <- !apply(is.na(geno) | geno==0, 1, any) hla.demo <- hla.demo[keep,] geno <- geno[keep,] attach(hla.demo) y.ord <- as.numeric(resp.cat) y.bin <-ifelse(y.ord==1,1,0) group.bin <- haplo.group(y.bin, geno, miss.val=0) print.haplo.group(group.bin) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/na.geno.keep.Rd0000644000176000001440000000157611656766745016114 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/na.geno.keep.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: na.geno.keep.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 19:46:11 sinnwell % Initial revision % \name{na.geno.keep} \alias{na.geno.keep} \title{ Remove rows with NA in covariates, but keep genotypes with NAs } \description{ Removes rows with NA in response or covariates, but keeps subjects with NAs in their genotypes if not missing all alleles. } \usage{ na.geno.keep(m) } \arguments{ \item{m}{ model matrix } } \value{ a model matrix with rows removed if exclusion criteria requires it } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/print.haplo.em.Rd0000644000176000001440000000255411656766745016477 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.em.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: print.haplo.em.Rd,v $ % Revision 1.4 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.3 2008/01/08 20:39:02 sinnwell % fix comments % % Revision 1.2 2008/01/08 15:54:14 sinnwell % minor change to desc % % Revision 1.1 2007/11/07 21:27:38 sinnwell % Initial revision % % Revision 1.2 2004/02/27 15:29:37 sinnwell % move haplo.em from keyword to 'see' % % Revision 1.1 2004/02/26 22:36:48 sinnwell % Initial revision \name{print.haplo.em} \alias{print.haplo.em} \title{ Print contents of a haplo.em object } \description{ Print a data frame with haplotypes and their frequencies. Likelihood information is also printed. } \usage{ \method{print}{haplo.em}(x, digits=max(options()$digits-2, 5), nlines=NULL, ...) } \arguments{ \item{x}{ A haplo.em object } \item{digits}{ number of significant digits to print for numeric values } \item{nlines}{ To shorten output, print the first 1:nlines rows of the large data frame. } \item{\dots }{ optional arguments for print } } \value{ Nothing is returned } \seealso{ \code{\link{haplo.em}} } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/print.haplo.cc.Rd0000644000176000001440000000352511656766745016462 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.cc.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % %$Log: print.haplo.cc.Rd,v $ %Revision 1.4 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.3 2008/01/08 20:39:17 sinnwell %fix comments % %Revision 1.2 2008/01/08 16:01:55 sinnwell %add comments from sgml file % %Revision 1.5 2005/05/09 21:10:46 sinnwell %entry for '...' % %Revision 1.4 2005/05/09 15:45:18 sinnwell %comma in \usage % %Revision 1.3 2005/05/09 15:25:48 sinnwell %remove ',' in <\see> % %Revision 1.2 2005/03/31 16:34:24 sinnwell %comment out example % %Revision 1.1 2004/04/23 21:25:46 sinnwell %Initial revision \name{print.haplo.cc} \alias{print.haplo.cc} \title{ Print a haplo.cc object } \description{ Display results for a haplotype analysis on a case-control study. } \usage{ \method{print}{haplo.cc}(x, order.by="score", digits=max(options()$digits-2, 5), nlines=NULL, ...) } \arguments{ \item{x}{ A haplo.cc object, made by the haplo.cc function. } \item{order.by}{ Order the printed data frame by haplotype score (score), haplotype alleles (haplotype), or haplotype frequency (freq). } \item{digits}{ Number of digits to display for the numeric columns of the data frame. } \item{nlines}{ Print the first nlines of the cc.df data frame of the haplo.cc object, keeps output short if desired. } \item{\dots }{ Dynamic parameter for the values of additional parameters for the print method. } } \value{ Nothing is returned. } \seealso{ \code{\link{haplo.cc}} } \examples{ ## for a haplo.cc object named cc.test, ## order results by haplotype # print.haplo.cc(cc.test, order.by="haplotype") } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/residuals.haplo.glm.Rd0000644000176000001440000000306411656766745017511 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/residuals.haplo.glm.Rd,v 1.1 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % $Log: residuals.haplo.glm.Rd,v $ % Revision 1.1 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % \name{residuals.haplo.glm} \alias{residuals.haplo.glm} \title{ Accessing residuals for haplo.glm fit } \description{ Access the residuals from a haplo.glm model fit } \usage{ \method{residuals}{haplo.glm}(object, type=c("deviance", "pearson", "working", "response"), ...) } \arguments{ \item{object}{ A haplo.glm object } \item{type}{ Type of residuals to return. Options are "deviance" (default), "pearson", "working", and "response". Partial residuals not supported in this method. } \item{\dots }{ Optional arguments } } \value{ Residuals for each person in the model. } \details{ Many of the subjects in a haplo.glm fit are expanded in the model matrix with weights used to reflect the posterior probability of the subject's haplotype pairs given their genotype. The working residuals within the fitted object are from this expanded model matrix, and the residuals in this method are calculated from the weighted fitted value for the subject across all their haplotype pairs. } \seealso{ \code{\link{haplo.glm}}, \code{\link{residuals.glm}}, \code{\link{fitted.haplo.glm}} } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.score.merge.Rd0000644000176000001440000000553711656766745017160 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.score.merge.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: haplo.score.merge.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 19:36:04 sinnwell % Initial revision % %Revision 1.4 2004/03/01 22:36:18 sinnwell %fix example % %Revision 1.3 2003/06/25 15:40:52 sinnwell %parameter names fixed in examples % %Revision 1.2 2003/03/12 22:33:13 sinnwell %fix comments% % %Revision 1.1 2003/01/17 16:57:06 sinnwell %Initial revision \name{haplo.score.merge} \alias{haplo.score.merge} \title{ Merge haplo.score And haplo.group Objects } \description{ Combine information from returned objects of haplo.score and haplo.group, 'score' and 'group' respectively. 'score' and 'group' are sorted differently and 'score' keeps a subset of all the haplotypes while 'group' has all of them. To combine results from the two objects, merge them by haplotype and sort by score of the haplotype. The merged object includes all haplotypes; i.e. those appearing in 'group', but the print default only shows haplotypes which have a score. } \usage{ haplo.score.merge(score, group) } \arguments{ \item{score}{ Object returned from haplo.score of class "haplo.score". } \item{group}{ Object returned from haplo.group of class "haplo.group". } } \value{ Data frame including haplotypes, score-statistics, score p-value, estimated haplotype frequency for all subjects, and haplotype frequency from group subsets. } \section{Side Effects}{ Warning: The merge will not detect if the group and score objects resulted from different subject phenotypes selected by memory-usage parameters, rm.geno.na and enum.limit. Users must use the same values for these parameters in haplo.score and haplo.group so the merged objects are consistent. } \details{ Haplo.score returns score statistic and p-value for haplotypes with an overall frequency above the user-specified threshold, skip.haplo. For haplotypes with frequencies below the threshold, the score and p-value will be NA. Overall haplotype frequencies and for sub-groups are estimated by haplo.group. } \seealso{ \code{\link{haplo.score}}, \code{\link{haplo.group}} } \examples{ data(hla.demo) geno <- as.matrix(hla.demo[,c(17,18,21:24)]) keep <- !apply(is.na(geno) | geno==0, 1, any) hla.demo <- hla.demo[keep,] geno <- geno[keep,] attach(hla.demo) y.ord <- as.numeric(resp.cat) y.bin <-ifelse(y.ord==1,1,0) group.bin <- haplo.group(y.bin, geno, miss.val=0) score.bin <- haplo.score(y.bin, geno, trait.type="binomial") score.merged <- haplo.score.merge(score.bin, group.bin) print(score.merged) } \keyword{scores} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/Ginv.Rd0000644000176000001440000000551711652020537014520 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/10/26 15:03:59 $ % $Header: /projects/genetics/cvs/cvsroot/mgenet/man/Ginv.Rd,v 1.2 2011/10/26 15:03:59 sinnwell Exp $ % $Locker: $ % $Log: Ginv.Rd,v $ % Revision 1.2 2011/10/26 15:03:59 sinnwell % take out unused sections in Rd % % Revision 1.1 2011/04/28 19:49:59 sinnwell % Ginv.Rd % % Revision 1.2 2008/01/08 20:26:29 sinnwell % change comment symbol % % Revision 1.1 2008/01/08 19:52:27 sinnwell % Initial revision % %revision 1.9 %date: 2006/08/07 15:37:41; author: sinnwell; state: Exp; lines: +6 -5 %add eps to , fix a few comments %---------------------------- %revision 1.8 %date: 2006/04/26 13:44:50; author: sinnwell; state: Exp; lines: +3 -0 %add eps %---------------------------- %revision 1.7 %date: 2006/03/07 22:01:36; author: sinnwell; state: Exp; lines: +4 -11 %made example runable %---------------------------- %revision 1.6 %date: 2005/03/18 17:06:10; author: sinnwell; state: Exp; lines: +10 -7 %notify use of LAPACK instead of LINPACK % %revision 1.5 %date: 2004/03/01 21:08:28; author: sinnwell; state: Exp; lines: +8 -6 %comment example % %revision 1.4 %date: 2003/03/12 20:46:25; author: sinnwell; state: Exp; lines: +3 -7 %remove sgml comments % %revision 1.3 %date: 2003/03/07 22:15:57; author: sinnwell; state: Exp; lines: +4 -4 %add keywords and fix syntax %---------------------------- %revision 1.2 %date: 2003/03/07 22:10:01; author: sinnwell; state: Exp; lines: +9 -6 %fix keywords %---------------------------- \name{Ginv} \alias{Ginv} \title{ Compute Generalized Inverse of Input Matrix } \description{ Singular value decomposition (svd) is used to compute a generalized inverse of input matrix. } \usage{ Ginv(x, eps=1e-6) } \arguments{ \item{x}{ A matrix. } \item{eps}{ minimum cutoff for singular values in svd of x } } \value{ List with components: \item{Ginv}{ Generalized inverse of x. } \item{rank}{ Rank of matrix x. } } \details{ The svd function uses the LAPACK standard library to compute the singular values of the input matrix, and the rank of the matrix is determined by the number of singular values that are at least as large as max(svd)*eps, where eps is a small value. For S-PLUS, the Matrix library is required (Ginv loads Matrix if not already done so). } \section{References}{ Press WH, Teukolsky SA, Vetterling WT, Flannery BP. Numerical recipes in C. The art of scientific computing. 2nd ed. Cambridge University Press, Cambridge.1992. page 61. Anderson, E., et al. (1994). LAPACK User's Guide, 2nd edition, SIAM, Philadelphia. } \seealso{ svd } \examples{ # for matrix x, extract the generalized inverse and # rank of x as follows x <- matrix(c(1,2,1,2,3,2),ncol=3) save <- Ginv(x) ginv.x <- save$Ginv rank.x <- save$rank } \keyword{matrix} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/print.haplo.scan.Rd0000644000176000001440000000174511656766745017023 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.scan.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % %$Log: print.haplo.scan.Rd,v $ %Revision 1.3 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.2 2008/01/08 21:48:39 sinnwell %branch from sgml % %Revision 1.1 2005/03/23 18:07:44 sinnwell %Initial revision \name{print.haplo.scan} \alias{print.haplo.scan} \title{ Print a haplo.scan object } \description{ Print a haplo.scan object } \usage{ \method{print}{haplo.scan}(x, digits=max(options()$digits - 2, 5), ...) } \arguments{ \item{x}{ An object created by haplo.scan } \item{digits}{ Significant digits shown for numeric data } \item{\dots }{ Options parameters for the print function } } \value{ NULL } \seealso{ \code{\link{haplo.scan}} } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.model.frame.Rd0000644000176000001440000000251311551405165017103 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2009/09/30 20:05:38 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.model.frame.Rd,v 1.4 2009/09/30 20:05:38 sinnwell Exp $ % $Locker: $ % $Log: haplo.model.frame.Rd,v $ % Revision 1.4 2009/09/30 20:05:38 sinnwell % rm keywords, or leave one with one from /doc/KEYWORDS % % Revision 1.3 2009/09/30 19:25:04 sinnwell % remove empty sections % % Revision 1.2 2008/04/29 17:20:59 sinnwell % rm allele.lev and miss.val % % Revision 1.1 2008/01/09 17:38:24 sinnwell % Initial revision % %Revision 1.3 2004/03/03 22:14:57 schaid %added allele.lev to work in R with character alleles % %Revision 1.2 2004/02/26 22:46:30 sinnwell %remove example % %Revision 1.1 2004/02/26 22:17:14 sinnwell %Initial revision \name{haplo.model.frame} \alias{haplo.model.frame} \title{ Sets up a model frame for haplo.glm } \description{ For internal use within the haplo.stats library } \usage{ haplo.model.frame(m, locus.label=NA, control=haplo.glm.control()) } \arguments{ \item{m}{ model.frame from evaluated formula } \item{locus.label }{ labels for loci in genotype matrix } \item{control}{ } } \value{ A model frame with haplotypes modeled as effects } \details{ See haplo.glm description in help file and user manual } \keyword{models} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.scan.Rd0000644000176000001440000001431111551405165015635 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2009/09/30 19:58:16 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.scan.Rd,v 1.4 2009/09/30 19:58:16 sinnwell Exp $ % $Locker: $ % $Log: haplo.scan.Rd,v $ % Revision 1.4 2009/09/30 19:58:16 sinnwell % remove keywords section % % Revision 1.3 2009/09/30 19:01:46 sinnwell % remove section{} and put in note{} % % Revision 1.2 2008/01/09 21:18:10 sinnwell % fixed alias for haplo.scan.obs % % Revision 1.1 2008/01/09 19:30:31 sinnwell % Initial revision % %Revision 1.6 2005/03/31 16:37:16 sinnwell %code-doc agree on param order % %Revision 1.5 2005/03/28 22:23:03 sinnwell %*** empty log message *** % %Revision 1.4 2005/03/24 16:45:10 schaid %*** empty log message *** % %Revision 1.3 2005/03/24 16:08:13 schaid %*** empty log message *** % %Revision 1.2 2005/03/24 14:41:32 sinnwell %add the max.loc vector % %Revision 1.1 2005/03/23 18:07:44 sinnwell %Initial revision \name{haplo.scan} \alias{haplo.scan} \alias{haplo.scan.obs} \alias{haplo.scan.sim} \title{ Search for a trait-locus by sliding a fixed-width window over each marker locus and scanning all possible haplotype lengths within the window } \description{ Search for haplotypes that have the strongest association with a binary trait (typically case/control status) by sliding a fixed-width window over each marker locus and scanning all possible haplotype lengths within the window. For each haplotype length, a score statistic is computed to compare the set of haplotypes with a given length between cases versus controls. The locus-specific score statistic is the maximum score statistic calculated on loci containing that locus. The maximum score statistic over all haplotype lengths within all possible windows is used for a global test for association. Permutations of the trait are used to compute p-values. } \usage{ haplo.scan(y, geno, width=4, miss.val=c(0, NA), em.control=haplo.em.control(), sim.control=score.sim.control()) haplo.scan.obs(y, em.obj, width) haplo.scan.sim(y.reord, save.lst, nloci) } \arguments{ \item{y}{ Vector of binary trait values, must be 1 for cases and 0 for controls. } \item{y.reord}{ Same as y, except the order is permuted } \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent alleles for each subject. } \item{width}{ Width of sliding the window } \item{miss.val }{ Vector of codes for missing values of alleles } \item{em.control }{ A list of control parameters to determine how to perform the EM algorithm for estimating haplotype frequencies when phase is unknown. The list is created by the function haplo.em.control - see this function for more details. } \item{sim.control }{ A list of control parameters to determine how simulations are performed for simulated p-values. The list is created by the function score.sim.control and the default values of this function can be changed as desired. See score.sim.control for details. } \item{em.obj}{ Object returned from haplo.em, performed on geno } \item{save.lst}{ Information on haplotypes needed for haplo.scan.sim, already calculated in haplo.scan } \item{nloci}{ number of markers } } \value{ A list that has class haplo.scan, which contains the following items: \item{call}{ The call to haplo.scan } \item{scan.df}{ A data frame containing the maximum test statistic for each window around each locus, and its simulated p-value. } \item{max.loc}{ The loci (locus) which contain(s) the maximum observed test statistic over all haplotype lengths and all windows. } \item{globalp}{ A p-value for the significance of the global maximum statistic. } \item{nsim}{ Number of simulations performed } } \details{ Search for a region for which the haplotypes have the strongest association with a binary trait by sliding a window of fixed width over each marker locus, and considering all haplotype lengths within each window. To acount for unknown linkage phase, the function haplo.em is called prior to scanning, to create a list of haplotype pairs and posterior probabilities. To illustrate the scanning, consider a 10-locus dataset. When placing a window of width 3 over locus 5, the possible haplotype lengths that contain locus 5 are three (loci 3-4-5, 4-5-6, and 5-6-7), two (loci 4-5, and 5-6) and one (locus 5). For each of these loci subsets a score statistic is computed, which is based on the difference between the mean vector of haplotype counts for cases and that for controls. The maximum of these score statistics, over all possible haplotype lengths within a window, is the locus-specific test statistic. The global test statistic is the maximum over all computed score statistics. To compute p-values, the case/control status is randomly permuted. Simulations are performed until precision criteria are met for all p-values; the criteria are controlled by score.sim.control. See the note for long run times. } \references{ \itemize{ \item{Cheng et al-1}{Cheng R, Ma JZ, Wright FA, Lin S, Gau X, Wang D, Elston RC, Li MD. "Nonparametric disequilibrium mapping of functional sites using haplotypes of multiple tightly linked single-nucleotide polymorphism markers". Genetics 164 (2003):1175-1187.} \item{Cheng et al-2}{Cheng R, Ma JZ, Elston RC, Li MD. "Fine Mapping Functional Sites or Regions from Case-Control Data Using Haplotypes of Multiple Linked SNPs." Annals of Human Genetics 69 (2005): 102-112. } } } \note{ For datasets with many estimated haplotypes, the run-time can be very long. } \seealso{ \code{\link{haplo.em}}, \code{\link{haplo.em.control}}, \code{\link{score.sim.control}} } \examples{ # create a random genotype matrix with 10 loci, 50 cases, 50 controls set.seed(1) tmp <- ifelse(runif(2000)>.3, 1, 2) geno <- matrix(tmp, ncol=20) y <- rep(c(0,1),c(50,50)) # search 10-locus region, typically don't limit the number of # simulations, but run time can get long with many simulations scan.obj <- haplo.scan(y, geno, width=3, sim.control = score.sim.control(min.sim=10, max.sim=20)) print(scan.obj) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/geno1to2.Rd0000644000176000001440000000363611530534042015247 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/02/21 19:08:18 $ % $Header: /projects/genetics/cvs/cvsroot/mgenet/man/geno1to2.Rd,v 1.1.1.1 2011/02/21 19:08:18 sinnwell Exp $ % $Locker: $ % %$Log: geno1to2.Rd,v $ %Revision 1.1.1.1 2011/02/21 19:08:18 sinnwell %"initial, general functions for R genetics at Mayo BSI % %Revision 1.4 2009/09/30 20:05:38 sinnwell %rm keywords, or leave one with one from /doc/KEYWORDS % %Revision 1.3 2009/09/30 19:19:23 sinnwell %remove empty sections % %Revision 1.2 2008/01/08 20:25:48 sinnwell %change comments % %Revision 1.1 2008/01/08 19:54:32 sinnwell %Initial revision % %Revision 1.5 2007/04/24 16:27:09 sinnwell %rm link to unlistToMat, no longer used % %Revision 1.4 2007/04/20 15:08:59 sinnwell %rm na.code, update example % %Revision 1.3 2007/04/18 17:16:17 sinnwell %add locus.label arg % %Revision 1.2 2007/04/16 20:13:05 sinnwell %*** empty log message *** % %Revision 1.1 2006/08/11 21:53:53 sinnwell %Initial revision \name{geno1to2} \alias{geno1to2} \title{ convert genotype matrix from 1-column 2-column } \description{ convert 1-column genotype matrix to 2-column genotype matrix, converting from a minor allele count (0,1,2) to (1/1, 1/2, 2/2) where 2 is the minor allele. (not supported for x-linked markers) } \usage{ geno1to2(geno, locus.label=NULL) } \arguments{ \item{geno}{ 1-column representation of genotype matrix for 2-allele loci. Values are 0, 1, or 2, usually the count of minor alleles } \item{locus.label }{ Vector of labels for loci, If a locus name is "A", its columns will be "A.1" and "A.2" } } \value{ a 2-column genotype matrix } \examples{ geno1 <- matrix(c(0,0,1, 1,0,2, 2,1,0), ncol=3, byrow=TRUE) geno1to2(geno1, locus.label=c("A", "B", "C")) ## demonstrate how NA and 3 will be coded geno1[1,3] <- NA geno1[1,1] <- 3 geno1to2(geno1) } \keyword{utilities} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/hla.demo.Rd0000644000176000001440000000523111656766745015323 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/hla.demo.Rd,v 1.6 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: hla.demo.Rd,v $ % Revision 1.6 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.5 2009/04/08 19:11:56 sinnwell % changed for version 2.9.1 % \name{hla.demo} \alias{hla.demo} \docType{data} \title{ HLA Loci and Serologic Response to Measles Vaccination } \description{ A data frame with genotypes at eleven HLA-region loci genotyped for 220 subjects, phase not known. Contains measles vaccination response with covariate data. } \usage{data(hla.demo)} \format{ A data frame with 220 observations on the following 26 variables. \describe{ \item{\code{resp}}{numeric, Quantitative response to Measles Vaccination} \item{\code{resp.cat}}{Category of vaccination response, a factor with levels \code{high} \code{low} \code{normal}} \item{\code{male}}{numeric, indicator of gener, 1=male, 0=female} \item{\code{age}}{numeric, subject's age} \item{\code{DPB.a1}}{first allele of genotype } \item{\code{DPB.a2}}{second allele of genotype } \item{\code{DPA.a1}}{first allele of genotype } \item{\code{DPA.a2}}{second allele of genotype} \item{\code{DMA.a1}}{first allele of genotype} \item{\code{DMA.a2}}{second allele of genotype} \item{\code{DMB.a1}}{first allele of genotype} \item{\code{DMB.a2}}{second allele of genotype} \item{\code{TAP1.a1}}{first allele of genotype } \item{\code{TAP1.a2}}{ second allele of genotype} \item{\code{TAP2.a1}}{first allele of genotype } \item{\code{TAP2.a2}}{second allele of genotype } \item{\code{DQB.a1}}{first allele of genotype} \item{\code{DQB.a2}}{second allele of genotype} \item{\code{DQA.a1}}{first allele of genotype} \item{\code{DQA.a2}}{second allele of genotype} \item{\code{DRB.a1}}{first allele of genotype} \item{\code{DRB.a2}}{second allele of genotype} \item{\code{B.a1}}{first allele of genotype} \item{\code{B.a2}}{second allele of genotype} \item{\code{A.a1}}{first allele of genotype} \item{\code{A.a2}}{second allele of genotype} } } \source{ Data set kindly provided by Gregory A. Poland, M.D. and the Mayo Clinic Vaccine Research Group for illustration only, and my not be used for publication. } \references{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434. } \examples{ data(hla.demo) } \keyword{datasets} haplo.stats/man/fitted.haplo.glm.Rd0000644000176000001440000000246511656766745017001 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/fitted.haplo.glm.Rd,v 1.1 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % $Log: fitted.haplo.glm.Rd,v $ % Revision 1.1 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % \name{fitted.haplo.glm} \alias{fitted.haplo.glm} \title{ Fitted values from haplo.glm fit } \description{ The fitted values for each person, collapsed over their expanded fitted values due to their multiple possible haplotype pairs } \usage{ \method{fitted}{haplo.glm}(object, ...) } \arguments{ \item{object}{ A haplo.glm object } \item{\dots }{ Optional arguments for the method } } \value{ vector of fitted values } \details{ Many of the subjects in a haplo.glm fit are expanded in the model matrix with weights used to reflect the posterior probability of the subject's haplotype pairs given their genotype. The working fitted values within the fitted object are from this expanded model matrix, and the fitted values from this method are calculated from the weighted fitted value for the subject across all their haplotype pairs. } \seealso{ \code{\link{haplo.glm}} } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/chisq.power.Rd0000644000176000001440000000175211650343616016060 0ustar ripleyusers\name{chisq.power} \alias{chisq.power} \alias{chisq.power.dif} \alias{chisq.sample.size} \title{ Power and sample size for the chi-square distribution } \description{ Power and sample size for the chi-square distribution given non-centrality, degrees of freedom, alpha, N (for chisq.power), and power (for chisq.sample.size) } \usage{ chisq.power(n, nc, df, alpha) chisq.power.dif(n, nc, df, alpha, power) chisq.sample.size(nc, df=df, alpha, power, lower=20, upper=100000) } \arguments{ \item{n}{ sample size (for power) } \item{nc}{ non-centrality parameter } \item{df}{ degrees of freedom } \item{alpha}{ type-I error rate } \item{power}{ desired power (for sample size) } \item{lower}{ lower bound for search space for sample size } \item{upper}{ upper bound for search space for sample size } } \value{ power, the difference in power from target power, and sample size, respectively for the three different functions } \keyword{power} % docclass is function % Converted by Sd2Rd version 43268. haplo.stats/man/geno.count.pairs.Rd0000644000176000001440000000677711663257352017033 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/23 21:00:26 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/geno.count.pairs.Rd,v 1.3 2011/11/23 21:00:26 sinnwell Exp $ % $Locker: $ % $Log: geno.count.pairs.Rd,v $ % Revision 1.3 2011/11/23 21:00:26 sinnwell % rm geno.recode from example % % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 20:56:47 sinnwell % Initial revision % %Revision 1.8 2004/03/17 16:53:36 sinnwell %raided to raised % %Revision 1.7 2004/03/15 15:53:57 sinnwell %summary.geno to summaryGeno % %Revision 1.6 2004/03/12 17:49:44 sinnwell %change 2^(h-1) to 2 raised (h-1) for Rd errors % %Revision 1.5 2004/03/01 21:09:47 sinnwell %make example run-able % %Revision 1.4 2003/04/21 20:15:26 sinnwell %correct usage section % %Revision 1.3 2003/04/15 12:59:30 schaid %updated description of details % %Revision 1.2 2003/04/14 13:41:14 sinnwell %description change % %Revision 1.1 2003/04/09 18:43:50 sinnwell %Initial revision \name{geno.count.pairs} \alias{geno.count.pairs} \title{ Counts of Total Haplotype Pairs Produced by Genotypes } \description{ Provide a count of all possible haplotype pairs for each subject, according to the phenotypes in the rows of the geno matrix. The count for each row includes the count for complete phenotypes, as well as possible haplotype pairs for phenotypes where there are missing alleles at any of the loci. } \usage{ geno.count.pairs(geno) } \arguments{ \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then geno has 2*K columns. Rows represent all observed alleles for each subject, their phenotype. } } \value{ Vector where each element gives a count of the number haplotype pairs that are consistent with a subject's phenotype, where a phenotype may include 0, 1, or 2 missing alleles at any locus. } \details{ When a subject has no missing alleles, and has h heterozygous sites, there are 2**(h-1) haplotype pairs that are possible ('**'=power). For loci with missing alleles, we consider all possible pairs of alleles at those loci. Suppose that there are M loci with missing alleles, and let the vector V have values 1 or 0 acccording to whether these loci are imputed to be heterozygous or homozygous, respectively. The length of V is M. The total number of possible states of V is 2**M. Suppose that the vector W, also of length M, provides a count of the number of possible heterozygous/homozygous states at the loci with missing data. For example, if one allele is missing, and there are K possible alleles at that locus, then there can be one homozygous and (K-1) heterozygous genotypes. If two alleles are missing, there can be K homozygous and K(K-1)/2 heterozygous genotypes. Suppose the function H(h+V) counts the total number of heterozygous sites among the loci without missing data (of which h are heterozygous) and the imputed loci (represented by the vector V). Then, the total number of possible pairs of haplotypes can be respresented as SUM(W*H(h+V)), where the sum is over all possible values for the vector V. } \seealso{ \code{\link{haplo.em}}, \code{\link{summaryGeno}} } \examples{ data(hla.demo) genohla <- hla.demo[,c(17,18,21:24)] geno <- setupGeno(genohla) count.geno <- geno.count.pairs(geno) print(count.geno) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/locus.Rd0000644000176000001440000000625511652020537014742 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/10/26 15:03:59 $ % $Header: /projects/genetics/cvs/cvsroot/mgenet/man/locus.Rd,v 1.2 2011/10/26 15:03:59 sinnwell Exp $ % $Locker: $ % $Log: locus.Rd,v $ % Revision 1.2 2011/10/26 15:03:59 sinnwell % take out unused sections in Rd % % Revision 1.1.1.1 2011/02/21 20:09:27 sinnwell % initial, genetics functions for Mayo BSI % % Revision 1.1 2008/01/09 19:43:36 sinnwell % Initial revision % \name{locus} \alias{locus} \title{ Creates an object of class "locus" } \description{ Creates an object containing genotypes for multiple individuals. The object can then use method functions developed for objects of class "locus". } \usage{ locus(allele1, allele2, chrom.label=NULL,locus.alias=NULL, x.linked=FALSE, sex=NULL, male.code="M", female.code="F", miss.val=NA) } \arguments{ \item{allele1}{ A vector containing the labels for 1 allele for a set of individuals, or optionally a matrix with 2 columns each containing an allele for each person. } \item{allele2}{ A vector containing the labels for the second allele for a set of individuals. If allele 1 is a matrix, allele 2 need not be specified. } \item{chrom.label }{ A label describing the chromosome the alleles belong to } \item{locus.alias }{ A vector containing one or more aliases describing the locus. The first alias in the vector will be used as a label for printing in some functions such as multilocus.print(). } \item{x.linked }{ A logical value denoting whether the chromosome is x linked } \item{sex}{ A vector containing the gender of each individual (required if x.linked=T) } \item{male.code }{ The code denoting a male in the sex vector } \item{female.code }{ The code denoting a female in the sex vector } \item{miss.val }{ a vector of codes denoting missing values for allele1 and allele2. Note that NA will always be treated as a missing value, even if not specified in miss.val. Also note that if multiple missing value codes are specified, the original missing value code for a specific individual can not be retrieved from the locus object. } } \value{ Returns an object of class locus which inherits from class model.matrix containing the following elements: \item{geno}{ a matrix with 2 columns where each row contains numeric codes for the 2 alleles for an individual. } \item{chrom.label}{ a chromosome label } \item{locus.alias}{ a vector of aliases for the locus } \item{x.linked}{ a logical value specifying if the locus is x-linked or not } \item{allele.labels}{ a vector of labels corresponding to the numeric codes in matrix geno (similar to levels in a factor) } \item{male.code}{ a code to be used to identify males for an x.linked locus. } \item{female.code}{ a code to be used to identify females for an x.linked locus. } } \examples{ b1 <- c("A","A","B","C","E","D") b2 <- c("A","A","C","E","F","G") loc1 <- locus(b1,b2,chrom=4,locus.alias="D4S1111") loc1 # a second example which uses more parameters, some may not be supported. c1 <- c(101,10, 112,112,21,112) c2 <- c(101,101,112, 100,21, 10) gender <- rep(c("M","F"),3) loc2 <- locus(c1,c2,chrom="X",locus.alias="DXS1234", x.linked=TRUE, sex=gender) loc2 } \keyword{classes} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/hapPower.demo.Rd0000644000176000001440000000214111551405165016315 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2009/04/27 21:21:57 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/hapPower.demo.Rd,v 1.5 2009/04/27 21:21:57 sinnwell Exp $ % $Locker: $ \name{hapPower.demo} \alias{hapPower.demo} \docType{data} \title{ Set of haplotypes and frequencies for power and sample size calculations } \description{ An example set of haplotypes and frequencies for power and sample size calculations in haplo.power.cc and haplo.power.qt } \usage{data(hapPower.demo)} \format{ A data frame with 21 observations on the following 6 variables. \describe{ \item{\code{loc.1}}{allele 1 in the haplotype } \item{\code{loc.2}}{allele 2 in the haplotype } \item{\code{loc.3}}{allele 3 in the haplotype } \item{\code{loc.4}}{allele 4 in the haplotype } \item{\code{loc.5}}{allele 5 in the haplotype } \item{\code{haplo.freq}}{numeric, frequency of haplotype} } } \references{ Schaid, DJ. Power and sample size for testing associations of haplotypes with complex traits. \emph{Ann Hum Genet} (2005) 70:116-130. } \examples{ data(hapPower.demo) } \keyword{datasets} haplo.stats/man/haplo.em.fitter.Rd0000644000176000001440000000371711656766745016642 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.em.fitter.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: haplo.em.fitter.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/08 22:28:36 sinnwell % Initial revision % %Revision 1.2 2004/02/26 22:30:08 sinnwell %remove example % %Revision 1.1 2004 \name{haplo.em.fitter} \alias{haplo.em.fitter} \title{ Compute engine for haplotype EM algorithm } \description{ For internal use within the haplo.stats library } \usage{ haplo.em.fitter(n.loci, n.subject, weight, geno.vec, n.alleles, max.haps, max.iter, loci.insert.order, min.posterior, tol, insert.batch.size, random.start, iseed1, iseed2, iseed3, verbose) } \arguments{ \item{n.loci }{ number of loci in genotype matrix } \item{n.subject }{ number of subjects in the sample } \item{weight}{ numeric weights } \item{geno.vec }{ vectorized genotype matrix } \item{n.alleles }{ numeric vector giving number of alleles at each marker } \item{max.haps }{ maximum unique haplotypes in the sample } \item{max.iter }{ maximum iterations to perform in the fitter } \item{loci.insert.order }{ order to insert loci for progressive insertion } \item{min.posterior }{ after insertion and maximization, discard haplotype pairs per person that do not meet minimum posterior prob } \item{tol}{ convergence tolerance for E-M steps } \item{insert.batch.size }{ number of markers to insert per batch } \item{random.start }{ } \item{iseed1}{ random seed for algorithm } \item{iseed2}{ random seed for algorithm } \item{iseed3}{ random seed for algorithm } \item{verbose}{ logical, print long, verbose output from E-M steps? } } \details{ For internal use within the haplo.stats library } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.em.control.Rd0000644000176000001440000001161511656766745017021 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.em.control.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: haplo.em.control.Rd,v $ % Revision 1.4 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.3 2008/04/15 20:13:52 sinnwell % fix a few words in min.post and max.haps.limit % % Revision 1.2 2008/02/05 16:31:58 sinnwell % change default for min.posterior % % Revision 1.1 2008/01/08 22:28:27 sinnwell % Initial revision % %Revision 1.8 2007/04/16 20:42:05 sinnwell %remove max.haps.limit % %Revision 1.7 2005/03/31 16:39:15 sinnwell %code-doc agree on max.iter % %Revision 1.6 2004/12/29 16:34:23 sinnwell %explain tol and max.iter better % %Revision 1.5 2004/03/01 21:16:43 sinnwell %comment out example % %Revision 1.4 2004/02/05 22:27:20 sinnwell %fix usage again, remove '<-function' % %Revision 1.3 2004/02/05 17:28:20 schaid %set defaults to new values %Revision 1.2 2003/08/26 17:57:06 schaid %edits by Dan Schaid . % %Revision 1.1 2003/08/22 20:23:05 sinnwell %Initial revision \name{haplo.em.control} \alias{haplo.em.control} \title{ Create the Control Parameters for the EM Computation of Haplotype Probabilities, with Progressive Insertion of Loci } \description{ Create a list of parameters that control the EM algorithm for estimating haplotype frequencies, based on progressive insertion of loci. Non-default parameters for the EM algorithm can be set as parameters passed to haplo.em.control. } \usage{ haplo.em.control(loci.insert.order=NULL, insert.batch.size = 6, min.posterior = 1e-09, tol = 1e-05, max.iter=5000, random.start=0, n.try = 10, iseed=NULL, max.haps.limit=2e6, verbose=0) } \arguments{ \item{loci.insert.order }{ Numeric vector with specific order to insert the loci. If this value is NULL, the insert order will be in sequential order (1, 2, ..., No. Loci). } \item{insert.batch.size }{ Number of loci to be inserted in a single batch. } \item{min.posterior }{ Minimum posterior probability of a haplotype pair, conditional on observed marker genotypes. Posteriors below this minimum value will have their pair of haplotypes "trimmed" off the list of possible pairs. If all markers in low LD, we recommend using the default. If markers have at least moderate LD, can increase this value to use less memory. } \item{tol}{ If the change in log-likelihood value between EM steps is less than the tolerance (tol), it has converged. } \item{max.iter }{ Maximum number of iterations allowed for the EM algorithm before it stops and prints an error. If the error is printed, double max.iter. } \item{random.start }{ If random.start = 0, then the inititial starting values of the posteriors for the first EM attempt will be based on assuming equal posterior probabilities (conditional on genotypes). If random.start = 1, then the initial starting values of the first EM attempt will be based on assuming a uniform distribution for the initial posterior probabilities. } \item{n.try }{ Number of times to try to maximize the lnlike by the EM algorithm. The first try uses, as initial starting values for the posteriors, either equal values or uniform random variables, as determined by random.start. All subsequent tries will use random uniform values as initial starting values for the posterior probabilities. } \item{iseed}{ An integer or a saved copy of .Random.seed. This allows simulations to be reproduced by using the same initial seed. } \item{max.haps.limit }{ Maximum number of haplotypes for the input genotypes. It is used as the amount of memory to allocate in C for the progressive-insertion E-M steps. Within haplo.em, the first step is to try to allocate the sum of the result of geno.count.pairs(), if that exceeds max.haps.limit, start by allocating max.haps.limit. If that is exceeded in the progressive-insertions steps, the C function doubles the memory until it can no longer request more. } \item{verbose}{ Logical, if TRUE, print procedural messages to the screen. If FALSE, do not print any messages. } } \value{ A list of the parameters passed to the function. } \details{ The default is to use n.try = 10. If this takes too much time, it may be worthwhile to decrease n.try. Other tips for computing haplotype frequencies for a large number of loci, particularly if some have many alleles, is to decrease the batch size (insert.batch.size), increase the memory (max.haps.limit), and increase the probability of trimming off rare haplotypes at each insertion step (min.posterior). } \seealso{ \code{\link{haplo.em}}, \code{\link{haplo.score}} } \examples{ # This is how it is used within haplo.score # > score.gauss <- haplo.score(resp, geno, trait.type="gaussian", # > em.control=haplo.em.control(insert.batch.size = 2, n.try=1)) } haplo.stats/man/anova.haplo.glm.Rd0000644000176000001440000000566711656766744016634 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:40 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/anova.haplo.glm.Rd,v 1.1 2011/11/10 15:29:40 sinnwell Exp $ --> % $Locker: $ --> % $Log: anova.haplo.glm.Rd,v $ % Revision 1.1 2011/11/10 15:29:40 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.4 2008/04/04 16:12:33 sinnwell % add note about returned value by invisible() % % Revision 1.3 2008/03/24 21:14:44 sinnwell % add show.missing argument % % Revision 1.2 2008/01/09 21:32:16 sinnwell % change comments to % % % Revision 1.1 2007/11/07 21:46:59 sinnwell % Initial revision % % Revision 1.2 2004/03/16 17:02:24 sinnwell % add return char to usage \name{anova.haplo.glm} \alias{anova.haplo.glm} \alias{anova.haplo.glmlist} \title{ Analysis of variance for haplo.glm model fit } \description{ Perform an analysis of variance between two haplo.glm model fits using the deviances from the fitted objects } \usage{ \method{anova}{haplo.glm}(object, ..., dispersion=NULL, test="Chisq") } \arguments{ \item{object}{ A haplo.glm or glm object } \item{\dots}{ More model fits to compare against the fit in the first argument } \item{dispersion }{ the dispersion parameter for the fitting family. By default it is obtained from the object(s) } \item{test}{ character string for the test of model comparison. Only "Chisq" supported for haplo.glm objects } } \value{ A data.frame of the anova class, with these columns: Df, Deviance, Resid.Df, Resid.Dev, p-value } \details{ Uses print.anova for the displayed result } \seealso{ \code{\link{haplo.glm}} } \examples{ data(hla.demo) geno <- as.matrix(hla.demo[,c(17,18,21:24)]) keep <- !apply(is.na(geno) | geno==0, 1, any) # SKIP THESE THREE LINES hla.demo <- hla.demo[keep,] # IN AN ANALYSIS geno <- geno[keep,] # attach(hla.demo) label <-c("DQB","DRB","B") y <- hla.demo$resp y.bin <- 1*(hla.demo$resp.cat=="low") # set up a genotype array as a model.matrix for inserting into data frame # Note that hla.demo is a data.frame, and we need to subset to columns # of interest. Also also need to convert to a matrix object, so that # setupGeno can code alleles and convert geno to 'model.matrix' class. geno <- setupGeno(geno, miss.val=c(0,NA)) # geno now has an attribute 'unique.alleles' which must be passed to # haplo.glm as allele.lev=attributes(geno)$unique.alleles, see below my.data <- data.frame(geno=geno, age=hla.demo$age, male=hla.demo$male, y=y, y.bin=y.bin) fit.gaus <- haplo.glm(y ~ male + geno, family = gaussian, na.action= "na.geno.keep", data=my.data, locus.label=label, control = haplo.glm.control(haplo.freq.min=0.02)) glmfit.gaus <- glm(y~male, family=gaussian, data=my.data) anova.haplo.glm(glmfit.gaus, fit.gaus) } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/x.sexcheck.Rd0000644000176000001440000000255611656766745015706 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/x.sexcheck.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: x.sexcheck.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 19:57:03 sinnwell % Initial revision % \name{x.sexcheck} \alias{x.sexcheck} \title{ consistency checks for x.linked locus } \description{ Given an x.linked locus object and a vector of gender codes, the function will check to make sure the gender codes match the codes used to originally define the locus, and that no individuals defined as males are heterozygous. } \usage{ x.sexcheck(x, sex, stop=FALSE) } \arguments{ \item{x}{ an object of class locus } \item{sex}{ a vector of codes identifying the gender of each individual contained in the locus object } \item{stop}{ if T , any warnings are converted to errors and execution is halted immediately } } \value{ T if one or more errors were found F if no errors were found } \seealso{ \code{\link{locus}} } \examples{ c1 <- c(101,10, 112,112,21,112) c2 <- c(101,101,112,100,21, 10) gender <- rep(c("M","F"),3) loc2 <- locus(c1,c2,chrom="X",locus.alias="DXS1234", x.linked=TRUE, sex=gender) loc2 } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.glm.Rd0000644000176000001440000003755212075056023015501 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2013/01/14 19:27:15 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.glm.Rd,v 1.6 2013/01/14 19:27:15 sinnwell Exp $ % $Locker: $ % $Log: haplo.glm.Rd,v $ % Revision 1.6 2013/01/14 19:27:15 sinnwell % add haplo.binomial % % Revision 1.5 2011/12/12 17:02:15 sinnwell % notes about LC-COLLATE, and update see-also % % Revision 1.4 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.3 2008/03/24 21:13:26 sinnwell % rm allele.lev and miss.val, recommend setupGeno in details, add missing in return object % % Revision 1.2 2008/03/19 21:32:38 sinnwell % change converge.em description % % Revision 1.1 2008/01/08 22:39:02 sinnwell % Initial revision % %Revision 1.9 2004/03/16 22:34:30 sinnwell %reduce data to make run faster % %Revision 1.8 2004/03/16 16:59:50 sinnwell %add return chars % %Revision 1.7 2004/03/12 18:02:10 sinnwell %add returns in usage % %Revision 1.6 2004/03/11 15:52:18 sinnwell %fix more with setupGeno % %Revision 1.5 2004/03/10 15:54:16 sinnwell %comments for allele.lev, final use of setupGeno and allele.lev in example % %Revision 1.4 2004/03/03 22:14:18 schaid %added allele.lev % %Revision 1.3 2004/03/01 21:22:57 sinnwell %fix example % %Revision 1.2 2004/02/16 17:26:08 sinnwell %change T/F to TRUE/FALSE for R code-doc agreement % %Revision 1.1 2003/09/16 16:02:02 schaid %Initial revision \name{haplo.glm} \alias{haplo.glm} \alias{print.haplo.glm} \title{ GLM Regression of Trait on Ambiguous Haplotypes } \description{ Perform glm regression of a trait on haplotype effects, allowing for ambiguous haplotypes. This method performs an iterative two-step EM, with the posterior probabilities of pairs of haplotypes per subject used as weights to update the regression coefficients, and the regression coefficients used to update the posterior probabilities. } \usage{ haplo.glm(formula=formula(data), family=gaussian, data=sys.parent(), weights, na.action="na.geno.keep", start=NULL, locus.label=NA, control=haplo.glm.control(), method="glm.fit", model=TRUE, x=FALSE, y=TRUE, contrasts=NULL, ...) } \arguments{ \item{formula}{ a formula expression as for other regression models, of the form response ~ predictors. For details, see the documentation for lm and formula. } \item{family}{ a family object. This is a list of expressions for defining the link, variance function, initialization values, and iterative weights for the generalized linear model. Supported families are: gaussian, binomial, poisson. Currently, only the logit link is implemented for binimial. } \item{data}{ a data frame in which to interpret the variables occurring in the formula. A CRITICAL element of the data frame is the matrix of genotypes, denoted here as "geno", although an informative name should be used in practice. This geno matrix is actually a matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent the alleles for each subject. It is also CRITICAL that this matrix is defined as a model.matrix, so the columns of the matrix are packaged together into a single matrix object. If geno is a matrix of alleles, then before adding it to the data frame, use the setupGeno() function, which will assign this correct class. The function will also recode alleles to numeric starting from 1, while saving the original alleles in the unique.alleles attribute. This attribute is required in haplo.glm. } \item{weights}{ the weights for observations (rows of the data frame). By default, all observations are weighted equally. } \item{na.action }{ a function to filter missing data. This is applied to the model.frame. The default value of na.action=na.geno.keep will keep observations with some (but not all) missing alleles, but exclude observations missing any other data (e.g., response variable, other covariates, weight). The EM algorithm for ambiguous haplotypes accounts for missing alleles. Similar to the usual glm, na.fail creates an error if any missing values are found, and a third possible alternative is na.exclude, which deletes observations that contain one or more missing values for any data, including alleles. } \item{start}{ a vector of initial values on the scale of the linear predictor. } \item{locus.label }{ vector of labels for loci. } \item{control}{ list of control parameters. The default is constructed by the function haplo.glm.control. The items in this list control the regression modeling of the haplotypes (e.g., additive, dominant, recessive effects of haplotypes; which haplotype is chosen as the baseline for regression; how to handle rare haplotypes; control of the glm function - maximum number of iterations), and the EM algorithm for estimating initial haplotype frequencies. See haplo.glm.control for details. } \item{method}{ currently, glm.fit is the only method allowed. } \item{model}{ logical, if model=TRUE, the model.frame is returned. } \item{x}{ logical, if x=TRUE, the model.matrix is returned. } \item{y}{ logical, if y=TRUE, the response variable is returned. } \item{contrasts}{ currently ignored } \item{\dots }{ other arguments that may be passed - currently ignored. } } \value{ An object of class "haplo.glm" is returned. The output object from haplo.glm has all the components of a glm object, with a few more. It is important to note that some of the returned components correpond to the "expanded" version of the data. This means that each observation is expanded into the number of terms in the observation's posterior distribution of haplotype pairs, given the marker data. For example, when fitting the response y on haplotype effects, the value of y[i], for the ith observation, is replicated m[i] times, where m[i] is the number of pairs of haplotypes consistent with the observed marker data. The returned components that are expanded are indicated below by [expanded] in the definition of the component. These expanded components may need to be collapsed, depending on the user's objectives. For example, when considering the influence of an observation, it may make sense to examine the expanded residuals for a single observation, perhaps plotted against the haplotypes for that observation. In contrast, it would not be sensible to plot all residuals against non-genetic covaraites, without first collapsing the expanded residuals for each observation. To collapse, one can use the average residual per observation, weighted according to the posterior probabilities. The appropriate weight can be computed as wt = fit\$weight.expanded * fit\$haplo.post.info\$post. Then, the weighted average can be calculated as tapply(fit\$residuals * wt, fit\$haplo.post.info\$indx, sum). \item{coefficients}{ the coefficients of the linear.predictors, which multiply the columns of the model matrix. The names of the coefficients are the names of the columns of the model matrix. For haplotype coefficients, the names are the concatentation of name of the geno matrix with a haplotype number. The haplotype number corresponds to the index of the haplotype. The default print will show the coefficients with haplotype number, along with the alleles that define the haplotype, and the estimated haplotype frequency. If the model is over-determined there will be missing values in the coefficients corresponding to inestimable coefficients. } \item{residuals}{ [expanded] residuals from the final weighted least squares fit; also known as working residuals, these are typically not interpretable without rescaling by the weights (see glm.object and residuals.haplo.glm). } \item{fitted.values}{ [expanded] fitted mean values, obtained by transforming linear.predictors using the inverse link function (see glm.object). } \item{effects}{ [expaded] orthogonal, single-degree-of-freedom effects (see lm.object). } \item{R}{ the triangular factor of the decomposition (see lm.object). } \item{rank}{ the computed rank (number of linearly independent columns in the model matrix), which is the model degrees of freedom - see lm.object. } \item{assign}{ the list of assignments of coefficients (and effects) to the terms in the model (see lm.object). } \item{df.residual}{ [expanded] number of degrees of freedom for residuals, corresponding to the expanded data. } \item{prior.weights}{ [expanded] input weights after expanding according to the number of pairs of haplotypes consistent with an observation's marker genotype data. } \item{family}{ a 3 element character vector giving the name of the family, the link and the variance function; mainly for printing purposes. } \item{linear.predictors}{ [expanded] linear fit, given by the product of the model matrix and the coefficients. In a glm, eta. } \item{deviance}{ up to a constant, minus twice the maximized log-likelihood. Similar to the residual sum of squares. } \item{null.deviance}{ the deviance corresponding to the model with no predictors. } \item{call}{ an image of the call that produced the object, but with the arguments all named and with the actual formula included as the formula argument. } \item{iter}{ the number of IRLS iterations used to compute the estimates, for the last step of the EM fit of coefficients. } \item{y}{ expanded response. } \item{contrasts}{ a list containing sufficient information to construct the contrasts used to fit any factors occurring in the model (see lm.object). } \item{lnlike}{ log-likelihood of the fitted model. } \item{lnlike.null}{ log-likelihood of the null model (intercept-only). } \item{lrt}{ likelihood ratio test statistic to test whether all coefficients (excepet intercept) are zero: 2*(lnlike - lnlike.null) } \item{terms}{ an object of mode expression and class term summarizing the formula, but not complete for the final model. Because this does not represent expansion of the design matrix for the haplotypes, it is typically not of direct relevance to users. } \item{control}{ list of all control parameters } \item{haplo.unique}{ the data.frame of unique haplotypes } \item{haplo.base}{ the index of the haplotype used as the base-line for the regression model. To see the actual haplotype definition, use the following: fit\$haplo.unique[fit\$haplo.base,], where fit is the saved haplo.glm object (e.g., fit <- haplo.glm(y ~ geno, ...) ). } \item{haplo.freq}{ the final estimates of haplotype frequencies, after completing EM steps of updating haplotype frequencies and regression coefficients. The length of haplo.freq is the number of rows of haplo.unique, and the order of haplo.freq is the same as that for the rows of haplo.unique. So, the frequencies of the unique haplotypes can be viewed as cbind(fit\$haplo.unique, fit\$haplo.freq). } \item{haplo.freq.init}{ the initial estimates of haplotype frequencies, based on the EM algorithm for estimating haplotype frequencies, ingnoring the trait. These can be compared with haplo.freq, to see the impact of using the regression model to update the haplotype frequencies. } \item{converge.em}{ T/F whether the EM-glm steps converged } \item{haplo.common}{ the indices of the haplotypes determined to be "common" enough to estimate their corresponding regression coefficients. } \item{haplo.rare}{ the indices of all the haplotypes determined to be too rare to estimate their specific regression coefficients. } \item{haplo.rare.term}{ T/F whether the "rare" term is included in the haplotype regression model. } \item{haplo.names}{ the names of the coefficients that represent haplotype effects. } \item{haplo.post.info}{ a data.frame of information regarding the posterior probabilites. The columns of this data.frame are: indx (the index of the input obsevation; if the ith observation is repeated m times, then indx will show m replicates of i; hence, indx will correspond to the "expanded" observations); hap1 and hap2 (the indices of the haplotypes; if hap1=j and hap2=k, then the two haplotypes in terms of alleles are fit\$haplo.unique[j,] and fit\$haplo.unique[k,]); post.init (the initial posterior probability, based on haplo.freq.init); post (the final posterior probability, based on haplo.freq). } \item{x}{ the model matrix, with [expanded] rows, if x=T. } \item{info}{ the observed information matrix, based on Louis' formula. The upper left submatrix is for the regression coefficient, the lower right submatrix for the haplotype frequencies, and the remaining is the information between regression coefficients and haplotype frequencies. } \item{var.mat}{ the variance-covariance matrix of regression coefficients and haplotype frequencies, based on the inverse of info. Upper left submatrix is for regression coefficients, lower right submatrix for haplotype frequencies. } \item{haplo.elim}{ the indices of the haplotypes eliminated from the info and var.mat matrices because their frequencies are less than haplo.min.info (the minimum haplotype frequency required for computation of the information matrix - see haplo.glm.control) } \item{missing}{ a matrix of logical values, indicating whether rows of data were removed for missing values in either genotype matrix (genomiss) or any other variables (yxmiss), such as y, other covariates, or weights. } \item{rank.info}{ rank of information (info) matrix. } } \details{ To properly prepare the data frame, the genotype matrix must be processed by setupGeno, and then included in the data frame with the response and other variables. For binomial family, the initialization of values gives warnings if non-integer number of successes, which is a concern in these models because of the weights of posterior probability of each haplotype pair per subject. We supress the warnings by defining a haplo.binomial family, which we use if family=binomial is used. } \section{References}{ Lake S, Lyon H, Silverman E, Weiss S, Laird N, Schaid D (2002) Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Human Heredity 55:56-65. } \seealso{ \code{\link{haplo.glm.control}}, \code{\link{haplo.em}}, \code{\link{haplo.model.frame}} } \examples{ cat(" FOR REGULAR USAGE, DO NOT DISCARD GENOTYPES WITH MISSING VALUES\n") cat(" WE ONLY SUBSET BY keep HERE SO THE EXAMPLES RUN FASTER\n") data(hla.demo) geno <- as.matrix(hla.demo[,c(17,18,21:24)]) keep <- !apply(is.na(geno) | geno==0, 1, any) # SKIP THESE THREE LINES hla.demo <- hla.demo[keep,] # IN AN ANALYSIS geno <- geno[keep,] # attach(hla.demo) label <-c("DQB","DRB","B") y <- hla.demo$resp y.bin <- 1*(hla.demo$resp.cat=="low") # set up a genotype array as a model.matrix for inserting into data frame # Note that hla.demo is a data.frame, and we need to subset to columns # of interest. Also also need to convert to a matrix object, so that # setupGeno can code alleles and convert geno to 'model.matrix' class. geno <- setupGeno(geno, miss.val=c(0,NA)) # geno now has an attribute 'unique.alleles' which must be passed to # haplo.glm as allele.lev=attributes(geno)$unique.alleles, see below my.data <- data.frame(geno=geno, age=hla.demo$age, male=hla.demo$male, y=y, y.bin=y.bin) fit.gaus <- haplo.glm(y ~ male + geno, family = gaussian, na.action= "na.geno.keep",allele.lev=attributes(geno)$unique.alleles, data=my.data, locus.label=label, control = haplo.glm.control(haplo.freq.min=0.02)) fit.gaus } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/printBanner.Rd0000644000176000001440000000173211654265574016110 0ustar ripleyusers\name{printBanner} \alias{printBanner} \title{ Print a nice banner } \description{ Print a centered banner that carries to multiple lines } \usage{ printBanner(str, banner.width=options()$width, char.perline=.75*banner.width, border="=") } \arguments{ \item{str}{ character string - a title within the banner } \item{banner.width }{ width of banner, the default is set to fit current options } \item{char.perline }{ number of characters per line for the title, the default is 75\% of the banner.width parameter } \item{border}{ type of character for the border } } \value{ nothing is returned } \details{ This function prints a nice banner in both R and S-PLUS } \seealso{ options } \examples{ printBanner("This is a pretty banner", banner.width=40, char.perline=30) # the output looks like this: # ======================================== # This is a pretty banner # ======================================== } % docclass is function % Converted by Sd2Rd version 43267. haplo.stats/man/setupGeno.Rd0000644000176000001440000000522011671431627015564 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/12/12 17:02:15 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/setupGeno.Rd,v 1.4 2011/12/12 17:02:15 sinnwell Exp $ % $Locker: $ % $Log: setupGeno.Rd,v $ % Revision 1.4 2011/12/12 17:02:15 sinnwell % notes about LC-COLLATE, and update see-also % % Revision 1.3 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.2 2008/01/09 21:21:56 sinnwell % *** empty log message *** % % Revision 1.1 2008/01/09 19:54:34 sinnwell % Initial revision % \name{setupGeno} \alias{setupGeno} \title{ Create a group of locus objects from a genotype matrix, assign to 'model.matrix' class. } \description{ The function makes each pair of columns a locus object, which recodes alleles to numeric and saves the original alleles as an attribute of the model.matrix. } \usage{ setupGeno(geno, miss.val=c(0,NA), locus.label=NULL) } \arguments{ \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent alleles for each subject. } \item{miss.val }{ A vector of codes denoting missing values for allele1 and allele2. Note that NA will always be treated as a missing value, even if not specified in miss.val. Also note that if multiple missing value codes are specified, the original missing value code for a specific individual can not be retrieved from the loci object. } \item{locus.label}{ vector of labels for the loci } } \value{ A 'model.matrix' object with the alleles recoded to numeric values, and the original values are stored in the 'unique.alleles' attribute. The ith item of the unique.alleles list is a vector of unique alleles for the ith locus. } \details{ This function contains the essential parts of the loci function, which is no longer within haplo.stats } \note{ A matrix that contains all elements of mode character will be sorted in alphabetic order. This order may differ across platforms according to your setting of LC_COLLATE. See the note in \code{haplo.em} about how this sort order affects results. } \seealso{ \code{\link{locus}}, \code{\link{haplo.glm}}, \code{\link{haplo.em}} } \examples{ # Create some loci to work with a1 <- 1:6 a2 <- 7:12 b1 <- c("A","A","B","C","E","D") b2 <-c("A","A","C","E","F","G") c1 <- c("101","10","115","132","21","112") c2 <- c("100","101","0","100","21","110") myGeno <- data.frame(a1,a2,b1,b2,c1,c2) myGeno <- setupGeno(myGeno) myGeno attributes(myGeno)$unique.alleles } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.em.Rd0000644000176000001440000001711511671431627015324 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/12/12 17:02:15 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.em.Rd,v 1.5 2011/12/12 17:02:15 sinnwell Exp $ % $Locker: $ % %$Log: haplo.em.Rd,v $ %Revision 1.5 2011/12/12 17:02:15 sinnwell %notes about LC-COLLATE, and update see-also % %Revision 1.4 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.3 2009/09/30 19:58:16 sinnwell %remove keywords section % %Revision 1.2 2009/09/30 19:17:51 sinnwell %remove empty sections % %Revision 1.1 2008/01/08 20:21:53 sinnwell %Initial revision % %Revision 1.15 2004/03/16 22:35:51 sinnwell %added empty space in example % %Revision 1.14 2004/03/16 15:56:04 sinnwell %alter returns for ps file % %Revision 1.13 2004/03/01 21:14:27 sinnwell %add example % %Revision 1.12 2004/02/26 22:53:55 sinnwell %remove alias-ed topics % %Revision 1.11 2004/02/23 20:26:07 sinnwell %add summary and print as topics, works as /alias for Rd % %Revision 1.10 2004/02/06 16:46:48 sinnwell %add parameter weights % %Revision 1.9 2003/10/15 14:28:48 schaid %*** empty log message *** % %Revision 1.8 2003/10/15 14:24:17 schaid %*** empty log message *** % %Revision 1.7 2003/09/19 21:40:48 schaid %*** empty log message *** % %Revision 1.6 2003/08/26 20:58:00 schaid %Major update of haplo.em, with new version using progressive insertion, and this helpfile reflecting the many changes in terms of parameters and returned values \name{haplo.em} \alias{haplo.em} \title{ EM Computation of Haplotype Probabilities, with Progressive Insertion of Loci } \description{ For genetic marker phenotypes measured on unrelated subjects, with linkage phase unknown, compute maximum likelihood estimates of haplotype probabilities. Because linkage phase is unknown, there may be more than one pair of haplotypes that are consistent with the oberved marker phenotypes, so posterior probabilities of pairs of haplotypes for each subject are also computed. Unlike the usual EM which attempts to enumerate all possible pairs of haplotypes before iterating over the EM steps, this "progressive insertion" algorithm progressively inserts batches of loci into haplotypes of growing lengths, runs the EM steps, trims off pairs of haplotypes per subject when the posterior probability of the pair is below a specified threshold, and then continues these insertion, EM, and trimming steps until all loci are inserted into the haplotype. The user can choose the batch size. If the batch size is chosen to be all loci, and the threshold for trimming is set to 0, then this algorithm reduces to the usual EM algorithm. } \usage{ haplo.em(geno, locus.label=NA, miss.val=c(0, NA), weight, control= haplo.em.control()) } \arguments{ \item{geno}{ matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent the alleles for each subject. } \item{locus.label }{ vector of labels for loci. } \item{miss.val }{ vector of values that represent missing alleles in geno. } \item{weight}{ weights for observations (rows of geno matrix). } \item{control}{ list of control parameters. The default is constructed by the function haplo.em.control. The default behavior of this function results in the following parameter settings: loci.insert.order=1:n.loci, insert.batch.size=min(4,n.loci), min.posterior= 0.0001, tol=0.00001, max.iter=500, random.start=0 (no random start), iseed=NULL (no saved seed to start random start), verbose=0 (no printout during EM iterations). See haplo.em.control for more details. } } \value{ list with components: \item{converge}{ indicator of convergence of the EM algorithm (1 = converge, 0 = failed). } \item{lnlike}{ value of lnlike at last EM iteration (maximum lnlike if converged). } \item{lnlike.noLD}{ value of lnlike under the null of linkage equilibrium at all loci. } \item{lr}{ likelihood ratio statistic to test the final lnlike against the lnlike that assumes complete linkage equilibrium among all loci (i.e., haplotype frequencies are products of allele frequencies). } \item{df.lr}{ degrees of freedom for likelihood ratio statistic. The df for the unconstrained final model is the number of non-zero haplotype frequencies minus 1, and the df for the null model of complete linkage equilibrium is the sum, over all loci, of (number of alleles - 1). The df for the lr statistic is df[unconstrained] - df[null]. This can result in negative df, if many haplotypes are estimated to have zero frequency, or if a large amount of trimming occurs, when using large values of min.posterior in the list of control parameters. } \item{hap.prob}{ vector of mle's of haplotype probabilities. The ith element of hap.prob corresponds to the ith row of haplotype. } \item{locus.label}{ vector of labels for loci, of length K (see definition of input values). } \item{subj.id}{ vector of id's for subjects used in the analysis, based on row number of input geno matrix. If subjects are removed, then their id will be missing from subj.id. } \item{rows.rem}{ now defunct, but set equal to a vector of length 0, to be compatible with other functions that check for rows.rem. } \item{indx.subj}{ vector for row index of subjects after expanding to all possible pairs of haplotypes for each person. If indx.subj=i, then i is the ith row of geno. If the ith subject has n possible pairs of haplotypes that correspond to their marker genotype, then i is repeated n times. } \item{nreps}{ vector for the count of haplotype pairs that map to each subject's marker genotypes. } \item{max.pairs}{ vector of maximum number of pairs of haplotypes per subject that are consistent with their marker data in the matrix geno. The length of max.pairs = nrow(geno). This vector is computed by geno.count.pairs. } \item{hap1code}{ vector of codes for each subject's first haplotype. The values in hap1code are the row numbers of the unique haplotypes in the returned matrix haplotype. } \item{hap2code}{ similar to hap1code, but for each subject's second haplotype. } \item{post}{ vector of posterior probabilities of pairs of haplotypes for a person, given their marker phenotypes. } \item{haplotype}{ matrix of unique haplotypes. Each row represents a unique haplotype, and the number of columns is the number of loci. } \item{control}{ list of control parameters for algorithm. See haplo.em.control } } \details{ The basis of this progressive insertion algorithm is from the sofware snphap by David Clayton. Although some of the features and control parameters of this S-PLUS version are modeled after snphap, there are substantial differences, such as extension to allow for more than two alleles per locus, and some other nuances on how the alogrithm is implemented. } \note{ Sorted order of haplotypes with character alleles is system-dependent, and can be controlled via the LC_COLLATE locale environment variable. Different locale settings can cause results to be non-reproducible even when controlling the random seed. } \seealso{ \code{\link{setupGeno}}, \code{\link{haplo.em.control}} } \examples{ data(hla.demo) attach(hla.demo) geno <- hla.demo[,c(17,18,21:24)] label <-c("DQB","DRB","B") keep <- !apply(is.na(geno) | geno==0, 1, any) save.em.keep <- haplo.em(geno=geno[keep,], locus.label=label) # warning: output will not exactly match print.haplo.em(save.em.keep) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/print.haplo.score.slide.Rd0000644000176000001440000000167211656766745020310 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.score.slide.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: print.haplo.score.slide.Rd,v $ % Revision 1.3 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.2 2008/01/08 21:56:53 sinnwell % add RCS keywords % \name{print.haplo.score.slide} \alias{print.haplo.score.slide} \title{ Print the contents of a haplo.score.slide object } \description{ Print the data frame returned from haplo.score.slide } \usage{ \method{print}{haplo.score.slide}(x, digits=max(options()$digits - 2, 5), ...) } \arguments{ \item{x}{ A haplo.score.slide object } \item{digits}{ Number of digits to print for numeric output } \item{\dots }{ Optional arguments for the print method } } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.hash.Rd0000644000176000001440000000266311656766745015667 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.hash.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: haplo.hash.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 17:36:56 sinnwell % Initial revision % \name{haplo.hash} \alias{haplo.hash} \title{ Integer Rank Codes for Haplotypes } \description{ Create a vector of integer codes for the input matrix of haplotypes. The haplotypes in the input matrix are converted to character strings, and if there are C unique strings, the integer codes for the haplotypes will be 1, 2, ..., C. } \usage{ haplo.hash(hap) } \arguments{ \item{hap}{ A matrix of haplotypes. If there are N haplotypes for K loci, hap have dimensions N x K. } } \value{ List with elements: \item{hash}{ Vector of integer codes for the input data (hap). The value of hash is the row number of the unique haplotypes given in the returned matrix hap.mtx. } \item{hap.mtx}{ Matrix of unique haplotypes. } } \details{ The alleles that make up each row in hap are pasted together as character strings, and the unique strings are sorted so that the rank order of the sorted strings is used as the integer code for the unique haplotypes. } \seealso{ haplo.em } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.glm.control.Rd0000644000176000001440000001070411656766745017175 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.glm.control.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % $Log: haplo.glm.control.Rd,v $ % Revision 1.4 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.3 2008/04/29 17:19:14 sinnwell % change defaults of freq.min and min.count % % Revision 1.2 2008/04/01 16:20:22 sinnwell % default for haplo.min.count in call set to 5 % % Revision 1.1 2008/01/08 22:39:25 sinnwell % Initial revision % %Revision 1.4 2004/03/12 18:04:08 sinnwell %add returns to usage % %Revision 1.3 2004/03/02 16:34:31 sinnwell %change T to TRUE % %Revision 1.2 2004/03/01 21:25:50 sinnwell %comment in an example % %Revision 1.1 2003/09/16 16:01:47 schaid %Initial revision \name{haplo.glm.control} \alias{haplo.glm.control} \title{ Create list of control parameters for haplo.glm } \description{ Create a list of control pararameters for haplo.glm. If no parameters are passed to this function, then all default values are used. } \usage{ haplo.glm.control(haplo.effect="add", haplo.base=NULL, haplo.min.count=NA, haplo.freq.min=.01, sum.rare.min=0.001, haplo.min.info=0.001, keep.rare.haplo=TRUE, eps.svd=sqrt(.Machine$double.eps), glm.c=glm.control(maxit=500), em.c=haplo.em.control()) } \arguments{ \item{haplo.effect }{ the "effect" of a haplotypes, which determines the covariate (x) coding of haplotypes. Valid options are "additive" (causing x = 0, 1, or 2, the count of a particular haplotype), "dominant" (causing x = 1 if heterozygous or homozygous carrier of a particular haplotype; x = 0 otherwise), and "recessive" (causing x = 1 if homozygous for a particular haplotype; x = 0 otherwise). } \item{haplo.base }{ the index for the haplotype to be used as the base-line for regression. By default, haplo.base=NULL, so that the most frequent haplotype is chosen as the base-line. } \item{haplo.min.count }{ The minimum number of expected counts for a haplotype from the sample to be included in the model. The count is based on estimated haplotype frequencies. Suggested minimum is 5. } \item{haplo.freq.min }{ the minimum haplotype frequency for a haplotype to be included in the regression model as its own effect. The haplotype frequency is based on the EM algorithm that estimates haplotype frequencies independent of trait. } \item{sum.rare.min }{ the sum of the "rare" haplotype frequencies must be larger than sum.rare.min in order for the pool of rare haplotypes to be included in the regression model as a separate term. If this condition is not met, then the rare haplotypes are pooled with the base-line haplotype (see keep.rare.haplo below). } \item{haplo.min.info }{ the minimum haplotype frequency for determining the contribution of a haplotype to the observed information matrix. Haplotypes with less frequency are dropped from the observed information matrix. The haplotype frequency is that from the final EM that iteratively updates haplotype frequencies and regression coefficients. } \item{keep.rare.haplo }{ TRUE/FALSE to determine if the pool of rare haplotype should be kept as a separate term in the regression model (when keep.rare.haplo=TRUE), or pooled with the base-line haplotype (when keep.rare.haplo=FALSE). } \item{eps.svd}{ argument to be passed to Ginv for the generalized inverse of the information matrix, helps to determine the number of singular values } \item{glm.c }{ list of control parameters for the usual glm.control (see glm.control). } \item{em.c }{ list of control parameters for the EM algorithm to estimate haplotype frequencies, independent of trait (see haplo.em.control). } } \value{ the list of above components } \seealso{ \code{\link{haplo.glm}}, \code{\link{haplo.em.control}}, \code{\link{glm.control}} } \examples{ # NOT RUN # using the data set up in the example for haplo.glm, # the control function is used in haplo.glm as follows # > fit <- haplo.glm(y ~ male + geno, family = gaussian, # > na.action="na.geno.keep", # > data=my.data, locus.label=locus.label, # > control = haplo.glm.control(haplo.min.count=5, # > em.c=haplo.em.control(n.try=1))) } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/vcov.haplo.glm.Rd0000644000176000001440000000220111656766745016463 0ustar ripleyusers% $Author: sinnwell $ --> % $Date: 2011/11/10 15:29:41 $ --> % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/vcov.haplo.glm.Rd,v 1.1 2011/11/10 15:29:41 sinnwell Exp $ --> % $Locker: $ --> % $Log: vcov.haplo.glm.Rd,v $ % Revision 1.1 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % \name{vcov.haplo.glm} \alias{vcov.haplo.glm} \title{variance-covariance matrix of a fitted haplo.glm object } \description{ Returns the variance-covariance matrix of the main parameters of a fitted haplo.glm object } \usage{ \method{vcov}{haplo.glm}(object, freq=TRUE, ...) } \arguments{ \item{object}{ A haplo.glm object } \item{freq}{ Logical. If TRUE, return the full covariance matrix including the entries for the frequency parameters } \item{\dots }{ Optional arguments for print method } } \value{ Variance-covariance matrix of model parameters } \details{ var.mat is pre-computed in haplo.glm, the generalized inverse of the Louis information matrix } \seealso{ \code{\link{haplo.glm}} } \keyword{glm} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.cc.Rd0000644000176000001440000001407311551405165015303 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2009/09/30 19:58:16 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.cc.Rd,v 1.5 2009/09/30 19:58:16 sinnwell Exp $ % $Locker: $ % %$Log: haplo.cc.Rd,v $ %Revision 1.5 2009/09/30 19:58:16 sinnwell %remove keywords section % %Revision 1.4 2009/09/30 19:03:54 sinnwell %rm section{side effects}, itemize the references % %Revision 1.3 2008/04/10 20:45:41 sinnwell %add eps.svd, leave haplo.min.count in haplo.glm.control % %Revision 1.2 2008/01/08 20:23:26 sinnwell %comments from ~~ to % % %Revision 1.1 2008/01/08 19:56:18 sinnwell %Initial revision % %Revision 1.4 2007/03/13 18:14:34 sinnwell %add weights % %Revision 1.3 2005/01/28 21:49:42 sinnwell %comment out example % %Revision 1.2 2005/01/04 20:22:17 sinnwell %change min.count to haplo.min.count % %Revision 1.1 2004/04/23 21:25:19 sinnwell %Initial revision \name{haplo.cc} \alias{haplo.cc} \title{ Haplotype Association Analysis in a Case-Control design } \description{ Combine results from haplo.score, haplo.group, and haplo.glm for case-control study designs. Analyze the association between the binary (case-control) trait and the haplotypes relevant to the unrelated individuals' genotypes. } \usage{ haplo.cc(y, geno, locus.label=NA, ci.prob=0.95, miss.val=c(0,NA), weights=NULL, eps.svd=1e-5, simulate=FALSE, sim.control=score.sim.control(), control=haplo.glm.control()) } \arguments{ \item{y}{ Vector of trait values, must be 1 for cases and 0 for controls. } \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent alleles for each subject. } \item{ci.prob }{ Probability level for confidence interval on the Odds Ratios of each haplotype to span the true value. } \item{locus.label }{ Vector of labels for loci, of length K (see definition of geno matrix) } \item{miss.val }{ Vector of codes for missing values of alleles } \item{weights}{ the weights for observations (rows of the data frame). By default, all observations are weighted equally. One use is to correct for over-sampling of cases in a case-control sample. } \item{eps.svd}{ epsilon value for singular value cutoff; to be used in the generalized inverse calculation on the variance matrix of the score vector. The degrees of freedom for the global score test is 1 less than the number of haplotypes that are scored (k-1). The degrees of freedom is calculated from the rank of the variance matrix for the score vector. In some instances of numeric instability, the singular value decomposition indicates full rank (k). One remedy has been to give a larger epsilon value. } \item{simulate}{ Logical: if [F]alse, no empirical p-values are computed; if [T]rue, simulations are performed within haplo.score. Specific simulation parameters can be controlled in the sim.control parameter list. } \item{sim.control }{ A list of control parameters to determine how simulations are performed for simulated p-values. The list is created by the function score.sim.control and the default values of this function can be changed as desired. See score.sim.control for details. } \item{control}{ A list of control parameters for managing the execution of haplo.cc. The list is created by the function haplo.glm.control, which also manages control parameters for the execution of haplo.em. } } \value{ A list including the haplo.score object (score.lst), vector of subject counts by case and control group (group.count), haplo.glm object (fit.lst), confidence interval probability (ci.prob), and a data frame (cc.df) with the following components: \item{haplotypes}{ The first K columns contain the haplotypes used in the analysis. } \item{Hap-Score}{ Score statistic for association of haplotype with the binary trait. } \item{p-val}{ P-value for the haplotype score statistic, based on a chi-square distribution with 1 degree of freedom. } \item{sim.p.val}{ Vector of p-values for score.haplo, based on simulations in haplo.score (omitted when simulations not performed). P-value of score.global based on simulations (set equal to NA when simulate=F). } \item{pool.hf}{ Estimated haplotype frequency for cases and controls pooled together. } \item{control.hf}{ Estimated haplotype frequency for control group subjects. } \item{case.hf}{ Estimated haplotype frequency for case group subjects. } \item{glm.eff}{ The haplo.glm function modeled the haplotype effects as: baseline (Base), additive haplotype effect (Eff), or rare haplotypes pooled into a single group (R). } \item{OR.lower}{ Lower limit of the Odds Ratio Confidence Interval. } \item{ OR }{ Odds Ratio based on haplo.glm model estimated coefficient for the haplotype. } \item{OR.upper}{ Upper limit of the Odds Ratio Confidence Interval. } } \details{ All function calls within haplo.cc are for the analysis of association between haplotypes and the case-control status (binomial trait). No additional covariates may be modeled with this function. Odd Ratios are in reference to the baseline haplotype. Odds Ratios will change if a different baseline is chosen using haplo.glm.control. } \references{ \itemize{ \item{Schaid et al}{Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434.} \item{Lake et al}{ Lake S, LH, Silverman E, Weiss S, Laird N, Schaid DJ. "Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous". Human Heredity. 55 (2003): 56-65} } } \seealso{ \code{\link{haplo.em}}, \code{\link{haplo.score}}, \code{\link{haplo.group}}, \code{\link{haplo.score.merge}}, \code{\link{haplo.glm}} \code{\link{print.haplo.cc}} } \examples{ # For a genotype matrix geno.test, case/control vector y.test # The function call will be like this # cc.test <- haplo.cc(y.test, geno.test, locus.label=locus.label, haplo.min.count=3, ci.prob=0.95) # } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/locator.haplo.Rd0000644000176000001440000000434511656766745016406 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/locator.haplo.Rd,v 1.2 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: locator.haplo.Rd,v $ % Revision 1.2 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.1 2008/01/09 19:41:02 sinnwell % Initial revision % %Revision 1.4 2004/03/02 21:55:33 sinnwell %comment out example % %Revision 1.3 2004/03/01 22:59:09 sinnwell %fix example % %Revision 1.2 2003/01/20 23:21:37 sinnwell %fixed RCS keywords \name{locator.haplo} \alias{locator.haplo} \title{ Find Location from Mouse Clicks and Print Haplotypes on Plot } \description{ Much like the R/Splus locator function is used to find x-y coordinates on a plot. Find all x-y coordinates that are chosen by the user's mouse clicks. Then print haplotype labels at the chosen positions. } \usage{ locator.haplo(obj) } \arguments{ \item{obj}{ An object (of class haplo.score) that is returned from haplo.score. } } \value{ List with the following components: \item{x.coord}{ Vector of x-coordinates. } \item{y.coord}{ Vector of y-coordinates. } \item{hap.txt}{ Vector of character strings for haplotypes. } } \details{ After plotting the results in obj, as from plot(obj), the function locator.haplo is used to place on the plot the text strings for haplotypes of interest. After the function call (e.g., locator.haplo(obj)), the user can click, with the left mouse button, on as many points in the plot as desired. Then, clicking with the middle mouse button will cause the haplotypes to be printed on the plot. The format of a haplotype is "a:b:c", where a, b, and c are alleles, and the separator ":" is used to separate alleles on a haplotype. The algorithm chooses the closest point that the user clicks on, and prints the haplotype either above the point (for points on the lower-half of the plot) or below the point (for points in the upper-half of the plot). } \seealso{ \code{\link{haplo.score}} } \examples{ # follow the pseudo-code # score.out <- haplo.score(y, geno, trait.type = "gaussian") # plot(score.out) # locator.haplo(score.out) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.score.slide.Rd0000644000176000001440000002040611656766745017151 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/haplo.score.slide.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: haplo.score.slide.Rd,v $ % Revision 1.4 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.3 2008/04/14 19:54:34 sinnwell % change eps.svd note % % Revision 1.2 2008/04/10 14:36:49 sinnwell % add eps.svd % % Revision 1.1 2008/01/09 19:38:58 sinnwell % Initial revision % %Revision 1.11 2007/04/12 21:52:57 sinnwell %add \s-arg %Revision 1.10 2007/01/25 22:45:26 sinnwell %add haplo.effect and min.count % %Revision 1.9 2005/03/03 20:50:55 sinnwell %change default for skip.haplo % %Revision 1.8 2004/03/24 14:40:26 sinnwell %comment out examples, except data setup, so users may uncomment and run % %Revision 1.7 2004/03/22 20:17:58 sinnwell %shorten example % %Revision 1.6 2004/03/16 22:27:33 sinnwell %put plot examples here to consolidate running the function % %Revision 1.5 2004/03/03 15:40:18 sinnwell %add labels in example function calls % %Revision 1.4 2004/03/02 20:27:28 sinnwell %binomial to ordinal in second example call %Revision 1.3 2004/03/01 22:46:41 sinnwell %fix examples % %Revision 1.2 2004/02/16 17:32:06 sinnwell %change F to FALSE % %Revision 1.1 2003/08/22 20:04:58 sinnwell %Initial revision \name{haplo.score.slide} \alias{haplo.score.slide} \title{ Score Statistics for Association of Traits with Haplotypes } \description{ Used to identify sub-haplotypes from a group of loci. Run haplo.score on all contiguous subsets of size n.slide from the loci in a genotype matrix (geno). From each call to haplo.score, report the global score statistic p-value. Can also report global and maximum score statistics simulated p-values. } \usage{ haplo.score.slide(y, geno, trait.type="gaussian", n.slide=2, offset = NA, x.adj = NA, min.count=5, skip.haplo=min.count/(2*nrow(geno)), locus.label=NA, miss.val=c(0,NA), haplo.effect="additive", eps.svd=1e-5, simulate=FALSE, sim.control=score.sim.control(), em.control=haplo.em.control()) } \arguments{ \item{y}{ Vector of trait values. For trait.type = "binomial", y must have values of 1 for event, 0 for no event. } \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then ncol(geno) = 2*K. Rows represent alleles for each subject. } \item{trait.type }{ Character string defining type of trait, with values of "gaussian", "binomial", "poisson", "ordinal". } \item{n.slide }{ Number of loci in each contiguous subset. The first subset is the ordered loci numbered 1 to n.slide, the second subset is 2 through n.slide+1 and so on. If the total number of loci in geno is n.loci, then there are n.loci - n.slide + 1 total subsets. } \item{offset}{ Vector of offset when trait.type = "poisson" } \item{x.adj }{ Matrix of non-genetic covariates used to adjust the score statistics. Note that intercept should not be included, as it will be added in this function. } \item{min.count }{ The minimum number of counts for a haplotype to be included in the model. First, the haplotypes selected to score are chosen by minimum frequency greater than skip.haplo (based on min.count, by default). It is also used when haplo.effect is either dominant or recessive. This is explained best in the recessive instance, where only subjects who are homozygous for a haplotype will contribute information to the score for that haplotype. If fewer than min.count subjects are estimated to be affected by that haplotype, it is not scored. A warning is issued if no haplotypes can be scored. } \item{skip.haplo }{ For haplotypes with frequencies < skip.haplo, categorize them into a common group of rare haplotypes. } \item{locus.label }{ Vector of labels for loci, of length K (see definition of geno matrix). } \item{miss.val }{ Vector of codes for missing values of alleles. } \item{haplo.effect }{ The "effect" pattern of haplotypes on the response. This parameter determines the coding for scoring the haplotypes. Valid coding options for heterozygous and homozygous carriers of a haplotype are "additive" (1, 2, respectively), "dominant" (1,1, respectively), and "recessive" (0, 1, respectively). } \item{eps.svd}{ epsilon value for singular value cutoff; to be used in the generalized inverse calculation on the variance matrix of the score vector. } \item{simulate}{ Logical, if [F]alse (default) no empirical p-values are computed. If [T]rue simulations are performed. Specific simulation parameters can be controlled in the sim.control parameter list. } \item{sim.control }{ A list of control parameters used to perform simulations for simulated p-values in haplo.score. The list is created by the function score.sim.control and the default values of this function can be changed as desired. } \item{em.control }{ A list of control parameters used to perform the em algorithm for estimating haplotype frequencies when phase is unknown. The list is created by the function haplo.em.control and the default values of this function can be changed as desired. } } \value{ List with the following components: \item{df}{ Data frame with start locus, global p-value, simulated global p-value, and simulated maximum-score p-value. } \item{n.loci}{ Number of loci given in the genotype matrix. } \item{simulate}{ Same as parameter description above. } \item{haplo.effect}{ The haplotype effect model parameter that was selected for haplo.score. } \item{n.slide}{ Same as parameter description above. } \item{locus.label}{ Same as parameter description above. } \item{n.val.haplo}{ Vector containing the number of valid simulations used in the maximum-score statistic p-value simulation. The number of valid simulations can be less than the number of simulations requested (by sim.control) if simulated data sets produce unstable variables of the score statistics. } \item{n.val.global}{ Vector containing the number of valid simulations used in the global score statistic p-value simulation. } } \details{ Haplo.score.slide is useful for a series of loci where little is known of the association between a trait and haplotypes. Using a range of n.slide values, the region with the strongest association will consistently have low p-values for locus subsets containing the associated haplotypes. The global p-value measures significance of the entire set of haplotypes for the locus subset. Simulated maximum score statistic p-values indicate when one or a few haplotypes are associated with the trait. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434. } \seealso{ \code{\link{haplo.score}}, \code{\link{plot.haplo.score.slide}}, \code{\link{score.sim.control}} } \examples{ data(hla.demo) # Continuous trait slide by 2 loci on all 11 loci, uncomment to run it. # Takes > 20 minutes to run # geno.11 <- hla.demo[,-c(1:4)] # label.11 <- c("DPB","DPA","DMA","DMB","TAP1","TAP2","DQB","DQA","DRB","B","A") # slide.gaus <- haplo.score.slide(hla.demo$resp, geno.11, trait.type = "gaussian", # locus.label=label.11, n.slide=2) # print(slide.gaus) # plot(slide.gaus) # Run shortened example on 9 loci # For an ordinal trait, slide by 3 loci, and simulate p-values: # geno.9 <- hla.demo[,-c(1:6,15,16)] # label.9 <- c("DPA","DMA","DMB","TAP1","DQB","DQA","DRB","B","A") # y.ord <- as.numeric(hla.demo$resp.cat) # data is set up, to run, run these lines of code on the data that was # set up in this example. It takes > 15 minutes to run # slide.ord.sim <- haplo.score.slide(y.ord, geno.9, trait.type = "ordinal", # n.slide=3, locus.label=label.9, simulate=TRUE, # sim.control=score.sim.control(min.sim=200, max.sim=500)) # note, results will vary due to simulations # print(slide.ord.sim) # plot(slide.ord.sim) # plot(slide.ord.sim, pval="global.sim") # plot(slide.ord.sim, pval="max.sim") } \keyword{scores} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/print.haplo.score.merge.Rd0000644000176000001440000000606011656766745020303 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.score.merge.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % %$Log: print.haplo.score.merge.Rd,v $ %Revision 1.3 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.2 2008/01/08 21:55:44 sinnwell %add comments % %Revision 1.14 2004/03/16 17:03:59 sinnwell %check return chars % %Revision 1.13 2004/03/12 18:07:20 sinnwell %add returns to usage % %Revision 1.12 2004/03/02 15:08:22 sinnwell %remove example, refer to haplo.score.merge.sgml % %Revision 1.11 2004/02/16 17:39:45 sinnwell %change F to FALSE in the call % %Revision 1.10 2004/02/06 19:08:27 sinnwell %*** empty log message *** % %Revision 1.9 2004/02/06 18:52:10 sinnwell %add comments for extra parameters % %Revision 1.8 2004/02/06 17:45:06 sinnwell %add '...' comment % %Revision 1.7 2003/06/19 22:04:36 sinnwell %update for parameter changes in the print method % %Revision 1.6 2003/03/19 16:08:42 sinnwell %remove spaces after sgml keywords for Rd conversion % %Revision 1.5 2003/03/13 21:50:43 sinnwell %fix examples again % %Revision 1.3 2003/03/13 21:26:04 sinnwell %fix sgml comments and try to find error for Rd % %Revision 1.2 2003/03/13 14:10:25 sinnwell %take out comments % %Revision 1.1 2003/01/17 16:58:56 sinnwell %Initial revision \name{print.haplo.score.merge} \alias{print.haplo.score.merge} \title{ Print a haplo.score.merge object } \description{ Method function to print a class of type haplo.score.merge } \usage{ \method{print}{haplo.score.merge}(x, order.by="score", all.haps=FALSE, digits=max(options()$digits-2, 5), nlines=NULL, ...) } \arguments{ \item{x}{ The object returned from haplo.score.merge (which has old class \{S\} haplo.score.merge). } \item{order.by}{ Column of the haplo.score.merge object by which to order the results } \item{all.haps}{ Logical, if (T)rue prints a row for all haplotypes. If (F)alse, the default, only prints the haplotypes kept in haplo.score for modelling. } \item{digits}{ Set the number of significant digits to print for the numeric output. } \item{nlines}{ Print the first 'nlines' rows of the large data frame for a short view of the results. } \item{\dots }{ Dynamic parameter for the values of additional parameters for the print method. } } \value{ Nothing is returned. } \details{ This is a print method function used to print information from the haplo.score.merge class. Because haplo.score.merge is a class, the generic print function can be used, which in turn calls this print.haplo.score.merge function. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Expected haplotype frequencies for association of traits with haplotypes when linkage phase is ambiguous. Submitted to Amer J Hum Genet. } \seealso{ haplo.score.merge, haplo.score, haplo.group } \examples{ #see example for haplo.score.merge } \keyword{scores} % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/print.haplo.score.Rd0000644000176000001440000000362711656766745017213 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/print.haplo.score.Rd,v 1.4 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % %$Log: print.haplo.score.Rd,v $ %Revision 1.4 2011/11/10 15:29:41 sinnwell %major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % %Revision 1.3 2008/04/04 16:15:59 sinnwell %add note about tbl returned by invisible % %Revision 1.2 2008/01/08 21:53:19 sinnwell %add comments % %Revision 1.6 2004/03/02 15:06:39 sinnwell %remove example, shown in haplo.score.sgml % %Revision 1.5 2004/02/06 18:51:55 sinnwell %add comment for '...' parameter % %Revision 1.4 2004/02/06 16:49:33 sinnwell %add digits parameter % %Revision 1.3 2003/08/27 20:52:38 schaid %*** empty log message *** % %Revision 1.2 2002/09/16 14:58:53 sinnwell %Fix RCS keywords \name{print.haplo.score} \alias{print.haplo.score} \title{ Print a haplo.score object } \description{ Method function to print a class of type haplo.score } \usage{ \method{print}{haplo.score}(x, digits, nlines=NULL, ...) } \arguments{ \item{x}{ The object returned from haplo.score (which has class haplo.score). } \item{digits}{ Number of digits to round the numeric output. } \item{nlines}{ Print the first 'nlines' rows of the large data frame for fast, short view of the results. } \item{\dots }{ Dynamic parameter for the values of additional parameters for the print method. } } \value{ If print is assigned, the object contains the table of haplotype scores that was printed by the method } \details{ This is a print method function used to print information from haplo.score class, with haplotype-specific information given in a table. Because haplo.score is a class, the generic print function can be used, which in turn calls this print.haplo.score function. } \seealso{ haplo.score } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/plot.haplo.score.Rd0000644000176000001440000000444111656766745017030 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/plot.haplo.score.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % $Log: plot.haplo.score.Rd,v $ % Revision 1.3 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.2 2008/01/08 20:28:21 sinnwell % fix comment % % Revision 1.1 2008/01/08 17:04:14 sinnwell % Initial revision % %Revision 1.6 2004/03/17 21:29:50 sinnwell %use keep to shorten example % %Revision 1.5 2004/03/02 14:53:00 sinnwell %fix example % %Revision 1.4 2004/02/06 17:44:16 sinnwell %add ... argument % %Revision 1.3 2003/09/22 16:33:37 sinnwell %update reference (?) % %Revision 1.2 2002/09/16 14:58:35 sinnwell %Fix RCS keywords % %Revision 1.1 2002/09/16 14:00:00 sinnwell %initial \name{plot.haplo.score} \alias{plot.haplo.score} \title{ Plot Haplotype Frequencies versus Haplotype Score Statistics } \description{ Method function to plot a class of type haplo.score } \usage{ \method{plot}{haplo.score}(x, ...) } \arguments{ \item{x}{ The object returned from haplo.score (which has class haplo.score). } \item{\dots }{ Dynamic parameter for the values of additional parameters for the plot method. } } \value{ Nothing is returned. } \details{ This is a plot method function used to plot haplotype frequencies on the x-axis and haplotype-specific scores on the y-axis. Because haplo.score is a class, the generic plot function can be used, which in turn calls this plot.haplo.score function. } \section{References}{ Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. "Score tests for association of traits with haplotypes when linkage phase is ambiguous." Amer J Hum Genet. 70 (2002): 425-434. } \seealso{ haplo.score } \examples{ data(hla.demo) geno <- as.matrix(hla.demo[,c(17,18,21:24)]) keep <- !apply(is.na(geno) | geno==0, 1, any) hla.demo <- hla.demo[keep,] geno <- geno[keep,] attach(hla.demo) label <- c("DQB","DRB","B") # For quantitative, normally distributed trait: score.gaus <- haplo.score(resp, geno, locus.label=label, trait.type = "gaussian") plot.haplo.score(score.gaus) ## try: locator.haplo(1) } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/summaryGeno.Rd0000644000176000001440000000400411656766745016137 0ustar ripleyusers% $Author: sinnwell $ % $Date: 2011/11/10 15:29:41 $ % $Header: /projects/genetics/cvs/cvsroot/haplo.stats/man/summaryGeno.Rd,v 1.3 2011/11/10 15:29:41 sinnwell Exp $ % $Locker: $ % % $Log: summaryGeno.Rd,v $ % Revision 1.3 2011/11/10 15:29:41 sinnwell % major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release % % Revision 1.2 2008/01/08 20:29:33 sinnwell % fix comments % % Revision 1.1 2008/01/08 18:25:51 sinnwell % Initial revision % % Revision 1.2 2004/03/02 15:17:29 sinnwell % take out example, simple usage % % Revision 1.1 2004/02/26 22:06:58 sinnwell % Initial revision \name{summaryGeno} \alias{summaryGeno} \title{ Summarize Full Haplotype Enumeration on Genotype Matrix } \description{ Provide a summary of missing allele information for each individual in the genotype matrix. The number of loci missing zero, one, or two alleles is computed, as well as the total number of haplotype pairs that could result from the observed phenotype. } \usage{ summaryGeno(geno, miss.val=0) } \arguments{ \item{geno}{ Matrix of alleles, such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then geno has 2*K columns. Rows represent all observed alleles for each subject. } \item{miss.val }{ Vector of codes for allele missing values. } } \value{ Data frame with columns representing the number of loci with zero, one, and two missing alleles, then the total haplotype pairs resulting from full enumeration of the phenotype. } \details{ After getting information on the individual loci, this function makes a call to geno.count.pairs(). The E-M steps to estimate haplotype frequencies considers haplotypes that could result from a phenotype with a missing allele. It will not remove a subject's phenotype, only the unlikely haplotypes that result from it. } \seealso{ \code{\link{geno.count.pairs}}, \code{\link{haplo.em}} } % docclass is function % Converted by Sd2Rd version 37351. haplo.stats/man/haplo.power.qt.Rd0000644000176000001440000001303011671425066016472 0ustar ripleyusers\name{haplo.power.qt} \alias{haplo.power.qt} \alias{haplo.power.qt.ncp} \title{ Compute either power or sample size for haplotype associations with a quantitative trait. } \description{ For a given set of haplotypes, their population frequencies, and assumed linear regression coefficients (additive model of haplotype effects on a quantitative trait), determine either the sample size to achieve a stated power or the power for a stated sample size. } \usage{ haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu, y.var, alpha, sample.size = NULL, power = NULL) } \arguments{ \item{haplo}{ matrix of haplotypes, with rows the different haplotypes and columns the alleles of the haplotypes. For H haplotypes of L loci, haplo has dimension H x L. } \item{haplo.freq }{ vector of length H for the population haplotype frequencies (corresponding to the rows of haplo) } \item{base.index }{ integer index of the haplotype considered to be the base-line for logistic regression (index between 1 and H); often, the most common haplotype is chosen for the base-line. } \item{haplo.beta }{ vector of length H for the haplotype effects: each beta is the amount of expected change per haplotype from the base-line average, and the beta for the base-line (indexed by base.index) is the beta for the intercept. } \item{y.mu }{ population mean of quantitative trait, y. } \item{y.var }{ popultaion variance of quantitative trait, y. } \item{alpha}{ type-I error rate } \item{sample.size }{ sample size (if power is to be calcualted). Either sample.size or power must be specified, but not both. } \item{power}{ desired power (if sample.size is to be calculated). Either sample.size or power must be specified, but not both. } } \value{ list with components: \item{ss.phased.haplo}{ sample size for phased haplotypes } \item{ss.unphased.haplo}{ sample size for unphased haplotypes } \item{power.phased.haplo}{ power for phased haplotypes } \item{power.unphased.haplo}{ power for unphased haplotypes } } \details{ Asympotic power calcuations are based on the non-centrality parameter of a non-central F distribution. This non-centrality parameter is determined by the specified regression coefficients ( values in haplo.beta), as well as the distribution of haplotypes (determined by haplo.freq). To account for haplotypes with unknown phase, all possible haplotype pairs are enumerated, and the EM algorithm is used to determine the posterior probabilities of pairs of haplotypes, conditional on unphased genotype data. Because this function uses the function haplo.em, the number of possible haplotypes can be large when there is a large number of loci (i.e., large number of columns in the haplo matrix). If too large, the function haplo.em will run out of memory, making this function (haplo.power.qt) fail. If this occurs, then consider reducing the "size" of the haplotypes, by reducing the number of columns of haplo, and adjusting the corresponding vectors (e.g., haplo.freq, haplo.beta). } \references{ Schaid, DJ. Power and sample size for testing associations of haplotypes with complex traits. Ann Hum Genet (2005) 70:116-130. } \seealso{ \code{\link{find.haplo.beta.qt}}, \code{\link{haplo.em}}, \code{\link{haplo.power.cc}} } \examples{ haplo <- rbind( c( 1, 2, 2, 1, 2), c( 1, 2, 2, 1, 1), c( 1, 1, 2, 1, 1), c( 1, 2, 1, 1, 2), c( 1, 2, 2, 2, 1), c( 1, 2, 1, 1, 1), c( 1, 1, 2, 2, 1), c( 1, 1, 1, 1, 2), c( 1, 2, 1, 2, 1), c( 1, 1, 1, 2, 1), c( 2, 2, 1, 1, 2), c( 1, 1, 2, 1, 2), c( 1, 1, 2, 2, 2), c( 1, 2, 2, 2, 2), c( 2, 2, 2, 1, 2), c( 1, 1, 1, 1, 1), c( 2, 1, 1, 1, 1), c( 2, 1, 2, 1, 1), c( 2, 2, 1, 1, 1), c( 2, 2, 1, 2, 1), c( 2, 2, 2, 1, 1)) dimnames(haplo)[[2]] <- paste("loc", 1:ncol(haplo), sep=".") haplo <- data.frame(haplo) haplo.freq <- c(0.170020121, 0.162977867, 0.123742455, 0.117706237, 0.097585513, 0.084507042, 0.045271630, 0.039235412, 0.032193159, 0.019114688, 0.019114688, 0.013078471, 0.013078471, 0.013078471, 0.013078471, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217) # define index for risk haplotypes (having alleles 1-1 at loci 2 and 3) haplo.risk <- (1:nrow(haplo))[haplo$loc.2==1 & haplo$loc.3==1] # define index for baseline haplotype base.index <- 1 # Because it can be easier to speficy genetic effect size in terms of # a regression model R-squared value (r2), we use an # auxiliary function to set up haplo.beta based on a specifed r2 value: tmp <- find.haplo.beta.qt(haplo,haplo.freq,base.index,haplo.risk, r2=0.01, y.mu=0, y.var=1) haplo.beta <- tmp$beta # Compute sample size for given power haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu=0, y.var=1, alpha=.05, power=.80) # Compute power for given sample size haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu=0, y.var=1, alpha=.05, sample.size = 2091) } \keyword{design} % docclass is function % Converted by Sd2Rd version 43268. haplo.stats/data/0000755000176000001440000000000012075615036013460 5ustar ripleyusershaplo.stats/data/seqhap.dat.tab.gz0000644000176000001440000001364011551342745016625 0ustar 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ÇÉumŠa¹7ß‘S³‡ìUOeÌ@†0N?È&¥ú(£T¡ŸÚ™ƒå>6ßWÈ×0Ô2Á¡ûQ-a¡J†LŸš’Îþz X>ZÆ8”ë”~Rklk¸#EbËjòlBâ¨ËV”›ÿ˜ðíÏûÓC7(³Zn%7Ùë{{^ýX†—4ŒEäQ-ýÌÝO"×0?W'„rP‘¼˜lWnv¾ÑÐöÒI=Ì”žæ»§˜Õ¥Âq’6£|)‡€9»‘Æ Wu£žAëR‡j=ÑH ù?~Ñ\uWhaplo.stats/NAMESPACE0000755000176000001440000000276412030625245013774 0ustar ripleyusersuseDynLib(haplo.stats) export(haplo.em, summary.haplo.em, print.haplo.em, haplo.em.control) export(haplo.score, print.haplo.score, plot.haplo.score, locator.haplo, score.sim.control, haplo.score.glm, haplo.score.podds) export(haplo.score.merge, haplo.group, print.haplo.score.merge, print.haplo.group) export(haplo.cc, print.haplo.cc) export(haplo.score.slide, print.haplo.score.slide, plot.haplo.score.slide) export(haplo.glm, summary.haplo.glm, print.haplo.glm, haplo.glm.control) export(haplo.binomial, residuals.haplo.glm, fitted.haplo.glm, vcov.haplo.glm, anova.haplo.glm) export(seqhap, plot.seqhap, print.seqhap) export(haplo.scan, print.haplo.scan, haplo.scan.obs, haplo.scan.sim, haplo.chistat) export(haplo.power.qt, haplo.power.qt.ncp, find.haplo.beta.qt) export(haplo.power.cc, haplo.power.cc.ncp) export(haplo.design, setupGeno, summaryGeno, na.geno.keep, geno1to2, Ginv, printBanner, geno.count.pairs, get.hapPair, locus) S3method(print, haplo.em) S3method(summary, haplo.em) S3method(print, haplo.score) S3method(plot, haplo.score) S3method(print, haplo.group) S3method(print, haplo.score.merge) S3method(print, haplo.glm) S3method(summary, haplo.glm) S3method(residuals, haplo.glm) S3method(fitted, haplo.glm) S3method(anova, haplo.glm) S3method(vcov, haplo.glm) S3method(print, summary.haplo.glm) S3method(print, haplo.cc) S3method(print, haplo.score.slide) S3method(plot, haplo.score.slide) S3method(print, seqhap) S3method(plot, seqhap) S3method(print, haplo.scan) haplo.stats/src/0000755000176000001440000000000012075615022013331 5ustar ripleyusershaplo.stats/src/louis_info.c0000644000176000001440000003005512075615036015653 0ustar ripleyusers/* $Author: schaid $ */ /* $Date: 2007/02/27 20:18:43 $ */ /* $Header: /projects/genetics/cvs/cvsroot/haplo.stats/src/louis_info.c,v 1.8 2007/02/27 20:18:43 schaid Exp $ */ /* $Locker: $ */ /* * $Log: louis_info.c,v $ * Revision 1.8 2007/02/27 20:18:43 schaid * changed long to int * * Revision 1.7 2004/02/02 17:08:41 schaid * removed some dead code * * Revision 1.6 2004/01/23 15:11:54 schaid * added parens for explicit precedence * * Revision 1.5 2003/10/09 16:55:56 schaid * added errmsg function * * Revision 1.4 2003/10/09 14:00:16 sinnwell * fix $Log keyword commenting * * Revision 1.3 2003/10/07 21:30:17 schaid * changed from Salloc to Calloc and Free (trying to be R compatible) * * Revision 1.2 2003/10/02 21:52:21 sinnwell * included S2R.h for portability to R. * * Revision 1.1 2003/09/16 16:02:31 schaid * Initial revision * */ #include #include #include #include #include static double **double_vec_to_mat(double *Yvec, int nrow, int ncol); static double **double_matrix(int nrow, int ncol); static double *double_vec(int n); static void errmsg(char *string); /* Louis Information matrix for GLM regression coefficients and estimated haplotype frequencies by EM algorithm */ void louis_info( int *len_tot, /* total length of: indx_subj, resid, vfunc, wt, h1, h2 */ int *indx_subj, /* vec of subj indices */ double *resid, /* vec of standardized residuals */ double *vfunc, /* vec of var function */ double *wt, /* vec of weights */ double *xvec, /* vec of xmatrix, col-major order (len=len_tot * ncov) */ int *ncov, /* number of glm covariates */ int *h1, /* vec of haplo index code for subjects' first haplo */ int *h2, /* vec of haplo index code for subjects' second haplo */ int *hap_base, /* scalar baseline haplotype index */ int *nhap, /* number of haplotypes (including base) = len hap_freq */ double *hap_freq, /* vec of haplo frequencies */ double *info11, /* infor matrix of GLM coefs, as vector col-major */ double *info12, /* info matrix of GLM coef, hap freq, in vec col-major */ double *info22) /* info matrix of hap freqs, in vec col-major */ { double **amat, **bmat, **cmat, **abmat, **x; double *tempvec1, *tempvec2; double t1, t2, t3, t4, baseFrqSqr; int i, r, r2, c, c1, c2, h, indx_start, indx_end, subj_id, nh, size_max; /* set up working vectors and matrices */ nh = *nhap - 1; size_max = nh > *ncov ? nh : *ncov; tempvec1 = double_vec(size_max); tempvec2 = double_vec(size_max); amat = double_matrix(size_max, size_max); bmat = double_matrix(size_max, size_max); abmat = double_matrix(size_max, size_max); cmat = double_matrix(size_max, size_max); /* design matrix, converted from S vec to matrix */ x = double_vec_to_mat(xvec, *len_tot, *ncov); /******************** compute info 11 *********************************************/ /* zero-out working arrays */ for(r=0;r<*ncov;r++){ for(c=0;c<*ncov;c++){ abmat[r][c] = 0.0; cmat[r][c] = 0.0; } } indx_start = 0; indx_end = *len_tot; while (indx_start < indx_end) { i = indx_start; subj_id = indx_subj[i]; /* zero-out working vec */ for(r=0;r< *ncov;r++) tempvec1[r] = 0.0; /* loop for each subject */ do { t1 = vfunc[i] - resid[i]*resid[i]; t2 = wt[i] * resid[i]; for(r=0;r< *ncov; r++){ for(c=0;c< *ncov; c++){ abmat[r][c]+= t1*wt[i] * x[i][r] * x[i][c]; } tempvec1[r]+= t2*x[i][r]; } i++; } while ( (i base. */ if( (h1[i]!= (*hap_base)) && (h2[i]!=(*hap_base) ) ){ /* both haps != base */ if(h1[i]==h2[i]){ c = h1[i] < *hap_base ? h1[i] : (h1[i]-1); t2 = 2.0/hap_freq[h1[i]]; tempvec2[c] += wt[i] * t2; for(r=0;r<*ncov;r++){ bmat[r][c] += t1 * x[i][r] * t2; } } else { c1 = h1[i] < *hap_base ? h1[i] : (h1[i]-1); t2 = 1.0/hap_freq[h1[i]]; tempvec2[c1] += wt[i] * t2; c2 = h2[i] < *hap_base ? h2[i] : (h2[i]-1); t3 = 1.0/hap_freq[h2[i]]; tempvec2[c2] += wt[i] * t3; for(r=0;r<*ncov;r++){ bmat[r][c1] += t1 * x[i][r] * t2; bmat[r][c2] += t1 * x[i][r] * t3; } } } else if ( (h1[i]== (*hap_base)) && (h2[i]==(*hap_base)) ){ /* both haps = base */ t2 = -2.0/hap_freq[*hap_base]; for(c=0;c #include #include #include #include #include #include #include "haplo_em_pin.h" /* Progressive insertion of loci into haplotypes with EM algorithm */ /*************** Global vars ******************************************************/ static int n_loci, *loci_used; /* used for qsort functions */ static HAP **ret_hap_list; /* stored for later return to S+ */ static HAPUNIQUE **ret_u_hap_list; static int ret_n_hap, ret_n_u_hap, ret_max_haps; /**********************************************************************************/ void haplo_em_pin( int *S_n_loci, /* number of loci */ int *n_subject, /* number of subjects */ double *weight, /* weight per subject */ int *geno_vec, /* vector of genotypes, col-major from */ /* n_subject x 2*n_loci matrix */ int *n_alleles, /* vector of number alleles per locus, */ /* length=n_loci */ int *max_haps, /* number of maximum haplotypes over all subjects */ /* - CRITICAL for memory alloc */ int *max_iter, /* max num. iters for each EM loop */ int *loci_insert_order, /* vector for order of insert of loci for */ /* progressive insertion; length = n_loci */ double *min_prior, /* trim haplo's with prior < min_prior */ double *min_posterior, /* trim subject's pair of haplos if */ /* post < min_posterior */ double *tol, /* convergence tolerance for change in lnlike in */ /* EM loop */ int *insert_batch_size, /* number of loci to insert in a batch before */ /* each EM loop; order of inserted */ /* loci determined by loci_insert_order */ int *converge, /* convergence indicator for EM */ double *S_lnlike, /* lnlike from final EM */ int *S_n_u_hap, /* number of unique haplotypes */ int *n_hap_pairs, /* total number of pairs of haplotypes over all */ /* subjects */ int *random_start, /* indicator of random posteriors should be */ /* generated at the start of each EM loop. */ /* 1 = Yes, 0 = No */ int *iseed1, /* seeds for AS183 random unif */ int *iseed2, int *iseed3, int *verbose) /* indicator if verbose pringing during run, */ /* for debugging. verbose=0 means no printing */ /* verbose=1 means lots of printing to screen */ { int i, j, k, iter, n_iter, insert_loc; int is, ie, n_batch; int n_u_hap, n_hap, n_trim, pair_id, len_hap_list, indx1, indx2; int **geno; double lnlike, lnlike_old; double *prior; HAP **hap_list; /* List of all haplotypes = array of pointers to hap structs */ HAPUNIQUE **u_hap_list; /* List of unique haplotypes */ HAP *h1, *h2; /* convert from S vecs to C structures */ n_loci = *S_n_loci; geno = int_vec_to_mat(geno_vec, *n_subject, 2*n_loci); if(*verbose){ REprintf("geno matrix:\n"); for(i=0;i< *n_subject;i++){ for (j=0; j< (2*n_loci); j++) { REprintf("%i ",geno[i][j]); } REprintf("\n"); } } prior = (double *) Calloc(*max_haps, double); if(prior==NULL){ errmsg("could not alloc mem for prior"); } /* array to keep track of loci used at any point in time */ loci_used = (int *) Calloc(n_loci, int); if(loci_used==NULL){ errmsg("could not alloc mem for loci_used"); } /* array of pointers to haplo information */ hap_list = (HAP **) Calloc(*max_haps, HAP* ); if(hap_list==NULL){ errmsg("could not alloc mem for hap_list"); } /* put geno data into haplo list */ pair_id = - 1; n_hap=0; for(i=0;i< *n_subject;i++){ pair_id++; indx1 = n_hap; n_hap++; indx2 = n_hap; n_hap++; hap_list[indx1] = new_hap(i, pair_id, weight[i], 0.0, 1.0); hap_list[indx2] = new_hap(i, pair_id, weight[i], 0.0, 1.0); k=0; for (j=0; j< n_loci; j++) { (hap_list[indx1])->loci[j] = geno[i][k++]; (hap_list[indx2])->loci[j] = geno[i][k++]; } } /* set seed for random unif generator, if needed */ if(*random_start){ ranAS183_seed(*iseed1, *iseed2, *iseed3); } /* begin haplotype algorithm */ if(*verbose){ REprintf("min_posterior = %8.5f\n",*min_posterior); REprintf("min_prior = %8.5f\n",*min_prior); REprintf("loci_insert_order = "); for(i=0;iid = id; result->pair_id = pair_id; result->wt = wt; result->post = post; result->keep = 1; loc = (int *) Calloc(n_loci, int); if (!loc) { errmsg("could not alloc mem for new hap"); Free(result); } result->loci = loc; return result; } /***************************************************************************/ static void write_hap_list(HAP** so, int n_hap){ int i,j; REprintf("subID wt hapPairID hapCode keep"); for(i=0;iid, so[i]->wt, so[i]->pair_id,so[i]->code,so[i]->keep); for(j=0;jloci[j]); } REprintf(" %6.4f", so[i]->post); REprintf("\n"); } } /***********************************************************************************/ static void write_unique_hap_list(HAPUNIQUE** so, int n_hap){ int i,j; REprintf("hapCode keep"); for(i=0;icode,so[i]->keep); for(j=0;jloci[j]); } REprintf(" %6.4f", so[i]->prior); REprintf("\n"); } } /****************************************************************************/ static void write_prior(int n, double *prior){ int i; REprintf("hapCode prior\n"); for(i=0;iloci; loc2 = two->loci; for (i=0; ia2) return +1; } return 0; } /***********************************************************************************/ static int CDECL cmp_hap_code(const void *to_one, const void *to_two){ HAP *one, *two; one = * (HAP **) to_one; two = * (HAP **) to_two; if((one->code) < (two->code)) return -1; if((one->code) > (two->code)) return 1; return 0; } /***********************************************************************************/ static int CDECL cmp_subId_hapPairId(const void *to_one, const void *to_two){ /* Using this comparision function with qsort results in a sort first on subj id, then on hap pair_id */ HAP *one, *two; one = * (HAP **) to_one; two = * (HAP **) to_two; if((one->id) < (two->id)) return -1; if((one->id) > (two->id)) return 1; if( (one->pair_id) < (two->pair_id)) return -1; if( (one->pair_id) > (two->pair_id)) return 1; return 0; } /***********************************************************************************/ static void unique_haps(int n_hap, HAP **hap_list, HAPUNIQUE **u_hap_list, double *prior) { /* assumes hap_list is sorted by either haplotype (cmp_hap) or haplotype code (cmp_trim) */ HAP **hs, **he, **h; hs = hap_list; he = hap_list + n_hap; while (hs < he) { h = hs; do { h++; } while ( (hcode == (*h)->code) ); *u_hap_list++ = copy_hap_unique(*hs, prior); hs = h; } } /***********************************************************************************/ static HAPUNIQUE* copy_hap_unique(HAP *old, double *prior) { HAPUNIQUE *result; int i; result = (HAPUNIQUE *) Calloc(1, HAPUNIQUE); if (result) { result->code = old->code; result->prior = prior[old->code]; result->keep = old->keep; result->loci = (int *) Calloc(n_loci, int); if (result->loci==NULL) { errmsg("could not alloc mem for copy_hap_unique"); Free(result); } for (i=0; iloci[i] = old->loci[i]; } return result; } /***********************************************************************************/ static int code_haps(int n_hap, HAP **hap_list) { /* assumes hap_list is sorted by either haplotype (cmp_hap) or haplotype code (cmp_trim) */ HAP **hs, **he, **h; int res = 0; hs = hap_list; he = hap_list + n_hap; while (hs < he) { h = hs; do { (*h)->code = res; h++; } while ((hcode == (*h)->code) ); res++; hs = h; } return res; } /***********************************************************************************/ static int hap_enum(HAP ***hap_list_ptr, double **prior_ptr, int *max_haps, int *n_alleles, int insert_loc, int n_hap, int *pair_id_ptr){ int i,j, a_poss,a1_poss,a2_poss, a1, a2,a1_new,a2_new; int n_al, n_miss; HAP *h1, *h2, *h1_new, *h2_new; j = n_hap - 1; loci_used[insert_loc] = 1; for(i=0;i<(n_hap-1);i+=2){ h1 = (*hap_list_ptr)[i]; h2 = (*hap_list_ptr)[i+1]; a1 = h1->loci[insert_loc]; a2 = h2->loci[insert_loc]; /* fill in missing allele values */ n_al = n_alleles[insert_loc]; n_miss = 0; if(a1==0) n_miss ++; if(a2==0) n_miss ++; switch(n_miss){ case 0: if((a1!=a2) && (num_het(h1,h2) > 1) ){ /* note that nhet = number of het loci that are currently in use, including new insert locus. Only need to consider reciprocal haplotype allele insertion if het at current insert locus, and total num of hets across all used loci > 1 */ insert_new_hap_pair(hap_list_ptr, prior_ptr, max_haps, insert_loc, h1, h2, a2, a1, pair_id_ptr, &j); } break; case 1: /* over-write haps for first possible alleles, to fill in one possible haplotype pair, and expand if needed */ if(a1==0){ a1_new = 1; a2_new = a2; } else { a1_new = a1; a2_new = 1; } h1 ->loci[insert_loc] = a1_new; h2 ->loci[insert_loc] = a2_new; (*hap_list_ptr)[i] = h1; (*hap_list_ptr)[i+1] = h2; if((a1_new!=a2_new) && (num_het(h1,h2) > 1) ){ insert_new_hap_pair(hap_list_ptr, prior_ptr, max_haps, insert_loc, h1, h2, a2_new, a1_new, pair_id_ptr, &j); } /* now consider all other values of missing allele */ for(a_poss=2;a_poss<=n_al;a_poss++){ if(a1==0){ a1_new = a_poss; a2_new = a2; } else { a1_new = a1; a2_new = a_poss; } insert_new_hap_pair(hap_list_ptr, prior_ptr, max_haps, insert_loc, h1, h2, a1_new, a2_new, pair_id_ptr, &j); /* pull out the newly inserted hap pair, to be used to determine number of heterozous sites, to determine whether new hap pair needs to be inserted */ h1_new = (*hap_list_ptr)[j-1]; h2_new = (*hap_list_ptr)[j]; if((a1_new!=a2_new) && (num_het(h1_new,h2_new) > 1) ){ insert_new_hap_pair(hap_list_ptr, prior_ptr, max_haps, insert_loc, h1, h2, a2_new, a1_new, pair_id_ptr, &j); } } break; case 2: /* over-write haps for first possible alleles, to fill in one possible haplotype pair, and expand if needed */ h1 ->loci[insert_loc] = 1; h2 ->loci[insert_loc] = 1; (*hap_list_ptr)[i] = h1; (*hap_list_ptr)[i+1] = h2; for(a1_poss=1;a1_poss<=n_al;a1_poss++){ for(a2_poss=a1_poss; a2_poss<=n_al;a2_poss++){ if( (a1_poss==1) && (a2_poss==1) ) continue; /* did this case above */ a1_new = a1_poss; a2_new = a2_poss; insert_new_hap_pair(hap_list_ptr, prior_ptr, max_haps, insert_loc, h1, h2, a1_new, a2_new, pair_id_ptr, &j); h1_new = (*hap_list_ptr)[j-1]; h2_new = (*hap_list_ptr)[j]; if((a1_new!=a2_new) && (num_het(h1_new,h2_new) > 1) ){ insert_new_hap_pair(hap_list_ptr, prior_ptr, max_haps, insert_loc, h1, h2, a2_new, a1_new, pair_id_ptr, &j); } } } break; default: errmsg("error for number missing alleles"); } } return (j + 1); /* return value is new number of haplos after all expanded */ } /***********************************************************************************/ static HAP* copy_hap(HAP *old) { HAP *result; int i; result = (HAP *) Calloc(1, HAP); if (result) { result->id = old->id; result->pair_id = old->pair_id; result->wt = old->wt; result->post = old->post; result->code = old->code; result->keep = old->keep; result->loci = (int *) Calloc(n_loci, int); if (result->loci==NULL) { errmsg("could not alloc mem for copy_hap"); Free(result); } for (i=0; iloci[i] = old->loci[i]; } return result; } /***********************************************************************************/ static int num_het(HAP* h1, HAP* h2){ int i, nhet; nhet = 0; for(i=0;iloci[i]!=h2->loci[i]) ) nhet++; } return nhet; } /***********************************************************************************/ static void hap_prior(int n_hap, HAP** hap_list, double *prior, int n_u_hap, double min_prior) { double total, a; int i; for(i=0; ipost * hap_list[i]->wt * hap_list[i]->keep; total += a; prior[hap_list[i]->code] += a; } for(i=0;iwt; subtotal = 0.0; n_trim = 0; /* numerator of post prob */ do { id = (*h)->id; h2 = h+1; gp = prior[(*h)->code] * prior[(*h2)->code] ; if ((*h)->code != (*h2)->code) gp *= 2.0; subtotal += gp; (*h)->post = (*h2)->post = gp; h = h2+1; } while ((hid)==id)); hn = h; if(subtotal > 0.0){ /* check if need to trim by post */ for (h=hs; hpost/subtotal < min_posterior) ? 0 : 1; if(keep==0){ /* trim pair of haps */ n_trim +=2; subtotal -= (*h)->post ; (*h)->post = 0.0; (*h)->keep = 0; (*(h+1))->post = 0.0; (*(h+1))->keep = 0; } } /* rescale if new subtotal > 0.0 */ if(subtotal > 0.0){ for (h=hs; hpost = (*h)->post/subtotal; } } /* zero post and trim all if new subtotal <= 0.0 */ else { for (h=hs; hpost =0.0; (*h)->keep = 0; } } } /* if original subtotal <= 0, zero post and trim all */ else { for (h=hs; hpost = 0.0; (*h)->keep = 0; } } (*lnlike) += (subtotal > 0.0) ? tmp_wt * log(subtotal) : 0.0; total_trim += n_trim; hs = hn; } return total_trim; } /*********************************************************************************/ static void set_posterior(int n_hap, HAP **hap_list, int *random_start){ HAP **hs, **he, **hn, **h, **h1, **h2; double u, subtotal, post; int id; hs = hap_list; he = hap_list + n_hap; /* fill numertators of post */ if(! (*random_start) ) { while(hs < he){ h1=hs; hs++; h2=hs; (*h1)->post = (*h2)->post = 1.0; hs++; } } else { while(hs < he){ u = ranAS183(); h1=hs; hs++; h2=hs; (*h1)->post = (*h2)->post = u; hs++; } } /* standardize so post sums to 1 per subject */ hs = hap_list; he = hap_list + n_hap; while(hs < he){ subtotal = 0.0; h = hs; do { id = (*h)->id; subtotal += (*h)->post; h += 2; } while ( (hid == id ) ); hn = h; /* new end for a subject */ for(h = hs; h < hn; h+=2){ post = (*h)->post/subtotal; (*h)->post = post; (*(h+1))->post = post; } hs = hn; /* new begin for next subject */ } return ; } /*********************************************************************************/ static int **int_matrix(int nrow, int ncol){ /* allocate int matrix with subscript range m[0 ..(nrow-1)][0..(ncol-1)] */ int i; int **m; /* allocate pointers to rows */ m=(int **) Calloc(nrow, int *); if (!m) errmsg("mem alloc failure 1 in int_matrix"); /* allocate vec of memory for each row */ for(i=0;iprior; u_hap_code[i] = ret_u_hap_list[i]->code; for(j=0;j<*S_n_loci;j++){ k++; u_hap[k] = ret_u_hap_list[i]->loci[j]; } } h = ret_hap_list; for(i=0; i<*n_pairs; i++){ subj_id[i] = (*h)->id; post[i] = (*h)->post; hap1_code[i] = (*h)->code; h++; hap2_code[i] = (*h)->code; h++; } return; } /***********************************************************************************/ void haplo_free_memory(void){ /* free memory saved for returned info */ int i; for(i=0;iloci != NULL) Free( ret_hap_list[i]->loci ); Free( ret_hap_list[i]); } } Free(ret_hap_list); ret_hap_list = NULL; for(i=0;iloci != NULL) Free( ret_u_hap_list[i]->loci ); Free( ret_u_hap_list[i] ); } } Free(ret_u_hap_list); ret_u_hap_list = NULL; return; } /***********************************************************************************/ /* Algorithm AS 183 Appl. Statist. (1982) vol.31, no.2 Returns a pseudo-random number rectangularly distributed between 0 and 1. The cycle length is 6.95E+12 (See page 123 of Applied Statistics (1984) vol.33), not as claimed in the original article. ix, iy and iz should be set to integer values between 1 and 30000 before the first entry. To do this, first call ranAS183_seed(iseed1,iseed2,iseed3), where iseed# are 3 int seeds between 1 and 30000. The 3 seeds are saved, but ix,iy,iz can change. NOTE: Feb 23, 2007 DJS changed long to int Translated from fortran to C. */ static int ix, iy, iz; static int ranAS183_seed(int iseed1, int iseed2, int iseed3) { int error; error=1; if( ( (iseed1 >=1) && (iseed1 <=30000)) && ( (iseed2 >=1) && (iseed2 <=30000) ) && ( (iseed3 >=1) && (iseed3 <=30000) )) error=0; if(error) return (error); ix = iseed1; iy = iseed2; iz = iseed3; return (error); } /***********************************************************************************/ static double ranAS183() { double u; ix = (171*ix) % 30269; iy = (172*iy) % 30307; iz = (170*iz) % 30323; u = (double)ix/30269.0 + (double)iy/30307.0 + (double)iz/30323.0; return ( u - (int) u ); } /***********************************************************************************/ static void errmsg(char *string){ /* Function to emulate "stop" of S+ - see page 134, S Programing, by Venables and Ripley */ PROBLEM "%s", string RECOVER(NULL_ENTRY); } /***********************************************************************************/ static void divideKeep(HAP **hap_list, int n, int *nReturn) { int i,j; HAP *temp; int nValid = 0; i = -1; for(j = i+1; jkeep !=0){ i++; temp = hap_list[i]; hap_list[i] = hap_list[j]; hap_list[j] = temp; } } for(i = 0; ikeep == 0) continue; nValid++; } *nReturn = nValid; return; } /***********************************************************************************/ static void add_more_memory(HAP ***hap_list, double **prior,int *max_haps){ /* check that max_haps will not exceed max limit for an int on a 32-bit processor */ if(*max_haps == INT_MAX) { errmsg("cannot increase max_haps, already at max limit"); } if((*max_haps) > INT_MAX/2) { *max_haps = INT_MAX; } else { *max_haps = 2 * (*max_haps); } *prior = (double *) Realloc(*prior, *max_haps, double); if(prior==NULL){ errmsg("could not realloc mem for prior"); } *hap_list = (HAP **) Realloc(*hap_list, *max_haps, HAP* ); if(hap_list==NULL){ errmsg("could not realloc mem for hap_list"); } return; } /***********************************************************************************/ static void insert_new_hap_pair(HAP ***hap_list_ptr, double **prior_ptr, int *max_haps, int insert_loc, HAP *h1_old, HAP *h2_old, int a1_new, int a2_new, int *pair_id_ptr, int *j){ loci_used[insert_loc] = 1; if( ((*j)+2) >= (*max_haps) ){ add_more_memory(hap_list_ptr, prior_ptr, max_haps); } /* update pair id, to be used for both haplotypes */ (*pair_id_ptr) ++; /* By using divideKeep, the number of haploytpes (nhap) is reduced to only those with keep=1, but the memory for those with keep=0 is still in place. So, when adding new haplotypes to the 'end' of the list, nhap gives a count that is shorter than the true length. If where we are adding a haplotype in a list is not NULL, then simply over write existing memory with old haplotype data, and then update this old info with new alleles at insterted locus position, as well a pair_id. If where we are adding points to NULL, then need to copy old haplotype info (while allocating memory), then update inserted allele and pair_id. */ /* First haplotype */ (*j)++; if( (*hap_list_ptr)[*j] !=NULL) { overwrite_hap((*hap_list_ptr)[*j], h1_old); } else { (*hap_list_ptr)[*j] = copy_hap(h1_old); } (*hap_list_ptr)[*j]->loci[insert_loc] = a1_new; (*hap_list_ptr)[*j]->pair_id = (*pair_id_ptr); /* Second haplotype */ (*j)++; if( (*hap_list_ptr)[*j] !=NULL) { overwrite_hap((*hap_list_ptr)[*j], h2_old); } else { (*hap_list_ptr)[*j] = copy_hap(h2_old); } (*hap_list_ptr)[*j]->loci[insert_loc] = a2_new; (*hap_list_ptr)[*j]->pair_id = (*pair_id_ptr); } /***********************************************************************************/ static void overwrite_hap(HAP *new, HAP *old) { int i; new->id = old->id; new->pair_id = old->pair_id; new->wt = old->wt; new->post = old->post; new->code = old->code; new->keep = old->keep; if(new->loci == NULL){ new->loci = (int *) Calloc(n_loci, int); } if(new->loci == NULL) { errmsg("could not alloc mem for overwrite_hap"); } for (i=0; iloci[i] = old->loci[i]; } } /***********************************************************************************/ void checkIntMax(int *intMax) { *intMax = INT_MAX; return ; } haplo.stats/src/seqhap.c0000644000176000001440000005736412075615036015002 0ustar ripleyusers/*Author: Yu, Zhaoxia*/ /*Date: 2007/04/02*/ /* Modified: Jason Sinnwell to do permutations until p.threshold met, as implemented in haplo.score permutations */ /* Date: 2008/9/22 */ #include #include #include #include /*ranAS183_seed reads three random seeds*/ static int ranAS183_seed(int, int, int); /*ranAS183 generates random values*/ static double ranAS183(); /*redefine haplotype memberships for a subset of SNPs from a set of SNPs*/ static int creatsubhap(); /*calculate the chi^2 statistics for a 2-by-h table*/ static double chisq2h(int *); /*calculate a Mantel-Haenszel statistic*/ static double mantel(int *); /*calculate r^2 for two give SNPs*/ static double r2test(int, int); /*search for the list SNPs that should be combined to a given SNP*/ static double combine(int *, int, int); /*permute disease status*/ static void permute(int *, double *, int *); /*calculate the P-value for a chi^2 statistic with given degrees of freedom*/ static double pchisq(double, double); static int *subjid, *hap1code, *hap2code, *disease, *newhap1code, *newhap2code, *inlist, inlist_length; /*inlist is the list of SNPs to be combined to a given SNP*/ /*inlist_length is the number of SNPs combined to a given SNP*/ static int **haplist; static double *post, *pos; /*posterior probabilities and SNPs' physical positions*/ static int *newhap1codesingle, *newhap2codesingle; static double r2_threshold, mh_threshold, haplo_freq_min, p_threshold; /*parameters*/ static int nsnp, nhap, nsub, npost, newnhap, flag, hap_df; void seqhap( int *nsnp_c, /*number of SNPs*/ int *nsub_c, /*number of subjects*/ int *npost_c, /*length of posterior probabilities*/ int *nhap_c, /*number of distinguishing haplotypes*/ int *subjid_c, /*subject ID*/ int *hap_c, /*a int vectors converted from the haplotype matrix*/ int *hap1_c, /*index for the first haplotype for each posterior*/ int *hap2_c, /*index for the second haplotype for each posterior*/ int *disease_c, /*disease status*/ double *post_c, /*posterior probabilities*/ double *pos_c, /*SNPs' physical positions*/ int *seed_c, /*random seeds*/ int *nperm_c, /*number of permutations to calculate P-values*/ int *min_perm_c, /* min number permutations in Besag/Clifford approach */ int *max_perm_c, /* max number permutations in Besag/Clifford approach */ double *p_threshold_c, /* perm p-value threshold */ double *lamda_c, /*threshold for the MH test*/ double *r2_threshold_c, /*threshold to ignore one marker when two are in high r^2*/ double *haplo_freq_min_c, /*the minimum haplotype frequency that should used*/ int *inlist_c, /*the list of SNPs combined to a given SNP*/ int *hap_df_c, /*the d.f. of the sequential haplotype test*/ double *hap_chi_c, /*the chi^2 statistic of the sequential hapltoype test*/ double *hap_p_point_c, /*pointwise P-values of the sequential haplotype test based on permutations*/ double *hap_p_region_c, /*the regional P-value of the sequential haplotype test based on permutations*/ int *sum_df_c, /*the d.f. of the sequential summary test*/ double *sum_chi_c, /*the chi^2 statistic of the sequential summary test*/ double *sum_p_point_c, /*pointwise P-values of the sequential summary test based on permutations*/ double *sum_p_region_c, /*the regional P-value of the sequential summary test based on permutations */ double *chi_chi_c, /*the chi^2 statistic of the single-SNP test*/ double *chi_p_point_c, /*pointwise P-values of the single-SNP test based on permutations*/ double *chi_p_region_c /*the regional P-value of the single-SNP test based on permutations*/ ) { /*read data passed from S*/ nsnp = *nsnp_c; r2_threshold = *r2_threshold_c; mh_threshold = *lamda_c; p_threshold = *p_threshold_c; int N_PERM = *nperm_c; int MIN_PERM = *min_perm_c; int MAX_PERM = *max_perm_c; nsub = *nsub_c; npost = *npost_c; nhap = *nhap_c; haplo_freq_min = *haplo_freq_min_c; FILE *fp; int nperm, si, i, j, k; double chi_stat0i[nsnp], chi_max=0, chi_max0=0, chi_pi[nsnp], chi_p=0, hap_stat0i[nsnp], hap_min=1, hap_min0=1, hap_pi[nsnp], hap_p=0, sum_stat0i[nsnp], sum_min=1, sum_min0=1, sum_pi[nsnp], sum_p=0; for(i=0; i=0) ) { sum_stat0i[si]=sum_stat0i[si] + combine(disease, si, k); k++; }/*search for the list of SNPs to be combined to SNP si and update the summary statistic*/ if(inlist_length==1) {hap_stat0i[si]=chi_stat0i[si]; hap_df=1;} else hap_stat0i[si] = chisq2h(disease); /*update the haplotype statistic*/ /*save for Splus*/ for(i=0; ichi_max0) chi_max0=chi_stat0i[si]; /*update the maximum*/ if(hap_stat0i[si]=0) ) { sum_tmp=sum_tmp + combine(perm_disease, si, k); k++; } doublek = inlist_length; sum_tmp = pchisq(doublek/2, sum_tmp/2); if(inlist_length==1) {hap_tmp=chi_tmp; hap_df=1;} else hap_tmp = chisq2h(perm_disease); doublek = hap_df; hap_tmp = pchisq(doublek/2, hap_tmp/2); /*global*/ if(chi_tmp > chi_max) chi_max=chi_tmp; if(hap_tmp < hap_min) hap_min=hap_tmp; if(sum_tmp < sum_min) sum_min=sum_tmp; /*pointwise*/ if(chi_tmp > chi_stat0i[si]) chi_pi[si]++; if(hap_tmp < hap_stat0i[si]) hap_pi[si]++; if(sum_tmp < sum_stat0i[si]) sum_pi[si]++; } /*global*/ if(chi_max > chi_max0) chi_p++; if(hap_min < hap_min0) hap_p++; if(sum_min < sum_min0) sum_p++; /* } old for() stop */ if( N_PERM >= MIN_PERM ) { /* added by JPS: apply Besag and Clifford permutation p-values rules to region p-values */ h_region = 1/((p_threshold * p_threshold) + 1/N_PERM); if( (h_region <= hap_p & h_region <= chi_p & h_region <= sum_p) | N_PERM == MAX_PERM) { doneperm = 1; } } } /*global P-values based on permutation*/ *chi_p_region_c = chi_p/N_PERM; *hap_p_region_c = hap_p/N_PERM; *sum_p_region_c = sum_p/N_PERM; *nperm_c = N_PERM; /*pointwisw P-vlaues based on permutation*/ for(si=0; si=0 && si+k pos[si+k]-pos[si]) { /*check si+k*/ flagr=1; if(r2test(si, si+k)=", keep growing on the right direction, but do not add si+k to inlist*/ { for(j=0; jmh_threshold){ mh_sum=mh_sum + mh_tmp; inlist_length++; inlist[inlist_length-1]=si+k; newnhap=creatsubhap();} else flagr=0; } /*if r2>r2_threshold, do NOT add si+k into inlist, but continue search; if r2mh_threshold, add si+k into inlist; if r2=", keep growing on the left direction, but do not add si-k to inlist*/ { for(j=0; jmh_threshold){ mh_sum=mh_sum + mh_tmp; inlist_length++; inlist[inlist_length-1]=si-k; newnhap=creatsubhap();} else flagl=0; } if(flagl!=1 && flagr!=1) flag=0; /* if either direction is kept for growing, stop*/ } else { /*check si-k*/ flagl=1; if(r2test(si,si-k)mh_threshold){ mh_sum=mh_sum + mh_tmp; inlist_length++; inlist[inlist_length-1]=si-k; newnhap=creatsubhap();} else flagl=0; } /*check si+k */ flagr=1; if(r2test(si, si+k)mh_threshold){ mh_sum=mh_sum + mh_tmp; inlist_length++; inlist[inlist_length-1]=si+k; newnhap=creatsubhap();} else flagr=0; } if(flagl!=1 && flagr!=1) flag=0;/*if neither direction is kept for growing, stop*/ } if(si-k<0 && si+kmh_threshold){ mh_sum=mh_sum + mh_tmp; inlist_length++; inlist[inlist_length-1]=si+k; newnhap=creatsubhap();} else flagr=0; } if(flagr!=1) flag=0; } if(si+k>=nsnp && si-k>0) { /*check si-k*/ flagl=1; if(r2test(si, si-k)mh_threshold){ mh_sum=mh_sum + mh_tmp; inlist_length++; inlist[inlist_length-1]=si-k; newnhap=creatsubhap();} else flagl=0; } if(flagl!=1) flag=0; } return(mh_sum); } /*permute disease status*/ static void permute(int *nondup_disease, double *perm_rand, int *perm_disease) { int i, j, tmpint, perm_order[nsub]; double tmp; for(i=0; i0.5 && n1plus[i]>0.5 && nplus0[i]>0.5 && nplus1[i]>0.5) /*a stratum is ignored if a stratum has counts <=2*/ { num = num + n00[i] - n0plus[i] * nplus0[i]/ntotal[i]; denom = denom + n0plus[i]*n1plus[i]*nplus0[i]*nplus1[i]/ (ntotal[i]*ntotal[i]*(ntotal[i]-1)); } else { if(maxcount < ntotal[i]) maxcount = ntotal[i]; }/*the else expression is not necessary and can be removed. It was used in an early version with an additional parameter.*/ n = n + ntotal[i]; } if(denom==0) return(denom); mh_stat = pow(num,2)/denom; return(mh_stat); } /*the chisq2h function calculates the chisquare statistic for a 2-by-h table */ static double chisq2h(int *d) { double n0[newnhap], n1[newnhap], n0sum=0, n1sum=0, nhapsum[newnhap]; double en0[newnhap], en1[newnhap], ntotal=0, chi2h_stat=0; int i, j; /*initialize*/ for(i=0; ihaplo_freq_min*ntotal) { trunhapsum[ntrunhap]=nhapsum[i]; trunn0[ntrunhap] = n0[i]; trunn1[ntrunhap] = n1[i]; ntrunhap++; } else { n0sum = n0sum - n0[i]; n1sum = n1sum - n1[i]; } } ntotal = n0sum + n1sum; for(i=0; i ITMAX) nrerror("a too large, ITMAX too small in gcf"); */ *gammcf=exp(-x+a*log(x)-(*gln))*h; } #undef ITMAX #undef EPS #undef FPMIN /* (C) Copr. 1986-92 Numerical Recipes Software 3#Q)$. */ #define ITMAX 100 #define EPS 3.0e-7 void gser (double *gamser, double a, double x, double *gln) { double gammln(double xx); /* void nrerror(char error_text[]); */ int n; double sum,del,ap; *gln=gammln(a); if (x <= 0.0) { /* if (x < 0.0) nrerror("x less than 0 in routine gser"); */ *gamser=0.0; return; } else { ap=a; del=sum=1.0/a; for (n=1;n<=ITMAX;n++) { ++ap; del *= x/ap; sum += del; if (fabs(del) < fabs(sum)*EPS) { *gamser=sum*exp(-x+a*log(x)-(*gln)); return; } } /* nrerror("a too large, ITMAX too small in routine gser"); */ return; } } #undef ITMAX #undef EPS /* (C) Copr. 1986-92 Numerical Recipes Software 3#Q)$. */ static int ix, iy, iz; static int ranAS183_seed(int iseed1, int iseed2, int iseed3) { int error; error=1; if( ( (iseed1 >=1) && (iseed1 <=30000)) && ( (iseed2 >=1) && (iseed2 <=30000) ) && ( (iseed3 >=1) && (iseed3 <=30000) )) error=0; if(error) return (error); ix = iseed1; iy = iseed2; iz = iseed3; return (error); } /***********************************************************************************/ static double ranAS183() { double u; ix = (171*ix) % 30269; iy = (172*iy) % 30307; iz = (170*iz) % 30323; u = (double)ix/30269.0 + (double)iy/30307.0 + (double)iz/30323.0; return ( u - (int) u ); } haplo.stats/src/haplo_em_pin.h0000644000176000001440000000742512075615036016151 0ustar ripleyusers/* $Author: schaid $ */ /* $Date: 2007/02/27 20:18:01 $ */ /* $Header: /projects/genetics/cvs/cvsroot/haplo.stats/src/haplo_em_pin.h,v 1.7 2007/02/27 20:18:01 schaid Exp $ */ /* $Locker: $ */ /* *License: * *Copyright 2003 Mayo Foundation for Medical Education and Research. * *This program is free software; you can redistribute it and/or modify it under the terms of *the GNU General Public License as published by the Free Software Foundation; either *version 2 of the License, or (at your option) any later version. * *This program is distributed in the hope that it will be useful, but WITHOUT ANY *WARRANTY; without even the implied warranty of MERCHANTABILITY or *FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for *more details. * *You should have received a copy of the GNU General Public License along with this *program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, *Boston, MA 02111-1307 USA * *For other licensing arrangements, please contact Daniel J. Schaid. * *Daniel J. Schaid, Ph.D. *Division of Biostatistics *Harwick Building û Room 775 *Mayo Clinic *200 First St., SW *Rochester, MN 55905 * *phone: 507-284-0639 *fax: 507-284-9542 *email: schaid@mayo.edu */ typedef struct HAP_T { int id; int code; int pair_id; int keep; int *loci; double post, wt; } HAP; typedef struct HAPUNIQUE_T { int code; int keep; int *loci; double prior; } HAPUNIQUE; static int iminarg1, iminarg2; # define imin(a,b) (iminarg1=(a), iminarg2=(b), \ (iminarg1) < (iminarg2) ? (iminarg1) : (iminarg2) ) /* Windows compatibility */ #ifdef _WINDOWS #define CDECL __cdecl #else #define CDECL #endif /************************** Function prototypes ***********************************/ static HAP* new_hap(int id, int pair_id, double wt, double prior, double post); static void write_hap_list(HAP** so, int n_hap); static int CDECL cmp_hap(const void *to_one, const void *to_two); static int CDECL cmp_subId_hapPairId(const void *to_one, const void *to_two); static int CDECL cmp_hap_code(const void *to_one, const void *to_two); static int code_haps(int n_hap, HAP **hap_list); static int hap_enum(HAP ***hap_list_ptr, double **prior_ptr, int *max_haps, int *n_alleles, int insert_loc, int n_hap, int *pair_id); static HAP* copy_hap(HAP *old); static int num_het(HAP* h1,HAP* h2); static void hap_prior(int n_hap, HAP** hap_list, double *prior, int n_u_hap, double min_prior); static int hap_posterior(int n_hap, HAP **hap_list, double *prior, int n_u_hap, double min_posterior, double *lnlike); static int **int_vec_to_mat(int *Yvec, int nrow, int ncol); static int **int_matrix(int nrow, int ncol); static void set_posterior(int n_hap, HAP **hap_list, int *random_start); static int ranAS183_seed(int iseed1, int iseed2, int iseed3); static double ranAS183(); static void errmsg(char *string); static void compact(HAP **hap_list, int n, int *nReturn); static HAPUNIQUE* copy_hap_unique(HAP *old, double *prior); static void unique_haps(int n_hap, HAP **hap_list, HAPUNIQUE **u_hap_list, double *prior); static int count_unique_haps(int n_hap, HAP **hap_list); static void write_prior(int n, double *prior); static void write_unique_hap_list(HAPUNIQUE** so, int n_hap); static void divideKeep(HAP **hap_list, int n, int *nReturn); static void add_more_memory(HAP ***hap_list, double **prior,int *max_haps); static void insert_new_hap_pair(HAP ***hap_list_ptr, double **prior_ptr, int *max_haps, int insert_loc, HAP *h1_old, HAP *h2_old, int a1_new, int a2_new, int *pair_id, int *j); static void overwrite_hap(HAP *new, HAP *old); void checkIntMax(int *intMax); haplo.stats/src/groupsum.c0000644000176000001440000000310512075615036015362 0ustar ripleyusers/* $Author: sinnwell $ */ /* $Date: 2003/10/07 21:21:27 $ */ /* $Header: /projects/genetics/cvs/cvsroot/haplo.stats/src/groupsum.c,v 1.2 2003/10/07 21:21:27 sinnwell Exp $ */ /* $Locker: $ */ /* * $Log: groupsum.c,v $ * Revision 1.2 2003/10/07 21:21:27 sinnwell * fix $Log keyword comments * * Revision 1.1 2003/09/16 16:00:44 schaid * Initial revision * */ #include #include /* groupsum Function Arguments: x: double pointer to an array. The values of x will be summed over a 'group' indicator provided by indx indx: integer pointer on an array. It is assumed that this indx array as sequential integer values. This is imporant, becuase the values in indx are used as array indices when summing over values of x. n: integer pointer to scalar. n = length of x and indx. grouptot: double pointer to array, which is the length of ngroup. ngroup: integer pointer to scalar; ngroup = length of grouptot. The values of x are summed according to the group indx, and total sums are stored in array grouptot. So, the ith element of grouptot is the total of x's that have indx=(i+1), because we use the zero-offset in C. Note that the error checking must be done is Splus, because this C code is intended to simly sum, for speed. */ void groupsum( double *x, int *indx, int *n, double *grouptot, int *ngroup ) { int i; for(i=0; i<*ngroup; i++) grouptot[i]=0.0; for (i=0; i<*n; i++){ grouptot[indx[i]-1] += x[i]; } return; } haplo.stats/LICENSE0000644000176000001440000000200011526250437013544 0ustar ripleyusersLicense: Copyright 2003 Mayo Foundation for Medical Education and Research. This program is free software; you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation; either version 2 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, Boston, MA 02111-1307 USA For other licensing arrangements, please contact Daniel J. Schaid. Daniel J. Schaid, Ph.D. Division of Biostatistics Harwick Building – Room 775 Mayo Clinic 200 First St., SW Rochester, MN 55905 phone: 507-284-0639 fax: 507-284-9542 email: schaid@mayo.edu haplo.stats/R/0000755000176000001440000000000012075615022012743 5ustar ripleyusershaplo.stats/R/haplo.glm.q0000644000176000001440000003574112075056510015021 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2013/01/14 19:32:24 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.glm.q,v 1.22 2013/01/14 19:32:24 sinnwell Exp $ #$Locker: $ #$Log: haplo.glm.q,v $ #Revision 1.22 2013/01/14 19:32:24 sinnwell #add haplo.binomial, no need glm.fit.nowarn # #Revision 1.21 2012/02/22 14:59:44 sinnwell #make assigning of names to var.mat allow for when haplo.elim=NA # #Revision 1.20 2012/02/03 21:36:59 sinnwell #fix small bug in haplo.glm in names for var.mat # #Revision 1.19 2011/11/23 20:34:02 sinnwell #release 1.4.81, updates with test scripts # #Revision 1.18 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.17 2008/04/14 19:46:26 sinnwell #make exception if yxmiss not added in na.geno.keep b/c no NAs # #Revision 1.16 2008/03/24 21:22:25 sinnwell #rm allele.lev, miss.val parameters, re-work model.frame code, yet leave old ode there. #return missing info from na.geno.keep # #Revision 1.15 2007/02/01 20:25:29 sinnwell #starting values for eta taken out of fit.null and updated correctly #at each step of while loop # #Revision 1.14 2006/10/25 15:06:17 sinnwell #rm Matrix library dependency, only done in Ginv.q # #Revision 1.13 2006/01/27 16:30:19 sinnwell #depends on Matrix library # #Revision 1.12 2005/01/25 23:04:06 sinnwell #use as.list(args(haplo.glm)) instead of formals when na.action not given #formals is for R only # #Revision 1.11 2005/01/25 22:25:22 sinnwell #take out print statements left from debugging # #Revision 1.10 2005/01/23 20:01:38 sinnwell #use Thomas Lumley hint from R-help, use formals of haplo.glm to set #default na.action to na.geno.keep. # #Revision 1.9 2005/01/19 16:14:39 sinnwell #default na.action not set to na.geno.keep, force it if missing(na.action) #m$na.action <- as.name("na.geno.keep") # #Revision 1.8 2005/01/04 17:37:22 sinnwell #set haplo.min.freq as a function of haplo.min.count #using a min expected count of haplotypes is better criteria # #Revision 1.7 2004/03/19 15:01:48 sinnwell #consider .C(PACKAGE= as part of '...' # #Revision 1.6 2004/03/17 21:11:12 sinnwell #separate calls of .C("groupsum" for R and Splus # #Revision 1.5 2004/03/03 22:13:16 schaid #added allele.lev to pass allele labels, to allow haplo.glm to work in R for character alleles # #Revision 1.4 2004/01/12 14:46:57 sinnwell #get around warnings for binomial trait in R # #Revision 1.3 2003/12/08 19:37:09 sinnwell #changed F,T to FALSE,TRUE # #Revision 1.2 2003/11/17 23:27:20 schaid #made compatible with R # #Revision 1.1 2003/09/16 16:01:54 schaid #Initial revision # haplo.glm <- function(formula = formula(data), family = gaussian, data = sys.parent(), weights, na.action="na.geno.keep", start=NULL, locus.label=NA, control = haplo.glm.control(), method = "glm.fit", model = TRUE, x = FALSE, y = TRUE, contrasts = NULL, ...) { call <- match.call() # Create a model.frame call with formula elements only frame.call <- call('model.frame', formula=formula) # Steps to assign args to model.frame call, Terry Therneau 7/2005 # assign desired parameters from Call to frame.call k=length(frame.call) ## because R doesn't automatically name model.frame column names ## let k keep track of index of last element of frame.call, ## and assign the name (only when using R) for(i in c('data', 'weights', 'subset', 'na.action', 'drop.unused.levels')) { if(!is.null(call[[i]])) { frame.call[[i]] <- call[[i]] k <- k+1 if(is.R()) names(frame.call)[k]=i } } # if no drop.unused.levels or na.action given, assign them if(is.null(frame.call$drop.unused.levels)) frame.call$drop.unused.levels <- TRUE if(is.null(frame.call$na.action)) frame.call$na.action=as.list(args(haplo.glm))$na.action # evaluate the call m <- eval(frame.call, sys.parent()) Terms <- attr(m, "terms") # save missing value information from model.frame, na.action if(!is.null(attributes(m)$yxmiss) & !is.null(attributes(m)$gmiss)) missing <- data.frame(yxmiss=attributes(m)$yxmiss, genomiss=attributes(m)$gmiss) # set design matrix contrasts contrasts.old <- options()$contrasts options(contrasts = c(factor="contr.treatment", ordered = "contr.poly")) on.exit(options(contrasts=contrasts.old)) # Extract weights per subject wt.subj <- model.weights(m) if(!length(wt.subj)) wt.subj <- rep(1, nrow(m)) else if(any(wt.subj < 0)) stop("negative weights not allowed") # for control, base minimum haplotype frequencies on haplo.min.count # as precedent over haplo.freq.min, the min count is 5 if(is.na(control$haplo.freq.min)) control$haplo.freq.min <- control$haplo.min.count/(2*nrow(m)) #### Modify model.frame ## Translate from unphased genotype matrix to haplotype design matrix ## Use haplo.model.frame to modify the model.frame, which ## calls haplo.em to estimate haplotype frequencies. haplo.mf <- haplo.model.frame(m, locus.label=locus.label, control=control) # Extract the model.frame created by haplo.model.frame m <- haplo.mf$m.frame if(method == "model.frame") return(m) #### From haplo.model.frame ## g.dat is a dataframe with indx.subj, hap1, hap2, where hap1 and hap2 are ## numeric codes for haplotypes ## haplo.rare.term, logical for if there is a rare haplotype term g.dat <- haplo.mf$g.dat haplo.unique <- haplo.mf$haplo.unique haplo.base <- haplo.mf$haplo.base haplo.freq <- haplo.freq.init <- haplo.mf$haplo.freq haplo.common <- haplo.mf$haplo.common haplo.rare.term <- haplo.mf$haplo.rare.term haplo.rare <- haplo.mf$haplo.rare ## Set up integer grouping variables (indices) for group sums haplo.group <- c(g.dat$hap1,g.dat$hap2) len.haplo.group <- length(haplo.group) n.haplo.group <- length(haplo.freq) subj.indx <- as.numeric(factor(g.dat$indx.subj)) len.subj.indx <- length(subj.indx) n.subj <- length(unique(subj.indx)) ## Setup weights after expanding each subject into pairs of haplotypes ## (i.e., possibly replicate weights according to replicates required ## for enumerating pairs of haplotypes) wt.expanded <- wt.subj[subj.indx] ## Compute priors and posteriors of pairs of haplotypes, given observed data. prior.coef <- ifelse(g.dat$hap1!=g.dat$hap2, 2, 1) prior <- prior.coef * haplo.freq[g.dat$hap1] * haplo.freq[g.dat$hap2] pr.pheno.init <- tapply(prior,g.dat$indx.subj,sum) nreps <- tapply(g.dat$indx.subj,g.dat$indx.subj,length) den <- rep(pr.pheno.init,nreps) post <- prior/den ## Keep initial post to return in haplo.post.info post.initial <- post # Keep count of true number of haplotypes for later use as denom # of haplotype frequenices n.hap <- 2 * sum(wt.subj) # First E-step: create new weights based on post. # Note that these weights are based on post, which was computed assuming # that there are no regression terms (i.e., all regression # beta's = 0). # wt.expanded is the original input weight vector, wt.subj, # (or set to 1's if not input), # after enumeration of all possible pairs of haplos. # Need to distinguish between wt.expanded and # working weights, which are wght.expanded * post w <- wt.expanded * post xvars <- as.character(attr(Terms, "variables")) xvars <- xvars[-1] if ((yvar <- attr(Terms, "response")) > 0) xvars <- xvars[-yvar] if(length(xvars) > 0) { xlevels <- lapply(m[xvars], levels) xlevels <- xlevels[!sapply(xlevels, is.null)] if(length(xlevels) == 0) xlevels <- NULL } else xlevels <- NULL a <- attributes(m) Y <- model.response(m, "numeric") X <- model.matrix(Terms, m, contrasts) start <- model.extract(m, start) offset <- model.offset(m) if (is.character(family)) family <- get(family) if (is.function(family)) family <- family() if (is.null(family$family)) { print(family) stop("`family' not recognized") } ## init for binomial does not allow non-integer fitted values ## use haplo.binomial init expression if(family$family =="binomial") { family$initialize=haplo.binomial()$initialize } if(missing(method)) method <- attr(family, "method") if(!is.null(method)) { if(!existsFunction(method)) stop(paste("unimplemented method:", method)) } else method <- "glm.fit" glm.fitter <- get(method) # Unlike the generic glm, we compute the Null model (Intercept-only) # here, instead of within the EM loop (to avoid recomputing the null # within each loop iteration). ## switch fitter for binomial because it gives unneeded warnings #if(family$family=="binomial") glm.fitter=glm.fit.nowarn ## FIXED WITH THE INIT FIX ABOVE ## get the null fit fit.null <- glm.fitter(x = X[, "(Intercept)", drop = FALSE], y = Y, weights = w, etastart = start, offset = offset, family = family, control=glm.control(maxit = control$maxit, epsilon = control$epsilon)) dfit <- dglm.fit(fit.null) prior <- prior*dfit pr.pheno <- tapply(prior, subj.indx, sum) lnlike.old <- lnlike.null <- sum(wt.subj*log(pr.pheno)) ################ ### EM loop ################ ## Set up arrays for group sums within EM loop prior.tot <- rep(0,n.subj) post.tot <- rep(0,n.haplo.group) converge.em <- FALSE # need a separate control.epsilon for EM, because need more # stringent check for change in lnLike for EM than for # glm.fit control.epislon.em <- min(c(control$epsilon, 0.000001)) iter <- 0 while(iter < control$maxit){ iter <- iter + 1 # M-step for regression beta's, using weights that depend on # earlier haplotype freqs and beta's fit <- glm.fitter(x = X, y = Y, weights = w, etastart = start, offset = offset, family = family, control=glm.control(maxit = control$maxit, epsilon = control$epsilon)) # Using new beta's, but earlier haplotype frequencies, update post, and # compute lnLike dfit <- dglm.fit(fit) prior <- prior.coef * haplo.freq[g.dat$hap1] * haplo.freq[g.dat$hap2] * dfit ## For the following, tapply was originally used, ## as pr.pheno <- tapply(prior,subj.indx, sum), but this took too much ## time within this EM loop, so a C function 'groupsum' is used instead. tmp.sum <- .C("groupsum", x=as.double(prior), indx=as.integer(subj.indx), n=as.integer(len.subj.indx), grouptot= as.double(prior.tot), ngroup=as.integer(n.subj), PACKAGE="haplo.stats") pr.pheno <- tmp.sum$grouptot den <- rep(pr.pheno,nreps) post <- prior/den lnlike.new <- sum(wt.subj*log(pr.pheno)) ## Create new weights based on post. These posteriors depend ## on the ith iteration of beta's, but the (i-1)th iteration of ## haplo.freq w <- wt.expanded * post ## M-step for haplotype frequencies, based on expected counts tmp.sum <- .C("groupsum", x=as.double(c(post*wt.expanded, post*wt.expanded)), indx=as.integer(haplo.group), n=as.integer(len.haplo.group), grouptot= as.double(post.tot), ngroup=as.integer(n.haplo.group), PACKAGE="haplo.stats") e.hap.count <- tmp.sum$grouptot haplo.freq <- e.hap.count/n.hap ## convergence checks if(abs(lnlike.new - lnlike.old) < control.epislon.em){ converge.em <- TRUE break } ## update starting values for eta, and update lnlike start <- X%*%fit$coeff lnlike.old <- lnlike.new } if(!converge.em) warning("Failed to converge during EM-glm loop") lnlike.final <- lnlike.new fit$iter <- iter fit$lnlike <- lnlike.final fit$lnlike.null <- lnlike.null fit$lrt <- list(lrt = 2*(lnlike.final - lnlike.null), df = fit$rank-1 ) ## Re-compute deviance and aic from collapsed fitted values ## 9/8/11 -JPS dev.resids <- family$dev.resids aic <- family$aic Y.collapsed <- tapply(Y, subj.indx, FUN=function(x) x[1]) mu.collapsed <- tapply(fit$fitted.values*wt.expanded*post, subj.indx,sum) #fit$deviance <- sum(dev.resids(Y.collapsed, mu.collapsed, wt.subj)) fit$deviance <- sum(dev.resids(Y, fit$fitted.values, wt.expanded*post)) fit$aic <- aic(Y.collapsed, length(Y.collapsed), mu.collapsed, wt.subj, fit$deviance) + 2*fit$rank ## item added for anova method, update 9/8/11 by JPS fit$method <- method ## Assign Expanded wts from wt.subj to prior.weights ## Non-expanded prior wts get from tapply(wt.subj, subj.indx, x[1]) fit$prior.weights <- wt.expanded if(!is.null(xlevels)) attr(fit, "xlevels") <- xlevels fit$terms <- Terms fit$formula <- as.vector(attr(Terms, "formula")) fit$call <- call fit$control <- control if(!is.null(attr(m, "na.action"))) fit$na.action <- attr(m, "na.action") fit$haplo.unique <- haplo.unique fit$haplo.base <- haplo.base fit$haplo.freq <- haplo.freq fit$haplo.freq.init <- haplo.freq.init fit$converge.em <- converge.em fit$haplo.common <- haplo.common fit$haplo.rare <- haplo.rare fit$haplo.rare.term <- haplo.rare.term fit$haplo.names <- haplo.mf$haplo.names ## data.frame for info on posteriors haplo.post.info <- cbind(g.dat, post.initial, post) names(haplo.post.info) <- c("indx", "hap1", "hap2", "post.init", "post") fit$haplo.post.info <- haplo.post.info ## estimation of the information and variance matrix. ## requires X matrix, so attach to fit, and de-attach ## later if not desired to be returned fit$x <- X infoLouis <- louis.info(fit, epsilon=control$eps.svd) fit$info <- infoLouis$info fit$var.mat <- infoLouis$var.mat fit$haplo.elim <- infoLouis$haplo.elim fit$rank.info <- infoLouis$rank elim.common <- which(fit$haplo.common %in%fit$haplo.elim) coeffnames <- names(fit$coefficients) if(length(haplo.common)) { coeffnames <- c(coeffnames, paste("hap", haplo.common, sep='.')) } if(length(haplo.rare)) { nrare <- length(haplo.rare) - sum(!is.na(fit$haplo.elim)) coeffnames <- c(coeffnames, rep("hap.rare", nrare)) } dimnames(fit$var.mat) <- list(coeffnames, coeffnames) fit$missing <- missing if(model) fit$model <- haplo.mf$m.frame ## fit$model <- m ## JPS changed to line above--9/16/11 if(!y) fit$y <- NULL if(!x) fit$x <- NULL ## 9/7/11 removed exception for Splus -JPS ## 9/23/11 add 2nd class "glm", so it can inherit some methods ## from glm, such as anova.glmlist class(fit) <- c("haplo.glm", "glm") return(fit) } haplo.stats/R/haplo.power.qt.q0000644000176000001440000000327511551405164016017 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/02/28 15:59:27 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.power.qt.q,v 1.1 2008/02/28 15:59:27 sinnwell Exp $ #$Locker: $ #$Log: haplo.power.qt.q,v $ #Revision 1.1 2008/02/28 15:59:27 sinnwell #Initial revision # haplo.power.qt <- function(haplo, haplo.freq, base.index, haplo.beta, y.mu, y.var, alpha, sample.size=NULL, power=NULL) { if(is.null(power) & is.null(sample.size)) { stop("Must specify either power or sample.size") } if(!is.null(power) & !is.null(sample.size)) { stop("Must specify only one of power or sample.size") } ncp <- haplo.power.qt.ncp(haplo=haplo, haplo.freq=haplo.freq, base.index=base.index, haplo.beta=haplo.beta, y.mu=y.mu, y.var=y.var) if(is.null(sample.size) & !is.null(power)) { ss.phased.haplo <- f.sample.size(nc=ncp$ncp.f.phased.haplo, df1=ncp$df, alpha=alpha, power=power) ss.unphased.haplo <- f.sample.size(nc=ncp$ncp.f.unphased.haplo, df1=ncp$df, alpha=alpha, power=power) power.phased.haplo <- power power.unphased.haplo <- power } if(is.null(power) & !is.null(sample.size)) { power.phased.haplo <- f.power(n=sample.size, nc=ncp$ncp.f.phased.haplo,df1=ncp$df, alpha=alpha) power.unphased.haplo <- f.power(n=sample.size, nc=ncp$ncp.f.unphased.haplo,df1=ncp$df, alpha=alpha) ss.phased.haplo <- sample.size ss.unphased.haplo <- sample.size } return(list(ss.phased.haplo=ss.phased.haplo, ss.unphased.haplo=ss.unphased.haplo, power.phased.haplo=power.phased.haplo, power.unphased.haplo=power.unphased.haplo)) } haplo.stats/R/haplo.cc.q0000644000176000001440000001654711656766744014657 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.cc.q,v 1.14 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: haplo.cc.q,v $ #Revision 1.14 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.13 2008/04/10 20:58:36 sinnwell #add eps.svd, only allow haplo.min.count in control() # #Revision 1.12 2007/03/30 20:02:39 sinnwell #control random seed values before each call # #Revision 1.11 2007/03/23 19:08:37 sinnwell #take out weights for haplo.glm, they don't work for haplo.glm in Splus # #Revision 1.10 2007/03/22 20:08:46 sinnwell #insert line to check weights for NULL before passing to haplo.glm # #Revision 1.9 2007/03/13 18:14:40 sinnwell #add weights parameter # #Revision 1.8 2005/06/03 14:32:58 sinnwell #adjust haplo.rare if l.t. haplo.min.info # #Revision 1.7 2005/03/10 17:36:16 sinnwell #make haplo.min.count persist in haplo.glm # #Revision 1.6 2005/01/04 20:22:29 sinnwell #min.count to haplo.min.count # #Revision 1.5 2004/12/02 15:56:12 sinnwell #logical vectors y==0 + y==1 to y==0 | y==1. R doesn't add logicals. # #Revision 1.4 2004/11/10 21:16:17 sinnwell #problems with setupGeno before haplo.glm # #Revision 1.3 2004/07/13 22:02:27 sinnwell #T to TRUE # #Revision 1.2 2004/06/09 18:57:55 sinnwell #fix for when glm.object$haplo.rare is zero length # #Revision 1.1 2004/04/23 21:24:56 sinnwell #Initial revision # ## Sinnwell JP and Schaid DJ ## Mayo Clinic, Rochester MN ## 1/2004 haplo.cc <- function(y, geno, locus.label=NA, ci.prob=0.95, miss.val=c(0,NA), weights=NULL, eps.svd=1e-5, simulate=FALSE, sim.control=score.sim.control(), control=haplo.glm.control()) { ## wrap the execution of haplo.score, haplo.group and haplo.glm ## into this function, specific for case-control (cc) studies. ## 1) calculate Odds Ratios for haplotype effects. ## 2) keep in mind it is a ratio relative to the baseline ## haplotype, which is often highly associated with the trait, ## shown by freq's and the score. ## 3) You may choose different, 'neutral' baseline by setting ## haplo.base to the index of haplo.unique from a previous run with same ## haps kept by haplo.freq.min, or haplo.min.count cutoffs # check for missing values in y and geno n.subj <- length(y) if(n.subj != nrow(geno)) stop("Different number of rows for y and geno!") exclude <- which(is.na(y)) tmp <- which(apply(is.na(geno),1,all)) exclude <- unique(c(exclude,tmp)) if(length(exclude)) { warning(paste("Subjects ", exclude, " removed for missing y or all alleles missing.")) geno <- geno[-exclude,] y <- y[-exclude] } if(is.null(control$em.control$iseed)) { runif(1) # use a random number, so the next .Random.seed value is used control$em.control$iseed <- .Random.seed } # check y to be 0's and 1's if(!all(y==0 | y==1)) stop("y must be binary with 0=controls and 1=cases") n.subj <- nrow(geno) # set skip.haplo and hap.freq.min for haplo.glm to be the same, meeting # min. number of expected counts per haplotypes haplo.min.count <- control$haplo.min.count haplo.freq.min <- control$haplo.freq.min if(is.na(haplo.min.count)) haplo.min.count <- haplo.freq.min*2*nrow(geno) if( !is.null(haplo.min.count) && haplo.min.count < 1) warning("haplo.min.count may be too small for reliable results\n") set.seed(control$em.control$iseed) score.lst <- haplo.score(y=y, geno=geno, trait.type="binomial", min.count=haplo.min.count, locus.label=locus.label, miss.val=miss.val, haplo.effect=control$haplo.effect, eps.svd=eps.svd, simulate=simulate, sim.control=sim.control, em.control=control$em.c) # get haplotype frequency estimates within the two groups set.seed(control$em.control$iseed) group.lst <- haplo.group(group=y, geno=geno, locus.label=locus.label, miss.val=miss.val, weight=weights, control=control$em.c) group.count <- group.lst$group.count names(group.count) <- c("control", "case") n.loci <- group.lst$n.loci # merge group and score data merge.df <- haplo.score.merge(score.lst, group.lst) names(merge.df)[(n.loci+score.lst$simulate+3):(n.loci+score.lst$simulate+5)] <- c("pool.hf", "control.hf", "case.hf") # prepare data for haplo.glm with binomial family logit link. # extract for Odds Ratios, exp(betas) geno.glm <- setupGeno(geno, miss.val=miss.val) glm.data <- data.frame(geno.glm, y=y) # weights are not supported for haplo.glm in S-PLUS--take out for now # if (is.null(weights)) weights=rep(1,n.subj) # will only get OR's for haplotypes with freq > haplo.freq.min, based on min.count # should be set same as skip.haplo so 1:1 merge of haps from merge.lst set.seed(control$em.control$iseed) fit.lst <- haplo.glm(y~geno.glm, family=binomial, data=glm.data, locus.label=locus.label, miss.val=miss.val, control=control) ncoef <- length(fit.lst$coef) # get OR's and variance estimates based on var(b's) # make base haplo coef zero b/c or will be 1 hap.coef <- (fit.lst$coefficients)[2:ncoef] se.bet <- sqrt(fit.lst$var.mat[cbind(2:ncoef, 2:ncoef)]) # find CI's for OR's transormed from CI's on Betas if(0 > ci.prob || ci.prob > 1) { warning("invalid value for ci.prob, setting to default 0.95") ci.prob <- 0.95 } norm.constant <- -1*qnorm((1-ci.prob)/2) lower.ci <- hap.coef - norm.constant*se.bet lower.ci <- c(NA,exp(lower.ci)) upper.ci <- hap.coef + norm.constant*se.bet upper.ci <- c(NA,exp(upper.ci)) hap.OR <- c(1,exp(hap.coef)) OR.df <- cbind(lower.ci, hap.OR, upper.ci) ## when a rare haplotype is below haplo.min.info, & not part of model ## need to remove from haplo.rare --JPS 6/2005 fit.lst$haplo.rare <- fit.lst$haplo.rare[fit.lst$haplo.freq[fit.lst$haplo.rare] > control$haplo.min.info] ## combine haps, OR's and CI's in a data.frame fit.df <- as.data.frame(fit.lst$haplo.unique)[c(fit.lst$haplo.base, fit.lst$haplo.common, fit.lst$haplo.rare),] # if rare term replicate rare coeff for every rare hap if(length(fit.lst$haplo.rare) > 0) { rare.df <- matrix(rep(OR.df[ncoef,],length(fit.lst$haplo.rare)),ncol=3,byrow=TRUE) if(control$keep.rare.haplo) { OR.df <- rbind(OR.df[-ncoef,],rare.df) } else OR.df <- rbind(OR.df,rare.df) } class.vec <- c("Base", rep("Eff",length(fit.lst$haplo.common)), rep("R", length(fit.lst$haplo.rare))) fit.df <- cbind(fit.df,class.vec,OR.df) names(fit.df)[(n.loci+1):(n.loci+4)] <- c("glm.eff","OR.lower","OR", "OR.upper") # format the hap columns so the df's will merge on the haps fit.df[,1:n.loci] <- format(fit.df[,1:n.loci]) merge.df[,1:n.loci] <- format(merge.df[,1:n.loci]) cc.df <- merge(merge.df, fit.df,by=1:n.loci,all.x=TRUE,all.y=TRUE) cc.lst <- list(cc.df=cc.df, group.count=group.count, score.lst=score.lst, fit.lst=fit.lst, ci.prob=ci.prob, exclude.subj=exclude) ## returned score and glm objects in the returned list for ## additional applications class(cc.lst) <- "haplo.cc" cc.lst } haplo.stats/R/haplo.glm.control.q0000644000176000001440000000714611656766744016523 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.glm.control.q,v 1.8 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: haplo.glm.control.q,v $ #Revision 1.8 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.7 2008/04/04 15:56:23 sinnwell #fix typo of haplo.min.count # #Revision 1.6 2008/04/04 15:48:18 sinnwell #enforce haplo.freq.min as .01, and override haplo.min.count # #Revision 1.5 2008/04/01 21:23:40 sinnwell #manage haplo.freq.min, which is overriden by haplo.min.count # #Revision 1.4 2005/01/04 17:36:47 sinnwell #use haplo.min.count as more important than haplo.freq.min # #Revision 1.3 2004/03/02 16:34:07 sinnwell #change T to TRUE # #Revision 1.2 2003/12/08 19:37:28 sinnwell # changed F,T to FALSE,TRUE # #Revision 1.1 2003/09/16 16:01:29 schaid #Initial revision # haplo.glm.control <- function(haplo.effect="add", haplo.base = NULL, haplo.min.count=NA, haplo.freq.min=.01, sum.rare.min=0.001, haplo.min.info=0.001, keep.rare.haplo=TRUE, eps.svd=sqrt(.Machine$double.eps), glm.c=glm.control(maxit=500), em.c=haplo.em.control()){ chk <- charmatch(haplo.effect, c("additive", "dominant", "recessive")) if(is.na(chk)) stop("Invalid haplo.effect") if(haplo.min.info < 0 | haplo.min.info > .9) { warning("The value of haplo.min.info is out of range, the default value of 0.001 is used instead") haplo.min.info <- 0.001 } # 1/2005 JPS # enourage the use of selecting haplotypes to model by a minimum expected count of 5 if(!is.null(match.call()$haplo.freq.min)) { if(haplo.freq.min < haplo.min.info | haplo.freq.min >= 1) { warning("invalid value for haplo.freq.min, setting to default of .01") haplo.freq.min <- .01 } if(!is.null(match.call()$haplo.min.count)) { warning("Both control parameters haplo.freq.min and haplo.min.count given; haplo.freq.min will be used") haplo.min.count <- NA } } else { if(!is.na(haplo.min.count)) { haplo.freq.min <- NA if(haplo.min.count <= 1) { warning("The value of haplo.min.count is too small, the count will default to 5/(2*n.subjects)") haplo.freq.min <- NA haplo.min.count <- 5 } } } if(sum.rare.min < 0 | sum.rare.min > .9) { warning("The value of sum.rare.min is out of range, the default value of 0.001 is used instead") sum.rare.min <- 0.001 } if(keep.rare.haplo!=TRUE & keep.rare.haplo!=FALSE){ warning("The value of keep.rare.haplo is invalid, the default value of TRUE is used instead") keep.rare.haplo=TRUE } if(eps.svd < .Machine$double.eps || eps.svd > 0.1) { warning(paste("The value of eps.svd is out of range, the default of ", sqrt(.Machine$double.eps), " is being used.", sep='')) eps.svd <- sqrt(.Machine$double.eps) } return(list(haplo.effect=haplo.effect, haplo.base = haplo.base, haplo.min.count=haplo.min.count, haplo.freq.min=haplo.freq.min, sum.rare.min=sum.rare.min, haplo.min.info=haplo.min.info, keep.rare.haplo=keep.rare.haplo, epsilon=glm.c$epsilon, eps.svd=eps.svd, maxit=glm.c$maxit, trace=glm.c$trace, em.control=em.c)) } haplo.stats/R/haplo.design.q0000644000176000001440000001047411551405163015507 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2007/03/31 19:26:20 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.design.q,v 1.3 2007/03/31 19:26:20 sinnwell Exp $ #$Locker: $ #$Log: haplo.design.q,v $ #Revision 1.3 2007/03/31 19:26:20 sinnwell #error for col.rare empty, made an exception to fix it. # #Revision 1.2 2007/03/13 15:51:52 sinnwell #change return obj back to data.frame, names work that way. # #Revision 1.1 2007/03/08 20:34:40 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.design <- function(obj, haplo.effect="additive", hapcodes=NA, min.count=5, haplo.base=NA) { # Set up a design matrix for haplotype effects # # 1. create a model matrix for all haplotypes in haplo.em object # 2. expand by subject.id, weight by posterior probs of hap-pair, then collapse # back down by subject.id # 3. select out the baseline # 4. remove columns not meeting minimum count # Input: # obj haplo.em object # # hapcodes: codes for haplo.em haps to make specific columns for # # haplo.effect the model matrix coding of haplotypes, additive, recessive, dominant # # haplo.base the baseline haplotype # # min.count the minimum count in the sample of the haplotype # for inclusion as a distinct model covariate # Check haplo.effect parameter, match to 3 options effCode <- charmatch(haplo.effect, c("additive", "dominant", "recessive")) if(is.na(effCode)) stop("Invalid haplo.effect") # CREATE HAPLOTYPE EFFECT COLUMNS uniqueHaplo <- sort(unique(c(obj$hap1code, obj$hap2code))) hap.colname <- paste("hap", uniqueHaplo, sep=".") # if hapcodes given, reduce haplotypes to make cols for if(!is.na(hapcodes[1])) { hapmatch <- match(hapcodes, uniqueHaplo) uniqueHaplo <- uniqueHaplo[hapmatch] hap.colname <- hap.colname[hapmatch] } # by default, set up as additive coding hap.mat <- 1 * outer(obj$hap1code, uniqueHaplo, "==") + 1 * outer(obj$hap2code, uniqueHaplo, "==") if(effCode==2) { # translate to dominant effect hap.mat <- 1*(hap.mat > 0) } if(effCode==3){ # translate to recessive effect hap.mat <- (hap.mat > 1) * 1 } # weight by posteriors, collapse over subjects nc <- ncol(hap.mat) effect.mat <- NULL for(j in 1:nc){ effect.mat <- cbind(effect.mat, tapply(hap.mat[,j] * obj$post, obj$subj.id, sum) ) } # if hapcodes not given, do other selection steps if(is.na(hapcodes[1])) { # if baseline is given, remove from model matrix # otherwise, keep all haplotype effects, leaving user to select out if(!is.na(haplo.base)) { col.base <- which(uniqueHaplo == haplo.base) effect.mat <- effect.mat[, -col.base, drop=FALSE] hap.colname <- hap.colname[-col.base] } # select out columns not having minimum count if(min.count > 0) { col.sum <- apply(effect.mat, 2, sum) col.rare <- which(col.sum < min.count) if(length(col.rare)) { effect.mat <- effect.mat[,-col.rare, drop=FALSE] hap.colname <- hap.colname[-col.rare] } } } if(length(hap.colname)==0) stop("Design matrix has no columns") effect.mat <- as.data.frame(effect.mat) names(effect.mat) <- hap.colname return(effect.mat) } haplo.stats/R/print.haplo.score.q0000644000176000001440000001145411551405164016504 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2008/04/08 19:21:24 $ # #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.score.q,v 1.17 2008/04/08 19:21:24 sinnwell Exp $ # #$Id: print.haplo.score.q,v 1.17 2008/04/08 19:21:24 sinnwell Exp $ # #$Locker: $ # #$Log: print.haplo.score.q,v $ #Revision 1.17 2008/04/08 19:21:24 sinnwell #haplo.effect back in x$ # #Revision 1.16 2008/04/08 16:45:08 sinnwell #haplo.effect now in x$control # #Revision 1.15 2008/04/04 16:14:28 sinnwell #return tbl with invisible # #Revision 1.14 2007/01/25 19:41:07 sinnwell #haplo.effect changed to x$haplo.effect # #Revision 1.13 2007/01/23 21:46:34 sinnwell #add banner to say which haplo.effect used, change spacing # #Revision 1.12 2007/01/04 16:02:45 sinnwell #exceptions for 1-row tbl output # #Revision 1.11 2005/03/29 16:27:27 sinnwell #*** empty log message *** # #Revision 1.10 2005/03/25 15:38:36 sinnwell #un-specify banner width, controlled by options. # #Revision 1.9 2004/04/07 14:08:59 sinnwell #use nlines for quick print # #Revision 1.8 2004/02/26 23:08:27 sinnwell #print.banner to printBanner # #Revision 1.7 2003/12/08 20:20:32 sinnwell # changed T,F to TRUE,FALSE # #Revision 1.6 2003/12/01 23:46:26 sinnwell #take out return statment. invisible will return the original object # #Revision 1.5 2003/08/26 16:37:57 sinnwell #change license # #Revision 1.4 2003/08/22 19:46:13 sinnwell #updated to handle updated simulation results, add new license # #Revision 1.3 2003/04/25 22:11:01 schaid #updated tbl to allow haplotype to be a data frame, as created by new haplo.em.pin function #change was to force haplotype to be a matrix, to be backwards compatible with prior print function # #Revision 1.2 2003/03/06 23:22:01 sinnwell #add license text # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # # print.haplo.score <- function(x, digits=max(options()$digits-2, 5), nlines=NULL, ...) # Sinnwell JP, Schaid DJ # Mayo Clinic Biostatistics 8/2003 { # print a haplo.score object, one that has the simulation handling # and used Progressive INsertion (PIN) if (!inherits(x, 'haplo.score')) stop("Not an object of class haplo.score!") printBanner(paste("Haplotype Effect Model: ", x$haplo.effect), border="-") # print of global score stats: printBanner("Global Score Statistics", border= "-") cat("\n") cat(paste("global-stat = ",round(x$score.global,digits),", df = ", x$df, ", p-val = ",round(x$score.global.p,digits),sep="")) # print separate section for sim p.vals and the conditions # under which they were made cat("\n\n") if(x$simulate) { printBanner("Global Simulation p-value Results", border="-") cat("\n") cat("Global sim. p-val = ",round(x$score.global.p.sim, digits),"\n") cat("Max-Stat sim. p-val = ",round(x$score.max.p.sim, digits), "\n") cat("Number of Simulations, Global: ", x$n.val.global, ", Max-Stat:", x$n.val.haplo) cat("\n\n") } # create table for haplotype specific stats tbl <- cbind(as.matrix(x$haplotype),round(x$hap.prob,digits), round(x$score.haplo,digits), round(x$score.haplo.p, digits)) # add on simulated p-values, rounded to digits if(x$simulate) tbl <- cbind(tbl,round(x$score.haplo.p.sim, digits)) ord <- order(x$score.haplo) tbl <- tbl[ord, ,drop=FALSE] if(!x$simulate) dimnames(tbl) <- list(NULL,c(x$locus.label,"Hap-Freq", "Hap-Score","p-val")) else dimnames(tbl) <- list(NULL,c(x$locus.label,"Hap-Freq", "Hap-Score","p-val","sim p-val")) printBanner("Haplotype-specific Scores", border= "-") cat("\n") if(is.null(nlines) ) print(tbl,quote=FALSE) else print(tbl[1:nlines,,drop=FALSE], quote=FALSE, ...) cat("\n") invisible(tbl) } haplo.stats/R/printBanner.q0000644000176000001440000000765711556342206015432 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/04/28 19:48:22 $ #$Header: /projects/genetics/cvs/cvsroot/mgenet/R/printBanner.q,v 1.1 2011/04/28 19:48:22 sinnwell Exp $ #$Locker: $ #$Log: printBanner.q,v $ #Revision 1.1 2011/04/28 19:48:22 sinnwell #is.R, printBanner, setupData # #Revision 1.4 2007/01/23 21:00:27 sinnwell #rm ending newline \n. Users can space if desired. # #Revision 1.3 2005/02/04 20:57:18 sinnwell #banner.width now based on options()$width #char.perline based on banner.width # #Revision 1.2 2004/06/25 15:56:48 sinnwell #now compatible with R, changed end when a line is done # #Revision 1.1 2004/02/26 21:34:55 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # printBanner <- function(str, banner.width=options()$width, char.perline=.75*banner.width, border = "="){ # char.perline was calculated taking the floor of banner.width/3 vec <- str new<-NULL onespace<-FALSE for(i in 1:nchar(vec)){ if (substring(vec,i,i)==' ' && onespace==FALSE){ onespace<-TRUE new<-paste(new,substring(vec,i,i),sep="")} else if (substring(vec,i,i)==' ' && onespace==TRUE) {onespace<-TRUE} else{ onespace<-FALSE new<-paste(new,substring(vec,i,i),sep="")} } where.blank<-NULL indx <- 1 for(i in 1:nchar(new)){ if((substring(new,i,i)==' ')){ where.blank[indx]<-i indx <- indx+1 } } # Determine the position in the where.blank vector to insert the Nth character position of "new" j<-length(where.blank)+1 # Add the Nth character position of the "new" string to the where.blank vector. where.blank[j]<-nchar(new) begin<-1 end<-max(where.blank[where.blank<=char.perline]) # If end.ok equals NA then the char.perline is less than the position of the 1st blank. end.ok <- is.na(end) # Calculate a new char.perline. if (end.ok==TRUE){ char.perline <- floor(banner.width/2) end<-max(where.blank[where.blank<=char.perline]) } cat(paste(rep(border, banner.width), collapse = ""),"\n") repeat { titleline<-substring(new,begin,end) n <- nchar(titleline) if(n < banner.width) { n.remain <- banner.width - n n.left <- floor(n.remain/2) n.right <- n.remain - n.left for(i in 1:n.left) titleline <- paste(" ",titleline,sep="") for(i in 1:n.right) titleline <- paste(titleline," ",sep="") n <- nchar(titleline) } cat(titleline,"\n") begin<-end+1 end.old <- end # Next line has a problem when used in R. Use print.banner.R until fixed. # Does max with an NA argument tmp <- where.blank[(end.old 1 het loci if(nhet <= 1) { return(list(h1 = matrix(h1, nrow = 1), h2 = matrix(h2, nrow = 1 ))) } # only need to flip at heterozygous loci, after 1st het locus: nloci <- length(h1) which <- (1:nloci)[het] which <- which[-1] h1.mtx <- h2.mtx <- matrix(NA, nrow = 2^(nhet - 1), ncol = nloci) h1.mtx[1, ] <- h1 h2.mtx[1, ] <- h2 indx.row <- 1 for(i in which) { nr <- sum(!is.na(h1.mtx[, 1])) for(j in 1:nr) { indx.row <- indx.row + 1 # used to move down to the next row of matrix # now for flipping alleles across loci if(i < nloci) { h1.mtx[indx.row, ] <- c(h1.mtx[j, 1:(i - 1)], h2.mtx[j, i], h1.mtx[j, (i + 1):nloci]) h2.mtx[indx.row, ] <- c(h2.mtx[j, 1:(i - 1)], h1.mtx[j, i], h2.mtx[j, (i + 1):nloci]) } if(i == nloci) { h1.mtx[indx.row, ] <- c(h1.mtx[j, 1:(i - 1)], h2.mtx[j, i]) h2.mtx[indx.row, ] <- c(h2.mtx[j, 1:(i - 1)], h1.mtx[j, i]) } } } return(list(h1 = h1.mtx, h2 = h2.mtx)) } haplo.stats/R/haplo.group.q0000644000176000001440000001333611551405164015373 0ustar ripleyusers# $Author: sinnwell $ # $Date: 2007/03/22 15:41:32 $ --> # $Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.group.q,v 1.12 2007/03/22 15:41:32 sinnwell Exp $ --> # $Locker: $ # $Log: haplo.group.q,v $ # Revision 1.12 2007/03/22 15:41:32 sinnwell # fix call to haplo.em # # Revision 1.11 2007/03/13 15:56:53 sinnwell # add weight for haplo.em on all people # # Revision 1.10 2003/12/08 20:10:59 sinnwell # changed T,F to TRUE,FALSE # # Revision 1.9 2003/10/15 16:13:10 schaid # changed em.control to control, to be consistent with haplo.em # # Revision 1.8 2003/08/28 14:22:50 sinnwell # re-fix for rows.rem # # Revision 1.7 2003/08/27 21:02:29 sinnwell # update for release 1.2.0 with PIN, keep rows.rem # # Revision 1.6 2003/08/26 16:39:04 sinnwell # change license statement # # Revision 1.5 2003/05/20 14:49:53 sinnwell # add more em control parameters # # Revision 1.4 2003/04/22 20:29:27 sinnwell # use is.R function # # Revision 1.3 2003/03/06 20:58:13 sinnwell # updates to make return obj a list and, and gnames # # Revision 1.2 2003/01/17 16:56:39 sinnwell # revision for haplo.score version 1.2 # # Revision 1.2 2002/09/16 14:46:42 sinnwell # Fix RCS keywords # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.group <- function(group, geno, locus.label=NA, miss.val=0, weight=NULL, control=haplo.em.control()) ## Developed by JP Sinnwell & DJ Schaid ## ## Mayo HSR Biostatistics ## ## 7/2002 ## ## update for allowing missing alleles 11/2002 ## update for haplo.em with Progressive Insertion 8/2003 { # Build a haplo.group object with a dataframe, number of loci, and counts by group # The dataframe will contain all possible haplotypes and expected frequencies # for the entire data set and the groups where the haplotype could exist group.name <- deparse(substitute(group)) # Check dims of group and geno nr <- nrow(geno) if(length(group)!=nr) stop("Dims of group and geno are not compatible") # Set number of loci n.loci <- ncol(geno)/2 if(n.loci != (floor(ncol(geno)/2)) ) stop("Odd number of cols of geno") # Make groups either numeric or character if (!is.numeric(group)) group <- as.character(group) # Check for missing group data miss.group <- is.na(group) | group=="NA" # Subset to non-missing group values: group <- group[!miss.group] geno <- geno[!miss.group,] # Create a haplo object (using haplo.em) using size-evaluation criteria haplo.all <- haplo.em(geno, locus.label, miss.val=miss.val, weight=weight, control=control) # Check convergence of EM if(!haplo.all$converge) stop("EM for haplo failed to converge") ## new subset of removed genorows based on enumeration criteria of haplo.em rem.geno <- haplo.all$rows.rem if(length(rem.geno)>0) { geno <- geno[-rem.geno,] group <- group[-rem.geno] } # Make initial dataframe with total groups haplotype.all <- haplo.all$haplotype prob.all <- haplo.all$hap.prob haplo.freq <- data.frame(haplotype.all, prob.all) # Subset haplotypes by group variable # Do not weight because sub-samples are not over-sampled. ugroup <- sort(unique(group)) gnames <- character(0) for (i.group in ugroup) { gnames <- c(gnames, paste(group.name, i.group, sep= "=")) group.sub <- group==i.group geno.sub <- geno[group.sub,] # Create haplo object for i.group # rows to be removed are already removed from first run of haplo.em haplo.tmp <- haplo.em(geno.sub, locus.label, miss.val=miss.val, control=control) # Check convergence of EM if(!haplo.tmp$converge) cat("Warning: EM failed to converge for group", i.group, "\n") # Create dataframe for the group with haplotypes and prob haplotype.sub <- haplo.tmp$haplotype prob.sub <- haplo.tmp$hap.prob df.sub <- data.frame(haplotype.sub,prob.sub) # Merge matching the haplotypes (cols 1:n.loci) and keep all rows # This will leave NA's where no match in sub group haplo.freq <- merge(haplo.freq, df.sub, by.x=1:n.loci, by.y=1:n.loci, all.x=TRUE) } # end for i.group # Create locus label if missing: if (all(is.na(locus.label))) { locus.label<- paste("loc-",1:n.loci,sep="") } # Set names for the dataframe names(haplo.freq) <- c(locus.label, "Total", gnames) # Get group frequencies group.count <- table(group) hapgroup <- list(group.df=haplo.freq, group.count=group.count, n.loci=n.loci) if(exists("is.R") && is.function(is.R) && is.R()) { class(hapgroup) <- c("haplo.group","data.frame") } else { setOldClass(c("haplo.group","data.frame")) oldClass(hapgroup) <- "haplo.group" } return(hapgroup) } haplo.stats/R/summary.haplo.em.q0000644000176000001440000000552511551405164016335 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/11/25 22:11:00 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/summary.haplo.em.q,v 1.9 2008/11/25 22:11:00 sinnwell Exp $ #$Locker: $ #$Log: summary.haplo.em.q,v $ #Revision 1.9 2008/11/25 22:11:00 sinnwell #return table of haps by invisible # #Revision 1.8 2007/11/07 21:33:37 sinnwell #add digits # #Revision 1.7 2004/04/06 20:40:00 sinnwell #use nlines to limit lines in vignettes # #Revision 1.6 2004/02/26 23:10:39 sinnwell #print.banner to printBanner # #Revision 1.5 2004/02/16 19:41:01 sinnwell #add '...' to make method for haplo.em object # #Revision 1.4 2003/12/08 20:24:09 sinnwell # changed T,F to TRUE,FALSE # #Revision 1.3 2003/10/15 15:41:18 schaid #added show.haplo option for showing haplotypes instead of their codes # #Revision 1.2 2003/08/26 22:09:38 sinnwell #added GPL License # #Revision 1.1 2003/08/26 21:00:25 schaid #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # summary.haplo.em <- function(object, show.haplo=FALSE, digits=max(options()$digits-2, 5), nlines=NULL, ...){ printBanner("Subjects: Haplotype Codes and Posterior Probabilities") if(show.haplo){ hap1 <- object$haplotype[object$hap1code,] hap2 <- object$haplotype[object$hap2code,] df <- data.frame(subj.id=object$subj.id, hap1=hap1, hap2=hap2, posterior=round(object$post,digits)) } else{ df <- data.frame(subj.id=object$subj.id, hap1code=object$hap1code, hap2code=object$hap2code, posterior=round(object$post, digits)) } if(is.null(nlines)) print(df) else print(df[1:nlines,]) printBanner("Number of haplotype pairs: max vs used") x <- object$max.pairs if(length(object$rows.rem) > 0 ){ x <- x[-object$rows.rem] } print(table(x, object$nreps)) invisible(df) } haplo.stats/R/locator.haplo.q0000644000176000001440000000461111551405164015676 0ustar ripleyusers#$Author: schaid $ # #$Date: 2003/10/15 17:17:35 $ # #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/locator.haplo.q,v 1.4 2003/10/15 17:17:35 schaid Exp $ # #$Id: locator.haplo.q,v 1.4 2003/10/15 17:17:35 schaid Exp $ # #$Locker: $ # #$Log: locator.haplo.q,v $ #Revision 1.4 2003/10/15 17:17:35 schaid #fixed format of hapotypes for text # #Revision 1.3 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.2 2003/03/06 23:18:02 sinnwell #add license text # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # locator.haplo <- function(obj){ h <- apply(format(obj$haplotype),1,paste, collapse=":") x <- obj$hap.prob y <- obj$score.haplo rng <- range(y) delta <- .05* (rng[2] - rng[1]) mid.rng <- sum(rng)/2 tmp <- locator() x.pt <- tmp$x y.pt <- tmp$y n.pt <- length(x.pt) x.coord <- NULL y.coord <- NULL hap.txt <- NULL for(i in 1:n.pt){ z <- (x-x.pt[i])^2 + abs(y-y.pt[i])^2 which <- z==min(z) h.txt <- h[which] x.tmp <- x[which] sgn <- if(y[which] < mid.rng) + 1 else -1 y.tmp <- y[which] + sgn*delta text(x.tmp,y.tmp,h.txt) x.coord <- c(x.coord,x.tmp) y.coord <- c(y.coord,y.tmp) hap.txt <- c(hap.txt, h.txt) } invisible() return(list(x.coord=x.coord,y.coord =y.coord, hap.txt=hap.txt)) } haplo.stats/R/geno.count.pairs.q0000644000176000001440000001113511551405163016323 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2003/12/08 19:33:33 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/geno.count.pairs.q,v 1.5 2003/12/08 19:33:33 sinnwell Exp $ #$Locker: $ #$Log: geno.count.pairs.q,v $ #Revision 1.5 2003/12/08 19:33:33 sinnwell #changed F to FALSE # #Revision 1.4 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.3 2003/04/14 17:23:00 schaid #when no missing alleles, added drop=F for h1 and h2, for when there is only one subject without missing data # #Revision 1.2 2003/04/11 19:30:19 sinnwell #move comments around # #Revision 1.1 2003/04/09 18:33:09 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # geno.count.pairs <- function(geno) ## Developed by Schaid, DJ 4/2003 { # Given a matrix of genotypes (pairs of columns for each locus), # compute number of possible pairs of haplotypes for each subject (the rows # of the geno matrix). # Assume missing values are all coded to NA, done easily by geno.recode() # define function to iteratively update number of hets # across loci, accounting for all possible combinations # of missing alleles across loci haplo.count.pairs <- function(nhet.vec,nhom.vec){ n.loci <- length(nhet.vec) cum.het <- 0 wt.het <- 1 for(locus in 1:n.loci){ n.het <- nhet.vec[locus] n.hom <- nhom.vec[locus] if(n.het>=1 & n.hom>=1){ cum.het <- as.vector(rbind(cum.het+1, cum.het)) wt.het <- as.vector(rbind(wt.het*n.het, wt.het*n.hom)) } if(n.het>=1 & n.hom==0){ cum.het <- cum.het + 1 wt.het <- wt.het * n.het } } cum.het <- ifelse(cum.het==0,1,cum.het) # patch in case no hets n.pairs <- sum(2^(cum.het-1)*wt.het) return(n.pairs) } # initial setup for counting pairs of haplotypes # assume missing values are all coded to NA nc <- ncol(geno) n.loci <- nc/2 nr <- nrow(geno) n.pairs <- numeric(nr) odd <- seq(from=1,to=2*n.loci,by=2) # find number of alleles at each locus n.alleles <- numeric(n.loci) for (i in 1:n.loci) { a1 <- geno[,2*i-1] a2 <- geno[,2*i] temp <- c(a1,a2) temp <- temp[!is.na(temp)] n.alleles[i] <- length(unique(temp)) } # count pairs of haplotypes for subjects without any missing alleles any.miss <- apply(is.na(geno),1,any) if(sum(!any.miss) > 0){ indx.nomiss <- (1:nr)[!any.miss] geno.nomiss <- geno[indx.nomiss,,drop=FALSE] h1 <- geno.nomiss[,odd,drop=FALSE] h2 <- geno.nomiss[,(odd+1),drop=FALSE] n.het <- apply(h1!=h2,1,sum) n.het <- ifelse(n.het==0,1,n.het) n.pairs[indx.nomiss] <- 2^(n.het-1) } # count pairs for subjects with missing alleles if(sum(any.miss) > 0){ indx.miss <- (1:nr)[any.miss] n.subj.miss <- length(indx.miss) geno.miss <- geno[indx.miss,,drop=FALSE] # count number of possible het, hom at each locus loc <- 0 het.mat <- hom.mat <- NULL for(i in odd){ a1 <- geno.miss[,i] a2 <- geno.miss[,(i+1)] loc <- loc+1 n.a <- n.alleles[loc] n.miss <- 1*(is.na(a1)) + 1*(is.na(a2)) n.het <- ifelse(a1!=a2,1,0) n.het <- ifelse(n.miss==1,(n.a-1), n.het) n.het <- ifelse(n.miss==2,n.a*(n.a-1)/2, n.het) n.hom <- ifelse(a1==a2,1,0) n.hom <- ifelse(n.miss==1,1,n.hom) n.hom <- ifelse(n.miss==2,n.a,n.hom) het.mat <- cbind(het.mat,n.het) hom.mat <- cbind(hom.mat,n.hom) } pairs.miss <- NULL for(i in 1:n.subj.miss){ pairs.miss <- c(pairs.miss, haplo.count.pairs(het.mat[i,], hom.mat[i,])) } n.pairs[indx.miss] <- pairs.miss } return(n.pairs) } haplo.stats/R/locus.q0000644000176000001440000000460711530543167014266 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2011/02/21 20:09:27 $ # #$Header: /projects/genetics/cvs/cvsroot/mgenet/R/locus.q,v 1.1.1.1 2011/02/21 20:09:27 sinnwell Exp $ # #$Locker: $ # #$Log: locus.q,v $ #Revision 1.1.1.1 2011/02/21 20:09:27 sinnwell #initial, genetics functions for Mayo BSI # #Revision 1.6 2003/12/08 19:49:00 sinnwell #done #changed T,F to TRUE,FALSE # #Revision 1.5 2003/09/19 15:40:09 sinnwell #fix class and oldClass stuff for R/S compatibility # #Revision 1.4 2003/01/17 15:55:36 det01 #Removed setOldClass(c("locus","model.matrix")) code #The code oldClass(geno) <- "locus" modified to oldClass(geno) <- "model.matrix" # #Revision 1.3 2002/12/13 17:47:35 det01 #Locus class inherits from model.matrix class # # locus <- function(allele1,allele2, chrom.label=NULL, locus.alias=NULL, x.linked=FALSE, sex=NULL, male.code="M", female.code="F", miss.val=NA) { # Title: Create an object of locus class if (missing(allele1)) stop("Error: allele1 is missing") if (missing(allele2)) { if (!is.matrix(allele1)) { stop("Error: allele1 not a matrix when allele2 is missing") } else { if (ncol(allele1)!=2) stop("Error: allele1 must be matrix with 2 columns when allele2 is missing") allele2 <- allele1[,2] allele1 <- allele1[,1] } } if (length(allele1)!=length(allele2)) stop("Error: allele vectors not of the same length") # convert factor to character: if ((any(is.factor(allele1))) | (any(is.factor(allele2)))){ allele1 <- as.character(allele1) allele2 <- as.character(allele2) } # fix miss.val so NA is kept as a missing code if (!any(is.na(miss.val))) miss.val <- c(miss.val,NA) n <- length(allele1) t <- factor(c(allele1,allele2),exclude=miss.val) a1 <- as.numeric(t[1:n]) a2 <- as.numeric(t[(n+1):(2*n)]) geno <- cbind(a1,a2) attr(geno,"chrom.label") <- chrom.label attr(geno,"locus.alias") <- locus.alias attr(geno,"x.linked") <- x.linked if(exists("is.R") && is.function(is.R) && is.R()) { class(geno) <- "model.matrix" } else { oldClass(geno) <- "model.matrix" } attr(geno,"allele.labels") <- levels(t) if (x.linked) { attr(geno,"male.code") <- male.code attr(geno,"female.code") <- female.code # Stop if x-linked related errors x.sexcheck(geno,sex,stop=TRUE) } return(geno) } haplo.stats/R/haplo.em.q0000644000176000001440000002371411671432012014634 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/12/12 17:04:10 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.em.q,v 1.19 2011/12/12 17:04:10 sinnwell Exp $ #$Locker: $ #$Log: haplo.em.q,v $ #Revision 1.19 2011/12/12 17:04:10 sinnwell #fix lnlike.noLD in return list # #Revision 1.18 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.17 2008/02/11 22:54:22 sinnwell #include subjects removed by PIN steps (low-LD, rare haps) in rows.rem and issue a warning to reduce min.posterior # #Revision 1.16 2007/10/16 19:07:12 sinnwell #remove intMax check and go with max.haps.limit of 2e6 from control #intMax was the highest index for integers, but too much memory to allocate in C # #Revision 1.15 2007/04/03 21:08:36 sinnwell #add PACKAGE in checkIntMax .C call # #Revision 1.14 2007/02/27 20:16:21 schaid # control max.haps.limit with checkIntMax (see haplo_em_pin) # #Revision 1.13 2004/07/09 14:36:22 sinnwell #warning for n.loci < 2 # #Revision 1.12 2004/03/18 23:31:28 sinnwell #keep haplotype matrix from data.frame, char vecs from factors # #Revision 1.11 2004/03/01 20:52:37 sinnwell #change T to TRUE for matrix() # #Revision 1.10 2004/02/02 23:00:01 sinnwell #insert ghost runif(1) line to init .Random.seed for R bug # #Revision 1.9 2003/09/19 21:38:45 schaid #fixed returned class to be R compatible # #Revision 1.8 2003/08/26 22:08:31 sinnwell #add GPL License # #Revision 1.7 2003/08/26 21:04:49 schaid #Major revision of haplo.em, by adding new functions and new C code to use progressive insertion of loci. # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.em <- function(geno, locus.label=NA, miss.val=c(0,NA), weight=NULL, control = haplo.em.control() ){ n.loci <- ncol(geno)/2 n.subject <- nrow(geno) subj.id <- 1:n.subject if(n.loci<2) stop("Must have at least 2 loci for haplotype estimation!") # set up weight if(any(is.null(weight))){ weight <- rep(1,n.subject) } if(any(weight<0)){ stop("negative weights not allowed") } if(length(weight)!=n.subject){ stop("Length of weight != number of subjects (nrow of geno)") } # Create locus label if not included if(all(is.na(locus.label))) locus.label<- paste("loc-",1:n.loci,sep="") if(length(locus.label)!=n.loci){ stop("length of locus.label != n.loci") } ## recode geno to integer values, accounting for missing values ## replaced loci with setupGeno (JPS: 10/20/2011) temp.geno <- setupGeno(geno, miss.val=miss.val, locus.label=locus.label) # Compute the max number of pairs of haplotypes over all subjects max.pairs <- geno.count.pairs(temp.geno) max.haps <- 2*sum(max.pairs) ## This system-max for integer values is used in haplo.em.control ## for setting max.haps.limit #intMax <- .C("checkIntMax", # intMax = as.integer(0), # PACKAGE="haplo.stats")$intMax if(max.haps > control$max.haps.limit) max.haps <- control$max.haps.limit # check whether to delete some rows - now defunct, but use # dummy to not break code that uses this in returned list rows.rem <- numeric(0) geno.vec <- as.vector(temp.geno) geno.vec <- ifelse(is.na(geno.vec),0,geno.vec) allele.labels <- attr(temp.geno, "unique.alleles") if(length(allele.labels)!=n.loci) stop("Number of loci in alleles list != n.loci") n.alleles <- numeric(n.loci) a.freq <- vector("list",n.loci) for(i in 1:n.loci){ n.alleles[i] <- length(allele.labels[[i]]) j <- (i-1)*2 + 1 p <- table(temp.geno[,c(j, (j+1))], exclude=NA) p <- p/sum(p) a.freq[[i]] <- list(p=p) } if(is.null(control$loci.insert.order)) { control$loci.insert.order <- 1:n.loci } # need zero-offset for loci-insert-order when # pass to C loci.insert.order <- (control$loci.insert.order - 1) if(length(loci.insert.order) != n.loci){ stop("length of loci.insert.order != n.loci") } if(sum( abs(sort(loci.insert.order) - (0:(n.loci-1)))) > 0){ stop("All loci are not accounted for in loci.insert.order") } if(control$insert.batch.size > n.loci){ control$insert.batch.size <- n.loci } if(!is.null(control$iseed)) { set.seed(control$iseed) } else { runif(1) control$iseed <- .Random.seed } # The seeds for the ranAS183 random number generator used in the C function # hwe_sim must be between 1 and 30000, but bigger is better (we think), so we # add 10000 seed.array <- runif(3) iseed1 = 10000 + 20000*seed.array[1] iseed2 = 10000 + 20000*seed.array[2] iseed3 = 10000 + 20000*seed.array[3] fit <- haplo.em.fitter( n.loci, n.subject, weight, geno.vec, n.alleles, max.haps, max.iter=control$max.iter, loci.insert.order, min.posterior=control$min.posterior, tol=control$tol, insert.batch.size=control$insert.batch.size, random.start=control$random.start, iseed1=iseed1, iseed2=iseed2, iseed3=iseed3, verbose=control$verbose) # if n.try > 1 try, remaining tries are random starts for posteriors if(control$n.try > 1){ for(i in 2:control$n.try){ seed.array <- runif(3) iseed1 = 10000 + 20000*seed.array[1] iseed2 = 10000 + 20000*seed.array[2] iseed3 = 10000 + 20000*seed.array[3] fit.new <- haplo.em.fitter( n.loci, n.subject, weight, geno.vec, n.alleles, max.haps, max.iter=control$max.iter, loci.insert.order, min.posterior=control$min.posterior, tol=control$tol, insert.batch.size=control$insert.batch.size, random.start=1, iseed1=iseed1, iseed2=iseed2, iseed3=iseed3, verbose=control$verbose) if(fit.new$tmp1$lnlike > fit$tmp1$lnlike) { fit <- fit.new } } } tmp1 <- fit$tmp1 tmp2 <- fit$tmp2 u.hap <- matrix(tmp2$u.hap,nrow=tmp2$n.u.hap,byrow=TRUE) # code alleles for haplotpes with original labels # use I() to keep char vectors to factors in making a data.frame haplotype <- data.frame(I(allele.labels[[1]][u.hap[,1]])) for(j in 2:n.loci){ haplotype <- cbind(haplotype, I(allele.labels[[j]][u.hap[,j]])) } # haplotype <- data.frame(haplotype) names(haplotype) <- locus.label # convert from 0-offset in C to 1-offset in S, and recode hap codes # to 1,2,..., n_uhap hap1code <- tmp2$hap1code + 1 hap2code <- tmp2$hap2code + 1 uhapcode <- tmp2$u.hap.code + 1 n1 <- length(uhapcode) n2 <- length(hap1code) tmp <- as.numeric(factor(c(uhapcode, hap1code, hap2code))) uhapcode <- tmp[1:n1] hap1code <- tmp[(n1+1):(n1+n2)] hap2code <- tmp[(n1+n2+1):(n1+2*n2)] uhap.df <- data.frame(uhapcode, tmp2$hap.prob, u.hap) names(uhap.df) <- c("hap.code","hap.prob",locus.label) indx.subj = tmp2$indx.subj + 1 # in rare cases of very low LD, a subject gets removed by the trimming # of haplotypes add warning and offer options in this case if(length(unique(tmp2$indx.subj)) < n.subject) { unique.subj <- unique(indx.subj) rows.rem <- c(rows.rem, which(is.na(match(1:n.subject, unique.subj)))) warning("Subject(s) ", paste(rows.rem,sep=','), " removed in trimming steps.\n Try decreasing min.posterior control parameter to reduce trimming.\n") } subj.used.id <- subj.id[indx.subj] # compute lnlike if no LD. This is a rough approximation which will # be accurate only if all haplotypes are considered in the list # of enumerated haplotypes. If there is no trimming # (min.posterior = 0), and it is possible to enumerate all # possible pairs of haplotypes, then hap.prob.noLD will sum # to 1. But, with trimming, this may not occur, so we # rescale to force them to sum to 1. This may not lead to # an accurate test for no LD by the likelihood ratio statistic. hap.prob.noLD <- a.freq[[1]]$p[u.hap[,1]] df.noLD <- length(a.freq[[1]]$p) - 1 for(j in 2:n.loci){ hap.prob.noLD <- hap.prob.noLD * a.freq[[j]]$p[u.hap[,j]] df.noLD <- df.noLD + length(a.freq[[j]]$p) - 1 } hap.prob.noLD <- hap.prob.noLD/sum(hap.prob.noLD) prior.noLD <- hap.prob.noLD[hap1code]*hap.prob.noLD[hap2code] prior.noLD <- ifelse(hap1code!=hap2code, 2*prior.noLD, prior.noLD) ppheno.noLD <- tapply(prior.noLD, indx.subj, sum) lnlike.noLD <- sum(log(ppheno.noLD)) lr <- 2*(tmp1$lnlike - lnlike.noLD) df.LD <- sum(tmp2$hap.prob > 0.0000001) - 1 df.lr <- df.LD - df.noLD obj <- list( lnlike=tmp1$lnlike, lnlike.noLD=lnlike.noLD, lr = lr, df.lr = df.lr, hap.prob = tmp2$hap.prob, hap.prob.noLD = hap.prob.noLD, converge = tmp1$converge, locus.label = locus.label, indx.subj = indx.subj, subj.id = subj.used.id, post = tmp2$post, hap1code = hap1code, hap2code = hap2code, haplotype = haplotype, nreps = table(indx.subj), rows.rem = rows.rem, max.pairs=max.pairs, control=control) class(obj) <- "haplo.em" return(obj) } haplo.stats/R/get.hapPair.q0000644000176000001440000000251511551405163015273 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/03/10 19:01:28 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/get.hapPair.q,v 1.1 2008/03/10 19:01:28 sinnwell Exp $ #$Locker: $ #$Log: get.hapPair.q,v $ #Revision 1.1 2008/03/10 19:01:28 sinnwell #Initial revision # # get list for haplotype-pairs, or phased genotypes, under HWE # return: 1) p.g: P(geno|hfreq, HWE) # 2) x.haplo: design matrix for haplotype pairs (additive) # 3) haplo.indx: index of hap pairs, referring to rows of haplo get.hapPair <- function(haplo, haplo.freq, base.index) { n.loci <- ncol(haplo) n.haplo <- nrow(haplo) haplo.indx <- expand.grid(1:n.haplo,1:n.haplo) haplo.indx <- cbind(haplo.indx[,2],haplo.indx[,1]) haplo.indx <- haplo.indx[haplo.indx[,1] <= haplo.indx[,2],] # Set up regression design matrices and beta coeff vectors # Design matrix using base.index as baseline, and assuming # haplotype effects are additive haplo.reg <- (1:n.haplo)[-base.index] x.haplo <- 1*outer(haplo.indx[,1], haplo.reg,"==") + 1*outer(haplo.indx[,2], haplo.reg,"==") # Compute prior genotype probs (geno = pair of haplotypes) p.g <- haplo.freq[haplo.indx[,1]] * haplo.freq[haplo.indx[,2]] p.g <- p.g * ifelse(haplo.indx[,1] == haplo.indx[,2], 1, 2) return(list(p.g=p.g, x.haplo=x.haplo, haplo.indx=haplo.indx)) } haplo.stats/R/print.haplo.score.slide.q0000644000176000001440000000421311551405164017576 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2007/11/27 20:55:31 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.score.slide.q,v 1.3 2007/11/27 20:55:31 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.score.slide.q,v $ #Revision 1.3 2007/11/27 20:55:31 sinnwell #re-build df data.frame with numeric as rounded by digits # #Revision 1.2 2003/09/19 16:48:38 sinnwell #fix digits syntax error # #Revision 1.1 2003/08/22 21:09:41 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # print.haplo.score.slide <- function(x, digits=max(options()$digits-2, 5), ...) # Developed by Schaid, DJ; Sinnwell, JP 2003 # Mayo Clinic Rochester, Div of Biostatistics { # print method for haplo.score.slide object. Only print the data frame portion # of the object. It has the start and end locus, # and the p-values of that call to haplo.score. df <- data.frame(start.loc=x$df$start.loc, score.global.p=round(x$df$score.global.p, digits), global.p.sim=round(x$df$global.p.sim, digits), max.p.sim=round(x$df$max.p.sim, digits)) print(df) invisible() } haplo.stats/R/haplo.score.q0000644000176000001440000004065012075056574015362 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2013/01/14 19:33:16 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.score.q,v 1.31 2013/01/14 19:33:16 sinnwell Exp $ #$Locker: $ #$Log: haplo.score.q,v $ #Revision 1.31 2013/01/14 19:33:16 sinnwell #small changes for 1.5.9 # #Revision 1.30 2011/12/05 20:56:10 sinnwell #final manual changes, updated test suite # #Revision 1.29 2011/11/23 20:34:02 sinnwell #release 1.4.81, updates with test scripts # #Revision 1.28 2009/04/09 14:31:37 sinnwell #*** empty log message *** # #Revision 1.27 2009/04/08 17:52:40 sinnwell # use R's pchisq with lower.tail=FALSE for more signif digits # #Revision 1.26 2008/04/08 20:26:22 sinnwell #add eps.svd, undo last changes with haplo.effect and control # #Revision 1.25 2008/04/07 21:54:51 sinnwell #make control parameter have eps.svd, haplo.effect, sim.control, em.control # #Revision 1.24 2008/04/04 14:15:17 sinnwell #change Ginv eps to 1e-5, sometimes gives full rank for v.score, when should be n.score-1 # #Revision 1.23 2008/04/01 20:53:07 sinnwell #added epsilon par to Ginv # #Revision 1.22 2007/02/26 22:01:12 sinnwell #remove row.rem code, it was deprecated in haplo.em #rows.rem is now miss, the index of rows removed in y, x.adj b/c of NA # # #Revision 1.21 2007/01/25 19:41:27 sinnwell #include haplo.effect for additive, recessive, dominant #include min.count as parameter, base skip.haplo on it. #Added a few comments for readability # #Revision 1.20 2006/10/25 15:09:54 sinnwell #rm Matrix library call, only done in Ginv.q # #Revision 1.19 2006/05/02 15:09:25 sinnwell #improve error messages # #Revision 1.18 2006/01/27 16:25:47 sinnwell #enforce dependency of Ginv on Matrix # #Revision 1.17 2005/11/01 14:49:22 sinnwell #*** empty log message *** # #Revision 1.16 2005/03/31 15:18:41 sinnwell #for g.inv of class Matrix, must have t(u.score)%*% g.inv # #Revision 1.15 2005/02/16 19:58:13 sinnwell #change some comments # #Revision 1.14 2004/12/29 17:35:18 sinnwell #default for skip.haplo is now 5/(nrow(geno)*2) # #Revision 1.13 2003/12/08 19:42:18 sinnwell # changed F,T to FALSE,TRUE # #Revision 1.12 2003/09/17 22:56:25 schaid #added check for var(u.score) < 0 when computing simulated haplo.score.sim # #Revision 1.11 2003/09/17 22:35:06 schaid #modified how max-stat and score.haplo simulated p-values account for NA #results (either NA for observed stat, or NA for simulated stats) # #Revision 1.10 2003/09/15 14:53:17 sinnwell #add in na.rm in score.max.sim calculation. #may be part of a bigger problem # #Revision 1.9 2003/09/11 21:27:54 sinnwell #change simulations to target both global and max for precision # #Revision 1.8 2003/08/27 21:19:06 sinnwell #*** empty log message *** # #Revision 1.7 2003/08/27 20:59:18 sinnwell #add rows.rem back into return list, it was needed in haplo.group # #Revision 1.6 2003/08/22 18:05:24 sinnwell #update for release of haplo.score 1.2.0 with 'PIN' # #Revision 1.4 2003/04/22 20:30:20 sinnwell #include use of is.R() # #Revision 1.3 2003/03/06 21:48:45 sinnwell #include license statement # #Revision 1.2 2003/01/17 16:57:06 sinnwell #revision for haplo.score version 1.2 # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.score <- function(y, geno, trait.type="gaussian", offset = NA, x.adj = NA, min.count=5, skip.haplo=min.count/(2*nrow(geno)), locus.label=NA, miss.val=c(0,NA), haplo.effect="additive", eps.svd=1e-5, simulate=FALSE, sim.control=score.sim.control(), em.control = haplo.em.control()) { call <- match.call() # Choose trait type: trait.int <- charmatch(trait.type, c("gaussian", "binomial", "poisson", "ordinal")) if(is.na(trait.int)) stop("Invalid trait type") if(trait.int == 0) stop("Ambiguous trait type") # Check dims of y and geno if(length(y)!=nrow(geno)) stop("length of y does not match number of rows in geno") n.loci <- ncol(geno)/2 if(n.loci != (floor(ncol(geno)/2)) )stop("geno has odd number of columns, need 2 columns per locus") # Check if Adjusted by Reg adjusted <- TRUE if(all(is.na(x.adj)) ) adjusted <- FALSE if(adjusted){ x.adj <- as.matrix(x.adj) if(nrow(x.adj)!=length(y)) stop("length of y does not match number of rows in x.adj") } # get haplo.effect effCode <- charmatch(casefold(haplo.effect), c("additive", "dominant", "recessive")) # General checks for missing data miss <- which(is.na(y)) if(adjusted) miss <- unique(c(miss, which(apply(is.na(x.adj),1,any)))) # If Poisson, check for errors and missing offset if(trait.int==3) { if(all(is.na(offset))) stop("Missing offset") miss <- unique(c(miss, which(is.na(offset)))) } # Subset to non-missing values: if(length(miss)) { y <- as.numeric(y[-miss]) geno <- geno[-miss,] if(adjusted) x.adj <- x.adj[-miss,,drop=FALSE] if(trait.int==3) offset <- offset[-miss] } # Create a haplo object (using EMhaps) haplo <- haplo.em(geno, locus.label, miss.val=miss.val, control = em.control) # Check convergence of EM if(!haplo$converge) stop("EM for haplo failed to converge") # If binomial, check for errors if(trait.int==2) { if(!all(y==1|y==0)) stop("Invalid y values") if(all(y==1) | all(y==0)) stop("No variation in y values") } # If Proportional Odds, recode and check y values if(trait.int==4){ y <- factor(y) y.lev <- levels(y) y <- as.numeric(y) if(max(y) < 3) stop("Less than 3 levels for y values") } n.subj <- length(y) # Computations for haplotype score statistics # code haplotypes per subject hap1 <- haplo$hap1code hap2 <- haplo$hap2code indx <- haplo$indx.subj post <- haplo$post nreps <- as.vector(haplo$nreps) uhap <- sort(unique(c(hap1,hap2))) # Choose to score haplotypes that have probabilities > skip.haplo which.haplo <- which(haplo$hap.prob >= skip.haplo) uhap <- uhap[which.haplo] x <- outer(hap1,uhap,"==") + outer(hap2,uhap,"==") # code x for additive haplotype effects x <- (1*outer(hap1,uhap,"==")) + (1*outer(hap2,uhap,"==")) if(effCode==2) { # translate x to dominant effect x <- 1*(x > 0) } if(effCode==3){ # translate x to recessive effect x <- (x > 1) * 1 } # apply posterior probs of the haplotype pair to the coding n.x <- ncol(x) x.post <- matrix(rep(NA, n.subj * n.x), ncol=n.x) for(j in 1:n.x){ x.post[,j] <- tapply(x[,j]*post, indx, sum) } # dominant and recessive models may have insufficient haplotype counts # if so, don't score them if(effCode > 1) { misshaps <- apply(x.post,2,sum) < min.count ##WARN for no haplotypes left to score if(all(misshaps)) stop(paste("Too few occurrences of haplotypes for model haplo.effect: ", haplo.effect, "\n")) # subset appropriate objects to reflect the reduction in haplotypes x.post <- x.post[,!misshaps,drop=FALSE] x <- x[,!misshaps,drop=FALSE] which.haplo <- which.haplo[!misshaps] } # SCORES FOR GLM's if(trait.int <= 3){ # If not adjusted, use summaries of y if(!adjusted){ mu <- switch(trait.int, mean(y), mean(y), sum(y)/sum(offset) ) a <- switch(trait.int, var(y), 1, 1) # if not adjusted, still need to set up x.adj, for intercept, # to be used by haplo.score.glm to compute score stat adjusted # for intercept x.adj <- matrix(rep(1,n.subj),ncol=1) } # If adjusted, use GLM to get fitted and residuals if(adjusted){ reg.out <- glm(y ~ x.adj, family=trait.type) # bind col of 1's for intercept: x.adj <- cbind(rep(1,n.subj),x.adj) mu <- reg.out$fitted.values a <- switch(trait.int, sum(reg.out$residuals^2)/reg.out$df.residual, 1, 1) } v <- switch(trait.int, 1/a, mu*(1-mu), mu ) # Now compute score statistics tmp <- haplo.score.glm(y, mu, a, v, x.adj, nreps, x.post, post, x) u.score <- tmp$u.score v.score <- tmp$v.score } # Scores for Proportional Odds if(trait.int==4) { if(adjusted){ require("rms") reg.out <- rms:::lrm(y ~ x.adj) K <- max(y) n.xadj <- ncol(x.adj) alpha <- reg.out$coef[1:(K-1)] beta <- reg.out$coeff[K:(K-1 + n.xadj)] tmp <- haplo.score.podds(y, alpha, beta, x.adj, nreps, x.post, post, x) } if(!adjusted){ tbl <- table(y) s <- 1- (cumsum(tbl)-tbl)/n.subj alpha <- - log((1-s[-1])/s[-1]) tmp <- haplo.score.podds(y, alpha, beta=NA, x.adj=NA, nreps, x.post, post, x) } u.score <- tmp$u.score v.score <- tmp$v.score } # Compute Score Statistics: tmp <- Ginv(v.score, eps=eps.svd) df <- tmp$rank g.inv <- tmp$Ginv score.global <- t(u.score)%*% g.inv %*%u.score score.haplo <- u.score / sqrt(diag(v.score)) score.max <- max(score.haplo^2, na.rm=TRUE) # Compute empirical p-values if simulate=TRUE if(!simulate) { score.global.p.sim <- NA score.haplo.p.sim <- rep(NA,length(score.haplo)) score.max.p.sim <- NA n.val.global <- NA n.val.haplo <- NA } else { # initialize rejection counts score.global.rej <- 0 score.haplo.rej <- rep(0,length(score.haplo)) score.max.rej <- 0 # initialize valid simulation counts. A simulation for the # global test can be invalid if the global statistic results # in an NA value. A simulation for the max stat, or the individual # haplotype scores, is declared invalid if any of the individual # haplotype score stats results in an NA value. However, there is # an exception. If the observed score statistic for an individual # haplotype is NA, this haplotype score is ignored in the simulations, # allowing the other haplotypes to have simulated p-values, and # the observed max stat ignores the score relating to this # haplotype with an NA value. n.val.global <- 0 n.val.haplo <- 0 score.haplo.sqr <- score.haplo^2 score.haplo.ok <- !is.na(score.haplo.sqr) if(trait.int<=3){ # Initialize mu.rand and v.rand, in case not adjusted (if adjusted, # then these will be over-ridden in simulation loop mu.rand <- mu v.rand <- v } ## Compute sequential Monte Carlo p-values as given by ## Besag and Clifford, Biometrika Jun 1991 ## Make sure max-stat and global pvals are accurate to ## within desired pval error range. ## Employ an extra rule: sample a min (default=1000) for enough ## samples to get good estimates of haplo.p.sim pvals done <- FALSE while(!done) { # random order rand.ord <- order(runif(n.subj)) if(trait.int <=3){ if(adjusted){ mu.rand <- mu[rand.ord] v.rand <- switch(trait.int, v, v[rand.ord], v[rand.ord]) } tmp <- haplo.score.glm(y[rand.ord], mu.rand, a, v.rand, x.adj[rand.ord,], nreps, x.post, post, x) } if(trait.int ==4){ if(adjusted) { tmp <- haplo.score.podds(y[rand.ord], alpha, beta, x.adj[rand.ord,,drop=FALSE],nreps, x.post, post, x) } if(!adjusted) { tmp <- haplo.score.podds(y[rand.ord], alpha, beta=NA, x.adj=NA,nreps, x.post, post, x) } } u.score <- tmp$u.score v.score <- tmp$v.score # Now compute score statistics tmp <- Ginv(v.score, eps=eps.svd) g.inv <- tmp$Ginv score.global.sim <- t(u.score) %*% g.inv %*% u.score # note that score.haplo.sim is squared, where score.haplo is not # because we want to keep the sign of score.haplo for returned # values score.haplo.sim <- ifelse(diag(v.score) < 0, NA, u.score^2 / diag(v.score) ) if(!is.na(score.global.sim)) { n.val.global <- n.val.global +1 if(score.global.sim >= score.global) score.global.rej <- score.global.rej +1 } ## for max stat, and individual haplotype scores, we require the ## same number of valid ## simulations, so that the haplotype-specific simuated ## p-values are all based on the ## same number of valid simulations. Without this, it would be impossible to ## know the confidence in the individual p-values. if(!any(is.na(score.haplo.sim))){ n.val.haplo <- n.val.haplo + 1 score.haplo.rej[score.haplo.ok] <- score.haplo.rej[score.haplo.ok] + ifelse(score.haplo.sim[score.haplo.ok] >= score.haplo.sqr[score.haplo.ok], 1, 0) score.max.sim <- max(score.haplo.sim[score.haplo.ok]) if(score.max.sim >= score.max) score.max.rej <- score.max.rej +1 } # h is target count of rejection obs to stop sampling # formula from Besag and Clifford h.global <- 1/(sim.control$p.threshold^2 + 1/max(1,n.val.global)) h.max <- 1/(sim.control$p.threshold^2 + 1/max(1,n.val.haplo)) # print the info out to screen if(sim.control$verbose) { cat("h.global:", round(h.global,5), ", global: ", score.global.rej, ", count: ", n.val.global, "\n") cat("h.max:", round(h.max,5), ", max-score: ", score.max.rej, ", count: ", n.val.haplo, "\n") } # done if reach max or enough rej values. If max is reached, # keep results and calculate p-vals at that point. if( (max(n.val.global,n.val.haplo) == sim.control$max.sim) | (h.global<=score.global.rej & h.max<=score.max.rej) ) done <- TRUE # not done if min.sim not met # this control is for haplo.sim values if(min(n.val.global, n.val.haplo) < sim.control$min.sim) done <- FALSE } score.global.p.sim <- score.global.rej / n.val.global score.haplo.p.sim <- rep(NA, length(score.haplo.rej)) score.haplo.p.sim[score.haplo.ok] <- score.haplo.rej[score.haplo.ok] / n.val.haplo score.max.p.sim <- score.max.rej / n.val.haplo } score.global.p <- if(is.R()) pchisq(score.global, df, lower.tail=FALSE) else 1 - pchisq(score.global,df) score.haplo.p <- if(is.R()) pchisq(score.haplo^2, 1, lower.tail=FALSE) else 1 - pchisq(score.haplo^2,1) # Create locus label if missing: if(all(is.na(locus.label))) { locus.label<- paste("loc-",1:n.loci,sep="") } obj <- (list(score.global=score.global, df=df,score.global.p=score.global.p, score.global.p.sim=score.global.p.sim, score.haplo=score.haplo,score.haplo.p=score.haplo.p, score.haplo.p.sim=score.haplo.p.sim, score.max.p.sim=score.max.p.sim, haplotype=haplo$haplotype[which.haplo,], hap.prob=haplo$hap.prob[which.haplo], locus.label=locus.label, simulate=simulate, call=call, haplo.effect=haplo.effect, n.val.global=n.val.global, n.val.haplo=n.val.haplo, rows.rem=miss)) if(exists("is.R") && is.function(is.R) && is.R()) { class(obj) <- "haplo.score" } else { oldClass(obj) <- "haplo.score" } return(obj) } haplo.stats/R/mf.gindx.q0000644000176000001440000000140311551405164014637 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2003/12/08 20:05:21 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/mf.gindx.q,v 1.2 2003/12/08 20:05:21 sinnwell Exp $ #$Locker: $ #$Log: mf.gindx.q,v $ #Revision 1.2 2003/12/08 20:05:21 sinnwell #changed rep(F, to rep(0,nvars) # #Revision 1.1 2003/09/16 16:02:57 schaid #Initial revision # mf.gindx <- function(m){ # determine which item in a model.frame is the genotype matrix nvars<- length(m) typevars <- rep(0,nvars) for(i in 1:nvars){ typevars[i] <- data.class(m[[i]]) } gindx <- (1:nvars)[typevars=="model.matrix" | typevars=="matrix"] if(length(gindx)==0) stop("No geno matrix in data frame") if(length(gindx) >1) stop("More than 1 geno matrix in data frame") return(gindx) } haplo.stats/R/na.geno.keep.q0000644000176000001440000000364611551405164015410 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/03/24 21:24:53 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/na.geno.keep.q,v 1.4 2008/03/24 21:24:53 sinnwell Exp $ #$Locker: $ #$Log: na.geno.keep.q,v $ #Revision 1.4 2008/03/24 21:24:53 sinnwell #rm geno rows missing all. #Put back on geno attributes, which removes requirement of allele.lev in haplo.glm #add yxmiss and gmiss attributes to m for missing yx or geno rows # #Revision 1.3 2004/02/26 17:31:02 schaid #changed F to FALSE # #Revision 1.2 2003/12/03 15:38:36 schaid #fixed subsetting to response & covariates to not drop dim, to retain matrix class # #Revision 1.1 2003/09/16 16:03:08 schaid #Initial revision # na.geno.keep <- function(m) { # determine which item in a model.frame is the genotype matrix gindx <- mf.gindx(m) # ignore genotype matrix when determining missing values for all # other variables (response and other covaraites) yxmiss <- apply(is.na(m[, -gindx, drop=FALSE]),1,any) # remove rows from genotype matrix that have all alleles missing gmiss <- apply(is.na(m[,gindx, drop=FALSE]), 1, all) # save attributes of geno, rows of m removed they would be dropped genoAttr <- attributes(m[,gindx]) allmiss <- yxmiss | gmiss m <- m[!allmiss,] # make adjustments to attributes b/c of subset genoAttr$dim[1] <- genoAttr$dim[1] - sum(allmiss) # if an allele is removed, remove it from unique.alleles nloc <- ncol(m[,gindx])/2 for(k in 1:nloc) { ualleles <- unique(c(m[,gindx][,(2*nloc-1)],m[,gindx][,2*nloc])) nalleles <- length(genoAttr$unique.alleles[[k]]) if(length(ualleles) < length(genoAttr$unique.alleles[[k]])) { genoAttr$unique.alleles[[k]] <- genoAttr$unique.alleles[[k]][!is.na(match(1:nalleles, ualleles))] } } # put back on attributes for(att in names(genoAttr)) { attr(m[,gindx], att) <- genoAttr[[att]] } attr(m, "yxmiss") <- yxmiss attr(m, "gmiss") <- gmiss return(m) } haplo.stats/R/print.haplo.glm.q0000644000176000001440000000573411656766744016200 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.glm.q,v 1.11 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.glm.q,v $ #Revision 1.11 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.10 2008/04/04 16:10:18 sinnwell #add show.missing and return coeffDF and hapDF by invisible # #Revision 1.9 2005/03/29 14:18:47 sinnwell #fix call to print within widths, different for R/Splus #® # #Revision 1.8 2004/10/22 22:08:27 sinnwell #do not drop matrix to vector when subsetting to haplo.unique #when only 1 haplotype # #Revision 1.7 2004/03/18 23:30:32 sinnwell #keep matrix from converting to data.frame, and char vecs to factors # #Revision 1.6 2004/02/26 23:05:23 sinnwell #print.banner to printBanner # #Revision 1.5 2004/02/06 16:34:17 sinnwell #fix 1-sided pval to 2-sided # #Revision 1.4 2003/12/08 20:16:49 sinnwell # changed T,F to TRUE,FALSE # #Revision 1.3 2003/11/17 23:28:19 schaid #made compatible with R # #Revision 1.2 2003/10/15 21:13:30 schaid #got rid of bug caused by use of 'fit' (should have been x) # #Revision 1.1 2003/09/16 16:03:15 schaid #Initial revision # print.haplo.glm <- function(x, print.all.haplo=FALSE, digits = max(options()$digits - 3, 5), ...){ ## function to piece togeth haplotype data.frame haplo.df<- function(x){ z <- x$haplo.common df <- as.matrix(x$haplo.unique[z,,drop=FALSE]) y <- x$haplo.freq[z] if(x$haplo.rare.term){ df <- rbind(df, rep("*",ncol(df))) y <- c(y, sum(x$haplo.freq[x$haplo.rare])) } # use dimnames to change row names do not convert from matrix to df dimnames(df)[[1]] <- x$haplo.names df <- rbind(df,x$haplo.unique[x$haplo.base,]) dimnames(df)[[1]][nrow(df)] <- "haplo.base" y <- c(y,x$haplo.freq[x$haplo.base]) data.frame(df,hap.freq=y) } cat("\nCall: ", paste(deparse(x$call), sep = "\n", collapse = "\n"), "\n\n", sep = "") if(length(x$coef)) { cat("Coefficients:\n") print.default(format(x$coefficients, digits = digits), print.gap = 2, quote = FALSE) } else cat("No coefficients\n\n") cat("\nHaplotypes:\n") hap.df <- haplo.df(x) print(hap.df, digits=digits) wt <- x$prior.weights * x$haplo.post.info$post df.residual <- sum(wt) - length(x$coef) df.null <- sum(wt) - 1 cat("\nDegrees of Freedom: ", df.null, "Total (i.e. Null); ", df.residual, "Residual\n") miss.tbl <- apply(1*x$missing, 2, sum) if(any(miss.tbl > 0)) { cat("\nSubjects removed by NAs in y or x, or all NA in geno\n") print(miss.tbl) } cat("\n Null Deviance: ", format(signif(x$null.deviance, digits)), "\n Residual Deviance: ", format(signif(x$deviance, digits)), "\n AIC: ", format(signif(x$aic, digits)), "\n\n") invisible(x) ##invisible(list(coeffDF=coeff.df, hapDF=hap.df)) } haplo.stats/R/print.haplo.cc.q0000644000176000001440000000512111551405164015750 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2005/03/30 16:40:08 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.cc.q,v 1.3 2005/03/30 16:40:08 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.cc.q,v $ #Revision 1.3 2005/03/30 16:40:08 sinnwell #remove banner.width from printBanner # #Revision 1.2 2004/12/02 15:55:51 sinnwell #round to signif for p-values # #Revision 1.1 2004/04/23 21:25:31 sinnwell #Initial revision # print.haplo.cc <- function(x, order.by="score", digits=max(options()$digits-2, 5), nlines=NULL, ...) { if (!inherits(x, 'haplo.cc')) stop("Not an object of class haplo.cc!") # Combine haplotypes and results # round numeric columns to set length digits n.loci <- ncol(x$score.lst$haplotype) df.out <- x$cc.df # print of global score stats: printBanner("Global Score Statistics", border= "-") cat(paste("global-stat = ",signif(x$score.lst$score.global,digits),", df = ", x$score.lst$df, ", p-val = ",signif(x$score.lst$score.global.p,digits),sep="")) # print separate section for sim p.vals and the conditions # under which they were made cat("\n\n") # print haplo.score simulation information if(x$score.lst$simulate) { printBanner("Global Simulation p-value Results", border="-") cat("Global sim. p-val = ",signif(x$score.lst$score.global.p.sim, digits),"\n") cat("Max-Stat sim. p-val = ",signif(x$score.lst$score.max.p.sim, digits), "\n") cat("Number of Simulations, Global: ", x$score.lst$n.val.global, ", Max-Stat:", x$score.lst$n.val.haplo) cat("\n\n") } # print counts for the two groups printBanner("Counts for Cases and Controls", border = "-") print(x$group.count) cat("\n\n") # print a banner for the data frame printBanner(paste("Haplotype Scores, p-values, Hap-Frequencies (hf), and Odds Ratios (", round(x$ci.prob*100, 0), "% CI)", sep=""), border = "-") # get the order and choose all.haps to print or not order.vec <- c("haplotype","score","freq") order.int <- pmatch(order.by, order.vec) if(all(is.na(order.int))) order.int <- 1 order.by <- order.vec[order.int] switch(order.by, score = { ord <- (1:nrow(x$cc.df))[order(x$cc.df$"Hap-Score")] }, freq = { ord <- (order(x$cc.df$"pool.hf"))[order(nrow(x$cc.df):1)] }, haplotype = { ord <- as.numeric(attributes(haplo.hash(df.out[,1:n.loci])$hap.mtx)$row.names) }) nlines <- if(is.null(nlines)) nrow(df.out) else nlines print(df.out[ord[1:nlines],], digits=digits, ...) invisible(df.out) } haplo.stats/R/print.haplo.score.merge.q0000644000176000001440000000776411551405164017613 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2005/03/30 16:40:22 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.score.merge.q,v 1.10 2005/03/30 16:40:22 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.score.merge.q,v $ #Revision 1.10 2005/03/30 16:40:22 sinnwell #remove banner.width from printBanner # #Revision 1.9 2004/04/07 14:08:59 sinnwell #use nlines for quick print # #Revision 1.8 2004/02/26 23:07:36 sinnwell #print.banner to printBanner # #Revision 1.7 2003/10/03 19:32:38 sinnwell #fix for R release, handles match.call different # #Revision 1.6 2003/08/26 16:37:57 sinnwell #change license # #Revision 1.5 2003/06/19 22:05:04 sinnwell #re-assign row numbers # #Revision 1.4 2003/06/19 13:46:02 sinnwell #add order.by and all.haps options. default is order by score and all.haps=F # #Revision 1.3 2003/04/15 18:40:24 sinnwell #fix merge.bin to x # #Revision 1.2 2003/03/06 22:08:40 sinnwell #insert license, and change getting n.loci # #Revision 1.1 2003/01/17 16:29:47 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # print.haplo.score.merge <- function(x, order.by="score", all.haps=FALSE, digits=max(options()$digits-2, 5), nlines=NULL, ...) { ### Print haplo.score.merge object to screen if (!inherits(x, 'haplo.score.merge')) stop("Not an object of class haplo.score.merge!") m.call <- match.call() noOrder <- is.na(pmatch("order.by", names(m.call))) noAll.haps <- is.na(pmatch("all.haps", names(m.call))) noDigits <- is.na(pmatch("digits", names(m.call))) if (!noOrder) order.by <- m.call[[3]] if (!noAll.haps) { if(!noOrder) all.haps <- m.call[[4]] else all.haps <- m.call[[3]] } # if(length(m.call[[3]])) order.by <- m.call[[3]] # if(length(m.call[[4]])) all.haps <- m.call[[4]] n.loci <- (1:length(names(x)))[names(x)=="Hap-Score"] - 1 order.vec <- c("score","freq","haplotype") order.int <- pmatch(order.by, order.vec) if(all(is.na(order.int))) order.int <- 1 order.by <- order.vec[order.int] #if all.haps not requested, then subset to only those w/ a score if(!all.haps) x <- x[1:length(na.omit(x$"Hap-Score")),] # Combine haplotypes and results # round numeric columns to set length digits df.print <- data.frame(x[,1:n.loci], round(x[,(n.loci+1):ncol(x)],digits)) # select between 3 different orderings switch(order.by, score = { ord <- 1:nrow(x) }, freq = { ord <- (1:nrow(x))[order(x$"Hap-Freq")] }, haplotype = { ord <- as.numeric(attributes(haplo.hash(df.print[,1:n.loci])$hap.mtx)$row.names) }) cat("\n\n") printBanner("Haplotype Scores, p-values, and Frequencies By Group", border = "-") df.print <- data.frame(df.print[ord,], row.names=NULL) if(is.null(nlines)) print(df.print, digits=digits, ...) else print(df.print[1:nlines,], digits=digits, ...) invisible() } haplo.stats/R/summaryGeno.q0000644000176000001440000000470611663003020015431 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/22 20:29:04 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/summaryGeno.q,v 1.3 2011/11/22 20:29:04 sinnwell Exp $ #$Locker: $ #$Log: summaryGeno.q,v $ #Revision 1.3 2011/11/22 20:29:04 sinnwell #use setupGeno instead of geno.recode # #Revision 1.2 2008/01/04 21:18:59 sinnwell #change column names of returned data.frame # #Revision 1.1 2004/02/26 22:07:13 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # summaryGeno <- function(geno, miss.val=0) ## created by Jason Sinnwell ## Division of Biostatistics ## Mayo Clinic Rochester ## Genetics Team 11/2002 { # Get allele tallies for each individual. Keep track of 0- 1- and 2-missing # alleles. Also, find the rows needed to fully enumerate the # individual's possible haplotypes. n.loci <- ncol(geno)/2 nr <- nrow(geno) geno <- setupGeno(geno,miss.val) count.geno <- geno.count.pairs(geno) loc0 <- numeric(nr) loc1 <- numeric(nr) loc2 <- numeric(nr) for (i in 1:nr) { first.indx <- seq(1,(2*n.loci-1),by=2) miss.one <- is.na(geno[i,first.indx]) | is.na(geno[i,first.indx+1]) miss.two <- is.na(geno[i,first.indx]) & is.na(geno[i,first.indx+1]) loc2[i] <- sum(miss.two) loc1[i] <- sum(miss.one-miss.two) loc0[i] <- sum(!miss.one) } tbl <- data.frame(missing0=loc0, missing1=loc1, missing2=loc2, N.enum.rows=count.geno) return(tbl) } haplo.stats/R/haplo.binomial.R0000644000176000001440000000324612075056531015773 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2013/01/14 19:32:41 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.binomial.R,v 1.1 2013/01/14 19:32:41 sinnwell Exp $ #$Locker: $ #$Log: haplo.binomial.R,v $ #Revision 1.1 2013/01/14 19:32:41 sinnwell #add haplo.binomial, no need glm.fit.nowarn # ## Purpose: Extracted from R 2.15.0 to "fix" the init expression to not give warnings ## for binomial fits beause of our non-integer weights, which are ## posterior prob of haplotypes for a subject haplo.binomial <- function (link = "logit") { save <- binomial() save$initialize <- expression({ if (NCOL(y) == 1) { if (is.factor(y)) y <- y != levels(y)[1L] n <- rep.int(1, nobs) y[weights == 0] <- 0 ## The only line that is different from binomial() in R 2.15.0 is ## disabling the lines that warn of non-integer counts ## if (any(y < 0 | y > 1)) stop("y values must be 0 <= y <= 1") mustart <- (weights * y + 0.5)/(weights + 1) m <- weights * y ##if (any(abs(m - round(m)) > 0.001)) ## warning("non-integer #successes in a binomial glm!") } else if (NCOL(y) == 2) { ## if (any(abs(y - round(y)) > 0.001)) ## warning("non-integer counts in a binomial glm!") n <- y[, 1] + y[, 2] y <- ifelse(n == 0, 0, y[, 1]/n) weights <- weights * n mustart <- (n * y + 0.5)/(n + 1) } else stop("for the binomial family, y must be a vector of 0 and 1's\n", "or a 2 column matrix where col 1 is no. successes and col 2 is no. failures") }) return(save) } haplo.stats/R/Ginv.R0000644000176000001440000001034411530543167014000 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2011/02/21 20:09:27 $ # #$Header: /projects/genetics/cvs/cvsroot/mgenet/R/Ginv.R,v 1.1.1.1 2011/02/21 20:09:27 sinnwell Exp $ # #$Id: Ginv.R,v 1.1.1.1 2011/02/21 20:09:27 sinnwell Exp $ # #$Locker: $ # #$Log: Ginv.R,v $ #Revision 1.1.1.1 2011/02/21 20:09:27 sinnwell #initial, genetics functions for Mayo BSI # #Revision 1.1 2006/10/25 14:39:02 sinnwell #Initial revision # #Revision 1.15 2006/04/25 21:24:08 sinnwell #pass epsilon as parameter, default the same # #Revision 1.14 2006/03/07 21:38:04 sinnwell #Matrix library is attached in other functions that call Ginv a lot #don't leave attached at the end of Ginv # #Revision 1.13 2006/01/23 21:22:40 sinnwell #leave Matrix attached if it wasn't already (in SPLUS) # #Revision 1.12 2006/01/09 16:38:10 sinnwell #check for x==0, return zero to agree with S:ginverse # #Revision 1.11 2005/09/19 14:36:11 sinnwell #explain change to svd.Matrix # #Revision 1.10 2005/09/09 13:36:06 sinnwell #make exception to only attach Matrix if not in search() # #Revision 1.9 2005/08/09 15:12:52 sinnwell #allow 1-d matrix, just 1/x and rank is 1 # #Revision 1.8 2005/06/20 19:40:38 sinnwell #for Splus give Ginv class matrix, not Matrix, dene # #Revision 1.7 2005/03/31 15:18:08 sinnwell #re-new Matrix class Ginv, problem was in haplo.score # #Revision 1.6 2005/03/30 16:35:02 sinnwell #revert to version 1.4, errors with Matrix class # #Revision 1.5 2005/03/17 22:35:02 sinnwell # because of numerical error 120 in haplo.scan svd.default with LINPACK #use LAPACK version of svd Splus: svd.Matrix; R it is svd(LINPACK=FALSE) # #Revision 1.4 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.3 2003/03/26 17:12:10 sinnwell #fix assign operator from '_' to <- # #Revision 1.2 2003/03/06 23:02:34 sinnwell #add license text # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # Ginv<-function(x, eps=1e-6) { # For S-PLUS, We use Matrix class svd method because # haplo.scan (of HaploStats had num. error with svd.default, # which uses LINPACK svd.Matrix uses LAPACK svd method. # In R, default is LAPACK in svd(), no action needed # In Oct 2006, R's package check gives an error for having # library(Matrix) in our code but not having it # 'require'-ed or 'suggest'-ed in DESCRIPTION.haplo.stats # Our solution is to keep two separate files, Ginv.q and Ginv.R # both keeping documentation on what the other method required # if any NA's cannot invert if(any(is.na(x))) stop("NA(s) encountered in matrix, cannot invert.") # In SPLUS, Check if Matrix library is attached, if not, attach here # and detach at the end. We use svd.Matrix # needMatrix <- TRUE if(length(x)>1) { #if(exists("is.R") && is.function(is.R) && is.R()) { savesvd <- svd(x, LINPACK=FALSE) U.svd<-savesvd$u V.svd<-savesvd$v d.svd<-savesvd$d maxd <- max(d.svd) w <- ifelse((d.svd/maxd) < eps, rep(0,length(d.svd)), 1/d.svd) rank<-sum(d.svd/maxd >= eps) Ginv <- V.svd %*% diag(w) %*% t(U.svd) } else { # x is 1 by 1 Ginv <- ifelse(x < eps, 0, 1/x) rank <- ifelse(x < eps, 0, 1) } list(Ginv=Ginv,rank=rank) } haplo.stats/R/louis.info.q0000644000176000001440000001115111656766744015237 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/louis.info.q,v 1.9 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: louis.info.q,v $ #Revision 1.9 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.8 2007/02/21 21:19:40 schaid #fixed call of Ginv by passing a smaller value of eps (see Machine tol for eps) . # #Revision 1.7 2004/03/19 15:02:14 sinnwell #have PACKAGE in all .C calls, part of '...' for Splus # #Revision 1.6 2004/03/17 20:54:32 sinnwell #two different calls for .C("louis_info" for R and Splus # #Revision 1.5 2004/03/02 16:53:48 sinnwell #fix typo # #Revision 1.4 2004/03/02 16:45:54 sinnwell #change call to resid.scaled.glm.fit # #Revision 1.3 2003/12/10 16:44:02 sinnwell #fix error caused by previous change of T to 1, F to 0 # #Revision 1.2 2003/12/08 19:59:50 sinnwell #changed T,F to TRUE,FALSE # #Revision 1.1 2003/09/16 16:02:21 schaid #Initial revision # louis.info <- function(fit, epsilon=1e-8){ # Compute Louis' Information Matrix for glm regression coefficients (which # include effects for haplotypes and non-genetic covariates) and # haplotype frequency estimates. Because information is not defined when # haplotype frequencies approach zero, the rows and columns of the # information matrix are eliminated for any haplotype frequencies # less than the threshold haplo.min.info haplo.min.info <- fit$control$haplo.min.info # base haplotype hap.base <- fit$haplo.base hap.freq <- fit$haplo.freq # subject-specific haplotypes h1 <- fit$haplo.post.info$hap1 h2 <- fit$haplo.post.info$hap2 # determine which haplotypes to remove from info matrix, # due to small frequencies, and eliminate observations # that are composed of at least one rare haplotype, and # fix up base haplotype index, in case its index is > # index of any eliminated haplotpes hap.id <- 1:length(hap.freq) hap.elim <- hap.id[hap.freq < haplo.min.info] if(length(hap.elim)>0){ # check if haplo.base is among those eliminated if(any(hap.elim == hap.base)) stop("Error - base haplotype frequency is too small - choose a different base") hap.keep <- hap.id[-hap.elim] hap.base <- (1:length(hap.keep))[hap.keep==hap.base] hap.freq <- hap.freq[hap.keep] h1 <- as.numeric(factor(h1,levels=hap.keep)) h2 <- as.numeric(factor(h2,levels=hap.keep)) keep <- ifelse(is.na(h1) | is.na(h2), FALSE, TRUE) h1 <- h1[keep] h2 <- h2[keep] } else { keep <- rep(TRUE,length(h1)) } # standardized residuals = {y - fit}/a(phi) resid.lst <- residScaledGlmFit(fit) resid <- resid.lst$resid[keep] a.phi <- resid.lst$a.phi # variance function = b''(theta) vfunc <- varfunc.glm.fit(fit) /a.phi vfunc <- vfunc[keep] ## From the glm fit, prior.weights are what go into glm, expanded to the size ## of the haplo.mf model matrix; weights are what ## come out after IRWLS (scaled and multiplied by post). ## We want the expanded prior weights times the last updated posterior wt <- fit$prior.weights * fit$haplo.post.info$post wt <- wt[keep] xvec <- as.vector(fit$x[keep,]) ncov <- ncol(fit$x) indx.subj <- fit$haplo.post.info$indx[keep] nhap <- length(hap.freq) len.tot <- length(indx.subj) info11 <- numeric(ncov^2) info12 <- numeric(ncov*(nhap-1)) info22 <- numeric((nhap-1)^2) size.max <- max(c(ncov, (nhap-1))) # zero-offset hap.base, h1, h2 for C hap.base <- hap.base - 1 h1 <- h1 - 1 h2 <- h2 - 1 tmp <- .C("louis_info", len.tot=as.integer(len.tot), indx.subj=as.integer(indx.subj), resid=as.double(resid), vfunc=as.double(vfunc), wt=as.double(wt), xvec=as.double(xvec), ncov=as.integer(ncov), h1=as.integer(h1), h2=as.integer(h2), hap.base=as.integer(hap.base), nhap=as.integer(nhap), hap.freq=as.double(hap.freq), info11=as.double(info11), info12=as.double(info12), info22=as.double(info22), PACKAGE='haplo.stats') nh <- nhap-1 info11 <- matrix(tmp$info11, ncol=ncov) info12 <- matrix(tmp$info12, ncol=nh) info22 <- matrix(tmp$info22, ncol=nh) info <- rbind( cbind(info11, info12), cbind(t(info12), info22) ) # v <- Ginv(info, eps=sqrt(.Machine$double.eps)) v <- Ginv(info, epsilon) var.mat <-v$Ginv rank <- v$rank if(length(hap.elim)==0) hap.elim <- NA return(list(info=info, var.mat=var.mat, rank = rank, haplo.base = hap.base +1, haplo.elim=hap.elim)) } haplo.stats/R/residuals.haplo.glm.q0000644000176000001440000000363511654051774017021 0ustar ripleyusers ## Purpose: residuals method for haplo.glm object ## Author: Jason Sinnwell ## Created: 9/26/2011 residuals.haplo.glm <- function (object, type = c("deviance", "pearson", "working", "response"), ...) { type <- match.arg(type) ## We do not implement predict for haplo.glm, so partial is not allowed if(type=="partial") stop("partial residuals not supported for haplo.glm\n") ## Fix elements of haplo.glm object so that it will work ## with residuals.glm function sindx <- object$haplo.post.info$indx hpost <- object$haplo.post.info$post ## create collapsed y mu.eta <- object$family$mu.eta y <- object$fitted.values + object$residuals * mu.eta(object$linear.predictors) object$y <- tapply(object$y, sindx, FUN=function(x) signif(x[1],digits=4)) ## collapse mu, and weights, and working residuals ## assign them back to object before calling residuals.glm on it mu <- tapply(object$fitted.values*hpost, sindx, sum) wts <- tapply(object$prior.weights, sindx, FUN <- function(x) x[1]) object$fitted.values <- mu object$residuals <- tapply(object$residuals*object$prior.weights*hpost, sindx,sum) object$prior.weights <- wts res <- residuals.glm(object, type=type) return(res) } ## Purpose: method to get fitted.values for haplo.glm object ## Author: Jason Sinnwell ## Created: 10/3/2011 fitted.haplo.glm <- function(object, ...) { sindx <- object$haplo.post.info$indx hpost <- object$haplo.post.info$post fits <- tapply(object$fitted.values*hpost, sindx, sum) return(fits) } ## Purpose: method to get var-cov matrix for haplo.glm object ## Author: Jason Sinnwell ## Created: 10/4/2011 vcov.haplo.glm <- function(object, freq=TRUE, ...) { if(freq) { return(object$var.mat) } else { return(object$var.mat[1:object$rank,1:object$rank]) } } haplo.stats/R/haplo.score.podds.q0000644000176000001440000001055311551405164016460 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2003/12/08 19:42:08 $ # #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.score.podds.q,v 1.4 2003/12/08 19:42:08 sinnwell Exp $ # #$Id: haplo.score.podds.q,v 1.4 2003/12/08 19:42:08 sinnwell Exp $ # #$Locker: $ # #$Log: haplo.score.podds.q,v $ #Revision 1.4 2003/12/08 19:42:08 sinnwell # changed F,T to FALSE,TRUE # #Revision 1.3 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.2 2003/03/06 23:15:59 sinnwell #add license text # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.score.podds <- function(y, alpha, beta=NA, x.adj=NA, nreps, x.post, post, x){ ################################################################### # # If U=c(u.a, u.e, u.g), where # u.a = score for alpha's # u.e = score for unambiguous (x.adj) covariates # u.g = score for ambiguous haplotypes # # Then the upper triangle of Var(U) can be partitioned as # # | v.aa v.ae v.ag | | | # V(U) = | v.ee v.eg | = | v.11 v.12 | # | v.gg | | v.gg | # # where v.12 is composed of v.aa, v.ae, v.ee # v.12 is composed of v.ag, v.eg # # and Var(u.g) = v.gg - v.12 * v.12(inv) * t(v.12) # # The following computes each of the submatrices as needed # to determine u.g and Var(u.g) # ################################################################## adjusted <- TRUE if(any(is.na(x.adj))) adjusted <- FALSE if(adjusted) n.xadj <- ncol(x.adj) n.x <- ncol(x) K <- max(y) # to make suscripting easier, append Inf to front of alpha, # as place-holder for alpha[1] = Inf alpha <- c(Inf, alpha) if(adjusted){ s <- ifelse(y==1, 1, 1/(1 + exp(-(alpha[y ] + x.adj %*% beta ))) ) s.p <- ifelse(y==K, 0, 1/(1 + exp(-(alpha[y+1] + x.adj %*% beta ))) ) } if(!adjusted){ s <- ifelse(y==1, 1, 1/(1 + exp(-(alpha[y ] ))) ) s.p <- ifelse(y==K, 0, 1/(1 + exp(-(alpha[y+1] ))) ) } w1 <- (s*(1-s) - s.p*(1-s.p))/(s - s.p) u.mtx <- w1 * x.post u.score <- apply(u.mtx,2,sum) # compute information matrix for alpha-beta (v.ab) and alpha-alpha (v.aa) tmp1 <- (s + s.p^2 - 2*s*s.p)*s.p*(1-s.p)/(s-s.p)^2 tmp2 <- (s.p + s^2 - 2*s*s.p)*s*(1-s)/(s-s.p)^2 tmp3 <- s.p*(1-s.p)*s*(1-s)/(s-s.p)^2 v.ag <- matrix(rep(0, (K-1)*n.x), ncol=n.x) if(adjusted) v.ae <- matrix(rep(0, (K-1)*n.xadj), ncol=n.xadj) v.aa <- matrix(rep(0,(K-1)^2),ncol=(K-1)) n.subj <- length(y) for(j in 2:K){ wt <- rep(0,n.subj) wt <- ifelse(y==(j-1), (tmp1 - tmp3), wt) wt <- ifelse(y==j, (tmp2 - tmp3), wt) v.ag[(j-1),] <- apply(wt * x.post, 2,sum) if(adjusted) v.ae[(j-1),] <- apply(wt * x.adj, 2,sum) v.aa[(j-1),(j-1)] <- sum(tmp1[y==(j-1)]) + sum(tmp2[y==j]) if(j < K) v.aa[(j-1), j] <- -sum(tmp3[y==j]) } # fill in lower tri of v.aa to make it symmetric v.aa <- v.aa + t( (col(v.aa) > row(v.aa))*v.aa ) # Louis' method for v.gg w2 <- s*(1-s) + s.p*(1-s.p) t1 <- rep( (w2 - w1^2), nreps) * post v.gg <- t(x*t1) %*% x + t(u.mtx) %*% u.mtx if(adjusted){ v.ee <- t(w2*x.adj) %*% x.adj v.eg <- t(w2*x.adj) %*% x.post v.11 <- rbind( cbind(v.aa, v.ae), cbind(t(v.ae),v.ee) ) v.12 <- rbind(v.ag,v.eg) v.score <- v.gg - t(v.12) %*% solve(v.11) %*% v.12 } if(!adjusted){ v.score <- v.gg - t(v.ag) %*% solve(v.aa) %*% v.ag } return(list(u.score=u.score, v.score=v.score)) } haplo.stats/R/plot.haplo.score.q0000644000176000001440000000331711551405164016325 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2003/08/26 16:39:04 $ # #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/plot.haplo.score.q,v 1.3 2003/08/26 16:39:04 sinnwell Exp $ # #$Id: plot.haplo.score.q,v 1.3 2003/08/26 16:39:04 sinnwell Exp $ # #$Locker: $ # #$Log: plot.haplo.score.q,v $ #Revision 1.3 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.2 2003/03/06 23:20:13 sinnwell #add license text # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # plot.haplo.score <- function(x, ...){ plot(x$hap.prob, x$score.haplo, xlab="Haplotype Frequency", ylab="Haploltype Score Statistic", ...) invisible() } haplo.stats/R/haplo.power.cc.ncp.q0000644000176000001440000002102011551405164016523 0ustar ripleyusers ##$Author: sinnwell $ ##$Date: 2008/04/29 14:36:25 $ ##$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.power.cc.ncp.q,v 1.4 2008/04/29 14:36:25 sinnwell Exp $ ##$Locker: $ ##$Log: haplo.power.cc.ncp.q,v $ ##Revision 1.4 2008/04/29 14:36:25 sinnwell ##T to TRUE ## ##Revision 1.3 2008/03/10 19:00:34 sinnwell ##call get.hapPair instead of re-used code ## ##Revision 1.2 2008/02/28 21:47:10 sinnwell ##*** empty log message *** ## ##Revision 1.1 2008/02/28 15:59:27 sinnwell ##Initial revision # haplo.power.cc.ncp <- function(haplo, haplo.freq, base.index, haplo.beta, case.frac, prevalence) { cont.frac <- 1 - case.frac haplo <- as.matrix(haplo) n.loci <- ncol(haplo) n.haplo <- nrow(haplo) # Error checks if(length(base.index) != 1) { stop("Length of base.index != 1") } if(length(haplo.beta) != n.haplo) { stop("Length of haplo.beta != number of haplotypes") } if(n.loci <2) { stop("Number of loci < 2") } if(length(haplo.freq) != n.haplo) { stop("Length haplo.freq != number of haplotypes") } # Create matrix of indices for all possible pairs of haplotypes # haplo.indx <- expand.grid(1:n.haplo,1:n.haplo) # haplo.indx <- cbind(haplo.indx[,2],haplo.indx[,1]) # haplo.indx <- haplo.indx[haplo.indx[,1] <= haplo.indx[,2],] # Set up regression design matrices and beta coeff vectors # haplo.reg <- 1:n.haplo # x.haplo <- 1*outer(haplo.indx[,1], haplo.reg,"==") + 1*outer(haplo.indx[,2], haplo.reg,"==") # Compute prior genotype probs (geno = pair of haplotypes) # p.g <- haplo.freq[haplo.indx[,1]] * haplo.freq[haplo.indx[,2]] # p.g <- p.g * ifelse(haplo.indx[,1] == haplo.indx[,2], 1, 2) hapPair.lst <- get.hapPair(haplo, haplo.freq, base.index) x.haplo <- hapPair.lst$x.haplo p.g <- hapPair.lst$p.g haplo.indx <- hapPair.lst$haplo.indx # now move base.index to first col of x, and first element of beta x.design <- cbind( rep(1,nrow(x.haplo)), x.haplo) #[,-base.index]) beta <- haplo.beta beta <- c(beta[base.index], beta[-base.index]) # Find intercept other <- list(x=x.design, p.x=p.g, beta=beta[-1], prev = prevalence) root <- uniroot(f=find.intercept.logistic, interval=c(-50,50),other=other) # Put intercept as first item in beta vector beta[1] <- root$root # function to compute P(Y|g) according to logistic reg model, # needed in subsequent steps py.g <- function(x,beta){ root <- exp(x%*%beta) p <- root/(1+root) return(p) } # Determine genotype (haplotype pair) frequencies for cases (pg.case) and # controls (pg.cont) pg.case <- py.g(x.design, beta) * p.g # P(y=1|g)P(g) pg.case <- as.vector(pg.case/sum(pg.case)) pg.cont <- (1-py.g(x.design, beta)) * p.g # P(y=0|g)P(g) pg.cont <- as.vector(pg.cont/sum(pg.cont)) #-------------- Complete Haplotype Data ------------------------------------------ df.complete <- ncol(x.haplo) # E[X|case] ex.case.complete <- apply(x.haplo * pg.case, 2, sum) # E[X|control] ex.cont.complete <- apply(x.haplo * pg.cont, 2, sum) delta.complete <- (ex.case.complete - ex.cont.complete) # E[Xbar] ex.xbar.complete <- (case.frac * ex.case.complete) + (cont.frac * ex.cont.complete) # Vx xDiff <- x.haplo - matrix(rep(ex.xbar.complete, nrow(x.haplo)),nrow=nrow(x.haplo), byrow=TRUE) vx.case <- t(xDiff * pg.case ) %*% (xDiff ) vx.cont <- t(xDiff * pg.cont ) %*% (xDiff ) vx.complete <- (case.frac*vx.case) + (cont.frac * vx.cont) ncp.complete <- case.frac*cont.frac*( t(delta.complete) %*% solve(vx.complete) %*% delta.complete) #-------------- Incomplete Haplotype Data ---------------------------------------- # Genotype matrix, ignoring haplotype phase information. geno.mat <- NULL for(i in 1:n.loci){ t1 <- haplo[haplo.indx[,1],i] t2 <- haplo[haplo.indx[,2],i] a1 <- ifelse(t1 < t2, t1, t2) a2 <- ifelse(t2 > t1, t2, t1) geno.mat <- cbind(geno.mat, a1, a2) } # Create haplo.group which gives a code for pairs of # haplotypes that fall into the same genotype group when phase is unk geno.hash <- haplo.hash(geno.mat) haplo.group <- geno.hash$hash # Create probabilities for haplotype groups p.haplo.group.case <- as.vector(tapply(pg.case, haplo.group, sum)) p.haplo.group.cont <- as.vector(tapply(pg.cont, haplo.group, sum)) # Create exemplary data of genotypes for case and controls, # with weights that represent their relative frequencies, # such that the weights sum to 1. geno.temp <- rbind(geno.hash$hap.mtx, geno.hash$hap.mtx) oldClass(geno.temp) <- "model.matrix" wt <- c(case.frac*p.haplo.group.case, cont.frac*p.haplo.group.cont) save.em <- haplo.em(geno=geno.temp, weight=wt, control=haplo.em.control(min.posterior=0)) n.haplo <- nrow(save.em$haplotype) hap.indx <- 1:n.haplo basehap <- hap.indx[save.em$hap.prob == max(save.em$hap.prob)][1] # Score haplotypes that are not rare (freq > 10e-4) and not the most frequent, which # is considered a baseline haplotype uhap <- hap.indx[hap.indx!=basehap &( save.em$hap.prob > 10e-4)] x <- 1*outer(save.em$hap1code, uhap, "==") + 1*outer(save.em$hap2code, uhap, "==") nx <- ncol(x) xstar <- NULL for(j in 1:nx){ xstar <- cbind(xstar, tapply(x[,j] * save.em$post,save.em$subj.id,sum)) } df.incomplete <- ncol(xstar) ncase <- length(p.haplo.group.case) case <- 1:ncase cont <- (ncase+1):(2*ncase) # note that xstar is same for cases and controls, because posteriors are the same for # cases and controls when running EM for haplotypes under Ho xstar <- xstar[case,] # E[X|case] ex.case.incomplete <- apply(xstar * p.haplo.group.case, 2, sum) # E[X|control] ex.cont.incomplete <- apply(xstar * p.haplo.group.cont, 2, sum) delta.incomplete <- ex.case.incomplete - ex.cont.incomplete # E[Xbar] ex.xbar.incomplete <- (case.frac * ex.case.incomplete) + (cont.frac * ex.cont.incomplete) # Vx xstar.diff <- (xstar - matrix(rep(ex.xbar.incomplete, nrow(xstar)),nrow=nrow(xstar), byrow=TRUE)) vx.case <- t(xstar.diff * p.haplo.group.case) %*% (xstar.diff) vx.cont <- t(xstar.diff * p.haplo.group.cont) %*% (xstar.diff) vx.incomplete <- (case.frac * vx.case) + (cont.frac * vx.cont) ncp.incomplete <- case.frac * cont.frac * t(delta.incomplete) %*% solve(vx.incomplete) %*% delta.incomplete # By running haplo.em on the unphased genotype data, the haplotype order is changed. To map haplotypes # between incomplete and complete haplotype data, we do the following. haplo.df.incomplete <- data.frame(save.em$haplotype, haplo.freq.incomp=save.em$hap.prob, hap.indx.incomp=hap.indx) haplo.df.complete <- data.frame(haplo, haplo.freq, hap.indx.comp=1:nrow(haplo)) haplo.merge <- merge(haplo.df.incomplete, haplo.df.complete, by.x=1:n.loci,by.y=1:n.loci,all=TRUE) # Need to subset to haplotypes that are scored for incomplete data (see above for how uhap was created) zed <- (hap.indx!=basehap) & ( save.em$hap.prob > 10e-4) haplo.merge <- haplo.merge[zed,] haplo.merge$x.score <- 1:nrow(haplo.merge) ord <- order(haplo.merge$hap.indx.comp) haplo.merge <- haplo.merge[ord,] ord <- haplo.merge$x.score delta.incomplete <- delta.incomplete[ord] ex.case.incomplete <- ex.case.incomplete[ord] ex.cont.incomplete <- ex.cont.incomplete[ord] tmp <- vx.incomplete[ord,] vx.incomplete <- tmp[,ord] return(list(ncp.phased.haplo = ncp.complete, df.phased.haplo = df.complete, ex.case.complete = ex.case.complete, ex.cont.complete = ex.cont.complete, delta.complete = delta.complete, vx.complete = vx.complete, ncp.unphased.haplo = ncp.incomplete, df.unphased.haplo = df.incomplete, ex.case.incomplete = ex.case.incomplete, ex.cont.incomplete = ex.cont.incomplete, delta.incomplete = delta.incomplete, vx.incomplete = vx.incomplete) ) } find.intercept.logistic <- function(b0,other) { # function to find intercept for logistic regression when # design matrix is specified, along with # population frequencies of rows, beta for non-intercept # effects, and prevalence (prev) x <- other$x p.x <- other$p.x beta <- other$beta prev <- other$prev z <- x %*% c(b0,beta) pd <- exp(z)/(1+exp(z)) return( sum(pd*p.x) - prev ) } haplo.stats/R/haplo.scan.q0000644000176000001440000000742011656766744015204 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.scan.q,v 1.7 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: haplo.scan.q,v $ #Revision 1.7 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.6 2008/12/02 20:23:57 sinnwell #add code to remove subjects with NA in y. # #Revision 1.5 2006/10/25 14:51:32 sinnwell #remove Matrix library load # #Revision 1.4 2006/01/27 16:30:10 sinnwell #dependency on Matrix library # #Revision 1.3 2005/03/28 22:26:31 sinnwell #change calls to haplo.scan.sim and haplo.scan.obs # #Revision 1.2 2005/03/23 23:13:17 sinnwell #return max.loc # #Revision 1.1 2005/03/23 18:07:08 sinnwell #Initial revision # # Jason Sinnwell and Dan Schaid # Mayo Clinic, Rochester MN USA haplo.scan <- function(y, geno, width=4, miss.val=c(0,NA), em.control=haplo.em.control(), sim.control=score.sim.control() ) # Given case/control status and unphased genotypes # For all locus subsets within width of a given locus, # Find the maximum chi-square stastistic for case/control status # 10 locus set, width=3, the max-stat for locus 5 is the max # for subsets 345, 456, 567, 45, 56, 5 # Perform simulations using permuted case/control status for evaluation of # significance of the max-stat for each locus, and also for a global-max-stat { call <- match.call() # check dimensions of parameters if(!(ncol(geno)%%2==0)) stop("geno has uneven number of columns") if(length(y) != nrow(geno)) stop("y and geno have different number of observations") # if any NA in y, rm subject from y and geno naY <- is.na(y) if(any(naY)) { y <- y[!naY] geno <- geno[!naY,] cat("Removing subjects with NA for y\n") } nloci <- ncol(geno)/2 # calculate statvec on observed data, # while saving information for all locus subsets em.obj <- haplo.em(geno, miss.val=miss.val, control=em.control) vec.save <- haplo.scan.obs(y=y, em.obj=em.obj, width=width) svec <- vec.save$svec maxstat.obs <- max(svec) maxstat.locus <- (1:nloci)[maxstat.obs==svec] # extract the information from sub-locus haplotypes to re-use in simulations save <- vec.save$save.lst # calculate svec on permuted data until: # a. simulate at least min.sim times # b. aim for p-value accuracy for small pvals (Besag and Clifford, 1991) # c. stop at max.sim if accuracy not met by then done <- FALSE nsim <- 0 global.rej <- 0 loc.rej <- numeric(nloci) p.threshold <- sim.control$p.threshold while(!done) { y.reord <- y[order(runif(length(y)))] simvec <- haplo.scan.sim(y.reord=y.reord, save.lst=save, nloci) nsim <- nsim+1 maxstat.sim <- max(simvec) global.rej <- global.rej + (maxstat.sim > maxstat.obs) loc.rej <- loc.rej + (simvec > svec) # h is target count of rejection obs to stop sampling # formula from Besag and Clifford 1991 h.count <- 1/(p.threshold^2 + 1/nsim) h.met <- c(global.rej, loc.rej) >= h.count # print simulation criteria out to screen if(sim.control$verbose) cat("h.count:", round(h.count,5), "nsim: ", nsim, "\n glob.rej:", global.rej, " loc.rej:", loc.rej, "\n") # done if reach max.sim or enough rej values. If max is reached, # keep results and calculate p-vals at that point. ## cat("nsim:", nsim, " h.count:", h.count, " h.met:", h.met, "\n") if((nsim >= sim.control$min.sim) & ( (nsim == sim.control$max.sim) | all(h.met) ) ) done <- TRUE } locp <- loc.rej/nsim globalp <- global.rej/nsim scan.obj <- list(call=call, scan.df=rbind(svec, locp), max.loc=maxstat.locus, globalp=globalp, nsim=nsim) oldClass(scan.obj) <- "haplo.scan" return(scan.obj) } haplo.stats/R/print.haplo.scan.q0000644000176000001440000000245411551405164016315 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2005/03/29 14:18:34 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.scan.q,v 1.4 2005/03/29 14:18:34 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.scan.q,v $ #Revision 1.4 2005/03/29 14:18:34 sinnwell #fix call again # #Revision 1.3 2005/03/28 22:22:11 sinnwell #print the call to fit width, different in R and Splus # #Revision 1.2 2005/03/23 23:13:34 sinnwell #print max.loc # #Revision 1.1 2005/03/23 18:07:08 sinnwell #Initial revision # print.haplo.scan <- function(x, digits=max(options()$digits-2, 5), ...) # print a haplo.scan object { scan.df <- as.data.frame(x$scan.df) loc.label <- paste("loc", 1:ncol(scan.df), sep='-') dimnames(scan.df) <- list(c("stat.obs", "sim.p-val"), loc.label) if(exists("is.R") && is.function(is.R) && is.R()) { x$call <- deparse(x$call, width.cutoff=40) cat("\n Call: ", x$call, sep="\n") } else { cat("\n Call: \n") dput(x$call) } cat("\n") printBanner("Locus Scan-statistic Simulated P-values") print(scan.df[2,,drop=FALSE], digits=digits) cat("\n\n") cat(" Loci with max scan statistic: ", x$max.loc, "\n") cat(" Max-Stat Simulated Global p-value: ", signif(x$globalp,digits), "\n", " Number of Simulations: ", x$nsim, "\n") invisible() } haplo.stats/R/haplo.hash.q0000644000176000001440000000352311551405164015157 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2003/08/26 16:39:04 $ # #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.hash.q,v 1.4 2003/08/26 16:39:04 sinnwell Exp $ # #$Id: haplo.hash.q,v 1.4 2003/08/26 16:39:04 sinnwell Exp $ # #$Locker: $ # #$Log: haplo.hash.q,v $ #Revision 1.4 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.3 2003/03/26 17:09:50 sinnwell #fix assign operator from '_' to <- # #Revision 1.2 2003/03/06 23:13:57 sinnwell #add license text # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.hash<-function(hap) { hash<-as.vector(unclass(factor(apply(hap,1,paste,collapse=",")))) hap.mtx <- hap[order(hash),1:ncol(hap)] hap.mtx <- hap.mtx[!(duplicated(sort(hash))),] return(list(hash=hash,hap.mtx=hap.mtx)) } haplo.stats/R/haplo.score.merge.q0000644000176000001440000000730411551405164016446 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2004/03/02 18:50:41 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.score.merge.q,v 1.7 2004/03/02 18:50:41 sinnwell Exp $ #$Locker: $ #$Log: haplo.score.merge.q,v $ #Revision 1.7 2004/03/02 18:50:41 sinnwell #fix T to TRUE # #Revision 1.6 2003/08/28 15:02:48 sinnwell #fix n.sim to simulate # #Revision 1.5 2003/08/26 16:39:04 sinnwell #change license statement # #Revision 1.4 2003/06/19 20:53:23 sinnwell #change "Hap-Prob" label to "Hap-Freq" # #Revision 1.3 2003/04/22 20:30:53 sinnwell #use is.R() function # #Revision 1.2 2003/03/06 20:34:59 sinnwell #revise to handle haplo.group list obj # #Revision 1.1 2003/01/17 16:29:47 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.score.merge <- function(score, group) # Created by JP Sinnwell/ DJ Schaid # Divisions of Biostatistics, Mayo Rochester # 10/2002 { ## Combine the returned objects of haplo.group and haplo.score ## Results will be sorted the same as haplo.score objects--by score.haplo. ## All haplotypes will be included, therefore some will not have ## haplo.score info b/c ones w/ low freqs were left out (skip.haplo). if(!inherits(score, "haplo.score")) stop( "Not an object of class haplo.score!") if(!inherits(group, "haplo.group")) stop( "Not an object of class haplo.group!") n.loci <- group$n.loci df.group <- group$group.df # Build data frames including desired data from haplo.group and haplo.score group.labels <- c("Hap-Freq", names(df.group)[(n.loci+2):ncol(df.group)]) df.score <- data.frame(score$haplotype, score$score.haplo, score$score.haplo.p) score.labels <- c(score$locus.label, "Hap-Score", "p-val") # attach on p.sim information if included in score object. if(score$simulate) { df.score <- data.frame(df.score, score$score.haplo.p.sim) score.labels <- c(score.labels,"sim p-val") } # merge score object onto group object by haplotypes. Geno includes all # haplotypes, score will map onto those and have NA's where score left those out. df.merge <- merge(df.score,df.group,by=1:n.loci,all.x=TRUE,all.y=TRUE) # sort by score statistics ord <- order(df.merge[[n.loci+1]]) df.merge <- df.merge[ord,] dimnames(df.merge) <- list( 1:nrow(df.merge), c(score.labels, group.labels)) # Make a class for haplo.score.merge for print method. # Make it act just like a data.frame. Has one added attribute: n.loci if(exists("is.R") && is.function(is.R) && is.R()) { class(df.merge) <- c("haplo.score.merge","data.frame") } else { setOldClass(c("haplo.score.merge","data.frame")) oldClass(df.merge) <- "haplo.score.merge" } return(df.merge) } haplo.stats/R/plot.haplo.score.slide.q0000644000176000001440000001312311551405164017420 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/01/04 20:47:47 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/plot.haplo.score.slide.q,v 1.12 2008/01/04 20:47:47 sinnwell Exp $ #$Locker: $ #$Log: plot.haplo.score.slide.q,v $ #Revision 1.12 2008/01/04 20:47:47 sinnwell #add ... to lines, allowing col(or) and lty specification. Make exception calls to axis in R and S, S allows srt and doesn't use col; R doesn't allow srt and uses color to undesirably color the axis # #Revision 1.11 2007/05/29 15:53:29 sinnwell #take out las and cex.axis, left for user to pass in ... # #Revision 1.10 2007/05/22 20:32:39 sinnwell #change cex to cex.axis, las does what srt did in Splus, 1=horizontal, 2-vertical # #Revision 1.9 2007/04/25 20:32:45 sinnwell #*** empty log message *** # #Revision 1.8 2007/04/12 20:49:51 sinnwell #re-set zero p-values for global to epsilon = 1e-10 # #Revision 1.7 2007/04/03 21:10:06 sinnwell #use epsilon as minimum p-value #give warnings if pval 1 && !x$simulate) stop("\nRequested to plot simulated p-values, but no simulations performed!") #if p-values are close to zero ( < epsilon) then find some minimum to plot # minimum depends on which pval choice epsilon <- 1e-10 switch(pval, global = { p <- x$df$score.global.p if(min(p[p>0]) < epsilon) epsilon <- min(p[p>0]) if(sum((p > epsilon)) < length(p)) cat(paste("Some p-values equivalent to zero, plotted as ", epsilon, "\n")) lnp <- (-1)*log10(ifelse(p < epsilon, epsilon, p)) ylabel="-log10(score.global.p)" }, global.sim = { eq.zero <- which(x$df$global.p.sim == 0) lnp <- (-1)*log10(x$df$global.p.sim) if(length(eq.zero)) { cat(paste("Some p-values are equivalent to zero, set to 0.5 / nsim \n")) lnp[eq.zero] <- (-1)*log10(.5/x$n.val.global[eq.zero]) } ylabel="-log10(global.p.sim)" }, max.sim = { eq.zero <- which(x$df$max.p.sim == 0) lnp <- (-1)*log10(x$df$max.p.sim) if(length(eq.zero)) { cat(paste("Some p-values are equivalent to zero, set to 0.5 / nsim \n")) lnp[eq.zero] <- (-1)*log10(.5/x$n.val.haplo[eq.zero]) } ylabel="-log10(max.p.sim)" }) # prepare x.axis marks for the loci, based on dist.vec x.axis.vec <- dist.vec-min(dist.vec) x.axis.vec <- x.axis.vec*(x$n.loci-1)/max(x.axis.vec) + 1 # for R, las controls label rotation on the x-axis labels # for Splus x-axis, convert las to srt (degrees) 1=horizontal (0deg) 2=perpendicular (90deg) # set below where necessary # plot outer region, then the axis with locus labels plot(x=c(1,x$n.loci),y=c(0,max(lnp)),type="n",ylab=ylabel,xlab="",xaxt="n", ...) if(is.R()) axis(1,at=x.axis.vec, labels=x$locus.label) else axis(1,at=x.axis.vec, labels=x$locus.label, ...) # plot a line for each set of n.slide loci at height of -log10p[i] for (i in x$df$start.loc) { end.loc <- i + x$n.slide - 1 lines(c(x.axis.vec[i],x.axis.vec[end.loc]),c(lnp[i],lnp[i]), ...) } invisible() } haplo.stats/R/plot.seqhap.q0000644000176000001440000001230711551405164015370 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2009/03/09 16:10:19 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/plot.seqhap.q,v 1.6 2009/03/09 16:10:19 sinnwell Exp $ #$Locker: $ #$Log: plot.seqhap.q,v $ #Revision 1.6 2009/03/09 16:10:19 sinnwell #for R use pchisq(, , lower=FALSE) to get precision on small p-vals # #Revision 1.5 2008/05/16 18:34:44 sinnwell #warnings for when perm pvals 0, set to 1/(n.sim+1) # #Revision 1.4 2008/05/09 20:59:58 sinnwell #add minp parameter # #Revision 1.3 2008/05/08 17:38:26 sinnwell #allow ylim, set minimum p as 1e-10, issue warning if pval not valid # #Revision 1.2 2007/05/25 18:17:15 sinnwell #rm par options cex.axis and las/srt, reserve for users # #Revision 1.1 2007/05/23 17:41:36 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # plot.seqhap <- function(x, pval="hap", single=TRUE, minp=.Machine$double.eps, ...) { ## plot method of seqhap object ## 1. x-axis: give locus labels in order, in "pos" chrom positions ## 2. y-axis: plot the -log10 of the p-val chosen ## 3. the pval parameter selects which ("hap","hap.sim","sum","sum.sim") to plot ## 4. Use minp as the smallest "allowable" p-value. ## Any p-value smaller will be set to log10(minp) if(!inherits(x, "seqhap")) stop("Not a seqhap object") ## if ylim is given in ..., pull it off and use it dots <- as.list(substitute(list(...)))[-1] ylim.indx <- match('ylim', names(dots)) ylim.user <- if(!is.na(ylim.indx)) eval(dots[ylim.indx]$ylim) else NULL single.p <- 1-pchisq(x$chi.stat,1) if(is.na(match(pval, c("hap", "sum", "hap.sim", "sum.sim")))) { warning("Invalid value for pval, set to default. \n") pval <- "hap" } switch(pval, "hap"={ if(is.R()) seqp <- pchisq(x$hap.stat, x$hap.df, lower.tail=FALSE) else seqp <- 1-pchisq(x$hap.stat,x$hap.df) ylabel <- '-log10(hap.pval)' }, "sum"={ if(is.R()) seqp <- pchisq(x$sum.stat,x$sum.df, lower.tail=FALSE) else 1-pchisq(x$sum.stat,x$sum.df) ylabel <- '-log10(sum.pval)' }, "hap.sim"={seqp <- ifelse(x$hap.p.point==0, 1/(x$n.sim+1), x$hap.p.point) if(any(seqp < 1/x$n.sim)) warning("One or more permutation p-value(s) set from 0 to 1/(n.sim+1)") ylabel <- '-log10(hap.sim.pval)' }, "sum.sim"={seqp <- ifelse(x$sum.p.point==0, 1/(x$n.sim+1), x$sum.p.point) if(any(seqp < 1/x$n.sim)) warning("One or more permutation p-value(s) set from 0 to 1/(n.sim+1)") ylabel <- '-log10(sum.sim.pval)' }) if(any(single.p < minp)) { warning(paste("One or more single-marker p-values too small to plot, set to ", minp, "\n")) single.p <- ifelse(single.p < minp, minp, single.p) } if(any(seqp < minp)) { warning(paste("One or more multi-marker p-values too small to plot, set to ", minp, "\n")) seqp <- ifelse(seqp < minp, minp, seqp) } log.single.p <- if(single) -log10(single.p) else NULL log.seqp <- -log10(seqp) ylim <- if(is.null(ylim.user)) c(0, max(3, log.single.p, log.seqp)) else ylim.user plot(x$pos, log.single.p,ylim=ylim, type="n",xaxt="n", xlab='', ylab=ylabel) #, ...) for(i in 1:length(x$pos)) { # plot a filled triangle for locus i at heigh of -log10p[i] points(x$pos[x$scanned.loci[i,1]], log.seqp[i], pch=17) if(sum(x$scanned.loci[i,]>0)>1) { scanned.loci.i <- sort(x$scanned.loci[i,]) scanned.loci.i <- scanned.loci.i[scanned.loci.i>0] #plot a line for each set of combined loci at height of -log10p[i] lines(c(x$pos[min(scanned.loci.i)],x$pos[max(scanned.loci.i)]),rep(log.seqp[i],2)) #plot an asterisk/circle on each locus combined at height of -log10p[i] points(x$pos[setdiff(scanned.loci.i, x$scanned.loci[i,1])],rep(log.seqp[i],length(scanned.loci.i)-1), ...) } } if(single) lines(x$pos,log.single.p,lty=2) if(is.R()) { #mgp for title change axis(1,at=x$pos, labels=x$locus.label, ...) # adj=0, las=2, cex.axis=.8 } else { axis(1,at=x$pos, labels=x$locus.label, ...) #cex.axis=.8, srt=90, adj=0 } invisible() } haplo.stats/R/haplo.model.frame.q0000644000176000001440000002455211551405164016432 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/03/24 22:21:29 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.model.frame.q,v 1.10 2008/03/24 22:21:29 sinnwell Exp $ #$Locker: $ #$Log: haplo.model.frame.q,v $ #Revision 1.10 2008/03/24 22:21:29 sinnwell #rm allele.lev, miss.val parameters # #Revision 1.9 2007/10/22 20:52:40 sinnwell #fix to allow effect of only rare haplo. Also some adjustments for this case in the dominant and recessive cases of the switch() # #Revision 1.8 2004/10/22 19:19:28 sinnwell #for recessive model, if sum(col[i]) is zero, subset accordingly #x.mat and haplo.common. Guard against 1-col left keep as data.frame # #Revision 1.7 2004/03/22 15:04:24 sinnwell #under last change for R, fixed stringsAsFactors problem # #Revision 1.6 2004/03/15 22:50:27 sinnwell #hapEM$haplotype is char for R, so convert to char, then integer # #Revision 1.5 2004/03/03 22:14:30 schaid #added allele.lev to allow this to work in R for character alleles # #Revision 1.4 2003/12/08 20:14:29 sinnwell # changed T,F to TRUE,FALSE # #Revision 1.3 2003/11/17 23:28:01 schaid #made compatible with R # #Revision 1.2 2003/10/06 15:45:49 sinnwell #change stop( ) line w/ '\n' char: R didn't understand # #Revision 1.1 2003/09/16 16:02:09 schaid #Initial revision # haplo.model.frame <- function(m, locus.label=NA, control=haplo.glm.control() ){ # Procedures to modify a glm model.frame by: # # 1. enumerating haplotypes, # 2. setup haplotype design matrix # 3. expand rows in the current model.frame (m), according to the # number of pairs of haplotypes consistent with a subject's marker data # 4. replace the model.matrix in m (which corresponds to unphased # genotpes) with a haplotype design matrix, and then return the # modified model.frame # Notes: # If there is a problem with "No haplotype freqs > haplo.min.freq" # the function has been changed to return an error message which # is then passed to the haplo.glm function. This prevents simulations # from crashing. # Input: # # m glm model.frame # # control = list with the following parameters: # # haplo.effect the model matrix coding of haplotypes # # haplo.base the baseline haplotype # # haplo.freq.min the minimum haplotype frequency for inclusion # of the haplotype as a distinct model covariate # # sum.rare.min the sum of the "rare" haplotype frequencies must # be larger than this number in order for a "rare" # haplotype term to be included in the model # # keep.rare.haplo a logical for inclusion of the rare haplotype in # the model. haplo.effect <- control$haplo.effect haplo.base <- control$haplo.base haplo.freq.min <- control$haplo.freq.min sum.rare.min <- control$sum.rare.min keep.rare.haplo <- control$keep.rare.haplo # check type of haplo.effect, by allowing partial matching, # and then code to abreviations chk <- charmatch(haplo.effect, c("additive", "dominant", "recessive")) if(is.na(chk)) stop("Invalid haplo.effect") if(chk == 0) stop("Ambiguous haplo.effect") haplo.effect <- c("add","dom","rec")[chk] # determine which factor in model frame is the geno matrix gindx <- mf.gindx(m) haplo.names <- names(m)[gindx] geno <- m[[gindx]] if(is.null(attributes(geno)$unique.alleles)) stop("Genotype matrix does not contain unique.alleles attribute, use setupGeno") allele.lev <- attributes(geno)$unique.alleles # Setup weights for use in EM wt <- model.extract(m, weights) if(!length(wt)){ wt <- rep(1, nrow(m)) } else if(any(wt < 0)){ stop("negative weights not allowed") } # EM algorithm for haplotype frequencies hapEM <- haplo.em(geno, locus.label=locus.label, miss.val=NA, weight=wt, control=control$em) if(!hapEM$converge){ stop("haplo.em failed to converge in haplo.model.frame. Try different control parameters for haplo.em.control - see haplo.glm.control") } # If any subects were removed by EM, need to remove them from model.frame if(length(hapEM$rows.rem)) { m <- m[-hapEM$rows.rem, , drop=FALSE] } # data for haplotype indices g.dat <- data.frame(hapEM$indx.subj, hapEM$hap1code, hapEM$hap2code) attr(g.dat,"names") <- c("indx.subj","hap1","hap2") indx.subj <- g.dat$indx.subj hap1code <- g.dat$hap1 hap2code <- g.dat$hap2 # haplotype frequencies haplo.freq <- hapEM$hap.prob ## Set up haplotype design matrix # create vector of unique haplotypes uhap <- sort(unique(c(hapEM$hap1code, hapEM$hap2code))) # if no base haplotype defined, then use most frequent haplotype as base if(is.null(haplo.base)) haplo.base <- uhap[haplo.freq == max(haplo.freq)] if(length(haplo.base) > 1) haplo.base <- haplo.base[1] if(sum(uhap==haplo.base)==0){ stop("Base haplotype not among possible haplotypes") } # check if any haplotypes remain after exclude base and rare haplotypes haplo.common <- uhap[(haplo.freq > haplo.freq.min) & uhap!=haplo.base] if(!keep.rare.haplo && length(haplo.common)==0) stop("No haplotypes effects to model") # now set up design matrix for add effects, with all haplotypes except base, # and later collapse over rare haplotypes x.common <- outer(hap1code, haplo.common, "==") + outer(hap2code, haplo.common, "==") haplo.rare <- uhap[(haplo.freq <= haplo.freq.min) & uhap!=haplo.base] x.rare <- outer(hap1code, haplo.rare, "==") + outer(hap2code, haplo.rare, "==") # find the haplotype frequencies for the rare haplotypes haplo.freq.rare <- haplo.freq[haplo.freq <= haplo.freq.min & uhap!=haplo.base] # now fix up design matrix for chosen haplo.effect # note: x.rare is added only if conditions for wanting it are # satisfied haplo.rare.term <- FALSE switch(haplo.effect, add = { x.hap <- x.common dimnames(x.hap) <- list(1:nrow(x.hap),haplo.common) if(length(haplo.rare)>0 & sum(haplo.freq.rare) > sum.rare.min & keep.rare.haplo == TRUE) { x.hap <- cbind(x.hap, apply(x.rare, 1, sum)) dimnames(x.hap) <- list(1:nrow(x.hap),c(haplo.common,"rare")) haplo.rare.term <- TRUE } }, dom = { x.hap <- if(ncol(x.common)) 1*(x.common >= 1) else x.common dimnames(x.hap) <- list(1:nrow(x.hap),haplo.common) if(length(haplo.rare)>0 & sum(haplo.freq.rare) > sum.rare.min & keep.rare.haplo == TRUE) { x.hap <- cbind(x.hap, 1*(apply(x.rare, 1, sum) >= 1) ) dimnames(x.hap) <- list(1:nrow(x.hap),c(haplo.common,"rare")) haplo.rare.term <- TRUE } }, rec = { x.hap <- if(ncol(x.common)) 1*(x.common == 2) else x.common dimnames(x.hap) <- list(1:nrow(x.hap),haplo.common) if(length(haplo.rare)>0 & sum(haplo.freq.rare) > sum.rare.min & keep.rare.haplo == TRUE) { x.hap <- cbind(x.hap, 1*(apply(x.rare, 1, sum) == 2)) dimnames(x.hap) <- list(1:nrow(x.hap),c(haplo.common,"rare")) haplo.rare.term <- TRUE } # because coding rec can result in columns of 0's, we need to check and # exclude cols of 0's ok <- apply(x.hap,2,sum) > 0 colname.ok <- dimnames(x.hap)[[2]][ok] if(sum(ok)==0) { stop("No homozygotes for rec haplo.effect") } else if(sum(ok)>0) { # subset x.hap, its dimnames and haplo.common # must also protect against 1 column left, don't drop to vector x.hap <- x.hap[,ok, drop=FALSE] dimnames(x.hap)[[2]] <- colname.ok if(length(haplo.common)) haplo.common <- haplo.common[ok[1:length(haplo.common)]] } }, stop("Method for haplo.effect not supported") ) # add a '.' before haplotype column name, so that names will be # cleaner when concatenating is done with other names x.names <- dimnames(x.hap)[[2]] haplo.names <- paste(haplo.names, x.names, sep=".") dimnames(x.hap)[[2]] <- paste(".",dimnames(x.hap)[[2]],sep="") if(exists("is.R") && is.function(is.R) && is.R()) { class(x.hap) <- "model.matrix" } else { oldClass(x.hap) <- "model.matrix" } # Now expand model.frame (by repeating rows) to account for enumerated haplotypes m <- m[indx.subj,] # replace the model.matrix object with haplotype design matrix, # keeping the old name of the chosen variable (model.matrix) m[[gindx]] <- x.hap attr(m,"row.names") <- 1:nrow(m) # The following code is used to create the allele labels for haplotypes. For R, # we need to use allele.lev (list of vectors, where each vector is the allele # labels for a locus). For S, we can either do the same, or rely on S's model.frame # to have taken care of this for us, when model.frame was called within haplo.glm if (is.R()) { if(is.null(allele.lev)){ stop("Missing allele.lev = list of vectors for labels of alleles\nCheck par list for haplo.glm") } nloci <- ncol(hapEM$haplotype) haplo.unique <- NULL for(j in 1:nloci){ haplo.unique <- cbind(haplo.unique, allele.lev[[j]][as.numeric(hapEM$haplotype[,j])] ) } dimnames(haplo.unique) <- dimnames(hapEM$haplotype) } else { if(!is.null(allele.lev)){ nloci <- ncol(hapEM$haplotype) haplo.unique <- NULL for(j in 1:nloci){ haplo.unique <- cbind(haplo.unique, allele.lev[[j]][as.numeric(hapEM$haplotype[,j])] ) } dimnames(haplo.unique) <- dimnames(hapEM$haplotype) } else { haplo.unique <- hapEM$haplotype } } return(list(m.frame = m, g.dat = g.dat, haplo.unique = haplo.unique, haplo.base = haplo.base, haplo.freq = haplo.freq, haplo.common = haplo.common, haplo.rare = haplo.rare, haplo.rare.term = haplo.rare.term, haplo.names=haplo.names)) } haplo.stats/R/seqhap.q0000644000176000001440000001262511656766744014442 0ustar ripleyusers#$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/seqhap.q,v 1.7 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: seqhap.q,v $ #Revision 1.7 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.6 2008/09/26 21:40:50 sinnwell #add sim.control parameters # #Revision 1.5 2007/05/25 15:38:53 sinnwell #change inlist to scanned.loci # #Revision 1.4 2007/05/23 18:02:33 sinnwell #add n.sim to result # #Revision 1.3 2007/05/23 14:13:08 sinnwell #add locus.label arg, and return pos in the return list # #Revision 1.2 2007/04/17 15:18:02 sinnwell #change F to FALSE for R check # #Revision 1.1 2007/04/06 19:30:46 sinnwell #Initial revision # #$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # #Required inputs: geno, disease, pos #geno: a (n-by-p) genotype matrix, where is n is the number of subjects, # and p is twice of the number of SNPs. #disease: a vector of length n. #pos: a vector of length (p/2). ############### Example ################# #mydata <- read.table("seqhap.dat") #mydata.y <- mydata[,1] #mydata.x <- mydata[,-1] #pos <- unlist(read.table("seqhap.pos")) #tmp <- seqhap(geno=mydata.x,disease=mydata.y,pos) ###################################### seqhap <- function(y, geno, pos, locus.label=NA, weight=NULL, mh.threshold=3.84, r2.threshold=.95, haplo.freq.min=0.005, miss.val=c(0,NA), sim.control=score.sim.control(), control=haplo.em.control()) { y=as.integer(factor(unlist(y)))-1 weight=unlist(weight) pos=unlist(pos) if(dim(geno)[1]!=length(y)) { print('error') return(0)} if(!is.null(weight) && dim(geno)[1]!=length(y)){ print('error') return(0)} nsnp <- dim(geno)[2]/2 nsub <- dim(geno)[1] # get haplotype frequencies obj <- haplo.em(geno, locus.label=locus.label, miss.val=miss.val,control=control) y <- y[obj$subj.id]#expand the disease status subjid <- obj$subj.id hapmatrix <- obj$haplotype nhap <- dim(hapmatrix)[1] hap1 <- obj$hap1code hap2 <- obj$hap2code if(!is.null(weight)) post <- weight[obj$subj.id]*obj$post else post <- obj$post seed <- sample(29999,3,replace=FALSE) npost <- length(obj$subj.id) #convert hap and inlist to vectors hap <-as.numeric(apply(hapmatrix,2,factor)) - 1 inlist <- numeric(nsnp*nsnp) tmp <- .C("seqhap", nsnp =as.integer(nsnp), nsub=as.integer(nsub), npost=as.integer(npost), nhap=as.integer(nhap), subjid=as.integer(subjid), hap=as.integer(hap), hap1=as.integer(hap1), hap2=as.integer(hap2), disease=as.integer(y), post=as.double(post), pos=as.double(pos), seed=as.integer(seed), n.sim=as.integer(sim.control$min.sim), min.sim=as.integer(sim.control$min.sim), max.sim=as.integer(sim.control$max.sim), p.threshold=as.double(sim.control$p.threshold), mh.threshold=as.double(mh.threshold), r2.threshold=as.double(r2.threshold), haplo.freq.min=as.double(haplo.freq.min), inlist=as.integer(inlist), hap.df=as.integer(numeric(nsnp)), hap.chi=as.double(numeric(nsnp)), hap.p.point=as.double(numeric(nsnp)), hap.p.region=as.double(0), sum.df=as.integer(numeric(nsnp)), sum.chi=as.double(numeric(nsnp)), sum.p.point=as.double(numeric(nsnp)), sum.p.region=as.double(0), chi.chi=as.double(numeric(nsnp)), chi.p.point=as.double(numeric(nsnp)), chi.p.region=as.double(0), PACKAGE="haplo.stats" ) ##convert inlist from vector to matrix inlist <- t(matrix(tmp$inlist,nsnp,nsnp)) results=list( converge=obj$converge, pos=pos, n.sim=tmp$n.sim, locus.label=obj$locus.label, scanned.loci=inlist, chi.stat=tmp$chi.chi, chi.p.point=tmp$chi.p.point, chi.p.region=tmp$chi.p.region, hap.stat=tmp$hap.chi, hap.df=tmp$hap.df, hap.p.point=tmp$hap.p.point, hap.p.region=tmp$hap.p.region, sum.stat=tmp$sum.chi, sum.df=tmp$sum.df, sum.p.point=tmp$sum.p.point, sum.p.region=tmp$sum.p.region) class(results) <- "seqhap" return(results) } haplo.stats/R/haplo.chistat.q0000644000176000001440000000274211551405163015674 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/04/01 20:55:08 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.chistat.q,v 1.3 2008/04/01 20:55:08 sinnwell Exp $ #$Locker: $ #$Log: haplo.chistat.q,v $ #Revision 1.3 2008/04/01 20:55:08 sinnwell #add eps to Ginv # #Revision 1.2 2005/03/28 22:28:02 sinnwell #changed from chistat # #Revision 1.1 2005/03/23 18:07:08 sinnwell #Initial revision # haplo.chistat <- function(h1, h2, post, y, nrep) { # calculate a test statistic based on case/control status # based on the differences between mean haplotype frequency in 2 groups # it is like a chisquare stat, but distribution is not known, # b/c multiple testing occurs tbl <- table(y) n.c <- tbl[1] n.d <- tbl[2] n.total <- n.c + n.d # set up the matrix for counts of unique haplotypes uhap <- sort(unique(c(h1,h2))) x <- 1*outer(h1, uhap, "==") + 1*outer(h2, uhap, "==") varx <- var(x) save.inv <- Ginv(varx, eps=sqrt(.Machine$double.eps)) vinv <- save.inv$Ginv df <- save.inv$rank # repeat the group variable as many times as nreps, # to match posteriors yrep <- rep(y,nrep) # multiply each row by the posterior prob of the person's hap pairs # then find mean of haplotype counts in each group # the length is number of haps x.d <- apply(post[yrep==1] * x[yrep==1,], 2, mean) x.c <- apply(post[yrep==0] * x[yrep==0,], 2, mean) delta <- matrix(x.d - x.c, ncol=1) stat <- t(delta)%*%vinv%*%delta * (n.d*n.c/n.total) return(stat) } haplo.stats/R/haplo.scan.sim.q0000644000176000001440000000262411551405164015750 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2005/03/24 22:08:56 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.scan.sim.q,v 1.2 2005/03/24 22:08:56 sinnwell Exp $ #$Locker: $ #$Log: haplo.scan.sim.q,v $ #Revision 1.2 2005/03/24 22:08:56 sinnwell #changed from scan.sim # #Revision 1.1 2005/03/23 18:07:08 sinnwell #Initial revision # # find a vector of maximum statistics for each locus # use simulated values for y # for all locus subsets, use saved h1.sub, h2.sub, post.sub, nrep # from scan.obs haplo.scan.sim <- function(y.reord, save.lst, nloci) { # save.lst is the information on hapcodes, posteriors, nrep for # all subsets which didn't result in 1-haplotype subsets # use them for simulations df.sim <- numeric(0) for(i in 1:length(save.lst)) { test <- haplo.chistat(y=y.reord, h1=save.lst[[i]]$h1.sub, h2=save.lst[[i]]$h2.sub, post=save.lst[[i]]$post.sub, nrep=save.lst[[i]]$nrep) df.sim <- rbind(df.sim, c(save.lst[[i]]$loci, test) ) } # for each locus, find the max chistat of those which were # calculated on a set of loci (mrow) which included that locus svec <- numeric(nloci) for(loc in 1:nloci) { # find max of chistats which came from subsets containing loc mrow <- (df.sim[,1] <= loc) & (loc <= df.sim[,2]) svec[loc] <- max(df.sim[mrow,3]) } return(svec) } haplo.stats/R/print.seqhap.q0000644000176000001440000000755111663003042015544 0ustar ripleyusers#$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.seqhap.q,v 1.6 2011/11/22 20:29:22 sinnwell Exp $ #$Locker: $ #$Log: print.seqhap.q,v $ #Revision 1.6 2011/11/22 20:29:22 sinnwell #take out S exception # #Revision 1.5 2009/03/04 14:57:30 sinnwell #for R use pchisq( x, p, lower=FALSE) instead of 1-pchisq # #Revision 1.4 2008/09/23 19:07:54 sinnwell #use digits on signif(p, digits) for region-based p-values # #Revision 1.3 2007/05/25 15:38:20 sinnwell #change inlist to scanned.loci # #Revision 1.2 2007/04/16 20:11:29 sinnwell #add ... # #Revision 1.1 2007/04/06 19:31:34 sinnwell #Initial revision # #$Author: sinnwell $ #$Date: 2011/11/22 20:29:22 $ # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # print.seqhap <- function(x, digits=max(options()$digits-2, 5), ...) { if(x$converge==0) warning("EM for haplotype probabilities failed to converge") else { printBanner("Single-locus Chi-square Test") cat("Regional permuted P-value based on single-locus test is ", signif(x$chi.p.region, digits),"\n") chi.test <- data.frame(chi.stat=round(x$chi.stat,digits), perm.point.p=x$chi.p.point, asym.point.p= round(pchisq(x$chi.stat,1, lower.tail=FALSE),digits)) row.names(chi.test) <- c(x$locus.label) print(chi.test) cat("\n\n") printBanner("Sequential Scan") cat("Loci Combined in Sequential Analysis\n") scanned.loci <- x$scanned.loci for(i in 1:dim(scanned.loci)[1]){ cat('seq-') cat(x$locus.label[i], scanned.loci[i,scanned.loci[i,]!=0], sep=" ","\n") } cat("\n\n") printBanner("Sequential Haplotype Test") cat("Regional permuted P-value based on sequential haplotype test is ", signif(x$hap.p.region, digits),"\n") hap.test <- data.frame(hap.stat=round(x$hap.stat,digits), df=x$hap.df, perm.point.p=x$hap.p.point, asym.point.p= round(pchisq(x$hap.stat,x$hap.df, lower.tail=FALSE),digits)) row.names(hap.test) <- paste(rep('seq-',length(x$locus.label)), x$locus.label,sep='') print(hap.test) cat("\n\n") printBanner("Sequential Sum Test") cat("Regional permuted P-value based on sequential sum test is ", signif(x$sum.p.region, digits),"\n") sum.test <- data.frame(sum.stat=round(x$sum.stat,digits), df=x$sum.df, perm.point.p=x$sum.p.point, asym.point.p = round(pchisq(x$sum.stat,x$sum.df, lower.tail=FALSE),digits)) row.names(sum.test) <- paste(rep('seq-',length(x$locus.label)), x$locus.label,sep='') print(sum.test) } invisible() } haplo.stats/R/geno1to2.q0000644000176000001440000000421011530534041014554 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/02/21 19:08:17 $ #$Header: /projects/genetics/cvs/cvsroot/mgenet/R/geno1to2.q,v 1.1.1.1 2011/02/21 19:08:17 sinnwell Exp $ #$Locker: $ #$Log: geno1to2.q,v $ #Revision 1.1.1.1 2011/02/21 19:08:17 sinnwell #"initial, general functions for R genetics at Mayo BSI # #Revision 1.6 2007/05/14 15:33:24 sinnwell #remove na.code # #Revision 1.5 2007/04/20 20:03:32 sinnwell #replace unlistToMat with do.call("cbind"), use rep in assigning loc names # #Revision 1.3 2007/04/20 15:06:09 sinnwell #rm na.code and miss.val, only allow 0,1,2 values, the rest are NA # #Revision 1.2 2007/04/18 17:10:57 sinnwell #add locus.label option # #Revision 1.1 2006/08/11 21:53:42 sinnwell #Initial revision # ## $Id: geno1to2.q,v 1.1.1.1 2011/02/21 19:08:17 sinnwell Exp $ ## Jason Sinnwell, with contribution by Harold Ye ## Mayo Clinic, Division of Biostatistics ## 8/2006 ## convert a geno matrix with allele counts to a matrix where each locus ## is represented by 2 columns. geno1to2 <- function(geno, locus.label=NULL) { # define function to convert a vector or 0,1,2 (or NA) to alleles 1-1,1-2,2-2, respectively # to be used in apply statement below one2two <- function(macvec) { a1 <- ifelse(is.na(macvec), NA, ifelse(macvec==0,1,ifelse(macvec==2,2,1))) a2 <- ifelse(is.na(macvec), NA, ifelse(macvec==0,1,ifelse(macvec==2,2,2))) return(cbind(a1,a2)) } # recode missing values to NA. ## Any value that is not 0, 1, 2, "0", "1", "2", is considered an NA values <- unique(as.vector(as.matrix(geno))) imatch <- match(values, c(0,1,2)) cmatch <- match(values, c("0","1","2")) miss.vec <- values[ apply(is.na(cbind(imatch, cmatch)), 1, all) ] miss.notNA <- miss.vec[!is.na(miss.vec)] if(length(miss.notNA)) { for(val in miss.notNA) { geno[geno==val] <- NA } } # apply one2two two <- lapply(as.list(as.data.frame(geno)), one2two) twomat <- do.call("cbind", two) twomat <- as.data.frame(twomat) if(is.null(locus.label)) locus.label <- paste("m", 1:ncol(geno), sep="") names(twomat) <- paste(rep(locus.label,rep(2,length(locus.label))), c(1,2), sep=".") return(twomat) } haplo.stats/R/score.sim.control.q0000644000176000001440000000515211551405164016513 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2003/12/08 20:22:37 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/score.sim.control.q,v 1.3 2003/12/08 20:22:37 sinnwell Exp $ #$Locker: $ #$Log: score.sim.control.q,v $ #Revision 1.3 2003/12/08 20:22:37 sinnwell # changed T,F to TRUE,FALSE # #Revision 1.2 2003/09/12 16:33:01 sinnwell #remove pval.choice # #Revision 1.1 2003/08/22 21:08:42 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # score.sim.control <- function(p.threshold = 0.25, min.sim = 1000, max.sim = 20000., verbose = FALSE) # Sinnwell JP, Schaid DJ 7/2003 # Mayo Clinic Rochester { # return a list of controls for simulations in haplo.score if(p.threshold < 0 | p.threshold > 0.9) { warning("The value of p.threshold is out of range, the devault value of 0.25 is used" ) p.threshold <- 0.25 } # if(is.na(pmatch(pval.choice, c("global", "max")))) { # warning("The value of p.val.choice should be 'global' or 'max'; the default value 'global' is used" # ) # pval.choice <- "global" # } if(min.sim < 1) { warning("The value of min.sim is out of range, the default value of 1000 is used" ) min.sim <- 1000 } if(max.sim < min.sim | max.sim > 100000000.) { warning("The value of max.sim is not valid! \n\n If less than min.sim, it is set equal to min.sim. \n\n If over 100,000,000 set to default of 20,000" ) if(max.sim < min.sim) max.sim <- min.sim else max.sim <- 20000. } return(list(p.threshold = p.threshold, min.sim = min.sim, max.sim = max.sim, verbose = verbose)) } haplo.stats/R/print.haplo.group.q0000644000176000001440000000537611551405164016533 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2005/03/29 19:21:53 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.group.q,v 1.8 2005/03/29 19:21:53 sinnwell Exp $ #$Id: print.haplo.group.q,v 1.8 2005/03/29 19:21:53 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.group.q,v $ #Revision 1.8 2005/03/29 19:21:53 sinnwell #make printBanner abide to options()$width # #Revision 1.7 2004/04/06 21:30:06 sinnwell #use nlines to limit output for demos # #Revision 1.6 2004/02/26 23:06:50 sinnwell #print.banner to printBanner # #Revision 1.5 2003/08/26 16:37:57 sinnwell #change license # #Revision 1.4 2003/03/06 22:04:56 sinnwell #update license and to handle haplo.group list obj # #Revision 1.3 2003/01/29 15:50:17 sinnwell #remove printing of rows.rem attr # #Revision 1.2 2003/01/17 16:58:38 sinnwell #revision for haplo.score version 1.2 # #Revision 1.1 2002/09/09 19:53:18 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # print.haplo.group <- function(x, digits=max(options()$digits-2, 5), nlines=NULL, ...) { ### Print haplo.group object with frequency table for group ### and estimated frequencies for haplotypes. if (!inherits(x, 'haplo.group')) stop("Not an object of class haplo.group!") n.loci <- x$n.loci n.group <- length(x$group.count) # Round expected frequencies to set length digits df.print<-data.frame((x$group.df)[,1:n.loci], round((x$group.df)[,(n.loci+1):(n.loci+n.group+1)],digits)) cat("\n") printBanner("Counts per Grouping Variable Value", border = "-") print(x$group.count) cat("\n\n") printBanner("Haplotype Frequencies By Group ", border = "-") if(is.null(nlines)) print(df.print) else print(df.print[1:nlines,]) invisible() } haplo.stats/R/varfunc.glm.fit.q0000644000176000001440000000224211551405164016132 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2003/12/24 17:35:55 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/varfunc.glm.fit.q,v 1.3 2003/12/24 17:35:55 sinnwell Exp $ #$Locker: $ #$Log: varfunc.glm.fit.q,v $ #Revision 1.3 2003/12/24 17:35:55 sinnwell #fix the check for "logit" and "log" links to work in S and R # #Revision 1.2 2003/11/17 23:27:53 schaid #made compatible with R # #Revision 1.1 2003/09/16 16:03:28 schaid #Initial revision # varfunc.glm.fit <- function(fit){ # Given a glm model fit, compute the variance function, b''(theta), # where theta = X'B switch(as.character(fit$family[1]), "Binomial"= , "binomial" = { if(grep("logit",casefold(fit$family[2][[1]])) < 0) stop("Only logit link for binomial") fit$fitted.values * (1 - fit$fitted.values) }, "Gaussian"=, "gaussian" = { rep(1, length(fit$fitted.values)) }, "Poisson"=, "poisson" = { if(grep("log",casefold(fit$family[2][[1]])) < 0) stop("Only log link for poisson") fit$fitted.values }, stop(paste("Variance function for",fit$family[1],"not defined")) ) } haplo.stats/R/find.haplo.beta.qt.q0000644000176000001440000001061311551405163016506 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/04/29 14:34:32 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/find.haplo.beta.qt.q,v 1.5 2008/04/29 14:34:32 sinnwell Exp $ #$Locker: $ #$Log: find.haplo.beta.qt.q,v $ #Revision 1.5 2008/04/29 14:34:32 sinnwell #T to TRUE # #Revision 1.4 2008/03/10 19:01:15 sinnwell # call get.hapPair instead of re-used code # #Revision 1.3 2008/03/05 15:28:07 sinnwell #rm useless code # #Revision 1.2 2008/02/28 21:49:27 sinnwell #take out commented check uniroot$message for failure # #Revision 1.1 2008/02/28 15:59:27 sinnwell #Initial revision # find.haplo.beta.qt <- function(haplo, haplo.freq, base.index, haplo.risk, r2, y.mu=0, y.var=1){ # Find beta's for risk haplotypes, for specified r2 root.save <- uniroot(find.beta.qt.phase.known, lower=0, upper=10, tol = 0.000001, haplo.risk=haplo.risk, base.index=base.index, haplo=haplo, haplo.freq=haplo.freq, r2=r2, y.mu=y.mu, y.var=y.var) beta.target <- root.save$root beta <- numeric(nrow(haplo)) beta[haplo.risk] <- beta.target beta.no.intercept <- beta[-base.index] beta[base.index] <- find.intercept.qt.phase.known(beta.no.intercept, base.index, haplo, haplo.freq, y.mu) return(list(r2=r2, beta=beta, base.index=base.index, haplo.risk=haplo.risk)) } find.beta.qt.phase.known <- function(beta.size, haplo.risk, base.index, haplo, haplo.freq, r2, y.mu, y.var){ # compute noncentrality parameter (ncp) for score stat of # haplotype effects for a quantitative trait, for both # genotypes (phased haplotypes) and diplotypes (un-phased haplotypes) # Create matrix of indices for all possible pairs of haplotypes haplo <- as.matrix(haplo) n.loci <- ncol(haplo) n.haplo <- nrow(haplo) # haplo.indx <- expand.grid(1:n.haplo,1:n.haplo) # haplo.indx <- cbind(haplo.indx[,2],haplo.indx[,1]) # haplo.indx <- haplo.indx[haplo.indx[,1] <= haplo.indx[,2],] # Set up regression design matrices and beta coeff vectors # Design matrix using base.index as baseline, and assuming # haplotype effects are additive # haplo.reg <- (1:n.haplo)[-base.index] # x.haplo <- 1*outer(haplo.indx[,1], haplo.reg,"==") + 1*outer(haplo.indx[,2], haplo.reg,"==") # Compute prior genotype probs (geno = pair of haplotypes) # p.g <- haplo.freq[haplo.indx[,1]] * haplo.freq[haplo.indx[,2]] # p.g <- p.g * ifelse(haplo.indx[,1] == haplo.indx[,2], 1, 2) hapPair.lst <- get.hapPair(haplo, haplo.freq, base.index) p.g <- hapPair.lst$p.g x.haplo <- hapPair.lst$x.haplo # Set up vector of beta's (leave intercept =0, since ignored) beta <- numeric(n.haplo) beta[haplo.risk] <- beta.size x.mu <- apply(x.haplo * p.g, 2, sum) # E[V] if no ambiguous haplotypes x.mu.mat <- matrix(rep(x.mu, nrow(x.haplo)), nrow=nrow(x.haplo), byrow=TRUE) delta.x <- x.haplo - x.mu.mat t2 <- delta.x * p.g vx.complete <- t(t2) %*% delta.x # Model R^2 for phase known haplotypes r2.phase.known <- (t(beta[-base.index]) %*% vx.complete %*% beta[-base.index])/y.var r2.diff <- r2.phase.known - r2 return(r2.diff) } find.intercept.qt.phase.known <- function(beta.no.intercept, base.index, haplo, haplo.freq, y.mu){ # Create matrix of indices for all possible pairs of haplotypes haplo <- as.matrix(haplo) # n.loci <- ncol(haplo) # n.haplo <- nrow(haplo) # haplo.indx <- expand.grid(1:n.haplo,1:n.haplo) # haplo.indx <- cbind(haplo.indx[,2],haplo.indx[,1]) # haplo.indx <- haplo.indx[haplo.indx[,1] <= haplo.indx[,2],] # Set up regression design matrices and beta coeff vectors # Design matrix using base.index as baseline, and assuming # haplotype effects are additive # haplo.reg <- (1:n.haplo)[-base.index] # x.haplo <- 1*outer(haplo.indx[,1], haplo.reg,"==") + 1*outer(haplo.indx[,2], haplo.reg,"==") # Compute prior genotype probs (geno = pair of haplotypes) # p.g <- haplo.freq[haplo.indx[,1]] * haplo.freq[haplo.indx[,2]] # p.g <- p.g * ifelse(haplo.indx[,1] == haplo.indx[,2], 1, 2) hapPair.lst <- get.hapPair(haplo, haplo.freq, base.index) x.mu <- apply(hapPair.lst$x.haplo * hapPair.lst$p.g, 2, sum) # Find intercept (beta for base.index haplotype) beta0 <- y.mu - t(beta.no.intercept) %*% x.mu return(beta0) } haplo.stats/R/haplo.scan.obs.q0000644000176000001440000000507311551405164015744 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2005/03/28 22:26:58 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.scan.obs.q,v 1.2 2005/03/28 22:26:58 sinnwell Exp $ #$Locker: $ #$Log: haplo.scan.obs.q,v $ #Revision 1.2 2005/03/28 22:26:58 sinnwell #changed from scan.obs # #Revision 1.1 2005/03/23 18:07:08 sinnwell #Initial revision # haplo.scan.obs <- function(y, em.obj, width) { # find a vector of maximum statistics for each locus # use observed values for y # for all locus subsets, save necessary h1.sub, h2.sub, post.sub, nrep # information for simulations # find haplotype probabilities, # re-use for needed posteriors on subsets id <- em.obj$subj.id nloci <- ncol(em.obj$haplotype) df <- numeric(0) # find all contiguous subsets of size 'width' or less within nloci save.lst <- list() i <- 1 for(k in 1:width) { start <- 1 end <- start+k-1 while(end<=nloci) { sub.loc <- start:end haplo.sub <- em.obj$haplotype[, sub.loc, drop=FALSE] sub.indx <- as.vector(unclass(factor(apply(haplo.sub, 1, paste, collapse = ",")))) # collapse prob of large haps into smaller p.sub <- tapply(em.obj$hap.prob,sub.indx, sum) # make the equivalent of new hap1code and hap2code # for subset of loci h1.sub <- sub.indx[em.obj$hap1code] h2.sub <- sub.indx[em.obj$hap2code] # find new priors for sub-haplotypes prior.sub <- p.sub[h1.sub]*p.sub[h2.sub] # heterozygous could happen two ways--twice the prob prior.sub <- ifelse(h1.sub==h2.sub, prior.sub, 2*prior.sub) denom <- tapply(prior.sub, id, sum) nrep <- table(id) post.sub <- prior.sub/rep(denom, nrep) if(length(table(c(h1.sub, h2.sub))) > 1) { # perform the test stat # don't need to keep anything for subset with only 1 possible hap test <- haplo.chistat(h1.sub, h2.sub, post.sub, y, nrep) df <- rbind(df, c(start, end, test)) save.lst[[i]] <- list(loci=c(start,end), h1.sub=h1.sub,h2.sub=h2.sub,post.sub=post.sub,nrep=nrep) i <- i+1 } start <- start+1 end <- end+1 } # end while() } # end for(width) # for each locus, find the max chistat of those which were # calculated on a set of loci (mrow) which included that locus maxstat.vec <- numeric(nloci) for(loc in 1:nloci) { # find max of chistats which came from subsets containing loc mrow <- (df[,1] <= loc) & (loc <= df[,2]) maxstat.vec[loc] <- max(df[mrow,3]) } return(list(svec=maxstat.vec,save.lst=save.lst)) } haplo.stats/R/chisq.power.q0000644000176000001440000000210211551405163015363 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/02/28 21:38:19 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/chisq.power.q,v 1.2 2008/02/28 21:38:19 sinnwell Exp $ #$Locker: $ #$Log: chisq.power.q,v $ #Revision 1.2 2008/02/28 21:38:19 sinnwell #take out comments of old code that checked for no root from uniroot # #Revision 1.1 2008/02/28 15:59:27 sinnwell #Initial revision # chisq.power <- function(n, nc, df, alpha) { # power based on sample size n, non-centrality nc, # degrees of freedom df, and type-I error alpha 1 - pchisq(qchisq(1-alpha, df), df, n*nc) } chisq.power.dif<- function(n, nc, df, alpha, power) { # difference from target power -- for finding sample size p.dif <- chisq.power(n, nc, df, alpha) - power return(p.dif) } chisq.sample.size <- function(nc, df=df, alpha, power, lower=20, upper=100000) { # sample size from noncentrality nc, degrees of freedom df save.uniroot <- uniroot(chisq.power.dif, lower=lower, upper=upper, nc=nc, df=df, alpha=alpha, power=power, tol=0.0001) ss <- ceiling(save.uniroot$root) return(ss) } haplo.stats/R/zzz.haplo.stats.R0000644000176000001440000000244712075056574016204 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2013/01/14 19:33:16 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/zzz.haplo.stats.R,v 1.4 2013/01/14 19:33:16 sinnwell Exp $ #$Locker: $ #$Log: zzz.haplo.stats.R,v $ #Revision 1.4 2013/01/14 19:33:16 sinnwell #small changes for 1.5.9 # #Revision 1.3 2012/12/28 21:39:36 sinnwell #version with update zzz file # #Revision 1.2 2011/12/05 20:56:10 sinnwell #final manual changes, updated test suite # #Revision 1.1 2004/07/02 14:18:11 sinnwell #Initial revision # #Revision 1.5 2003/10/06 15:45:17 sinnwell #dyn.load haplo.stats, not haplo.score # #Revision 1.4 2003/08/26 16:41:23 sinnwell #change License statement # #Revision 1.3 2003/03/20 22:26:56 sinnwell #remove source() command # #Revision 1.2 2003/03/17 16:45:41 sinnwell #autoload data in hla.demo.q in .First.Lib() # #Revision 1.1 2003/03/06 23:25:55 sinnwell #Initial revision # #.onLoad <- function(lib, pkg) { # library.dynam("haplo.stats", pkg, lib) #} #.onAttach <- function(lib, pkg) { # library.dynam("haplo.stats", pkg, lib) #} ##.First.lib <- function(lib, pkg) { ## ##library.dynam("haplo.stats", pkg, lib) ##} ##.Last.lib <- function(libpath) { ## library.dynam.unload("haplo.stats", libpath) ##} .onUnload <- function(libpath) { library.dynam.unload("haplo.stats", libpath) } haplo.stats/R/haplo.em.control.q0000644000176000001440000001055111551405163016312 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/02/05 16:31:18 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.em.control.q,v 1.7 2008/02/05 16:31:18 sinnwell Exp $ #$Locker: $ #$Log: haplo.em.control.q,v $ #Revision 1.7 2008/02/05 16:31:18 sinnwell #change default for min.posteror to 1e-9 for when all lowLD markers, sometimes a subject is completely removed. # #Revision 1.6 2007/10/16 19:08:30 sinnwell #put max.haps.limit back in, and make the max allowed by intMax by checkIntMax in C, set limit at 2e6 as that seemed to work in previous versions # #Revision 1.5 2007/02/27 20:14:03 schaid #removed max.haps.limit, which is now controlled by checkIntMax in haplo.em and in haplol_em_pin # #Revision 1.4 2005/03/02 15:12:31 schaid #changed max.iter to 5000 # #Revision 1.3 2003/11/17 23:28:10 schaid #made compatible with R # #Revision 1.2 2003/08/26 22:09:38 sinnwell #added GPL License # #Revision 1.1 2003/08/26 21:02:09 schaid #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.em.control <- function(loci.insert.order=NULL, insert.batch.size = 6, min.posterior=1e-9, tol=0.00001, max.iter=5000, random.start=0, n.try = 10, iseed=NULL, max.haps.limit = 2e6, verbose=0) { if(min.posterior < 0 | min.posterior > .8) { warning("The value of min.posterior is out of range, the devault value of 1e-9 is used instead") min.posterior <- 1e-9 } if(tol < 0 | tol > .5) { warning("The value of tol is out of range, the default value of 0.00001 is used instead") tol <- 0.00001 } if(max.iter < 0) { warning("The value of max.iter is < 0, the default value of 5000 is used instead") max.iter <- 5000 } if(random.start !=0 & random.start != 1){ warning("The value of random.start is not valid, the default value of 0 is used instead") random.start <- 0 } if(n.try < 1){ warning("The value of n.try is not valid, the default value of 10 is used instead") n.try <- 10 } # max.haps.limit is used to allow user to specify max number of hap pairs. # -If run-time is an issue with a small data set, set to a low number # -If set too-low for number of haplotypes, the C functions must request more, which takes extra time # Employ the system's intMax as the upper limit allowed by integer index (int representation in R) # In most situations, the process is unable to allocate memory for intMax, # which is roughly 5-6G of total memory in haplo.em test cases intMax <- .C("checkIntMax", intMax = as.integer(0), PACKAGE="haplo.stats")$intMax if(max.haps.limit < 1000 | max.haps.limit > intMax) { warning("The value of max.haps.limit is not valid, the default value of 2e6 is used instead") max.haps.limit = 2e6 } return(list(loci.insert.order=loci.insert.order, insert.batch.size = insert.batch.size, min.posterior=min.posterior, tol=tol, max.iter=max.iter, random.start=random.start, n.try=n.try, iseed=iseed, max.haps.limit=max.haps.limit, verbose=verbose)) } haplo.stats/R/f.power.q0000644000176000001440000000200311551405163014501 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/02/28 15:59:27 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/f.power.q,v 1.1 2008/02/28 15:59:27 sinnwell Exp $ #$Locker: $ #$Log: f.power.q,v $ #Revision 1.1 2008/02/28 15:59:27 sinnwell #Initial revision # f.power <- function(n, nc, df1, alpha){ # power based on sample size n, non-centrality nc, # degrees of freedom df1 and df2, and type-I error alpha df2 <- n - df1 -1 if(df2 < 0) df2 <- 1 1 - pf(qf(1-alpha, df1, df2), df1, df2, n*nc) } f.power.dif <- function(n, nc, df1, alpha, power) { # difference from target power -- for finding sample size p.dif <- f.power(n, nc, df1, alpha) - power return(p.dif) } f.sample.size <- function(nc, df1, alpha, power, lower=20, upper=10000){ # sample size from noncentrality nc, degrees of freedom df root <- ceiling(uniroot(f.power.dif, lower=lower, upper=upper, nc=nc, df1=df1, alpha=alpha, power=power, tol=0.0001)$root) return(root) } haplo.stats/R/haplo.score.slide.q0000644000176000001440000001062711551405164016451 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/04/10 14:32:18 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.score.slide.q,v 1.9 2008/04/10 14:32:18 sinnwell Exp $ #$Locker: $ #$Log: haplo.score.slide.q,v $ #Revision 1.9 2008/04/10 14:32:18 sinnwell #add eps.svd # #Revision 1.8 2007/03/08 14:38:51 sinnwell #*** empty log message *** # #Revision 1.7 2007/01/25 20:31:42 sinnwell #add haplo.effect and min.count, new features in haplo.score # #Revision 1.6 2006/10/25 15:09:15 sinnwell #rm Matrix library call, only done in Ginv # #Revision 1.5 2006/01/27 16:26:08 sinnwell #dependency of Ginv on Matrix # #Revision 1.4 2005/03/30 17:40:33 sinnwell #shorten df column names # #Revision 1.3 2005/03/03 20:51:08 sinnwell #change defaults for skip.haplo # #Revision 1.2 2003/12/08 19:43:53 sinnwell # changed F,T to FALSE,TRUE # #Revision 1.1 2003/08/22 21:05:45 sinnwell #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.score.slide <- function(y, geno, trait.type="gaussian", n.slide=2, offset = NA, x.adj = NA, min.count=5, skip.haplo=min.count/(2*nrow(geno)), locus.label=NA, miss.val=c(0,NA), haplo.effect="additive", eps.svd=1e-5, simulate=FALSE, sim.control=score.sim.control(), em.control=haplo.em.control()) # Developed by Schaid, DJ; Sinnwell, JP 2003 # Mayo Clinic Rochester, Div of Biostatistics { # check that n.slide <= n.loci n.loci <- ncol(geno)/2 if(n.slide == 1 | n.slide > n.loci) { warning("n.slide out of range, using default of 2 instead") n.slide <- 2 } start.locus <- 1:(n.loci-(n.slide-1)) if(missing(locus.label)) locus.label <- 1:n.loci n.site <- length(start.locus) score.global.p <- rep(NA,n.site) score.global.p.sim <- rep(NA,n.site) score.max.p.sim <- rep(NA,n.site) n.val.haplo <- rep(NA,n.site) n.val.global <- rep(NA,n.site) for (i in start.locus){ # subset geno and locus.label to analyze col.start <- (i-1)*2 + 1 col.end <- (col.start - 1) + 2*n.slide geno.slide <- geno[, (col.start:col.end)] temp <- haplo.score(y=y, geno=geno.slide, trait.type=trait.type, offset = offset, x.adj = x.adj, haplo.effect=haplo.effect, min.count=min.count, skip.haplo=skip.haplo, miss.val=miss.val, eps.svd=eps.svd, simulate=simulate, sim.control=sim.control, em.control = em.control) # keep global, global.sim and max.sim p-values score.global.p[i] <- temp$score.global.p score.global.p.sim[i] <- temp$score.global.p.sim score.max.p.sim[i] <- temp$score.max.p.sim # keep total simulations done n.val.haplo[i] <- temp$n.val.haplo n.val.global[i] <- temp$n.val.global } score.slide <- list(df=data.frame(start.loc=start.locus, score.global.p, global.p.sim=score.global.p.sim, max.p.sim=score.max.p.sim), n.loci=n.loci, haplo.effect=haplo.effect, simulate=simulate, n.slide=n.slide, locus.label=locus.label, n.val.haplo=n.val.haplo, n.val.global=n.val.global) if(exists("is.R") && is.function(is.R) && is.R()) { class(score.slide) <- "haplo.score.slide" } else { oldClass(score.slide) <- "haplo.score.slide" } return(score.slide) } haplo.stats/R/haplo.power.cc.q0000644000176000001440000000332611551405164015755 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/02/28 15:59:27 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.power.cc.q,v 1.1 2008/02/28 15:59:27 sinnwell Exp $ #$Locker: $ #$Log: haplo.power.cc.q,v $ #Revision 1.1 2008/02/28 15:59:27 sinnwell #Initial revision # haplo.power.cc <- function(haplo, haplo.freq, base.index, haplo.beta, case.frac, prevalence, alpha, sample.size=NULL, power=NULL){ if(is.null(power) & is.null(sample.size)) { stop("Must specify either power or sample.size") } if(!is.null(power) & !is.null(sample.size)) { stop("Must specify only one of power or sample.size") } ncp <- haplo.power.cc.ncp(haplo, haplo.freq, base.index, haplo.beta, case.frac, prevalence) if(is.null(sample.size) & !is.null(power)) { ss.phased.haplo <- chisq.sample.size(nc=ncp$ncp.phased.haplo, df=ncp$df.phased.haplo, alpha=alpha, power=power) ss.unphased.haplo <- chisq.sample.size(nc=ncp$ncp.unphased.haplo, df=ncp$df.unphased.haplo, alpha=alpha, power=power) power.phased.haplo <- power power.unphased.haplo <- power } if(is.null(power) & !is.null(sample.size)) { power.phased.haplo <- chisq.power(n=sample.size, nc=ncp$ncp.phased.haplo, df=ncp$df.phased.haplo, alpha=alpha) power.unphased.haplo <- chisq.power(n=sample.size, nc=ncp$ncp.unphased.haplo, df=ncp$df.unphased.haplo, alpha=alpha) ss.phased.haplo <- sample.size ss.unphased.haplo <- sample.size } return(list(ss.phased.haplo=ss.phased.haplo, ss.unphased.haplo=ss.unphased.haplo, power.phased.haplo=power.phased.haplo, power.unphased.haplo=power.unphased.haplo)) } haplo.stats/R/haplo.em.fitter.q0000644000176000001440000001035611551405163016132 0ustar ripleyusers#$Author: schaid $ #$Date: 2007/02/27 20:15:24 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.em.fitter.q,v 1.5 2007/02/27 20:15:24 schaid Exp $ #$Locker: $ #$Log: haplo.em.fitter.q,v $ #Revision 1.5 2007/02/27 20:15:24 schaid #control max.haps.limit with checkIntMax (see haplo.em and haplo_em_pin) # #Revision 1.4 2004/03/19 15:02:44 sinnwell #keep PACKAGE in all .C calls, required for R, '...' for Splus # #Revision 1.3 2004/03/17 21:06:24 sinnwell #separate calls for .C( for R and Splus # #Revision 1.2 2003/08/26 22:09:38 sinnwell #added GPL License # #Revision 1.1 2003/08/26 21:02:24 schaid #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # haplo.em.fitter <- function( n.loci, n.subject, weight, geno.vec, n.alleles, max.haps, max.iter, loci.insert.order, min.posterior, tol, insert.batch.size, random.start, iseed1, iseed2, iseed3, verbose){ converge <- 0 min.prior <- 0.0 n.unique <- 0 lnlike <- 0.0 n.u.hap <- 0 n.hap.pairs <- 0 on.exit( .C("haplo_free_memory", PACKAGE="haplo.stats") ) tmp1 <- .C("haplo_em_pin", n.loci=as.integer(n.loci), n.subject=as.integer(n.subject), weight=as.double(weight), geno.vec=as.integer(geno.vec), n.alleles = as.integer(n.alleles), max.haps = as.integer(max.haps), max.iter=as.integer(max.iter), loci.insert.order=as.integer(loci.insert.order), min.prior=as.double(min.prior), min.posterior=as.double(min.posterior), tol=as.double(tol), insert.batch.size=as.integer(insert.batch.size), converge=as.integer(converge), lnlike=as.double(lnlike), n.u.hap=as.integer(n.u.hap), n.hap.pairs=as.integer(n.hap.pairs), random.start=as.integer(random.start), iseed1=as.integer(iseed1), iseed2=as.integer(iseed2), iseed3=as.integer(iseed3), verbose=as.integer(verbose), PACKAGE="haplo.stats") tmp2 <- .C("haplo_em_ret_info", n.u.hap=as.integer(tmp1$n.u.hap), n.loci=as.integer(tmp1$n.loci), n.pairs=as.integer(tmp1$n.hap.pairs), hap.prob=as.double(numeric(tmp1$n.u.hap)), u.hap=as.integer(numeric(tmp1$n.u.hap*tmp1$n.loci)), u.hap.code=as.integer(numeric(tmp1$n.u.hap)), indx.subj=as.integer(numeric(tmp1$n.hap.pairs)), post=as.double(numeric(tmp1$n.hap.pairs)), hap1code=as.integer(numeric(tmp1$n.hap.pairs)), hap2code=as.integer(numeric(tmp1$n.hap.pairs)), PACKAGE="haplo.stats") obj <- list(tmp1=tmp1, tmp2=tmp2) return(obj) } haplo.stats/R/setupGeno.q0000644000176000001440000000416211551405164015103 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2007/04/19 20:59:18 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/setupGeno.q,v 1.4 2007/04/19 20:59:18 sinnwell Exp $ #$Locker: $ #$Log: setupGeno.q,v $ #Revision 1.4 2007/04/19 20:59:18 sinnwell #add locus.label # #Revision 1.3 2004/03/10 21:21:16 sinnwell #remove excess parms and attributes # #Revision 1.2 2004/03/10 15:45:56 sinnwell #make the same as loci function instead # # original version had some similar contents to this function. # This is copying much code from loci(), but it is better named # for users as setupGeno setupGeno <- function(geno, miss.val = c(0,NA),locus.label=NULL) { # Title: Create an object of class model.matrix loci <- NULL unique.alleles <- list(NULL) if(missing(geno)) stop("Error: Required argument geno is missing") if(!is.data.frame(geno) & !is.matrix(geno)) stop("Error: Argument geno is not a data.frame or matrix") if(ncol(geno) %% 2) stop("Error: Number of columns in geno object is not an even number") exp.num.loc <- ncol(geno)/2 if(is.null(locus.label)) locus.label <- paste("loc",1:exp.num.loc, sep="-") for(i in 1:exp.num.loc) { tmp <- locus(geno[, (i * 2 - 1)], geno[, i * 2], chrom.label = NULL, locus.alias=locus.label[i], x.linked = FALSE, sex = NULL, male.code = "M", female.code = "F", miss.val = miss.val) ualleles <- attr(tmp, "allele.labels") tmp <- as.matrix(tmp) dimnames(tmp)[[2]][1] <- paste(locus.label[i], dimnames(tmp)[[2]][1], sep = ".") dimnames(tmp)[[2]][2] <- paste(locus.label[i], dimnames(tmp)[[2]][2], sep = ".") loci <- cbind(loci, tmp) unique.alleles[[i]] <- ualleles } # assign class model.matrix so it can be put into a data.frame # and to hold the unique.alleles attributes # negative is that subsetting does not work. if(exists("is.R") && is.function(is.R) && is.R()) { class(loci) <- "model.matrix" } else { oldClass(loci) <- "model.matrix" } attr(loci, "unique.alleles") <- unique.alleles return(loci) } haplo.stats/R/residScaledGlmFit.q0000644000176000001440000000367211656766744016510 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/11/10 15:29:40 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/residScaledGlmFit.q,v 1.2 2011/11/10 15:29:40 sinnwell Exp $ #$Locker: $ #$Log: residScaledGlmFit.q,v $ #Revision 1.2 2011/11/10 15:29:40 sinnwell #major update to hapglm, minor changes to Rd files, prepare for version 1.5.0 release # #Revision 1.1 2004/02/26 22:35:38 sinnwell #Initial revision # #Revision 1.3 2003/12/24 17:38:51 sinnwell # fix the check for "logit" and "log" links to work in S and R # #Revision 1.2 2003/11/17 23:27:43 schaid #made compatible with R # #Revision 1.1 2003/09/16 16:03:20 schaid #Initial revision # residScaledGlmFit <- function(fit){ # Given a glm model fit, compute scaled residual, {y - fit}/a(phi), and a(phi) # # For normal, a.phi = mse # binom, a.phi = 1 # pois, a.phi = 1 # resid <- NULL a.phi <- 1 ## JPS 9/26/11 -- replace weights.expanded by prior.weights wt <- fit$prior.weights * fit$haplo.post.info$post switch(as.character(fit$family[1]), "Binomial"= , "binomial" = { if(grep("logit",as.character(casefold(fit$family[2][[1]]))) < 0) stop("Only logit link for binomial") resid <- (fit$y - fit$fitted.values) }, "Gaussian"=, "gaussian" = { y <- fit$y mu <- fit$fitted.values # Should df be reduced for estimation of haplotype freqs? df.residual <- sum(wt) - length(fit$coef) mse <- sum(wt*(y-mu)^2)/df.residual resid <- (y - mu) / mse a.phi <- mse }, "Poisson"=, "poisson" = { if(grep("log", casefold(fit$family[2][[1]])) <0) stop("Only log link for poisson") resid <- (fit$y - fit$fitted.values) }, stop(paste("Residual glm fit for",fit$family[1],"not defined")) ) return(list(resid=resid, a.phi=a.phi)) } haplo.stats/R/print.haplo.em.q0000644000176000001440000000537211551405164015774 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2009/04/08 18:40:58 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/print.haplo.em.q,v 1.9 2009/04/08 18:40:58 sinnwell Exp $ #$Locker: $ #$Log: print.haplo.em.q,v $ #Revision 1.9 2009/04/08 18:40:58 sinnwell #*** empty log message *** # #Revision 1.8 2009/04/08 17:52:05 sinnwell #use R's pchisq with lower.tail=FALSE for more signif digits # #Revision 1.7 2008/12/12 22:18:43 sinnwell #return invisible(df) # #Revision 1.6 2008/02/11 22:52:27 sinnwell #edit the message for missing rows # #Revision 1.5 2007/11/07 21:03:39 sinnwell #add digits # #Revision 1.4 2004/04/06 20:39:39 sinnwell #use nlines to limit printouts in vignettes # #Revision 1.3 2004/02/26 23:04:28 sinnwell #print.banner to printBanner # #Revision 1.2 2003/08/26 22:09:38 sinnwell #added GPL License # #Revision 1.1 2003/08/26 20:59:40 schaid #Initial revision # # License: # # Copyright 2003 Mayo Foundation for Medical Education and Research. # # This program is free software; you can redistribute it and/or modify it under the terms of # the GNU General Public License as published by the Free Software Foundation; either # version 2 of the License, or (at your option) any later version. # # This program is distributed in the hope that it will be useful, but WITHOUT ANY # WARRANTY; without even the implied warranty of MERCHANTABILITY or # FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for # more details. # # You should have received a copy of the GNU General Public License along with this # program; if not, write to the Free Software Foundation, Inc., 59 Temple Place, Suite 330, # Boston, MA 02111-1307 USA # # For other licensing arrangements, please contact Daniel J. Schaid. # # Daniel J. Schaid, Ph.D. # Division of Biostatistics # Harwick Building – Room 775 # Mayo Clinic # 200 First St., SW # Rochester, MN 55905 # # phone: 507-284-0639 # fax: 507-284-9542 # email: schaid@mayo.edu # print.haplo.em <- function(x, digits=max(options()$digits-2, 5), nlines=NULL, ...){ printBanner("Haplotypes") df <- data.frame(x$haplotype,round(x$hap.prob,digits)) names(df) <- c(x$locus.label, "hap.freq") if(is.null(nlines)) print(df) else print(df[1:nlines,]) invisible() if(x$converge==0) warning("EM failed to converge") printBanner("Details") pval <- NA if(x$df.lr > 0) { if(is.R()) { pval = pchisq(x$lr, x$df.lr, lower.tail=FALSE) } else { pval = 1-pchisq(x$lr, x$df.lr) } } cat("lnlike = ",round(x$lnlike,digits),"\n") cat("lr stat for no LD = ",round(x$lr,digits),", df = ",x$df.lr,", p-val = ",round(pval,digits),"\n") if(length(x$rows.rem > 0)) { cat("\nResults may be incomplete because one or more subjects was removed\n") } invisible(df) } haplo.stats/R/haplo.power.qt.ncp.q0000644000176000001440000000776011551405164016601 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2008/04/29 17:15:39 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/haplo.power.qt.ncp.q,v 1.4 2008/04/29 17:15:39 sinnwell Exp $ #$Locker: $ #$Log: haplo.power.qt.ncp.q,v $ #Revision 1.4 2008/04/29 17:15:39 sinnwell #F to FALSE # #Revision 1.3 2008/04/29 14:36:36 sinnwell #T to TRUE # #Revision 1.2 2008/03/10 19:01:07 sinnwell # call get.hapPair instead of re-used code # #Revision 1.1 2008/02/28 15:59:27 sinnwell #Initial revision # haplo.power.qt.ncp <- function(haplo, haplo.freq, base.index, haplo.beta, y.mu, y.var){ # compute noncentrality parameter (ncp) for score stat of # haplotype effects for a quantitative trait, for both # phased haplotypes and un-phased haplotypes # Create matrix of indices for all possible pairs of haplotypes haplo <- as.matrix(haplo) n.loci <- ncol(haplo) # haplo.indx <- expand.grid(1:n.haplo,1:n.haplo) # haplo.indx <- cbind(haplo.indx[,2],haplo.indx[,1]) # haplo.indx <- haplo.indx[haplo.indx[,1] <= haplo.indx[,2],] # Set up regression design matrices and beta coeff vectors # Design matrix using base.index as baseline, and assuming # haplotype effects are additive # haplo.reg <- (1:n.haplo)[-base.index] # x.haplo <- 1*outer(haplo.indx[,1], haplo.reg,"==") + 1*outer(haplo.indx[,2], haplo.reg,"==") # Compute prior genotype probs (geno = pair of haplotypes) # p.g <- haplo.freq[haplo.indx[,1]] * haplo.freq[haplo.indx[,2]] # p.g <- p.g * ifelse(haplo.indx[,1] == haplo.indx[,2], 1, 2) hapPair.lst <- get.hapPair(haplo, haplo.freq, base.index) p.g <- hapPair.lst$p.g x.haplo <- hapPair.lst$x.haplo haplo.indx <- hapPair.lst$haplo.indx # number of degrees of freedom; excludes intercept df <- ncol(x.haplo) x.mu <- apply(x.haplo * p.g, 2, sum) # E[V] if no ambiguous haplotypes x.mu.mat <- matrix(rep(x.mu, nrow(x.haplo)), nrow=nrow(x.haplo), byrow=TRUE) delta.x <- x.haplo - x.mu.mat t2 <- delta.x * p.g vx.complete <- t(t2) %*% delta.x # Genotype matrix, ignoring haplotype phase information. geno.mat <- NULL for(i in 1:n.loci){ t1 <- haplo[haplo.indx[,1],i] t2 <- haplo[haplo.indx[,2],i] a1 <- ifelse(t1 < t2, t1, t2) a2 <- ifelse(t2 > t1, t2, t1) geno.mat <- cbind(geno.mat, a1, a2) } # create haplo.group which gives a code for pairs of # haplotypes that fall into the same genotype group when phase is unk geno.hash <- haplo.hash(geno.mat) haplo.group <- geno.hash$hash # order by haplo.group ord <- order(haplo.group) p.g <- p.g[ord] haplo.group <- haplo.group[ord] x.haplo <- x.haplo[ord,] # create posterior probabilities of haplotype pairs, # conditional on haplo.group p.haplo.group <- tapply(p.g, haplo.group, sum) nrep <- tapply(haplo.group, haplo.group, length) denom <- rep(p.haplo.group, nrep) post <- p.g/denom # E[V] matrix and E[U] vector n.group <- length(unique(haplo.group)) nx <- ncol(x.haplo) vx.incomplete <- matrix(numeric(nx^2), nrow=nx) for(i in 1:n.group){ zed <- (haplo.group == i) tmp.x.mu <- as.vector(apply(x.haplo[zed,,drop=FALSE] * post[zed], 2, sum)) tmp.delta <- (tmp.x.mu - x.mu) vx.incomplete <- vx.incomplete + ( (tmp.delta %o% tmp.delta) * p.haplo.group[i]) } # Model R^2 for incomplete and complete observed haplotypes r2.phase.unknown <- (t(haplo.beta[-base.index]) %*% vx.incomplete %*% haplo.beta[-base.index])/y.var r2.phase.known <- (t(haplo.beta[-base.index]) %*% vx.complete %*% haplo.beta[-base.index])/y.var # NCP's ncp.chi.phase.known <- r2.phase.known ncp.chi.phase.unknown <- r2.phase.unknown ncp.f.phase.known <- r2.phase.known/(1 - r2.phase.known) ncp.f.phase.unknown <- r2.phase.unknown/(1 - r2.phase.unknown) return(list(ncp.chi.phased.haplo = ncp.chi.phase.known, ncp.f.phased.haplo = ncp.f.phase.known, ncp.chi.unphased.haplo = ncp.chi.phase.unknown, ncp.f.unphased.haplo = ncp.f.phase.unknown, df=df)) } haplo.stats/R/x.sexcheck.q0000644000176000001440000000350711551405164015177 0ustar ripleyusers#$Author: sinnwell $ # #$Date: 2006/10/25 19:31:34 $ # #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/R/x.sexcheck.q,v 1.6 2006/10/25 19:31:34 sinnwell Exp $ # #$Locker: $ # #$Log: x.sexcheck.q,v $ #Revision 1.6 2006/10/25 19:31:34 sinnwell #change T to TRUE and F to FALSE # #Revision 1.5 2003/01/17 15:58:53 det01 #Modified routine to check for class model.matrix # #Revision 1.4 2003/01/13 16:50:11 det01 #Modified check.geno data structure # #Revision 1.3 2002/12/13 17:49:44 det01 #*** empty log message *** # # x.sexcheck <- function(x,sex,stop=FALSE) { #Title: Consistency checks for x.linked loci if (stop) { old.options <- options(warn=2) on.exit(options(old.options)) } if (missing(x)) { warning("required argument x not found") return(TRUE) } if (missing(sex)) { warning("required argument sex not found") return(TRUE) } if (class(x)!="model.matrix") { warning("argument x must be of class locus") return(TRUE) } if (!attr(x,"x.linked")) return(FALSE) if (length(sex) != nrow(x)) { warning("length of sex not equal to number of individuals in x") return(TRUE) } if (any(is.na(sex))) { warning("missing a sex code for one or more individuals in x") return(TRUE) } male.code=attr(x,"male.code") female.code=attr(x,"female.code") if (any(!(sex==male.code | sex==female.code))) { warning("one or more values in sex do not match male.code or female.code attributes of x") return(TRUE) } male <- sex==male.code if(sum(male)>0) { miss <- is.na(x) check.geno <- (male & !miss) vec.check.geno <- apply(check.geno,1,sum) check.geno <- vec.check.geno>0 if(any(x[check.geno,1]!=x[check.geno,2])) { warning("heterozygous male found for x.linked loci") return(TRUE) } } return(FALSE) } haplo.stats/tests/0000755000176000001440000000000012075615021013703 5ustar ripleyusershaplo.stats/tests/test.haplo.power.R0000644000176000001440000000732412075615021017250 0ustar ripleyusers#$Author: sinnwell $ #$Date: 2011/12/05 20:53:27 $ #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/test/test.haplo.power.R,v 1.1 2011/12/05 20:53:27 sinnwell Exp $ #$Locker: $ #$Log: test.haplo.power.R,v $ #Revision 1.1 2011/12/05 20:53:27 sinnwell #changed from .q to .R, to work with R check # #Revision 1.1 2011/04/28 20:08:12 sinnwell #new makefile, pulls R/man files from mgenet, rlocal # ## package: haplo.stats ## test script: haplo.power ## settings verbose=TRUE Sys.setlocale("LC_COLLATE", "C") Sys.getlocale('LC_COLLATE') require(haplo.stats) set.seed(10) if(verbose) cat("prepare a 5-marker set of haplotypes\n") haplo <- rbind( c( 1, 2, 2, 1, 2), c( 1, 2, 2, 1, 1), c( 1, 1, 2, 1, 1), c( 1, 2, 1, 1, 2), c( 1, 2, 2, 2, 1), c( 1, 2, 1, 1, 1), c( 1, 1, 2, 2, 1), c( 1, 1, 1, 1, 2), c( 1, 2, 1, 2, 1), c( 1, 1, 1, 2, 1), c( 2, 2, 1, 1, 2), c( 1, 1, 2, 1, 2), c( 1, 1, 2, 2, 2), c( 1, 2, 2, 2, 2), c( 2, 2, 2, 1, 2), c( 1, 1, 1, 1, 1), c( 2, 1, 1, 1, 1), c( 2, 1, 2, 1, 1), c( 2, 2, 1, 1, 1), c( 2, 2, 1, 2, 1), c( 2, 2, 2, 1, 1)) dimnames(haplo)[[2]] <- paste("loc", 1:ncol(haplo), sep=".") haplo <- data.frame(haplo) haplo.freq <- c(0.170020121, 0.162977867, 0.123742455, 0.117706237, 0.097585513, 0.084507042, 0.045271630, 0.039235412, 0.032193159, 0.019114688, 0.019114688, 0.013078471, 0.013078471, 0.013078471, 0.013078471, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217, 0.006036217) ## define index for risk haplotypes (having alleles 1-1 at loci 2 and 3) haplo.risk <- (1:nrow(haplo))[haplo$loc.2==1 & haplo$loc.3==1] ## define index for baseline haplotype base.index <- 1 ############ Example for Case-control power/sample size ## specify OR for risk haplotypes or <- 1.25 ## determine beta regression coefficients for risk haplotypes haplo.beta <- numeric(length(haplo.freq)) haplo.beta[haplo.risk] <- log(or) # Note that non-risk haplotypes have beta=0, as does the intercept # (haplotype with base.index value). if(verbose) cat("Compute total sample size for given power\n") ss.cc <- haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac=.5, prevalence=.1, alpha=.05, power=.8) if(verbose) cat("Compute power for given sample size\n") power.cc <- haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac=.5, prevalence=.1, alpha=.05, sample.size=11978) ############ Example for Quantitative trait power/sample size # Because it can be easier to speficy genetic effect size in terms of # a regression model R-squared value (r2), we use an # auxiliary function to set up haplo.beta based on a specifed r2 value: tmp <- find.haplo.beta.qt(haplo,haplo.freq,base.index,haplo.risk, r2=0.01, y.mu=0, y.var=1) haplo.beta <- tmp$beta # Compute sample size for given power ss.qt <- haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu=0, y.var=1, alpha=.05, power=.80) # Compute power for given sample size power.qt <- haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu=0, y.var=1, alpha=.05, sample.size = 2091) print(ss.cc) print(power.cc) print(ss.qt) print(power.qt) haplo.stats/tests/snapFUN.s0000644000176000001440000001222612075615021015404 0ustar ripleyusers # Jason Sinnwell # Mayo Division of Biostatistics # 3/2007 # make a function that takes a single haplotype block simulated from snap that # 1) compares phased haplotype frequencies from snap to those estimated from haplo.em # 2) compare posterior probabilities estimated from haplo.em to the actual phased haplotype pair # As input, take one block of phased haplotypes, which is one column from SNaP that looks like: # V1 # 1 2,1,2,2,1,1,1,2.1,2,1,1,1,1,2,2,2,1 # 2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 # 3 1,1,1,2,1,1,1,2.2,2,2,1,2,2,1,2,2,1 checkPhase <- function(snapfile, blocknum=1, miss.val=c(0,NA), em.control=haplo.em.control()) { ## Splus:genetics and R:haplo.stats required for haplo.em ## slocal and rlocal required for strsplit() dat <- read.table(snapfile, sep=" ", stringsAsFactors=FALSE) hap1 <- hap2 <- charhap1 <- charhap2 <- NULL nsubj <- nrow(dat) for(k in 1:nsubj) { blockhap1 <- strsplit(dat[k,1],split="\\.")[[1]][blocknum] blockhap2 <-strsplit(dat[k,2],split="\\.")[[1]][blocknum] hapvec1 <- as.numeric(strsplit(blockhap1, split=',')[[1]]) hapvec2 <- as.numeric(strsplit(blockhap2, split=',')[[1]]) hap1 <- rbind(hap1, hapvec1) hap2 <- rbind(hap2, hapvec2) charhap1 <- c(charhap1, paste(hapvec1,collapse="")) charhap2 <- c(charhap2, paste(hapvec2,collapse="")) } nloc <- ncol(hap1) hapgeno <- cbind(hap1,hap2) col.indx <- as.vector(matrix(c(1:(2*nloc)), nrow=2,byrow=TRUE)) geno <- hapgeno[,col.indx] # run haplo.em, estimated hap freq em.block <- haplo.em(geno, control=em.control, miss.val=miss.val) # construct data.frame of hap-pairs estimated by haplo.em for each # subject, with post prob of hap-pair, merge with snap haplotype pairs emhaps <- data.frame(subj=em.block$subj.id, emhap1=apply(em.block$haplotype[em.block$hap1code,],1, paste, collapse=""), emhap2=apply(em.block$haplotype[em.block$hap2code,], 1, paste, collapse=""), post=em.block$post) snaphaps <- data.frame(subj=1:nsubj, snaphap1=charhap1, snaphap2=charhap2) merge.em.snap <- merge(emhaps, snaphaps, all.x=TRUE, by="subj") # compute snap hap freqs, join with freqs estimated from haplo.em haps.freq <- table(c(charhap1, charhap2))/(2*nsubj) em.charhaps <- apply(em.block$haplotype, 1, paste, collapse="") indx.snap.to.em <- match(names(haps.freq),em.charhaps) freq.frame <- data.frame(haplotype=em.charhaps, em.freq=em.block$hap.prob, snap.freq=0) freq.frame$snap.freq[indx.snap.to.em] <- haps.freq return(list(merge.em.snap, freq.frame)) } # simulate an effect based on a person's haplotypes # simulate an additive, dominant, or recessive effect simHapEff <- function(snapfile, blocknum=1, causehap, haplo.effect="additive", pen=.5, spurious=.01) { effcode=match(haplo.effect, c("additive", "dominant", "recessive")) dat <- read.table(snapfile, sep=" ",stringsAsFactors=FALSE) hap1 <- hap2 <- charhap1 <- charhap2 <- NULL nsubj <- nrow(dat) for(k in 1:nsubj) { blockhap1 <- strsplit(dat[k,1],split="\\.")[[1]][blocknum] blockhap2 <-strsplit(dat[k,2],split="\\.")[[1]][blocknum] hapvec1 <- as.numeric(strsplit(blockhap1, split=',')[[1]]) hapvec2 <- as.numeric(strsplit(blockhap2, split=',')[[1]]) charhap1 <- c(charhap1, paste(hapvec1,collapse="")) charhap2 <- c(charhap2, paste(hapvec2,collapse="")) } if(nchar(causehap) != nchar(charhap1[1])) stop("causehap not correct length") count.causehap <- 1*(charhap1==causehap) + 1*(charhap2==causehap) bin.resp <- ifelse(count.causehap==0, 1*(runif(nsubj) < spurious), ifelse(count.causehap==1, 1*(runif(nsubj) < if(effcode<3) pen else spurious), if(effcode==1) 1*((runif(nsubj) < pen) | (runif(nsubj) < pen)) else 1*(runif(nsubj) < pen))) return(bin.resp) } simLocEff <- function(snapfile, blocknum, locnum, allele, effect="additive", pen=.5, spur=.01) { effcode=match(haplo.effect, c("additive", "dominant", "recessive")) dat <- read.table(snapfile, sep=" ", stringsAsFactors=FALSE) hap1 <- hap2 <- allele1 <- allele2 <- NULL nsubj <- nrow(dat.in) for(k in 1:nsubj) { blockhap1 <- strsplit(dat[k,1],split="\\.")[[1]][blocknum] blockhap2 <- strsplit(dat[k,2],split="\\.")[[1]][blocknum] hapvec1 <- as.numeric(strsplit(blockhap1, split=',')[[1]]) hapvec2 <- as.numeric(strsplit(blockhap2, split=',')[[1]]) allele1 <- c(allele1, paste(hapvec1,collapse="")) allele2 <- c(allele2, paste(hapvec2,collapse="")) } count.allele <- 1*(allele1==allele) + 1*(allele2==allele) bin.resp <- ifelse(count.allele==0, 1*(runif(nsubj) < spurious), ifelse(count.allele==1, 1*(runif(nsubj) < if(effcode<3) pen else spurious), if(effcode==1) 1*((runif(nsubj) < pen) | (runif(nsubj) < pen)) else 1*(runif(nsubj) < pen))) return(bin.resp) } simLoc2Eff <- function(snapfile, locnum, effect="additive", pen=.5, spur=.01) { return(affected) } haplo.stats/tests/snapData.csv0000644000176000001440000001744012075615021016161 0ustar ripleyusers"y.bin","loc1.1","loc1.2","loc2.1","loc2.2","loc3.1","loc3.2","loc4.1","loc4.2","loc5.1","loc5.2","loc6.1","loc6.2","loc7.1","loc7.2" "1",1,1,2,1,1,1,1,1,1,1,2,1,1,1,2 "2",1,1,2,1,1,1,2,1,1,1,2,1,1,1,2 "3",1,1,1,1,1,1,2,1,1,2,2,2,2,2,2 "4",1,1,1,1,1,1,1,1,1,2,2,2,2,1,2 "5",2,1,1,1,2,NA,1,1,1,1,2,1,2,1,2 "6",1,1,1,1,2,1,1,1,1,2,2,1,2,1,2 "7",1,1,1,1,1,1,1,1,2,1,2,1,2,2,2 "8",1,1,2,1,2,1,1,1,1,1,2,1,2,2,2 "9",1,1,2,1,1,1,2,1,2,1,1,1,1,2,2 "10",1,1,1,1,1,1,2,1,2,1,1,1,1,2,2 "11",1,1,2,1,1,1,1,1,2,NA,1,1,2,2,2 "12",1,1,1,1,1,1,1,2,2,1,1,1,1,2,2 "13",2,1,2,1,2,1,1,1,2,1,2,1,2,2,2 "14",1,1,1,NA,1,1,1,1,2,1,2,1,2,2,2 "15",1,1,2,1,1,1,1,1,1,2,2,2,2,1,2 "16",1,1,1,1,1,1,2,1,2,1,1,1,1,2,2 "17",1,1,1,1,1,1,1,1,2,1,2,1,2,1,2 "18",1,2,2,1,1,1,1,2,2,1,2,1,2,2,2 "19",2,1,1,1,2,1,2,1,2,1,2,1,2,1,2 "20",1,1,1,1,1,1,1,1,1,2,2,1,2,1,2 "21",2,1,2,1,2,1,1,2,2,1,2,1,2,2,2 "22",1,1,1,1,1,1,2,1,1,2,2,1,2,1,1 "23",2,1,1,1,2,2,2,2,2,2,2,2,2,2,2 "24",1,1,2,1,1,1,2,1,1,2,2,1,2,1,1 "25",2,1,1,2,2,1,2,1,1,1,2,1,1,1,1 "26",2,1,1,1,2,1,1,1,1,2,2,1,2,1,2 "27",1,2,2,1,1,1,1,1,2,1,1,1,1,2,2 "28",2,1,2,2,2,1,2,1,1,2,2,1,1,1,1 "29",1,1,1,1,1,1,2,1,1,1,2,1,2,1,2 "30",2,1,2,1,2,1,1,1,1,1,2,1,2,1,1 "31",1,1,2,1,2,1,1,1,2,1,2,1,2,1,2 "32",2,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "33",2,1,2,2,2,1,2,1,1,1,1,1,1,1,2 "34",1,1,1,1,1,1,1,1,1,1,2,1,2,1,2 "35",2,1,1,1,2,2,2,1,1,1,2,1,2,1,2 "36",1,1,1,1,1,1,1,1,2,1,1,1,1,1,2 "37",1,1,1,1,2,1,2,1,1,1,2,1,1,1,2 "38",2,1,2,1,2,1,2,1,1,1,2,1,2,1,2 "39",1,1,1,1,1,2,2,2,2,1,2,1,2,2,2 "40",1,1,2,1,1,1,1,1,1,1,2,1,1,1,1 "41",1,1,1,1,2,1,2,1,1,1,1,1,1,2,2 "42",1,1,2,1,1,1,1,1,1,1,2,1,2,2,2 "43",2,1,1,1,2,2,2,1,1,1,2,1,2,1,2 "44",2,1,2,1,2,1,1,1,2,2,2,2,2,2,2 "45",1,1,2,1,1,1,1,1,2,1,2,1,2,2,2 "46",1,1,2,1,1,1,1,1,1,2,2,1,1,1,1 "47",1,1,1,1,2,1,1,1,1,1,2,1,2,2,2 "48",1,1,2,1,1,1,1,1,2,1,2,1,1,1,2 "49",1,1,1,1,1,1,1,1,1,1,2,1,2,1,2 "50",2,1,1,1,2,2,2,1,2,1,2,1,2,2,2 "51",2,1,1,1,2,1,2,1,1,1,2,1,2,1,1 "52",1,1,1,1,2,1,2,1,2,1,1,1,1,2,2 "53",1,1,1,1,1,1,1,1,1,2,2,1,2,1,1 "54",1,1,1,1,1,2,2,1,1,2,2,1,2,1,2 "55",1,1,1,1,2,2,2,1,1,1,1,1,1,1,2 "56",1,1,1,1,1,1,1,1,1,2,2,2,2,1,2 "57",2,1,1,1,2,1,2,1,1,NA,1,1,2,2,2 "58",1,1,2,1,1,1,2,1,1,1,1,1,1,1,1 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"115",1,1,2,1,2,1,1,1,1,1,1,1,1,2,2 "116",1,1,2,1,2,1,1,1,1,1,2,1,1,1,2 "117",1,1,1,1,1,1,1,1,1,1,1,1,1,2,2 "118",1,1,2,1,1,1,1,1,2,1,1,1,1,2,2 "119",1,1,1,1,1,NA,2,2,2,1,2,NA,1,2,2 "120",1,1,1,1,1,1,2,1,2,1,2,1,2,1,2 "121",1,1,1,1,1,2,2,1,1,2,2,1,2,1,2 "122",1,1,2,1,2,1,1,1,2,1,2,1,2,2,2 "123",1,1,1,1,1,1,2,1,2,1,2,1,2,1,2 "124",1,1,2,1,1,1,1,1,1,1,1,1,1,2,2 "125",1,1,1,1,1,1,2,1,2,1,2,1,2,1,2 "126",1,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "127",1,1,1,1,2,1,2,1,1,2,2,2,2,1,2 "128",1,1,1,1,2,1,1,1,1,1,1,1,1,1,2 "129",1,1,2,1,2,1,2,1,2,1,2,1,2,2,2 "130",1,1,2,1,2,1,1,1,1,1,1,1,1,1,2 "131",1,1,1,1,2,2,2,2,2,1,1,1,1,2,2 "132",1,1,1,1,2,1,1,1,2,1,2,1,1,1,2 "133",1,1,1,1,1,1,1,2,2,1,1,1,1,2,2 "134",1,1,1,1,2,1,2,1,2,2,2,1,2,1,2 "135",2,2,2,2,2,1,1,1,1,1,2,1,2,1,2 "136",1,1,2,1,1,1,1,1,2,1,2,1,2,2,2 "137",1,1,1,1,1,1,2,1,1,1,1,1,1,1,1 "138",1,1,2,1,1,1,2,1,1,1,2,1,2,2,2 "139",1,1,1,1,1,1,1,1,1,1,2,1,2,2,2 "140",1,1,1,1,1,2,2,1,2,1,1,1,1,2,2 "141",1,2,2,1,1,1,1,1,2,1,1,1,1,2,2 "142",1,1,1,1,1,1,2,1,1,1,2,1,2,2,2 "143",1,1,2,1,2,1,1,1,1,1,2,1,1,1,1 "144",1,1,1,1,1,2,2,1,1,2,2,1,2,1,1 "145",1,1,1,1,1,2,2,1,1,2,2,1,1,1,1 "146",1,1,2,1,1,1,1,1,2,1,2,1,2,2,2 "147",1,1,1,1,1,1,2,1,2,1,2,1,2,1,2 "148",2,1,2,2,2,1,2,1,2,1,1,1,1,2,2 "149",1,1,2,1,1,1,1,1,1,1,1,1,1,1,2 "150",2,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "151",1,1,1,1,2,1,1,1,1,1,2,1,1,1,1 "152",1,1,1,1,2,1,2,2,2,NA,2,1,2,2,2 "153",1,1,2,1,1,1,2,1,1,2,2,2,2,1,2 "154",1,1,1,1,2,2,2,1,1,2,2,1,2,1,1 "155",2,2,2,1,2,1,1,1,1,1,2,1,2,1,2 "156",1,1,2,1,2,1,1,1,1,1,1,1,1,2,2 "157",1,1,1,1,1,1,1,1,1,2,2,1,2,1,2 "158",1,1,1,1,1,1,1,1,1,NA,1,1,1,1,2 "159",1,1,1,1,2,1,2,1,1,2,2,1,1,1,1 "160",1,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "161",1,1,2,1,1,1,2,1,2,1,2,1,2,1,2 "162",2,1,1,2,2,2,2,1,2,1,1,1,1,1,2 "163",1,1,2,1,2,1,2,1,1,1,2,1,2,1,2 "164",1,1,1,1,1,1,2,1,1,1,2,1,2,1,2 "165",1,1,2,1,2,1,1,1,2,2,2,1,2,1,2 "166",1,1,1,1,1,1,2,1,1,1,1,1,1,1,1 "167",1,1,2,1,1,1,1,1,1,2,2,1,1,1,1 "168",1,1,1,1,2,1,2,1,1,2,2,1,2,1,1 "169",2,1,2,1,2,1,1,1,2,2,2,2,2,1,2 "170",1,1,1,1,1,1,1,1,2,1,2,1,2,1,2 "171",2,1,2,2,2,1,1,1,2,1,1,1,1,1,2 "172",1,1,2,1,1,1,1,1,2,1,1,1,1,2,2 "173",1,1,1,1,1,1,1,1,1,1,2,1,2,2,2 "174",2,1,2,1,2,1,2,1,2,2,2,1,2,1,2 "175",1,1,1,1,1,1,2,1,1,1,2,1,2,1,2 "176",1,1,2,1,1,1,1,1,1,1,2,1,1,1,1 "177",1,1,2,1,1,1,1,1,1,2,2,1,2,1,2 "178",1,1,1,1,2,1,2,1,1,1,1,1,1,1,2 "179",1,1,1,1,1,1,1,1,2,2,2,1,2,1,2 "180",1,1,2,1,1,1,1,1,2,1,1,1,1,1,2 "181",1,1,1,1,2,1,1,1,2,1,1,1,1,2,2 "182",1,1,1,1,1,1,1,1,2,1,2,1,2,2,2 "183",1,1,1,1,1,1,1,NA,1,1,1,1,1,1,2 "184",1,1,1,1,1,1,1,1,1,1,1,1,1,1,2 "185",1,1,2,1,1,1,1,2,2,1,2,NA,1,2,2 "186",2,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "187",2,1,2,2,2,1,1,1,1,1,2,1,2,1,2 "188",1,1,1,1,2,1,1,NA,1,2,2,1,1,1,1 "189",1,NA,2,1,1,1,2,2,2,1,2,1,2,2,2 "190",1,1,1,1,1,1,1,1,1,2,2,1,2,1,1 "191",1,1,1,1,1,2,2,1,2,1,1,1,1,2,2 "192",1,1,2,1,1,1,1,1,2,1,1,1,1,1,2 "193",1,1,1,1,2,1,2,1,1,2,2,1,2,1,2 "194",1,1,1,1,2,1,2,1,2,1,2,1,2,2,2 "195",2,1,2,1,2,1,1,NA,2,1,2,1,2,2,2 "196",1,1,2,1,2,1,2,1,1,1,2,1,1,1,2 "197",1,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "198",2,1,1,2,2,2,2,1,2,1,1,1,1,1,2 "199",1,1,1,1,1,1,1,1,1,1,2,1,2,1,2 "200",2,2,2,2,2,1,1,1,1,2,2,1,2,1,1 "201",1,1,1,1,2,1,2,1,1,1,2,1,1,NA,2 "202",1,1,2,1,1,1,1,1,1,2,2,1,2,1,2 "203",2,NA,2,1,2,1,1,1,2,2,2,1,2,1,2 "204",2,1,1,2,2,2,2,1,1,1,2,1,1,1,2 "205",2,1,2,2,2,1,1,1,2,1,1,1,1,2,2 "206",2,2,2,2,2,1,1,1,1,2,2,1,2,1,2 "207",2,2,2,2,2,1,1,1,2,2,2,1,2,1,2 "208",2,1,2,1,2,1,1,1,2,1,2,1,2,1,2 "209",2,1,2,1,2,1,1,1,1,2,2,1,2,1,1 "210",2,1,2,2,2,1,1,2,2,2,2,2,2,2,2 "211",2,1,2,1,2,1,1,1,2,2,2,2,2,1,2 "212",2,1,2,1,2,1,1,1,1,2,2,2,2,1,2 "213",2,1,1,2,2,2,2,1,1,1,2,1,1,1,2 "214",2,1,1,2,2,1,1,2,2,1,1,1,1,2,2 "215",2,1,2,2,2,1,2,1,2,2,2,2,2,NA,2 "216",2,1,1,1,2,1,2,1,1,2,2,1,2,1,2 "217",2,1,1,1,2,1,1,1,1,1,2,1,2,1,2 "218",2,1,1,1,2,1,2,1,1,1,2,1,2,1,2 "219",2,1,2,1,2,1,2,1,2,1,2,1,2,2,2 "220",2,2,2,2,2,1,1,1,1,1,2,1,1,1,1 haplo.stats/tests/test.Ginv.Rout.save0000644000176000001440000000620012075615021017372 0ustar ripleyusers R version 2.14.0 (2011-10-31) Copyright (C) 2011 The R Foundation for Statistical Computing ISBN 3-900051-07-0 Platform: x86_64-unknown-linux-gnu (64-bit) R is free software and comes with ABSOLUTELY NO WARRANTY. You are welcome to redistribute it under certain conditions. Type 'license()' or 'licence()' for distribution details. R is a collaborative project with many contributors. Type 'contributors()' for more information and 'citation()' on how to cite R or R packages in publications. Type 'demo()' for some demos, 'help()' for on-line help, or 'help.start()' for an HTML browser interface to help. Type 'q()' to quit R. > > > ## package: haplo.stats > ## test script: Ginv > > ## settings > > verbose=TRUE > > require(haplo.stats) Loading required package: haplo.stats > > # test Ginv on a matrix that is knowns to cause problems for LINPACK > # implementation of svd used in Ginv. > > # this varx matrix comes from running haplo.scan (within haplo.stats) > # on the 11-loci hla.demo dataset. > source("dump.varx.s") > > # Jason Sinnwell 3/2004 > > if(verbose) cat("setting up data...\n") setting up data... > > if(verbose) cat("test matrix (441x441) that causes error in LINPACK, but not LAPACK svd\n") test matrix (441x441) that causes error in LINPACK, but not LAPACK svd > > ginv.varx <- Ginv(varx) > > # Ginv.q version 1.4 is known to fail and get a numerical error > > # ginv.varx$Ginv[1:5,1:5] > > ginv.varx.eps <- Ginv(varx, eps=1e-4) > > # ginv.varx.eps$Ginv[1:5,1:5] > > if(verbose) cat("the zero matrix should give ginv=0, rank=0\n") the zero matrix should give ginv=0, rank=0 > zeroMat <- matrix(0) > epsMat <- matrix(1e-7) > zeroGinv <- Ginv(zeroMat) > epsGinv <- Ginv(epsMat) > > # a matrix with an NA should give a warning > # naMat <- matrix(c(1,0,NA,0,2,1,1,1,3),ncol=3) > # na.ginv <- Ginv(naMat) > > > # if(verbose) cat("sinking print results to a file\n") > > #if(update) { > # sink(file=goldfile) > #} else { > # sink("sink.Ginv.out") > #} > > ## print all testable results (via a diff command) to a file > print(ginv.varx$Ginv[1:5,1:5]) [,1] [,2] [,3] [,4] [,5] [1,] 129.30181529 2.020565287 -10.048992 -4.276933e-03 1.4289919 [2,] 2.02056529 129.301815287 -10.048992 -4.276852e-03 1.4289919 [3,] -10.04899156 -10.048991553 3239.425101 4.098196e+00 -10.6405650 [4,] -0.00427691 -0.004276945 4.098196 8.731269e+03 -0.5958503 [5,] 1.42899185 1.428991852 -10.640565 -5.958504e-01 255.3999184 > > ginv.varx$rank [1] 327 > > print(ginv.varx.eps$Ginv[1:5,1:5]) [,1] [,2] [,3] [,4] [,5] [1,] 129.216281 1.935031 -9.689699 -1.161165 1.343310 [2,] 1.935031 129.216281 -9.689699 -1.161165 1.343310 [3,] -9.689699 -9.689699 3237.757722 -11.376206 -10.280652 [4,] -1.161165 -1.161165 -11.376206 6101.228011 -1.754314 [5,] 1.343310 1.343310 -10.280652 -1.754314 255.314089 > > ginv.varx.eps$rank [1] 325 > > print(zeroGinv) $Ginv [,1] [1,] 0 $rank [,1] [1,] 0 > > print(epsGinv) $Ginv [,1] [1,] 0 $rank [,1] [1,] 0 > > #sink() > > > > > haplo.stats/tests/dump.varx.s0000644000176000001440002314755112075615022016036 0ustar ripleyusers"varx" <- matrix(c(0.001960297231393539, -3.8569547100708898e-06, -3.8569547100708898e-06, -3.8569547100709059e-06 , -1.9284773550354449e-06, -1.9284773550354449e-06, -3.8569547100708898e-06, -3.8569547100708898e-06, -4.8211933875886112e-07, -4.8211933875886122e-07, -9.690598709053238e-05, -9.6423867751772722e-05, -2.4105966937943272e-06, -4.8211933875886112e-07, -1.4463580162766105e-06, -4.8211933875886849e-06, -3.8569547100709587e-05, -9.6423867751772245e-07, -4.4354979165815103e-05, -4.8211933875886122e-07, -7.7139094201417762e-06, 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You are welcome to redistribute it under certain conditions. Type 'license()' or 'licence()' for distribution details. R is a collaborative project with many contributors. Type 'contributors()' for more information and 'citation()' on how to cite R or R packages in publications. Type 'demo()' for some demos, 'help()' for on-line help, or 'help.start()' for an HTML browser interface to help. Type 'q()' to quit R. > > ## package: haplo.stats > ## test script: haplo.glm > ## created: 11/23/2011 > > ## settings > verbose=TRUE > require(haplo.stats) Loading required package: haplo.stats > Sys.setlocale("LC_COLLATE", "C") [1] "C" > Sys.getlocale('LC_COLLATE') [1] "C" > > > if(verbose) cat("setting up data...\n") setting up data... > > > # prepare the hla dataset, > # runs a lot longer, and MS alleles don't all start w/ 1, 2... > label <-c("DQB","DRB","B") > > data(hla.demo) > > y <- hla.demo$resp > y.bin <- 1*(hla.demo$resp.cat=="low") > geno <- as.matrix(hla.demo[,c(17,18,21:24)]) > geno <- setupGeno(geno, miss.val=c(0,NA)) > > # geno now has an attribute 'unique.alleles' which must be passed to > # haplo.glm as allele.lev=attributes(geno)$unique.alleles, see below > > hla.data <- data.frame(geno=geno, age=hla.demo$age, male=hla.demo$male, + y=y, y.bin=y.bin) > > seed <- c(17, 53, 1, 40, 37, 0, 62, 56, 5, 52, 12, 1) > > > if(verbose) cat("fit a binary trait\n") fit a binary trait > set.seed(seed) > fit.hla.bin <- haplo.glm(y.bin ~ male + geno, family = binomial, + na.action="na.geno.keep", data=hla.data, locus.label=label, + control = haplo.glm.control(haplo.min.count=8)) > > y.bin <- 1*(hla.demo$resp.cat=="low") > y.bin[2] <- NA > geno.hla <- as.matrix(hla.demo[,c(17,18,21:24)]) > geno.hla[2,5] <- 2 > geno.hla[3,] <- rep(NA, 6) > geno.hla <- setupGeno(geno.hla, miss.val=c(0,NA)) > > my.hla <- data.frame(geno.hla=geno.hla, age=hla.demo$age, male=hla.demo$male, + y=y, y.bin=y.bin) > > if(verbose) cat(" hla binary trait with subject that are removed\n") hla binary trait with subject that are removed > > set.seed(seed) > fit.hla.miss <- haplo.glm(y.bin ~ male + geno.hla, family = binomial, + na.action="na.geno.keep", + data=my.hla, locus.label=label, + control = haplo.glm.control(haplo.min.count=8)) > > > if(verbose) cat(" gaussian with covariates, additive\n") gaussian with covariates, additive > > set.seed(seed) > fit.hla.gaus.gender <- haplo.glm(y ~ male + geno, family = gaussian, + na.action="na.geno.keep", + data=hla.data, locus.label=label, + control = haplo.glm.control(haplo.min.count=5)) > > > if(verbose) cat("SNAP data with resp and resp with added variance\n") SNAP data with resp and resp with added variance > snapDF <- read.table("snapData.csv",header=TRUE, sep=",", stringsAsFactors=FALSE) > > geno.rec <- setupGeno(snapDF[,-c(1:9)]) > snap.data <- data.frame(resp=hla.demo$resp, respvar=hla.demo$resp*100, geno=geno.rec) > > set.seed(seed) > fit.resp.hla <- haplo.glm(resp~geno, trait.type="gaussian",data=snap.data) > > set.seed(seed) > fit.respvar.hla <- haplo.glm(respvar~geno, trait.type="gaussian",data=snap.data) > > > cat("summary function\n") summary function > > print(summary(fit.hla.bin)) Call: haplo.glm(formula = y.bin ~ male + geno, family = binomial, data = hla.data, na.action = "na.geno.keep", locus.label = label, control = haplo.glm.control(haplo.min.count = 8)) Deviance Residuals: Min 1Q Median 3Q Max -1.5559 -0.7996 -0.6473 1.0591 2.4348 Coefficients: coef se t.stat pval (Intercept) 1.5457 0.6547 2.3610 0.019 male -0.4802 0.3308 -1.4518 0.148 geno.17 -0.7227 0.8011 -0.9022 0.368 geno.34 0.3641 0.6798 0.5356 0.593 geno.77 -0.9884 0.7328 -1.3489 0.179 geno.78 -1.4093 0.8543 -1.6496 0.101 geno.100 -2.5907 1.1278 -2.2971 0.023 geno.138 -2.7156 0.8524 -3.1860 0.002 geno.rare -1.2610 0.3537 -3.5647 0.000 (Dispersion parameter for binomial family taken to be 1) Null deviance: 263.50 on 219 degrees of freedom Residual deviance: 233.46 on 211 degrees of freedom AIC: 251.11 Number of Fisher Scoring iterations: 61 Haplotypes: DQB DRB B hap.freq geno.17 21 7 44 0.02303 geno.34 31 4 44 0.02843 geno.77 32 4 60 0.03057 geno.78 32 4 62 0.02354 geno.100 51 1 35 0.02977 geno.138 62 2 7 0.05181 geno.rare * * * 0.70880 haplo.base 21 3 8 0.10405 > > > cat("fitted values for hlabin, hla-gaussian, hla-gaussian-hi-variance\n") fitted values for hlabin, hla-gaussian, hla-gaussian-hi-variance > > print(fitted(fit.hla.bin)[1:20]) 1 2 3 4 5 6 7 0.16731775 0.14603996 0.18900543 0.35127197 0.27363264 0.58486358 0.08084418 8 9 10 11 12 13 14 0.18900543 0.13827600 0.05807279 0.70193476 0.27363264 0.27363264 0.07189116 15 16 17 18 19 20 0.27363264 0.05807279 0.27363264 0.08084418 0.05160521 0.18900543 > > print(fitted(fit.resp.hla)[1:20]) 1 2 3 4 5 6 7 8 2.103807 2.103807 1.582207 1.836332 1.717294 1.852390 1.833624 1.833624 9 10 11 12 13 14 15 16 2.085040 2.085040 1.833624 2.085040 1.833624 1.833624 1.836332 2.085040 17 18 19 20 1.872242 1.833624 1.878187 1.852390 > print(fitted(fit.respvar.hla)[1:20]) 1 2 3 4 5 6 7 8 210.3807 210.3807 158.2207 183.6332 171.7294 185.2390 183.3624 183.3624 9 10 11 12 13 14 15 16 208.5040 208.5040 183.3624 208.5040 183.3624 183.3624 183.6332 208.5040 17 18 19 20 187.2242 183.3624 187.8187 185.2390 > > cat("vcov for hlabin, hla-gaussian, hla-gaussian-hi-variance\n") vcov for hlabin, hla-gaussian, hla-gaussian-hi-variance > > print(vcov(fit.hla.bin)[1:20,1:20]) (Intercept) male geno.17 geno.34 (Intercept) 4.286068e-01 -7.286859e-02 -2.369174e-01 -1.797403e-01 male -7.286859e-02 1.094177e-01 2.759410e-02 -1.127116e-02 geno.17 -2.369174e-01 2.759410e-02 6.416982e-01 1.083349e-01 geno.34 -1.797403e-01 -1.127116e-02 1.083349e-01 4.621889e-01 geno.77 -1.826304e-01 -1.742249e-02 6.363300e-02 7.424582e-02 geno.78 -1.830799e-01 1.523853e-02 1.116368e-01 9.141079e-02 geno.100 -2.479206e-01 4.863320e-02 1.482704e-01 1.109024e-01 geno.138 -2.351610e-01 3.135952e-02 1.061650e-01 6.035697e-02 geno.rare -2.147912e-01 1.203242e-02 1.143876e-01 9.399166e-02 hap.17 6.505154e-06 9.187782e-07 -3.913309e-06 -3.651328e-06 hap.34 -4.058363e-08 3.310615e-08 1.093231e-08 -1.238478e-09 hap.77 -4.058363e-08 3.310615e-08 1.093231e-08 -1.238479e-09 hap.78 -6.819269e-07 -3.284993e-08 3.005300e-07 2.951258e-07 hap.100 5.142374e-06 1.405853e-06 6.123139e-06 -3.077285e-06 hap.138 1.400870e-05 2.515390e-06 -1.502512e-05 -1.087524e-05 hap.rare -4.058363e-08 3.310615e-08 1.093231e-08 -1.238478e-09 hap.rare -4.058363e-08 3.310615e-08 1.093231e-08 -1.238479e-09 hap.rare -4.058363e-08 3.310615e-08 1.093231e-08 -1.238478e-09 hap.rare -4.058363e-08 3.310615e-08 1.093231e-08 -1.238478e-09 hap.rare -8.116726e-08 6.621231e-08 2.186462e-08 -2.476957e-09 geno.77 geno.78 geno.100 geno.138 (Intercept) -1.826304e-01 -1.830799e-01 -2.479206e-01 -2.351610e-01 male -1.742249e-02 1.523853e-02 4.863320e-02 3.135952e-02 geno.17 6.363300e-02 1.116368e-01 1.482704e-01 1.061650e-01 geno.34 7.424582e-02 9.141079e-02 1.109024e-01 6.035697e-02 geno.77 5.369312e-01 8.946411e-02 5.851395e-02 9.916736e-02 geno.78 8.946411e-02 7.298554e-01 1.138247e-01 8.993085e-02 geno.100 5.851395e-02 1.138247e-01 1.271987e+00 1.155486e-01 geno.138 9.916736e-02 8.993085e-02 1.155486e-01 7.265402e-01 geno.rare 9.748933e-02 8.481883e-02 1.142810e-01 1.156036e-01 hap.17 -3.833112e-06 -3.191332e-06 -3.688969e-06 -3.788547e-06 hap.34 -2.569089e-09 8.519476e-10 1.374934e-08 8.440416e-09 hap.77 -2.569089e-09 8.519475e-10 1.374934e-08 8.440416e-09 hap.78 3.153900e-07 2.239790e-07 3.148840e-07 3.458891e-07 hap.100 -4.343015e-06 -2.129393e-06 8.133788e-07 -3.342440e-06 hap.138 -1.246208e-05 -8.450638e-06 -9.202162e-06 -8.244963e-06 hap.rare -2.569089e-09 8.519476e-10 1.374934e-08 8.440416e-09 hap.rare -2.569089e-09 8.519473e-10 1.374934e-08 8.440416e-09 hap.rare -2.569089e-09 8.519475e-10 1.374934e-08 8.440416e-09 hap.rare -2.569089e-09 8.519474e-10 1.374934e-08 8.440416e-09 hap.rare -5.138178e-09 1.703895e-09 2.749868e-08 1.688083e-08 geno.rare hap.17 hap.34 hap.77 (Intercept) -2.147912e-01 6.505154e-06 -4.058363e-08 -4.058363e-08 male 1.203242e-02 9.187782e-07 3.310615e-08 3.310615e-08 geno.17 1.143876e-01 -3.913309e-06 1.093231e-08 1.093231e-08 geno.34 9.399166e-02 -3.651328e-06 -1.238478e-09 -1.238478e-09 geno.77 9.748933e-02 -3.833112e-06 -2.569089e-09 -2.569089e-09 geno.78 8.481883e-02 -3.191332e-06 8.519477e-10 8.519475e-10 geno.100 1.142810e-01 -3.688969e-06 1.374934e-08 1.374934e-08 geno.138 1.156036e-01 -3.788547e-06 8.440416e-09 8.440416e-09 geno.rare 1.251353e-01 -3.686750e-06 2.651266e-08 2.651266e-08 hap.17 -3.686750e-06 5.522765e-06 -1.211535e-08 -1.211535e-08 hap.34 2.651266e-08 -1.211535e-08 5.153579e-06 -1.171072e-08 hap.77 2.651266e-08 -1.211535e-08 -1.171072e-08 5.153579e-06 hap.78 4.742211e-07 -1.215234e-08 -1.174647e-08 -1.174647e-08 hap.100 -3.576378e-06 -3.043843e-08 -2.961202e-08 -2.961202e-08 hap.138 -6.493743e-06 -1.890139e-08 -1.933344e-08 -1.933344e-08 hap.rare 2.651266e-08 -1.211535e-08 -1.171072e-08 -1.171072e-08 hap.rare 2.651266e-08 -1.211535e-08 -1.171072e-08 -1.171072e-08 hap.rare 2.651266e-08 -1.211535e-08 -1.171072e-08 -1.171072e-08 hap.rare 2.651266e-08 -1.211535e-08 -1.171072e-08 -1.171072e-08 hap.rare 5.302532e-08 -2.423069e-08 -2.342144e-08 -2.342144e-08 hap.78 hap.100 hap.138 hap.rare (Intercept) -6.819269e-07 5.142374e-06 1.400870e-05 -4.058363e-08 male -3.284993e-08 1.405853e-06 2.515390e-06 3.310615e-08 geno.17 3.005300e-07 6.123139e-06 -1.502512e-05 1.093231e-08 geno.34 2.951258e-07 -3.077285e-06 -1.087524e-05 -1.238478e-09 geno.77 3.153900e-07 -4.343015e-06 -1.246208e-05 -2.569090e-09 geno.78 2.239790e-07 -2.129393e-06 -8.450638e-06 8.519474e-10 geno.100 3.148840e-07 8.133788e-07 -9.202162e-06 1.374934e-08 geno.138 3.458891e-07 -3.342440e-06 -8.244963e-06 8.440416e-09 geno.rare 4.742211e-07 -3.576378e-06 -6.493743e-06 2.651266e-08 hap.17 -1.215234e-08 -3.043843e-08 -1.890139e-08 -1.211535e-08 hap.34 -1.174647e-08 -2.961202e-08 -1.933344e-08 -1.171072e-08 hap.77 -1.174647e-08 -2.961202e-08 -1.933344e-08 -1.171072e-08 hap.78 5.185142e-06 -2.971114e-08 -1.934632e-08 -1.174647e-08 hap.100 -2.971114e-08 1.531426e-05 -2.285419e-06 -2.961202e-08 hap.138 -1.934632e-08 -2.285419e-06 1.169032e-05 -1.933344e-08 hap.rare -1.174647e-08 -2.961202e-08 -1.933344e-08 5.153579e-06 hap.rare -1.174647e-08 -2.961202e-08 -1.933344e-08 -1.171072e-08 hap.rare -1.174647e-08 -2.961202e-08 -1.933344e-08 -1.171072e-08 hap.rare -1.174647e-08 -2.961202e-08 -1.933344e-08 -1.171072e-08 hap.rare -2.349293e-08 -5.922404e-08 -3.866689e-08 -2.342144e-08 hap.rare hap.rare hap.rare hap.rare (Intercept) -4.058363e-08 -4.058363e-08 -4.058363e-08 -8.116726e-08 male 3.310615e-08 3.310615e-08 3.310615e-08 6.621231e-08 geno.17 1.093231e-08 1.093231e-08 1.093231e-08 2.186462e-08 geno.34 -1.238478e-09 -1.238478e-09 -1.238478e-09 -2.476957e-09 geno.77 -2.569089e-09 -2.569089e-09 -2.569089e-09 -5.138179e-09 geno.78 8.519475e-10 8.519473e-10 8.519475e-10 1.703894e-09 geno.100 1.374934e-08 1.374934e-08 1.374934e-08 2.749868e-08 geno.138 8.440416e-09 8.440416e-09 8.440416e-09 1.688083e-08 geno.rare 2.651266e-08 2.651266e-08 2.651266e-08 5.302532e-08 hap.17 -1.211535e-08 -1.211535e-08 -1.211535e-08 -2.423069e-08 hap.34 -1.171072e-08 -1.171072e-08 -1.171072e-08 -2.342144e-08 hap.77 -1.171072e-08 -1.171072e-08 -1.171072e-08 -2.342144e-08 hap.78 -1.174647e-08 -1.174647e-08 -1.174647e-08 -2.349293e-08 hap.100 -2.961202e-08 -2.961202e-08 -2.961202e-08 -5.922404e-08 hap.138 -1.933344e-08 -1.933344e-08 -1.933344e-08 -3.866689e-08 hap.rare -1.171072e-08 -1.171072e-08 -1.171072e-08 -2.342144e-08 hap.rare 5.153579e-06 -1.171072e-08 -1.171072e-08 -2.342144e-08 hap.rare -1.171072e-08 5.153579e-06 -1.171072e-08 -2.342144e-08 hap.rare -1.171072e-08 -1.171072e-08 5.153579e-06 -2.342144e-08 hap.rare -2.342144e-08 -2.342144e-08 -2.342144e-08 1.028374e-05 > > print(vcov(fit.resp.hla)) (Intercept) geno.1 geno.4 geno.6 (Intercept) 2.837201e-02 -2.071631e-02 -1.502146e-02 -1.406472e-02 geno.1 -2.071631e-02 4.043155e-02 9.222185e-03 5.812454e-03 geno.4 -1.502146e-02 9.222185e-03 2.342751e-02 3.457185e-03 geno.6 -1.406472e-02 5.812454e-03 3.457185e-03 4.652068e-02 geno.7 -2.008168e-02 1.406808e-02 8.103901e-03 5.095411e-03 hap.1 1.053539e-04 -3.185121e-05 -9.000795e-05 3.168979e-04 hap.4 -2.451704e-06 2.663340e-05 -2.768077e-05 1.353547e-05 hap.6 -9.366677e-05 -8.669757e-06 1.169792e-04 -3.828639e-04 hap.7 9.366677e-05 8.669757e-06 -1.169792e-04 3.828639e-04 geno.7 hap.1 hap.4 hap.6 (Intercept) -2.008168e-02 1.053539e-04 -2.451704e-06 -9.366677e-05 geno.1 1.406808e-02 -3.185121e-05 2.663340e-05 -8.669757e-06 geno.4 8.103901e-03 -9.000795e-05 -2.768077e-05 1.169792e-04 geno.6 5.095411e-03 3.168979e-04 1.353547e-05 -3.828639e-04 geno.7 2.867042e-02 -5.580922e-05 -3.899676e-07 6.437945e-05 hap.1 -5.580922e-05 3.257357e-04 -5.365650e-05 -1.040102e-04 hap.4 -3.899676e-07 -5.365650e-05 3.358155e-04 -4.208869e-05 hap.6 6.437945e-05 -1.040102e-04 -4.208869e-05 2.897352e-04 hap.7 -6.437945e-05 1.291242e-05 -8.822859e-05 -1.304451e-04 hap.7 (Intercept) 9.366677e-05 geno.1 8.669757e-06 geno.4 -1.169792e-04 geno.6 3.828639e-04 geno.7 -6.437945e-05 hap.1 1.291242e-05 hap.4 -8.822859e-05 hap.6 -1.304451e-04 hap.7 4.679148e-04 > print(vcov(fit.respvar.hla)) (Intercept) geno.1 geno.4 geno.6 (Intercept) 2.837201e+02 -2.071631e+02 -1.502146e+02 -1.406472e+02 geno.1 -2.071631e+02 4.043155e+02 9.222185e+01 5.812454e+01 geno.4 -1.502146e+02 9.222185e+01 2.342751e+02 3.457185e+01 geno.6 -1.406472e+02 5.812454e+01 3.457185e+01 4.652068e+02 geno.7 -2.008168e+02 1.406808e+02 8.103901e+01 5.095411e+01 hap.1 1.053539e-02 -3.185121e-03 -9.000795e-03 3.168979e-02 hap.4 -2.451704e-04 2.663340e-03 -2.768077e-03 1.353547e-03 hap.6 -9.366677e-03 -8.669757e-04 1.169792e-02 -3.828639e-02 hap.7 9.366677e-03 8.669757e-04 -1.169792e-02 3.828639e-02 geno.7 hap.1 hap.4 hap.6 (Intercept) -2.008168e+02 1.053539e-02 -2.451704e-04 -9.366677e-03 geno.1 1.406808e+02 -3.185121e-03 2.663340e-03 -8.669757e-04 geno.4 8.103901e+01 -9.000795e-03 -2.768077e-03 1.169792e-02 geno.6 5.095411e+01 3.168979e-02 1.353547e-03 -3.828639e-02 geno.7 2.867042e+02 -5.580922e-03 -3.899676e-05 6.437945e-03 hap.1 -5.580922e-03 3.257357e-04 -5.365650e-05 -1.040102e-04 hap.4 -3.899676e-05 -5.365650e-05 3.358155e-04 -4.208869e-05 hap.6 6.437945e-03 -1.040102e-04 -4.208869e-05 2.897352e-04 hap.7 -6.437945e-03 1.291242e-05 -8.822859e-05 -1.304451e-04 hap.7 (Intercept) 9.366677e-03 geno.1 8.669757e-04 geno.4 -1.169792e-02 geno.6 3.828639e-02 geno.7 -6.437945e-03 hap.1 1.291242e-05 hap.4 -8.822859e-05 hap.6 -1.304451e-04 hap.7 4.679148e-04 > > cat("residuals for hlabin, hla-gaussian, hla-gaussian-hi-variance\n") residuals for hlabin, hla-gaussian, hla-gaussian-hi-variance > > print(residuals(fit.hla.bin, type="deviance")[1:20]) 1 2 3 4 5 6 7 -0.6051498 -0.5619090 -0.6472927 -0.9303136 1.6099496 -1.3260076 -0.4106084 8 9 10 11 12 13 14 -0.6472927 -0.5455644 -0.3459112 -1.5559196 -0.7996241 -0.7996241 -0.3862804 15 16 17 18 19 20 -0.7996241 -0.3459112 -0.7996241 -0.4106084 -0.3255285 -0.6472927 > print(residuals(fit.hla.bin, type="pearson")[1:20]) 1 2 3 4 5 6 7 -0.4482614 -0.4135396 -0.4827565 -0.7358519 1.6292743 -1.1869485 -0.2965718 8 9 10 11 12 13 14 -0.4827565 -0.4005800 -0.2483006 -1.5345912 -0.6137702 -0.6137702 -0.2783161 15 16 17 18 19 20 -0.6137702 -0.2483006 -0.6137702 -0.2965718 -0.2332664 -0.4827565 > print(residuals(fit.hla.bin, type="response")[1:20]) 1 2 3 4 5 6 -0.16731775 -0.14603996 -0.18900543 -0.35127197 0.72636736 -0.58486358 7 8 9 10 11 12 -0.08084418 -0.18900543 -0.13827600 -0.05807279 -0.70193476 -0.27363264 13 14 15 16 17 18 -0.27363264 -0.07189116 -0.27363264 -0.05807279 -0.27363264 -0.08084418 19 20 -0.05160521 -0.18900543 > > print(residuals(fit.resp.hla)[1:20]) 1 2 3 4 5 6 7 1.5971931 -0.9248069 0.0777934 0.1306677 -0.9212944 -0.6993900 -0.5256235 8 9 10 11 12 13 14 0.2523765 -0.9300405 -0.5340405 -0.6046235 0.2879595 0.5963765 0.3823765 15 16 17 18 19 20 0.5286677 0.8419595 0.6857580 -0.7366235 0.7558135 -0.1523900 > print(residuals(fit.respvar.hla)[1:20]) 1 2 3 4 5 6 7 8 159.71931 -92.48069 7.77934 13.06677 -92.12944 -69.93900 -52.56235 25.23765 9 10 11 12 13 14 15 16 -93.00405 -53.40405 -60.46235 28.79595 59.63765 38.23765 52.86677 84.19595 17 18 19 20 68.57580 -73.66235 75.58135 -15.23900 > > > proc.time() user system elapsed 91.809 0.531 92.927 haplo.stats/tests/test.haplo.em.R0000644000176000001440000000464712075615021016522 0ustar ripleyusers ## package: haplo.stats ## test script: haplo.em ## settings verbose=TRUE require(haplo.stats) Sys.setlocale("LC_COLLATE", "C") Sys.getlocale("LC_COLLATE") if(verbose) cat("prepare two datasets, one with char alleles, the other 3 loci from hla data\n") # make ficticious data set with an intention of some trend in # haplotypes having H-allele at locus-H with F-allele at locus-F geno.char <- matrix(c('F','f','g','G','h1','h1', 'F','F','g','G','H','h1', 'F','f','g','G','h2','h2', 'f','f','g','G','h2','h1', 'F','F','g','G','H','h2', 'f','f','G','G','h1','h2', 'F','f','G','g','h2','h2', 'F','F','g','G','h1','z', 'F','f','z','z','h1','h1', 'F','f','G','g','h1','h2', 'F','f','G','G','h1','h2', 'F','F','g','G','h1','z', 'F','f','z','z','h1','h1', 'f','f','G','g','h1','h2'), nrow=14,byrow=T) char.label <- c("F","G","H") data(hla.demo) hla.sub <- hla.demo[,c(1,2,3,4,17,18,21:24)] geno.hla <- hla.sub[,-c(1:4)] hla.label=c("DQB","DRB","HLA.B") seed <- c(33, 10, 39, 6, 16, 0, 40, 24, 12, 60, 7, 1) if(verbose) cat("character alleles\n") geno.char.recode <- setupGeno(geno.char, miss.val="z") geno.char.recode set.seed(seed) em.char <- haplo.em(geno.char, miss.val='z',locus.label=char.label, control = haplo.em.control()) print.haplo.em(em.char, digits=5) summary(em.char, digits=5, show.haplo=TRUE) summary.haplo.em(em.char, digits=5) if(verbose) cat("hla data, 3 loci\n") set.seed(seed) em.hla3 <- haplo.em(geno.hla, locus.label=hla.label, miss.val=0, control = haplo.em.control()) print.haplo.em(em.hla3, digits=5) if(verbose) cat("snap SNP data, unphased\n") snapDF <- read.table("snapData.csv",header=TRUE, sep=",", stringsAsFactors=FALSE) geno.snap <- setupGeno(geno=snapDF[,-1]) set.seed(seed) em.snap <- haplo.em(geno=geno.snap) print(em.snap, digits=5) if(verbose) cat("Check Phase against SNaP data, phased\n") snapfile <- "snap.sim.phased.dat" source("snapFUN.s") set.seed(seed) block1.phase <- checkPhase(snapfile, blocknum=1) set.seed(seed) block2.phase <- checkPhase(snapfile, blocknum=2) print(block1.phase[[2]]) print(block1.phase[[1]][1:50,]) # long output 1120 lines print(block2.phase[[2]]) haplo.stats/tests/test.haplo.power.Rout.save0000644000176000001440000001240412075615021020730 0ustar ripleyusers R version 2.15.0 (2012-03-30) Copyright (C) 2012 The R Foundation for Statistical Computing ISBN 3-900051-07-0 Platform: x86_64-unknown-linux-gnu (64-bit) R is free software and comes with ABSOLUTELY NO WARRANTY. You are welcome to redistribute it under certain conditions. Type 'license()' or 'licence()' for distribution details. R is a collaborative project with many contributors. Type 'contributors()' for more information and 'citation()' on how to cite R or R packages in publications. Type 'demo()' for some demos, 'help()' for on-line help, or 'help.start()' for an HTML browser interface to help. Type 'q()' to quit R. > #$Author: sinnwell $ > #$Date: 2011/12/05 20:53:27 $ > #$Header: /projects/genetics/cvs/cvsroot/haplo.stats/test/test.haplo.power.R,v 1.1 2011/12/05 20:53:27 sinnwell Exp $ > #$Locker: $ > #$Log: test.haplo.power.R,v $ > #Revision 1.1 2011/12/05 20:53:27 sinnwell > #changed from .q to .R, to work with R check > # > #Revision 1.1 2011/04/28 20:08:12 sinnwell > #new makefile, pulls R/man files from mgenet, rlocal > # > ## package: haplo.stats > ## test script: haplo.power > > ## settings > > verbose=TRUE > Sys.setlocale("LC_COLLATE", "C") [1] "C" > Sys.getlocale('LC_COLLATE') [1] "C" > > require(haplo.stats) Loading required package: haplo.stats > > > set.seed(10) > > if(verbose) cat("prepare a 5-marker set of haplotypes\n") prepare a 5-marker set of haplotypes > > haplo <- rbind( + c( 1, 2, 2, 1, 2), + c( 1, 2, 2, 1, 1), + c( 1, 1, 2, 1, 1), + c( 1, 2, 1, 1, 2), + c( 1, 2, 2, 2, 1), + c( 1, 2, 1, 1, 1), + c( 1, 1, 2, 2, 1), + c( 1, 1, 1, 1, 2), + c( 1, 2, 1, 2, 1), + c( 1, 1, 1, 2, 1), + c( 2, 2, 1, 1, 2), + c( 1, 1, 2, 1, 2), + c( 1, 1, 2, 2, 2), + c( 1, 2, 2, 2, 2), + c( 2, 2, 2, 1, 2), + c( 1, 1, 1, 1, 1), + c( 2, 1, 1, 1, 1), + c( 2, 1, 2, 1, 1), + c( 2, 2, 1, 1, 1), + c( 2, 2, 1, 2, 1), + c( 2, 2, 2, 1, 1)) > dimnames(haplo)[[2]] <- paste("loc", 1:ncol(haplo), sep=".") > haplo <- data.frame(haplo) > > haplo.freq <- c(0.170020121, 0.162977867, 0.123742455, 0.117706237, 0.097585513, 0.084507042, + 0.045271630, 0.039235412, 0.032193159, 0.019114688, 0.019114688, 0.013078471, + 0.013078471, 0.013078471, 0.013078471, 0.006036217, 0.006036217, 0.006036217, + 0.006036217, 0.006036217, 0.006036217) > > ## define index for risk haplotypes (having alleles 1-1 at loci 2 and 3) > haplo.risk <- (1:nrow(haplo))[haplo$loc.2==1 & haplo$loc.3==1] > > ## define index for baseline haplotype > base.index <- 1 > > > ############ Example for Case-control power/sample size > > ## specify OR for risk haplotypes > or <- 1.25 > > ## determine beta regression coefficients for risk haplotypes > > haplo.beta <- numeric(length(haplo.freq)) > haplo.beta[haplo.risk] <- log(or) > > # Note that non-risk haplotypes have beta=0, as does the intercept > # (haplotype with base.index value). > > if(verbose) cat("Compute total sample size for given power\n") Compute total sample size for given power > > ss.cc <- haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac=.5, prevalence=.1, alpha=.05, power=.8) > > if(verbose) cat("Compute power for given sample size\n") Compute power for given sample size > > power.cc <- haplo.power.cc(haplo, haplo.freq, base.index, haplo.beta, case.frac=.5, prevalence=.1, alpha=.05, sample.size=11978) > > > ############ Example for Quantitative trait power/sample size > > > # Because it can be easier to speficy genetic effect size in terms of > # a regression model R-squared value (r2), we use an > # auxiliary function to set up haplo.beta based on a specifed r2 value: > > > tmp <- find.haplo.beta.qt(haplo,haplo.freq,base.index,haplo.risk, r2=0.01, y.mu=0, y.var=1) > haplo.beta <- tmp$beta > > # Compute sample size for given power > > ss.qt <- haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu=0, y.var=1, alpha=.05, power=.80) > > # Compute power for given sample size > > power.qt <- haplo.power.qt(haplo, haplo.freq, base.index, haplo.beta, y.mu=0, y.var=1, alpha=.05, sample.size = 2091) > > > print(ss.cc) $ss.phased.haplo [1] 11978 $ss.unphased.haplo [1] 15982 $power.phased.haplo [1] 0.8 $power.unphased.haplo [1] 0.8 > print(power.cc) $ss.phased.haplo [1] 11978 $ss.unphased.haplo [1] 11978 $power.phased.haplo [1] 0.8000002 $power.unphased.haplo [1] 0.6376728 > print(ss.qt) $ss.phased.haplo [1] 2091 $ss.unphased.haplo [1] 2826 $power.phased.haplo [1] 0.8 $power.unphased.haplo [1] 0.8 > print(power.qt) $ss.phased.haplo [1] 2091 $ss.unphased.haplo [1] 2091 $power.phased.haplo [1] 0.8000338 $power.unphased.haplo [1] 0.6291769 > > > proc.time() user system elapsed 1.046 0.070 1.217 haplo.stats/tests/test.methods.haplo.glm.R0000644000176000001440000000624012075615021020331 0ustar ripleyusers ## package: haplo.stats ## test script: haplo.glm ## created: 11/23/2011 ## settings verbose=TRUE require(haplo.stats) Sys.setlocale("LC_COLLATE", "C") Sys.getlocale('LC_COLLATE') if(verbose) cat("setting up data...\n") # prepare the hla dataset, # runs a lot longer, and MS alleles don't all start w/ 1, 2... label <-c("DQB","DRB","B") data(hla.demo) y <- hla.demo$resp y.bin <- 1*(hla.demo$resp.cat=="low") geno <- as.matrix(hla.demo[,c(17,18,21:24)]) geno <- setupGeno(geno, miss.val=c(0,NA)) # geno now has an attribute 'unique.alleles' which must be passed to # haplo.glm as allele.lev=attributes(geno)$unique.alleles, see below hla.data <- data.frame(geno=geno, age=hla.demo$age, male=hla.demo$male, y=y, y.bin=y.bin) seed <- c(17, 53, 1, 40, 37, 0, 62, 56, 5, 52, 12, 1) if(verbose) cat("fit a binary trait\n") set.seed(seed) fit.hla.bin <- haplo.glm(y.bin ~ male + geno, family = binomial, na.action="na.geno.keep", data=hla.data, locus.label=label, control = haplo.glm.control(haplo.min.count=8)) y.bin <- 1*(hla.demo$resp.cat=="low") y.bin[2] <- NA geno.hla <- as.matrix(hla.demo[,c(17,18,21:24)]) geno.hla[2,5] <- 2 geno.hla[3,] <- rep(NA, 6) geno.hla <- setupGeno(geno.hla, miss.val=c(0,NA)) my.hla <- data.frame(geno.hla=geno.hla, age=hla.demo$age, male=hla.demo$male, y=y, y.bin=y.bin) if(verbose) cat(" hla binary trait with subject that are removed\n") set.seed(seed) fit.hla.miss <- haplo.glm(y.bin ~ male + geno.hla, family = binomial, na.action="na.geno.keep", data=my.hla, locus.label=label, control = haplo.glm.control(haplo.min.count=8)) if(verbose) cat(" gaussian with covariates, additive\n") set.seed(seed) fit.hla.gaus.gender <- haplo.glm(y ~ male + geno, family = gaussian, na.action="na.geno.keep", data=hla.data, locus.label=label, control = haplo.glm.control(haplo.min.count=5)) if(verbose) cat("SNAP data with resp and resp with added variance\n") snapDF <- read.table("snapData.csv",header=TRUE, sep=",", stringsAsFactors=FALSE) geno.rec <- setupGeno(snapDF[,-c(1:9)]) snap.data <- data.frame(resp=hla.demo$resp, respvar=hla.demo$resp*100, geno=geno.rec) set.seed(seed) fit.resp.hla <- haplo.glm(resp~geno, trait.type="gaussian",data=snap.data) set.seed(seed) fit.respvar.hla <- haplo.glm(respvar~geno, trait.type="gaussian",data=snap.data) cat("summary function\n") print(summary(fit.hla.bin)) cat("fitted values for hlabin, hla-gaussian, hla-gaussian-hi-variance\n") print(fitted(fit.hla.bin)[1:20]) print(fitted(fit.resp.hla)[1:20]) print(fitted(fit.respvar.hla)[1:20]) cat("vcov for hlabin, hla-gaussian, hla-gaussian-hi-variance\n") print(vcov(fit.hla.bin)[1:20,1:20]) print(vcov(fit.resp.hla)) print(vcov(fit.respvar.hla)) cat("residuals for hlabin, hla-gaussian, hla-gaussian-hi-variance\n") print(residuals(fit.hla.bin, type="deviance")[1:20]) print(residuals(fit.hla.bin, type="pearson")[1:20]) print(residuals(fit.hla.bin, type="response")[1:20]) print(residuals(fit.resp.hla)[1:20]) print(residuals(fit.respvar.hla)[1:20]) haplo.stats/tests/test.Ginv.R0000644000176000001440000000246612075615021015717 0ustar ripleyusers ## package: haplo.stats ## test script: Ginv ## settings verbose=TRUE require(haplo.stats) # test Ginv on a matrix that is knowns to cause problems for LINPACK # implementation of svd used in Ginv. # this varx matrix comes from running haplo.scan (within haplo.stats) # on the 11-loci hla.demo dataset. source("dump.varx.s") # Jason Sinnwell 3/2004 if(verbose) cat("setting up data...\n") if(verbose) cat("test matrix (441x441) that causes error in LINPACK, but not LAPACK svd\n") ginv.varx <- Ginv(varx) # Ginv.q version 1.4 is known to fail and get a numerical error # ginv.varx$Ginv[1:5,1:5] ginv.varx.eps <- Ginv(varx, eps=1e-4) # ginv.varx.eps$Ginv[1:5,1:5] if(verbose) cat("the zero matrix should give ginv=0, rank=0\n") zeroMat <- matrix(0) epsMat <- matrix(1e-7) zeroGinv <- Ginv(zeroMat) epsGinv <- Ginv(epsMat) # a matrix with an NA should give a warning # naMat <- matrix(c(1,0,NA,0,2,1,1,1,3),ncol=3) # na.ginv <- Ginv(naMat) # if(verbose) cat("sinking print results to a file\n") #if(update) { # sink(file=goldfile) #} else { # sink("sink.Ginv.out") #} ## print all testable results (via a diff command) to a file print(ginv.varx$Ginv[1:5,1:5]) ginv.varx$rank print(ginv.varx.eps$Ginv[1:5,1:5]) ginv.varx.eps$rank print(zeroGinv) print(epsGinv) #sink() haplo.stats/tests/snap.sim.phased.dat0000644000176000001440000021450012075615021017372 0ustar ripleyusers2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 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1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 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1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 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1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 2,1,2,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,2,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,2,1,2,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 2,1,1,1,2,2,1,2.1,1,2,1,2,2,1,2,2,1 2,1,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 2,1,1,1,2,2,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 1,1,1,2,2,1,2,2.1,1,1,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 2,1,1,1,2,2,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,1,1,1,2,2,2,1,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,1,1,2,2,1,2,2,1 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,2,2,2,1,1,1,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,1,1,1,2.2,2,2,1,1,1,1,2,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,1,1,1,2.2,2,1,1,1,2,2,2,1,1 2,1,2,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 1,1,1,2,2,1,2,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,2,1,2,2.1,2,2,1,1,1,2,2,1,1 1,1,1,2,2,1,2,2.2,2,2,1,2,2,2,2,2,1 1,2,2,1,2,2,1,1.2,1,1,2,2,1,1,1,2,2 2,1,1,1,2,2,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,2,2,1,2,2,1,1.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,2,1,1,2,2 2,1,2,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.2,1,1,2,2,1,1,1,2,2 1,1,1,2,1,1,1,2.2,2,2,1,2,2,2,2,2,1 1,1,1,2,1,1,1,2.1,1,2,1,2,2,1,2,2,1 haplo.stats/tests/test.haplo.em.Rout.save0000644000176000001440000005302612075615021020202 0ustar ripleyusers R version 2.15.0 (2012-03-30) Copyright (C) 2012 The R Foundation for Statistical Computing ISBN 3-900051-07-0 Platform: x86_64-unknown-linux-gnu (64-bit) R is free software and comes with ABSOLUTELY NO WARRANTY. You are welcome to redistribute it under certain conditions. Type 'license()' or 'licence()' for distribution details. R is a collaborative project with many contributors. Type 'contributors()' for more information and 'citation()' on how to cite R or R packages in publications. Type 'demo()' for some demos, 'help()' for on-line help, or 'help.start()' for an HTML browser interface to help. Type 'q()' to quit R. > > ## package: haplo.stats > ## test script: haplo.em > > ## settings > verbose=TRUE > > require(haplo.stats) Loading required package: haplo.stats > > Sys.setlocale("LC_COLLATE", "C") [1] "C" > Sys.getlocale("LC_COLLATE") [1] "C" > > if(verbose) cat("prepare two datasets, one with char alleles, the other 3 loci from hla data\n") prepare two datasets, one with char alleles, the other 3 loci from hla data > > # make ficticious data set with an intention of some trend in > # haplotypes having H-allele at locus-H with F-allele at locus-F > geno.char <- matrix(c('F','f','g','G','h1','h1', + 'F','F','g','G','H','h1', + 'F','f','g','G','h2','h2', + 'f','f','g','G','h2','h1', + 'F','F','g','G','H','h2', + 'f','f','G','G','h1','h2', + 'F','f','G','g','h2','h2', + 'F','F','g','G','h1','z', + 'F','f','z','z','h1','h1', + 'F','f','G','g','h1','h2', + 'F','f','G','G','h1','h2', + 'F','F','g','G','h1','z', + 'F','f','z','z','h1','h1', + 'f','f','G','g','h1','h2'), nrow=14,byrow=T) > char.label <- c("F","G","H") > > data(hla.demo) > > hla.sub <- hla.demo[,c(1,2,3,4,17,18,21:24)] > geno.hla <- hla.sub[,-c(1:4)] > hla.label=c("DQB","DRB","HLA.B") > > seed <- c(33, 10, 39, 6, 16, 0, 40, 24, 12, 60, 7, 1) > > if(verbose) cat("character alleles\n") character alleles > > geno.char.recode <- setupGeno(geno.char, miss.val="z") > > geno.char.recode loc-1.a1 loc-1.a2 loc-2.a1 loc-2.a2 loc-3.a1 loc-3.a2 [1,] 1 2 2 1 2 2 [2,] 1 1 2 1 1 2 [3,] 1 2 2 1 3 3 [4,] 2 2 2 1 3 2 [5,] 1 1 2 1 1 3 [6,] 2 2 1 1 2 3 [7,] 1 2 1 2 3 3 [8,] 1 1 2 1 2 NA [9,] 1 2 NA NA 2 2 [10,] 1 2 1 2 2 3 [11,] 1 2 1 1 2 3 [12,] 1 1 2 1 2 NA [13,] 1 2 NA NA 2 2 [14,] 2 2 1 2 2 3 attr(,"class") [1] "model.matrix" attr(,"unique.alleles") attr(,"unique.alleles")[[1]] [1] "F" "f" attr(,"unique.alleles")[[2]] [1] "G" "g" attr(,"unique.alleles")[[3]] [1] "H" "h1" "h2" > > set.seed(seed) > em.char <- haplo.em(geno.char, miss.val='z',locus.label=char.label, + control = haplo.em.control()) > > print.haplo.em(em.char, digits=5) ================================================================================ Haplotypes ================================================================================ F G H hap.freq 1 F G H 0.08935 2 F G h1 0.14326 3 F G h2 0.00000 4 F g H 0.00000 5 F g h1 0.16268 6 F g h2 0.14042 7 f G h1 0.08733 8 f G h2 0.24150 9 f g h1 0.13545 10 f g h2 0.00000 ================================================================================ Details ================================================================================ lnlike = -37.1622 lr stat for no LD = 10.98653 , df = 2 , p-val = 0.00411 > summary(em.char, digits=5, show.haplo=TRUE) ================================================================================ Subjects: Haplotype Codes and Posterior Probabilities ================================================================================ subj.id hap1.F hap1.G hap1.H hap2.F hap2.G hap2.H posterior 5 1 F g h1 f G h1 0.42305 2 1 F G h1 f g h1 0.57695 2.1 2 F G h1 F g H 0.00000 1 2 F G H F g h1 1.00000 6 3 F g h2 f G h2 1.00000 7 4 f G h1 f g h2 0.00000 8 4 f G h2 f g h1 1.00000 1.1 5 F G H F g h2 1.00000 7.1 6 f G h1 f G h2 1.00000 6.1 7 F g h2 f G h2 1.00000 1.2 8 F G H F g h1 0.25095 2.2 8 F G h1 F g H 0.00000 2.3 8 F G h1 F g h1 0.40212 3 8 F G h2 F g h1 0.00000 2.4 8 F G h1 F g h2 0.34694 2.5 9 F G h1 f G h1 0.18357 2.6 9 F G h1 f g h1 0.28450 5.1 9 F g h1 f G h1 0.20861 5.2 9 F g h1 f g h1 0.32331 2.7 10 F G h1 f g h2 0.00000 5.3 10 F g h1 f G h2 0.76212 3.1 10 F G h2 f g h1 0.00000 6.2 10 F g h2 f G h1 0.23788 2.8 11 F G h1 f G h2 1.00000 3.2 11 F G h2 f G h1 0.00000 1.3 12 F G H F g h1 0.25095 2.9 12 F G h1 F g H 0.00000 2.10 12 F G h1 F g h1 0.40212 3.3 12 F G h2 F g h1 0.00000 2.11 12 F G h1 F g h2 0.34694 2.12 13 F G h1 f G h1 0.18357 2.13 13 F G h1 f g h1 0.28450 5.4 13 F g h1 f G h1 0.20861 5.5 13 F g h1 f g h1 0.32331 7.2 14 f G h1 f g h2 0.00000 8.1 14 f G h2 f g h1 1.00000 ================================================================================ Number of haplotype pairs: max vs used ================================================================================ x 1 2 4 5 1 1 0 0 0 2 3 5 0 0 4 0 0 3 0 5 0 0 0 2 > summary.haplo.em(em.char, digits=5) ================================================================================ Subjects: Haplotype Codes and Posterior Probabilities ================================================================================ subj.id hap1code hap2code posterior 1 1 5 7 0.42305 2 1 2 9 0.57695 3 2 2 4 0.00000 4 2 1 5 1.00000 5 3 6 8 1.00000 6 4 7 10 0.00000 7 4 8 9 1.00000 8 5 1 6 1.00000 9 6 7 8 1.00000 10 7 6 8 1.00000 11 8 1 5 0.25095 12 8 2 4 0.00000 13 8 2 5 0.40212 14 8 3 5 0.00000 15 8 2 6 0.34694 16 9 2 7 0.18357 17 9 2 9 0.28450 18 9 5 7 0.20861 19 9 5 9 0.32331 20 10 2 10 0.00000 21 10 5 8 0.76212 22 10 3 9 0.00000 23 10 6 7 0.23788 24 11 2 8 1.00000 25 11 3 7 0.00000 26 12 1 5 0.25095 27 12 2 4 0.00000 28 12 2 5 0.40212 29 12 3 5 0.00000 30 12 2 6 0.34694 31 13 2 7 0.18357 32 13 2 9 0.28450 33 13 5 7 0.20861 34 13 5 9 0.32331 35 14 7 10 0.00000 36 14 8 9 1.00000 ================================================================================ Number of haplotype pairs: max vs used ================================================================================ x 1 2 4 5 1 1 0 0 0 2 3 5 0 0 4 0 0 3 0 5 0 0 0 2 > > > if(verbose) cat("hla data, 3 loci\n") hla data, 3 loci > set.seed(seed) > em.hla3 <- haplo.em(geno.hla, locus.label=hla.label, miss.val=0, + control = haplo.em.control()) > > print.haplo.em(em.hla3, digits=5) ================================================================================ Haplotypes ================================================================================ DQB DRB HLA.B hap.freq 1 21 1 8 0.00232 2 21 2 7 0.00227 3 21 2 18 0.00227 4 21 3 8 0.10421 5 21 3 18 0.00229 6 21 3 35 0.00565 7 21 3 44 0.00360 8 21 3 45 0.00227 9 21 3 49 0.00227 10 21 3 57 0.00238 11 21 3 70 0.00227 12 21 4 62 0.00455 13 21 7 7 0.01415 14 21 7 13 0.01076 15 21 7 18 0.00493 16 21 7 35 0.00236 17 21 7 44 0.02149 18 21 7 50 0.00455 19 21 7 57 0.00227 20 21 7 62 0.00767 21 21 8 18 0.00227 22 21 8 63 0.00227 23 21 9 51 0.00227 24 21 10 8 0.00227 25 31 1 27 0.00455 26 31 2 44 0.00228 27 31 2 57 0.00227 28 31 3 8 0.00455 29 31 4 13 0.00515 30 31 4 14 0.00227 31 31 4 27 0.00495 32 31 4 35 0.00455 33 31 4 41 0.00227 34 31 4 44 0.02849 35 31 4 60 0.00686 36 31 7 44 0.00455 37 31 7 61 0.00227 38 31 8 35 0.00227 39 31 8 39 0.00227 40 31 8 45 0.00227 41 31 8 52 0.00227 42 31 8 60 0.00455 43 31 11 7 0.00233 44 31 11 18 0.00466 45 31 11 27 0.00618 46 31 11 35 0.01753 47 31 11 37 0.00699 48 31 11 38 0.00699 49 31 11 44 0.01028 50 31 11 49 0.00466 51 31 11 51 0.01113 52 31 11 56 0.00233 53 31 11 60 0.00237 54 31 11 61 0.00466 55 31 11 62 0.00612 56 31 13 8 0.00465 57 31 13 14 0.00227 58 31 13 41 0.00455 59 31 13 57 0.00217 60 31 14 58 0.00248 61 31 14 63 0.00248 62 32 1 7 0.00227 63 32 1 35 0.00222 64 32 1 62 0.00000 65 32 2 44 0.00287 66 32 3 35 0.00232 67 32 3 51 0.00227 68 32 4 7 0.02044 69 32 4 8 0.00469 70 32 4 14 0.00455 71 32 4 35 0.00000 72 32 4 44 0.00237 73 32 4 45 0.00167 74 32 4 51 0.00227 75 32 4 55 0.00249 76 32 4 60 0.03061 77 32 4 62 0.02349 78 32 7 39 0.00455 79 32 7 57 0.00455 80 32 8 7 0.00682 81 32 9 51 0.00227 82 32 10 39 0.00227 83 33 7 7 0.00455 84 33 7 57 0.00682 85 33 9 8 0.00227 86 33 9 46 0.00227 87 33 9 48 0.00227 88 33 9 60 0.00682 89 33 10 51 0.00227 90 42 4 35 0.00227 91 42 8 18 0.00227 92 42 8 55 0.00227 93 42 8 60 0.00227 94 51 1 8 0.00468 95 51 1 14 0.00233 96 51 1 18 0.00247 97 51 1 27 0.01439 98 51 1 35 0.03015 99 51 1 39 0.00233 100 51 1 44 0.01772 101 51 1 47 0.00233 102 51 1 48 0.00233 103 51 1 51 0.00752 104 51 1 58 0.00233 105 51 1 60 0.00233 106 51 2 51 0.00227 107 51 4 27 0.00227 108 51 8 7 0.00455 109 51 10 7 0.00294 110 51 10 14 0.00227 111 51 10 18 0.00227 112 51 10 35 0.00161 113 51 10 37 0.00455 114 51 14 56 0.00248 115 52 2 27 0.00227 116 52 2 42 0.00227 117 52 2 56 0.00455 118 52 2 62 0.00455 119 52 4 39 0.00227 120 52 8 60 0.00227 121 53 8 57 0.00227 122 53 9 51 0.00227 123 53 14 35 0.00248 124 53 14 38 0.00496 125 53 14 44 0.00248 126 53 14 51 0.00248 127 53 14 55 0.00496 128 61 2 44 0.00227 129 61 2 60 0.00227 130 61 2 61 0.00455 131 61 2 62 0.00227 132 61 4 52 0.00227 133 61 8 44 0.00227 134 61 13 39 0.00227 135 61 13 44 0.00227 136 62 2 7 0.04904 137 62 2 8 0.00456 138 62 2 18 0.01538 139 62 2 27 0.00455 140 62 2 35 0.01149 141 62 2 44 0.01378 142 62 2 60 0.00514 143 62 4 7 0.00228 144 62 4 45 0.00287 145 62 7 57 0.00227 146 62 8 35 0.00227 147 62 8 37 0.00227 148 62 10 51 0.00227 149 62 11 55 0.00233 150 62 13 51 0.00227 151 62 14 51 0.00248 152 63 2 7 0.01364 153 63 2 44 0.00227 154 63 4 48 0.00227 155 63 8 18 0.00227 156 63 8 58 0.00227 157 63 10 44 0.00227 158 63 13 7 0.01349 159 63 13 35 0.00305 160 63 13 38 0.00709 161 63 13 44 0.01655 162 63 13 55 0.00451 163 63 13 60 0.00575 164 63 13 62 0.00866 165 64 2 51 0.00227 166 64 11 38 0.00233 167 64 13 7 0.00954 168 64 13 14 0.00455 169 64 13 35 0.00673 170 64 13 44 0.00236 171 64 13 51 0.00227 172 64 13 57 0.00227 173 64 13 60 0.00410 174 64 13 61 0.00227 175 64 13 63 0.00682 ================================================================================ Details ================================================================================ lnlike = -1846.904 lr stat for no LD = 585.1133 , df = 124 , p-val = 0 > > if(verbose) cat("snap SNP data, unphased\n") snap SNP data, unphased > snapDF <- read.table("snapData.csv",header=TRUE, sep=",", stringsAsFactors=FALSE) > > geno.snap <- setupGeno(geno=snapDF[,-1]) > set.seed(seed) > em.snap <- haplo.em(geno=geno.snap) > > print(em.snap, digits=5) ================================================================================ Haplotypes ================================================================================ loc-1 loc-2 loc-3 loc-4 loc-5 loc-6 loc-7 hap.freq 1 1 1 1 1 1 1 1 0.05224 2 1 1 1 1 1 1 2 0.10459 3 1 1 1 1 2 1 1 0.05135 4 1 1 1 1 2 2 1 0.04930 5 1 1 1 1 2 2 2 0.08467 6 1 1 1 2 1 1 2 0.06263 7 1 1 1 2 2 2 2 0.01625 8 1 1 2 1 1 1 1 0.01442 9 1 1 2 1 1 1 2 0.03359 10 1 1 2 1 2 1 1 0.02221 11 1 1 2 1 2 2 1 0.02690 12 1 1 2 1 2 2 2 0.01553 13 1 1 2 2 1 1 2 0.02063 14 1 1 2 2 2 2 2 0.01659 15 1 2 1 1 1 1 1 0.00939 16 1 2 1 1 1 1 2 0.01357 17 1 2 1 1 2 1 1 0.01453 18 1 2 1 1 2 2 2 0.00042 19 1 2 1 2 1 1 2 0.01404 20 1 2 1 2 2 2 2 0.00357 21 1 2 2 1 1 1 1 0.02140 22 1 2 2 1 1 1 2 0.02601 23 1 2 2 1 2 1 1 0.03226 24 1 2 2 1 2 2 1 0.01598 25 1 2 2 1 2 2 2 0.00000 26 1 2 2 2 1 1 2 0.02312 27 1 2 2 2 2 2 2 0.01539 28 2 1 1 1 1 1 1 0.00548 29 2 1 1 1 1 1 2 0.01909 30 2 1 1 1 2 1 1 0.03244 31 2 1 1 1 2 2 2 0.01361 32 2 1 1 2 1 1 2 0.03394 33 2 1 1 2 2 2 2 0.00816 34 2 2 1 1 1 1 1 0.01587 35 2 2 1 1 1 1 2 0.02942 36 2 2 1 1 2 1 1 0.02506 37 2 2 1 1 2 2 1 0.01688 38 2 2 1 1 2 2 2 0.01136 39 2 2 1 2 2 2 2 0.02814 ================================================================================ Details ================================================================================ lnlike = -1210.329 lr stat for no LD = 139.7221 , df = 30 , p-val = 0 > > > if(verbose) cat("Check Phase against SNaP data, phased\n") Check Phase against SNaP data, phased > snapfile <- "snap.sim.phased.dat" > source("snapFUN.s") > set.seed(seed) > block1.phase <- checkPhase(snapfile, blocknum=1) > set.seed(seed) > block2.phase <- checkPhase(snapfile, blocknum=2) > > > print(block1.phase[[2]]) haplotype em.freq snap.freq 1 11112211 5.515622e-02 0.0545 2 11121112 3.348438e-01 0.3355 3 11122122 1.565000e-01 0.1565 4 12212211 1.553438e-01 0.1560 5 12221112 9.815621e-02 0.0975 6 21112212 1.120000e-01 0.1120 7 21221112 8.800000e-02 0.0880 8 22212212 1.644158e-09 0.0000 > print(block1.phase[[1]][1:50,]) # long output 1120 lines subj emhap1 emhap2 post snaphap1 snaphap2 1 1 11121112 21221112 1.000000e+00 21221112 11121112 2 2 11122122 12212211 1.000000e+00 12212211 11122122 3 3 11121112 11121112 1.000000e+00 11121112 11121112 4 4 12212211 12212211 1.000000e+00 12212211 12212211 5 5 11121112 12212211 9.057297e-01 12212211 11121112 6 5 11112211 12221112 9.427027e-02 12212211 11121112 7 6 11121112 21221112 1.000000e+00 21221112 11121112 8 7 12212211 21221112 1.000000e+00 12212211 21221112 9 8 11112211 11122122 1.000000e+00 11112211 11122122 10 9 11121112 11122122 1.000000e+00 11121112 11122122 11 10 12212211 12221112 1.000000e+00 12212211 12221112 12 11 11121112 11122122 1.000000e+00 11121112 11122122 13 12 12221112 21221112 1.000000e+00 21221112 12221112 14 13 11121112 12212211 9.057297e-01 11121112 12212211 15 13 11112211 12221112 9.427027e-02 11121112 12212211 16 14 11112211 11121112 1.000000e+00 11121112 11112211 17 15 11112211 21112212 1.000000e+00 21112212 11112211 18 16 12221112 21112212 9.999999e-01 12221112 21112212 19 16 11121112 22212212 1.097747e-07 12221112 21112212 20 17 11122122 12212211 1.000000e+00 12212211 11122122 21 18 11121112 11121112 1.000000e+00 11121112 11121112 22 19 11121112 12221112 1.000000e+00 12221112 11121112 23 20 11121112 11121112 1.000000e+00 11121112 11121112 24 21 21112212 21221112 1.000000e+00 21221112 21112212 25 22 11121112 11122122 1.000000e+00 11121112 11122122 26 23 11121112 12212211 9.057297e-01 11121112 12212211 27 23 11112211 12221112 9.427027e-02 11121112 12212211 28 24 11121112 11121112 1.000000e+00 11121112 11121112 29 25 11122122 21112212 1.000000e+00 11122122 21112212 30 26 11121112 11121112 1.000000e+00 11121112 11121112 31 27 11122122 12212211 1.000000e+00 11122122 12212211 32 28 12212211 21221112 1.000000e+00 12212211 21221112 33 29 11122122 12221112 1.000000e+00 11122122 12221112 34 30 11121112 21112212 1.000000e+00 21112212 11121112 35 31 11121112 11122122 1.000000e+00 11122122 11121112 36 32 11122122 21112212 1.000000e+00 11122122 21112212 37 33 11122122 21221112 1.000000e+00 11122122 21221112 38 34 11121112 11122122 1.000000e+00 11122122 11121112 39 35 21112212 21221112 1.000000e+00 21221112 21112212 40 36 11121112 12221112 1.000000e+00 11121112 12221112 41 37 12212211 12212211 1.000000e+00 12212211 12212211 42 38 11121112 11121112 1.000000e+00 11121112 11121112 43 39 11121112 11121112 1.000000e+00 11121112 11121112 44 40 12212211 21112212 1.000000e+00 21112212 12212211 45 40 11112211 22212212 1.142559e-08 21112212 12212211 46 41 11121112 12212211 9.057297e-01 12212211 11121112 47 41 11112211 12221112 9.427027e-02 12212211 11121112 48 42 12212211 21221112 1.000000e+00 12212211 21221112 49 43 11121112 11122122 1.000000e+00 11121112 11122122 50 44 12212211 21112212 1.000000e+00 21112212 12212211 > print(block2.phase[[2]]) haplotype em.freq snap.freq 1 1111221221 5.200000e-02 0.0520 2 1121221221 1.965000e-01 0.1965 3 1221112211 9.650000e-02 0.0965 4 2112211122 2.105000e-01 0.2105 5 2112221122 5.400000e-02 0.0540 6 2211122211 9.300000e-02 0.0930 7 2221111222 1.010000e-01 0.1010 8 2221121222 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Fo“颣ÆXõÅ>™üu’Ë<ía7Nîe9Ï yzÏ]Àéæ ¼Ëåk8îü!þß™éÃowúIŽë_8k8dÌã>vE¦?^ä«&Ñßèô9«¬_> endstream endobj startxref 287641 %%EOF haplo.stats/inst/doc/GPL.txt0000644000176000001440000003545111526250437015464 0ustar ripleyusers GNU GENERAL PUBLIC LICENSE Version 2, June 1991 Copyright (C) 1989, 1991 Free Software Foundation, Inc. 59 Temple Place, Suite 330, Boston, MA 02111-1307 USA Everyone is permitted to copy and distribute verbatim copies of this license document, but changing it is not allowed. Preamble The licenses for most software are designed to take away your freedom to share and change it. By contrast, the GNU General Public License is intended to guarantee your freedom to share and change free software--to make sure the software is free for all its users. This General Public License applies to most of the Free Software Foundation's software and to any other program whose authors commit to using it. (Some other Free Software Foundation software is covered by the GNU Library General Public License instead.) You can apply it to your programs, too. When we speak of free software, we are referring to freedom, not price. Our General Public Licenses are designed to make sure that you have the freedom to distribute copies of free software (and charge for this service if you wish), that you receive source code or can get it if you want it, that you can change the software or use pieces of it in new free programs; and that you know you can do these things. To protect your rights, we need to make restrictions that forbid anyone to deny you these rights or to ask you to surrender the rights. These restrictions translate to certain responsibilities for you if you distribute copies of the software, or if you modify it. For example, if you distribute copies of such a program, whether gratis or for a fee, you must give the recipients all the rights that you have. You must make sure that they, too, receive or can get the source code. And you must show them these terms so they know their rights. We protect your rights with two steps: (1) copyright the software, and (2) offer you this license which gives you legal permission to copy, distribute and/or modify the software. Also, for each author's protection and ours, we want to make certain that everyone understands that there is no warranty for this free software. If the software is modified by someone else and passed on, we want its recipients to know that what they have is not the original, so that any problems introduced by others will not reflect on the original authors' reputations. Finally, any free program is threatened constantly by software patents. We wish to avoid the danger that redistributors of a free program will individually obtain patent licenses, in effect making the program proprietary. To prevent this, we have made it clear that any patent must be licensed for everyone's free use or not licensed at all. The precise terms and conditions for copying, distribution and modification follow. GNU GENERAL PUBLIC LICENSE TERMS AND CONDITIONS FOR COPYING, DISTRIBUTION AND MODIFICATION 0. This License applies to any program or other work which contains a notice placed by the copyright holder saying it may be distributed under the terms of this General Public License. The "Program", below, refers to any such program or work, and a "work based on the Program" means either the Program or any derivative work under copyright law: that is to say, a work containing the Program or a portion of it, either verbatim or with modifications and/or translated into another language. (Hereinafter, translation is included without limitation in the term "modification".) Each licensee is addressed as "you". Activities other than copying, distribution and modification are not covered by this License; they are outside its scope. The act of running the Program is not restricted, and the output from the Program is covered only if its contents constitute a work based on the Program (independent of having been made by running the Program). Whether that is true depends on what the Program does. 1. You may copy and distribute verbatim copies of the Program's source code as you receive it, in any medium, provided that you conspicuously and appropriately publish on each copy an appropriate copyright notice and disclaimer of warranty; keep intact all the notices that refer to this License and to the absence of any warranty; and give any other recipients of the Program a copy of this License along with the Program. You may charge a fee for the physical act of transferring a copy, and you may at your option offer warranty protection in exchange for a fee. 2. 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These actions are prohibited by law if you do not accept this License. Therefore, by modifying or distributing the Program (or any work based on the Program), you indicate your acceptance of this License to do so, and all its terms and conditions for copying, distributing or modifying the Program or works based on it. 6. Each time you redistribute the Program (or any work based on the Program), the recipient automatically receives a license from the original licensor to copy, distribute or modify the Program subject to these terms and conditions. You may not impose any further restrictions on the recipients' exercise of the rights granted herein. You are not responsible for enforcing compliance by third parties to this License. 7. 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END OF TERMS AND CONDITIONS haplo.stats/inst/NEWS.Rd0000644000176000001440000003543512075270163014577 0ustar ripleyusers\name{NEWS} \title{NEWS file for the haplo.stats package} \section{Changes in version 1.6.0}{ \itemize{ \item Removed .First.lib and .Last.lib b/c handled via namespace \item Updated test scripts to set LC_COLLATE and check values after set } } \section{Changes in version 1.5.6}{ \itemize{ \item Removed glm.fit.nowarn because glm.fit changed from R 2.15.0 \item Added haplo.binomial for family=binomial in haplo.glm. Will work with either, and within haplo.glm it uses the initialize expression for haplo.binomial to ignore warnings of non-integer number of successes because we use posterior probability of a haplotype pair per subject as weights } } \section{Changes in version 1.5.4}{ \itemize{ \item Fixed haplo.glm bug in assigning names to var.mat when haplo.elim=NA \item replaced printf statements with REprintf (from R_ext/Print.h) in verbose C code sections \item Placed raw manual in rnw directory at top level, as suggested by Andreas Tille (2/11/2012) } } \section{Changes in version 1.5.2}{ \itemize{ \item Added methods for haplo.glm object: anova, residuals, vcov, fitted \item Updated haplo.glm to work more like glm object with methods \item Took out S-PLUS functionality for haplo.glm \item Remove notes for S-PLUS usage in documentation \item Added eps.svd argument to haplo.glm.control to give users control over calculation information matrix rank \item Remove loci, geno.recode, allele.recode, which is now handled with setupGeno \item Add test suite with .R and .Rout.save files \item Major update to user manual in doc/ \item Suggest Harrell's rms package instead of Design for haplo.score with ordinal traits \item Add NAMESPACE and NEWS files } } \section{Release Notes for version 1.4.4}{ \itemize{ \item No major updates to code. Updates are mostly for Rd files to keep up with changing requirements for packages. \item In functions that use 1-pchisq( ), replace with pchisq(, , lower=FALSE) for better precision. Precision is lost subtracting a small p-value from 1.00, so computing it directly without making the digits line up for the double-precision subraction }} \section{Release Notes for version 1.4.1}{ \itemize{ \item For the seqhap function, adapt the permutation rules used in haplo.score's sim.control parameter to ensure accuracy and precision thresholds for permutation p-values. The permutations are carried out in seqhap.c, so the parameters p.threshold, min.sim, and max.sim are passed to the C code to permute the response until precision criteria met. No longer use n.sim parameter; now sim.control=score.sim.control() handles the permutations. \item The user manual has been updated from version 1.3.1 to reflect all the updates since then, and will be placed on Dan Schaid's software page, in addition to its current location within the package \item help files for example datasets now pass R check. }} \section{ Release notes for version 1.3.8}{ \itemize{ \item plot.seqhap, we handle very small p-values better by having a minimum allowable asymptotic p-value of .Machine.double$eps, and permutation p-value of 1/(n.sim+1). It will also handle a ylim value if passed. Add more useful warning messages for when p-values are fixed for plotting. \item haplo.score, add eps.svd argument. In some assocation tests from haplo.score, we have observed extremely significant values for the global association test statistic. The degrees of freedom for the global test is the rank of the score vector's covariance matrix. We found the source of the problem was having too low a cutoff (epsilon) for svd values for determining rank of the covariance matrix. We increased the default for the epsilon from 1e-6 to 1e-5 and allow it to be changed by the user as the eps.svd parameter in any function that uses haplo.score (haplo.score.slide, haplo.cc). \item Update haplo.cc parameters. We remove haplo.min.count as a top-level parameter; it can only be used in the control() function, just as in haplo.glm. Note that haplo.freq.min can also be used. The eps.svd parameter is also added, as noted for haplo.score. }} \section{Releast notes for version 1.3.6}{ \itemize{ \item Add haplo.power.qt and haplo.power.cc. Power and sample size calculations for haplotype association studies. Calculations are performed given a set of haplotypes, their freqs, and their beta coefficients, which can be converted by log(OR) for case-control (cc) or calculated for quantitative trait (qt) by R2 variance explained by gene association. For qt, use the find.haplo.beta.qt to get these beta coefficients. \item Add dataset hapPower.demo, an example dataset for demonstrating the haplo.power.qt/cc functions in example() and in the manual. \item In past versions of haplo.em, a change was made to pre-calculate how much memory would be needed for all haplotype pairs, and issued a warning if that memory could not be allocated. It stopped calculations that could have been completed by progressive insertion & trimming steps because rare haplotypes are trimmed off and memory rarely meets the max. So the warning is taken off. \item Add min.posterior to haplo.em.control to give control to the user versus the old default set at 1e-7. In rare cases of some datasets that had low LD and 10 or more markers, the trimming steps actually trimmed away all haplotypes for a given person and the person was removed. We have changed min.posterior to 1e-9 and put in warnings and check for this occuring. Note, we have only observed this in simulated data on very rare occasions. \item Remove allele.lev and miss.val parameters from call to haplo.glm. We used to require the use of allele.lev as a parameter for haplo.glm, and allow miss.val to specify codes for missing alleles in the genotype matrix. However, we require using setupGeno to prepare the genotype matrix to be used in haplo.glm, after it is added to the data.frame to be passed to haplo.glm. miss.val is completely taken care of there, and allele.lev is assigned as an attribute of geno. We have re-worked the formula and na.geno.keep to recognize these values when it finds geno in the formula; therefore, these parameters are not required in haplo.glm. \item More strict exclusion using na.geno.keep. We used to keep all subjects who were missing any number of alleles. However, if a subject is missing all alleles, they slow the calcualtions down, and don't add any information to the analysis. This function still removes subjects missing y or covariate values, and now removes subjects missing all their alleles. After the removal, the attributes of the genotype matrix are re-calculated and retained for its use in haplo.model.frame. \item In haplo.model.frame for haplo.glm, get allele.lev from geno in m[[]], not as passed paremeter from haplo.glm. \item In haplo.glm.control, enforce the default setting for haplo.min.count and haplo.freq.min in the function delcaration. In the declaration they were NA, but a default min.count of 5 was enforced. We have changed the default of haplo.freq.min of .01 to be enforced, and the delcaration now reflects the enforced default. \item Ginv.R for R and Ginv.q for Splus. Splus version 8.0.1 has a problem in its use of the svd fortran function, as called by svd.Matrix. We contacted Insightful and they fixed it for version 8.0.4. We include the svd.Matrix function from version 7 and 8.0.4 in the Ginv.q file, but only load it if the Splus version matches 8.0.1. \item louis.info.c -- Prior efforts to make all long integer values as int was not completed for this function. The result was the package didn't work on linux 64bit machines. Now it doesn't use long, and it should work on most platforms. \item louis.info.q -- When the variance of a quantitative trait is so high that the the information matrix becomes ill-conditioned, the Ginv determines the information matrix singular, and the standard errors are incorrect. Change the epsilon parameter for the generalized inverse to about 1e-8, versus the old default in Ginv of 1e-6. }} \section{Release Notes for version 1.3.0 }{ \itemize{ \item Add new function, seqhap, sequential haplotype selection in a set of loci, for choosing loci for haplotype associations, as described in Yu and Schaid, 2007. The method performs three tests for association of a binary trait over a set of bi-allelic loci. When evaluating each locus, loci close to it are added in a sequential manner based on the Mantel-Haenszel test. \item geno1to2: convert geno from 1- to 2-column convert 1-column minor-allele-count matrix to two-column allele codes \item Make plot.haplo.score.slide better-handle near-zero pvalues. For asymptotic pvalues near zero, set to epsilon. For simulated p-values, set to 0.5 divided by the number of simulations performed. \item New function, haplo.design, create design matrix for haplotypes. In response to many requests made for getting columns for haplotype effects to use in glm, survival, or other regression models, we created a function to set up this kind of design matrix. There are issues surrounding the use of these effect columns, as outlined in the user manual. \item Ginv: svd problems continue. The Matrix library svd function has changed for Splus 8.0.1. Therefore, revert back to the default svd function in getting the generalized inverse. }} \section{Release notes for version 1.2.5}{ \itemize{ \item haplo.glm: Iterative steps efficiency. In consecutive steps of the IRWLS steps in haplo.glm, the starting values for re-fitting the glm model were not updated to be the most recently updated values. This now saves about 20% of run time in haplo.glm. \item haplo.score: haplo.effect allow additive, dominant, recessive A new option to make haplo.score more flexible. Previously the scores for haplotypes were computed assuming an additive effect for all haplotypes. A new parameter, haplo.effect, is in place to allow either additive, dominant, or recessive effects. \item haplo.score: min.count parameter. The cut-off for selecting haplotypes to score is either by a minimum frequency, skip.haplo, or a new option, min.count. The min.count is based on the same idea as that used in haplo.glm, where the minimum expected count of haplotypes in the population is enough such that accurate estimates of parameters and standard errors are computed. The min.count became needed when haplo.effect was added because under the dominant or recessive models, the number of persons actually having a haplotype effect could be fewer than the expected count over the population (i.e., haplotype pair h1/h2 is coded as 0 for both under recessive model, and h1/h1 is coded as 1 under dominant). \item haplo.em -- improved reliability of C routines. Previously problems had been observed with running haplo.em and haplo.glm on linux 64-bit machines, because of issues with the storage of integers in R. In R, all integers are stored as int, which are stored differently on 64-bit and 32-bit machines. We get around this problem by using all int types for integers, which are only used for indices of other data structures. We find out the max value for integers on the system, and if the indices are going to exceed the max, issue a warning from C. \item haplo.glm and Ginv: improvement of standard error calculations Under some extreme circumstances, such as haplo.glm modeling haplotypes with rare frequencies, or a high amount of variance in the response, the standard error estimates were unreliable. The issue came out in the Ginv function in haplo.stats, which needed a smaller epsilon to decide on the rank of the information matrix. }} \section{ Release notes for version 1.2.0 }{ \itemize{ \item haplo.em: fixed memory leak. Versions up to 1.1.1 had either one or two memory leaks in haplo.em. They are fixed. \item All .C functions: Long Integers warning for 64-bit machine Due to problems with long integers between 32-bit and 64-bit machines using R, all integers used in C functions will use unsigned integers. \item Allow haplo.effect="recessive" in haplo.glm. The estimation stops if no columns are left in the model.matrix for homozygotes with the haplotype, and for haplotypes that do not have any subjects with a posterior probability of being homozygous for the haplotype, those subjects are grouped into the baseline effect. Guidelines for rare haplotypes are explained further in the manual. \item haplo.glm: na.action, when not specified got set to something besides the intended 'na.geno.keep'. Now the default setting works. \item haplo.cc: New Function for Case-Control Analysis New function added to combine methods of haplo.score, haplo.group and haplo.glm into one set of output for Case-Control data. Choose haplotypes for analysis by haplo.min.count only, not a frequency cut-off. \item Set the new default for skip.haplo to be 5/(nrow(geno)*2) \item In haplo.glm: haplo.freq.min and haplo.min.count control parameters Haplotypes used in the glm are still chosen by haplo.freq.min, but the default is based on a minimum expected count of 5 in the sample. The better choice for selecting haplotypes is haplo.min.count. The issue is documented in the manual and help files. \item Describe the max-stat simulated p-value in more detail in the user manual and help file \item haplo.em.control and haplo.em: defaults for control parameters changed The default for control parameter: max.iter=5000, changed from 500 insert.batch.size = 6, changed from 4 \item locus function warning. The genetics package for R has a function named locus which does not agree with locus from haplo.stats. We do not plan to change it, so be aware of the possible clash if you use these two packages. \item New function haplo.scan, for analyzing a genome region with case-control data. Search for a trait-locus by sliding a fixed-width window over each marker locus and scanning all possible haplotype lengths within the window }} \section{ Release Notes for version 1.1.1 }{ \itemize{ \item haplo.glm: Warnings for non-integer weights glm.fit for R does not allow non-integer weights for subjects, whereas S-PLUS does. Use a glm.fit.nowarn function for R to ignore warnings. \item haplo.glm: Character Alleles Settings for strings as factors causes confusion for keeping orinial character allele values. To ensure consistency of allele codes, use setupGeno() and then in the haplo.glm call, use allele.lev as documented in the manual and help files. \item Add haplo.score.slide function, which rus haplo.score on all contiguous subsets of size n.slide from the loci in a genotype matrix(geno). \item haplo.score simulations controlled for precision. Employ simulation precision criteria for p-values, adopted from Besag and Clifford [1991]. Control simulations with score.sim.control. }} haplo.stats/rnw/0000755000176000001440000000000012075615022013350 5ustar ripleyusershaplo.stats/rnw/manualHaploStats.Rnw0000644000176000001440000027101011734075242017326 0ustar ripleyusers%\VignetteIndexEntry{haplo.stats} %\VignetteKeywords{haplotype, score, glm} %\VignetteDepends{haplo.stats} %\VignettePackage{haplo.stats} \RequirePackage[T1]{fontenc} \RequirePackage{graphicx,ae,fancyvrb} \IfFileExists{upquote.sty}{\RequirePackage{upquote}}{} \setkeys{Gin}{width=0.8\textwidth} \DefineVerbatimEnvironment{Sinput}{Verbatim}{fontfamily=courier, fontshape=sl, fontseries=b, xleftmargin=.25cm} \DefineVerbatimEnvironment{Soutput}{Verbatim}{fontfamily=courier, fontshape=sl, xleftmargin=.5cm} \documentclass[11pt]{article} \def\version{version 1.5.0} \def\Rversion{version 2.14.0} \def\package{{\sl haplo.stats}} \def\Explain{\paragraph{\large {\bf Explanation of Results \vspace{.1in}} \\}} \usepackage{Sweave} \usepackage{fullpage} \usepackage{hyperref} %\textwidth 6.5in %\oddsidemargin 0in %\evensidemargin 0in %\textheight 7.7in \title{{\bf Haplo Stats} \\ (\version) \vspace{.25in}\\ Statistical Methods for Haplotypes When Linkage Phase is Ambiguous \vspace{1.5in}\\ } \author{Jason P. Sinnwell\thanks{sinnwell@mayo.edu} and Daniel J. Schaid \\ Mayo Clinic Division of Health Sciences Research\\Rochester MN USA \vspace{.25in} \\} \date{{\today} \vspace{2in}} \begin{document} \maketitle \pagebreak \tableofcontents \pagebreak \section{Introduction} Haplo Stats is a suite of R routines for the analysis of indirectly measured haplotypes. The statistical methods assume that all subjects are unrelated and that haplotypes are ambiguous (due to unknown linkage phase of the genetic markers), while also allowing for missing alleles. The user-level functions in Haplo Stats are: \begin{itemize} \item{{\sl haplo.em:}\ \ for the estimation of haplotype frequencies and posterior probabilities of haplotype pairs for each subject, conditional on the observed marker data} \item{{\sl haplo.glm:}\ \ generalized linear models for the regression of a trait on haplotypes, with the option of including covariates and interactions} \item{{\sl haplo.score:}\ \ score statistics to test associations between haplotypes and a variety of traits, including binary, ordinal, quantitative, and Poisson} \item{{\sl haplo.score.slide:} \ \ haplo.score computed on sub-haplotypes of a larger region} \item{{\sl seqhap:}\ \ sequentially scan markers in enlarging a haplotype for association with a trait} \item{{\sl haplo.cc:} \ \ run a combined analysis for haplotype frequencies, scores, and regression results for a case-control study} \item{{\sl haplo.power.qt/haplo.power.cc:}\ \ power or sample size calculatins for quantitative or binary trait} \item{{\sl haplo.scan:}\ \ search for a trait locus for all sizes of sub-haplotypes within a fixed maximum window width for all markers in a region} \item{{\sl haplo.design:} \ \ create a design matrix for haplotype effects} \end{itemize} \noindent This manual explains the basic and advanced usage of these routines, with guidelines for running the analyses and interpreting results. We provide many of these details in the function help pages, which are accessed within an R session using {\sl help(haplo.em)}, for example. We also provide brief examples in the help files, which can be run in the R session with {\sl example(haplo.em)}. \subsection{Updates} This version of Haplo Stats contains updates to {\sl haplo.glm} in section~\ref{hapGLM} and new methods written for it that resemble glm class methods. These methods include residuals, fitted.values, vcov, and anova, and they are detailed in section~\ref{glmMethods}. For full history of updates see the NEWS file, or type {\sl news(package=''haplo.stats'')} in the R command prompt. \subsection{Operating System and Installation} Haplo Stats \version\ is written for R (\Rversion). It has been uploaded to the Comprehensive R Archive Network (CRAN), and is made available on various operating systems through CRAN. Package installation within R is made simple from within R using {\sl install.packages(``haplo.stats'')}, but other procedures for installing R packages can be found at the R project website (http://www.r-project.org). \subsection{R Basics} For users who are new to the R environment, we demonstrate some basic concepts. In the following example we create a vector of character alleles and use the {\sl table} function to get allele counts. We first show how to save the results of {\sl table(snp)} into an R session variable, {\sl tab}. We show that {\sl tab} is an object of the {\sl table} class, and use the print and summary methods that are defined for {\sl table} objects. Note that when you enter just {\sl tab} or {\sl table(snp)} at the prompt, the print method is invoked. <>= snp <- c("A", "T", "T", "A", "A", "T", "T") tab <- table(snp) tab class(tab) print.table(tab) summary(tab) tab[2] table(snp) @ \noindent The routines in \package\ are computationally intensive and return lots of information in the returned object. Therefore, we assign classes to the returned objects and provide various methods for each of them. \section{Data Setup} We first show some typical steps when you first load a package and look for details on a function of interest. In the sample code below, we load \package, check which functions are available in the package, view a help file, and run the example that is within the help file. <>= # load the library, load and preview at demo dataset library(haplo.stats) ls(name="package:haplo.stats") help(haplo.em) example(haplo.em) @ <>= options(width=80) rm(list=ls()) library(haplo.stats, lib.loc="~/Rlib") @ \subsection{Example Data} The \package\ package contains three example data sets. The primary data set used in this manual is named {\sl (hla.demo)}, which contains 11 loci from the HLA region on chromosome 6, with covariates, qualitative, and quantitative responses. Within {\sl /haplo.stats/data/hla.demo.tab} the data is stored in tab-delimited format. Typically data stored in this format can be read in using {\sl read.table()}. Since the data is provided in the package, we load the data in R using {\sl data()} and view the names of the columns. Then to make the columns of {\sl hla.demo} accessible without typing it each time, we attach it to the current session. <>= # load and preview demo dataset stored in ~/haplo.stats/data/hla.demo.tab data(hla.demo) names(hla.demo) # attach hla.demo to make columns available in the session attach(hla.demo) @ The column names of {\sl hla.demo} are shown above. They are defined as follows: \begin{itemize} \item{\bf resp:\ }{quantitative antibody response to measles vaccination} \item{\bf resp.cat:\ }{a factor with levels "low", "normal", "high", for categorical antibody response} \item{\bf male:\ }{gender code with {\sl 1="male"}, {\sl 0="female"}} \item{\bf age:\ }{age (in months) at immunization} \end{itemize} \noindent The remaining columns are genotypes for 11 HLA loci, with a prefix name (e.g., "DQB") and a suffix for each of two alleles (".a1" and ".a2"). The variables in {\sl hla.demo}\ can be accessed by typing {\sl hla.demo\$}\ before their names, such as {\sl hla.demo\$resp}. Alternatively, it is easier for these examples to attach {\sl hla.demo}, (as shown above with {\sl attach()}) so the variables can be accessed by simply typing their names. \subsection{Creating a Genotype Matrix} Many of the functions require a matrix of genotypes, denoted below as {\sl geno}. This matrix is arranged such that each locus has a pair of adjacent columns of alleles, and the order of columns corresponds to the order of loci on a chromosome. If there are K loci, then the number of columns of {\sl geno} is $2K$. Rows represent the alleles for each subject. For example, if there are three loci, in the order A-B-C, then the 6 columns of {\sl geno} would be arranged as A.a1, A.a2, B.a1, B.a2, C.a1, C.a2. For illustration, three of the loci in {\sl hla.demo} will be used to demonstrate some of the functions. Create a separate data frame for 3 of the loci, and call this {\sl geno}. Then create a vector of labels for the loci. <>= geno <- hla.demo[,c(17,18,21:24)] label <-c("DQB","DRB","B") @ \noindent The {\sl hla.demo} data already had alleles in two columns for each locus. For many SNP datasets, the data is in a one column format, giving the count of the minor allele. To assist in converting this format to two columns, a function named {\sl geno1to2} has been added to the package. See its help file for more details. \subsection{Preview Missing Data: {\sl summaryGeno}} Before performing a haplotype analysis, the user will want to assess missing genotype data to determine the completeness of the data. If many genotypes are missing, the functions may take a long time to compute results, or even run out of memory. For these reasons, the user may want to remove some of the subjects with a lot of missing data. This step can be guided by using the {\sl summaryGeno}\ function, which checks for missing allele information and counts the number of potential haplotype pairs that are consistent with the observed data (see the Appendix for a description of this counting scheme). The codes for missing alleles are defined by the parameter {\sl miss.val}, a vector to define all possible missing value codes. Below, the result is saved in {\sl geno.desc}, which is a data frame, so individual rows may be printed. Here we show the results for subjects 1-10, 80-85, and 135-140, some of which have missing alleles. <>= geno.desc <- summaryGeno(geno, miss.val=c(0,NA)) print(geno.desc[c(1:10,80:85,135:140),]) @ \noindent The columns with {\sl 'loc miss-'} illustrate the number of loci missing either 0, 1, or 2 alleles, and the last column, {\sl num\_enum\_rows}, illustrates the number of haplotype pairs that are consistent with the observed data. In the example above, subjects indexed by rows 81 and 137 have missing alleles. Subject \#81 has one locus missing two alleles, while subject \#137 has two loci missing two alleles. As indicated by {\sl num\_enum\_rows}, subject \#81 has 1,800 potential haplotype pairs, while subject \#137 has nearly 130,000. The 130,000 haplotype pairs is considered a large number, but {\sl haplo.em}, {\sl haplo.score}, and {\sl haplo.glm} complete in roughly 3-6 minutes (depending on system limits or control parameter settings). If person \#137 were removed, the methods would take less than half that time. It is preferred to keep people if they provide information to the analysis, given that run time and memory usage are not too much of a burden. When a person has no genotype information, they do not provide information to any of the methods in \package. Furthermore, they cause a much longer run time. Below, using the {\sl table} function on the third column of {\sl geno.desc}, we can tabulate how many people are missing two alleles at any at of the three loci. If there were people missing two alleles at all three loci, they should be removed. The second command below shows how to make an index of which people to remove from {\sl hla.demo} because they are missing all their alleles. <>= # find if there are any people missing all alleles table(geno.desc[,3]) @ <>= ## create an index of people missing all alleles miss.all <- which(geno.desc[,3]==3) # use index to subset hla.demo hla.demo.updated <- hla.demo[-miss.all,] @ \subsection{Random Numbers and Setting Seed \label{seed} } Random numbers are used in several of the functions (e.g., to determine random starting frequencies within {\sl haplo.em}, and to compute permutation p-values in {\sl haplo.score}). To reproduce calculations involving random numbers, we set the seed values stored in a vector called {\sl .Random.seed}. This vector can be set using {\sl set.seed()} before any function which uses random numbers. Section \ref{glmBaseline} shows one example of setting the seed for {\sl haplo.glm}. We illustrate setting the seed below. <>= # this is how to set the seed for reproducing results where haplo.em is # involved, and also if simulations are run. In practice, don't reset seed. seed <- c(17, 53, 1, 40, 37, 0, 62, 56, 5, 52, 12, 1) set.seed(seed) @ \section{Haplotype Frequency Estimation: {\sl haplo.em}} \subsection{Algorithm} For genetic markers measured on unrelated subjects, with linkage phase unknown, {\sl haplo.em} computes maximum likelihood estimates of haplotype probabilities. Because there may be more than one pair of haplotypes that are consistent with the observed marker phenotypes, posterior probabilities of haplotype pairs for each subject are also computed. Unlike the usual EM which attempts to enumerate all possible haplotype pairs before iterating over the EM steps, our {\em progressive insertion} algorithm progressively inserts batches of loci into haplotypes of growing lengths, runs the EM steps, trims off pairs of haplotypes per subject when the posterior probability of the pair is below a specified threshold, and then continues these insertion, EM, and trimming steps until all loci are inserted into the haplotype. The user can choose the batch size. If the batch size is chosen to be all loci, and the threshold for trimming is set to 0, then this reduces to the usual EM algorithm. The basis of this progressive insertion algorithm is from the "snphap" software by David Clayton\cite{Clayton}. Although some of the features and control parameters of {\sl haplo.em} are modeled after {\sl snphap}, there are substantial differences, such as extension to allow for more than two alleles per locus, and some other nuances on how the algorithm is implemented. \subsection{Example Usage \label{hapEM}} We use {\sl haplo.em} on {\sl geno} for the 3 loci defined above and save the result in an object named {\sl save.em}, which has the {\sl haplo.em} class. The print method would normally print all 178 haplotypes from {\sl save.em}, but to keep the results short for this manual, we give a quick glance of the output by using the option {\sl nlines=10}, which prints only the first 10 haplotypes of the full results. The {\sl nlines} parameter has been employed in some of Haplo Stats' print methods for when there are many haplotypes. In practice, it is best to exclude this parameter so that the default will print all results. <>= set.seed(seed) @ <>= save.em <- haplo.em(geno=geno, locus.label=label, miss.val=c(0,NA)) names(save.em) print(save.em, nlines=10) @ \Explain The print methods shows the haplotypes and their estimated frequencies, followed by the final log-likelihood statistic and the {\sl lr stat for no LD}, which is the likelihood ratio test statistic contrasting the {\sl lnlike} for the estimated haplotype frequencies versus the {\sl lnlike} under the null assuming that alleles from all loci are in linkage equilibrium. We note that the trimming by the progressive insertion algorithm can invalidate the {\sl lr stat} and the degrees of freedom ({\sl df}).\\ \subsection{Summary Method} The {\sl summary} method for a {\sl haplo.em} object on {\sl save.em} shows the list of haplotypes per subject, and their posterior probabilities: <>= summary(save.em, nlines=7) @ \Explain The first part of the {\sl summary} output lists the subject id (row number of input {\sl geno} matrix), the codes for the haplotypes of each pair, and the posterior probabilities of the haplotype pairs. The second part gives a table of the maximum number of pairs of haplotypes per subject, versus the number of pairs used in the final posterior probabilities. The haplotype codes remove the clutter of illustrating all the alleles of the haplotypes, but may not be as informative as the actual haplotypes themselves. To see the actual haplotypes, use the {\sl show.haplo=TRUE} option, as in the following example. <>= # show full haplotypes, instead of codes summary(save.em, show.haplo=TRUE, nlines=7) @ \subsection{Control Parameters for {\sl haplo.em} \label{emControl}} A set of control parameters can be passed together to {\sl haplo.em} as the ``{\sl control}" argument. This is a list of parameters that control the EM algorithm based on progressive insertion of loci. The default values are set by a function called {\sl haplo.em.control} (see {\sl help(haplo.em.control)} for a complete description). Although the user can accept the default values, there are times when control parameters may need to be adjusted. These parameters are defined below: \begin{itemize} \item{} {\bf insert.batch.size:\ } Number of loci to be inserted in a single batch. \item{} {\bf min.posterior:\ } Minimum posterior probability of haplotype pair, conditional on observed marker genotypes. Posteriors below this minimum value will have their pair of haplotypes "trimmed" off the list of possible pairs. \item{}{\bf max.iter:\ } Maximum number of iterations allowed for the EM algorithm before it stops and prints an error. \item{}{\bf n.try:\ } Number of times to try to maximize the {\sl lnlike} by the EM algorithm. The first try will use, as initial starting values for the posteriors, either equal values or uniform random variables, as determined by {\sl random.start}. All subsequent tries will use uniform random values as initial starting values for the posterior probabilities. \item{}{\bf max.haps.limit:\ } Maximum number of haplotypes for the input genotypes. Within haplo.em, the first step is to try to allocate the sum of the result of geno.count.pairs(), if that exceeds max.haps.limit, start by allocating max.haps.limit. If that is exceeded in the progressive-insertions steps, the C function doubles the memory until it can longer request more. \end{itemize} One reason to adjust control parameters is for finding the global maximum of the log-likelihood. It can be difficult in particular for small sample sizes and many possible haplotypes. Different maximizations of the log-likelihood may result in different results from {\sl haplo.em}, {\sl haplo.score}, or {\sl haplo.glm} when rerunning the analyses. The algorithm uses multiple attempts to maximize the log-likelihood, starting each attempt with random starting values. To increase the chance of finding the global maximum of the log-likelihood, the user can increase the number of attempts ({\sl n.try}), increase the batch size ({\sl insert.batch.size}), or decrease the trimming threshold for posterior probabilities ({\sl min.posterior}). Another reason to adjust control parameters is when the algorithm runs out of memory because there are too many haplotypes. If {\sl max.haps.limit} is exceeded when a batch of markers is added, the algorithm requests twice as much memory until it runs out. One option is to set {\sl max.haps.limit} to a different value, either to make {\sl haplo.em} request more memory initially, or to request more memory in smaller chunks. Another solution is to make the algorithm trim the number of haplotypes more aggressively by decreasing {\sl insert.batch.size} or increasing {\sl min.posterior}. Any changes to these parameters should be made with caution, and not drastically different from the default values. For instance, the default for {\sl min.posterior} used to be $1e-7$, and in some rare circumstances with many markers in only moderate linkage disequilibrium, some subjects had all their possible haplotype pairs trimmed. The default is now set at $1e-9$, and we recommend not increasing {\sl min.posterior} much greater than $1e-7$. The example below gives the command for increasing the number of tries to $20$, and the batch size to $2$, since not much more can be done for three markers. <>= # demonstrate only the syntax of control parameters save.em.try20 <- haplo.em(geno=geno, locus.label=label, miss.val=c(0, NA), control = haplo.em.control(n.try = 20, insert.batch.size=2)) @ \subsection{Haplotype Frequencies by Group Subsets} To compute the haplotype frequencies for each level of a grouping variable, use the function {\sl haplo.group}. The following example illustrates the use of a binomial response based on {\sl resp.cat}, {\sl y.bin}, that splits the subjects into two groups. <>= set.seed(seed) @ <>= ## run haplo.em on sub-groups ## create ordinal and binary variables y.bin <- 1*(resp.cat=="low") group.bin <- haplo.group(y.bin, geno, locus.label=label, miss.val=0) print(group.bin, nlines=15) @ \Explain The {\sl group.bin} object can be very large, depending on the number of possible haplotypes, so only a portion of the output is illustrated above (limited again by {\sl nlines}). The first section gives a short summary of how many subjects appear in each of the groups. The second section is a table with the following columns: \begin{itemize} \item The first column gives row numbers. \item The next columns (3 in this example) illustrate the alleles of the haplotypes. \item {\sl Total} are the estimated haplotype frequencies for the entire data set. \item The last columns are the estimated haplotype frequencies for the subjects in the levels of the group variable ({\sl y.bin=0} and {\sl y.bin=1} in this example). Note that some haplotype frequencies have an {\sl NA}, which appears when the haplotypes do not occur in the subgroups. \end{itemize} \section{Power and Sample Size for Haplotype Association Studies\label{hapPower}} It is known that using haplotypes has greater power than single-markers to detect genetic association in some circumstances. There is little guidance, however, in determining sample size and power under different circumstances, some of which include: marker type, dominance, and effect size. The \package\ package now includes functions to calculate sample size and power for haplotype association studies, which is flexible to handle these multiple circumstances. Based on work in Schaid 2005\cite{Schaid 2005}, we can take a set of haplotypes with their population frequencies, assign a risk to a subset of the haplotypes, then determine either the sample size to achieve a stated power, or the power for a stated sample size. Sample size and power can be calculated for either quantitative traits or case-control studies. \subsection{Quantitative Traits: {\sl haplo.power.qt}\label{powerQT}} We assume that quantitative traits will be modeled by a linear regression. Some well-known tests for association between haplotypes and the trait include score statistics\cite{Schaid et al. 2002} and an F-test\cite{Zaykin}. For both types of tests, power depends on the amount of variance in the trait that is explained by haplotypes, or a multiple correlation coefficient, $R^{2}$. Rather than specifying the haplotype coefficients directly, we calculate the vector of coefficients based on an $R^{2}$ value. In the example below, we load an example set of haplotypes that contain 5 markers, and specify the indices of the at-risk haplotypes; in this case, whichever haplotype has allele $1$ at the 2nd and 3rd markers. We set the first haplotype (most common) as the baseline. With these values we calculate the vector of coefficients for haplotype effects from {\sl find.haplo.beta.qt} using an $R^{2}=0.01$. Next, we use {\sl haplo.power.qt} to calculate the sample size for the set of haplotypes and their coefficients, type-I error (alpha) set to $0.05$, power at 80\%, and the same mean and variance used to get haplotype coefficients. Then we use the sample size needed for 80\% power for un-phased haplotypes ($2,826$) to get the power for both phased and un-phased haplotypes. <>= # load a set of haplotypes (hap-1 from Schaid 2005) data(hapPower.demo) #### an example using save.em hla markers may go like this. # keep <- which(save.em$hap.prob > .004) # get an index of non-rare haps # hfreq <- save.em$hap.prob[keep] # hmat <- save.em$haplotype[keep,] # hrisk <- which(hmat[,1]==31 & hmat[,2]==11) # contains 3 haps with freq=.01 # hbase <- 4 # 4th hap has mas freq of .103 #### ## separate the haplotype matrix and the frequencies hmat <- hapPower.demo[,-6] hfreq <- hapPower.demo[,6] ## Define risk haplotypes as those with "1" allele at loc2 and loc3 hrisk <- which(hmat$loc.2==1 & hmat$loc.3==1) # define index for baseline haplotype hbase <- 1 hbeta.list <- find.haplo.beta.qt(haplo=hmat, haplo.freq=hfreq, base.index=hbase, haplo.risk=hrisk, r2=.01, y.mu=0, y.var=1) hbeta.list ss.qt <- haplo.power.qt(hmat, hfreq, hbase, hbeta.list$beta, y.mu=0, y.var=1, alpha=.05, power=.80) ss.qt power.qt <- haplo.power.qt(hmat, hfreq, hbase, hbeta.list$beta, y.mu=0, y.var=1, alpha=.05, sample.size=2826) power.qt @ \subsection{Case-Control Studies: {\sl haplo.power.cc} \label{powerCC}} The steps to compute sample size and power for case-control studies is similar to the steps for quantitative traits. If we assume a log-additive model for haplotype effects, the haplotype coefficients can be specified first as odds ratios (OR), and then converted to logistic regression coefficients according to $log(OR)$. In the example below, we assume the same baseline and risk haplotypes defined in section~\ref{powerQT}, give the risk haplotypes an odds ratio of 1.50, and specify a population disease prevalance of 10\%. We also assume cases make up 50\% ({\sl case.frac}) of the study\'s subjects. We first compute the sample size for this scenario for Type-I error (alpha) at $0.05$ and 80\% power, and then compute power for the sample size required for un-phased haplotypes ($4,566$). <>= ## get power and sample size for quantitative response ## get beta vector based on odds ratios cc.OR <- 1.5 # determine beta regression coefficients for risk haplotypes hbeta.cc <- numeric(length(hfreq)) hbeta.cc[hrisk] <- log(cc.OR) # Compute sample size for stated power ss.cc <- haplo.power.cc(hmat, hfreq, hbase, hbeta.cc, case.frac=.5, prevalence=.1, alpha=.05, power=.8) ss.cc # Compute power for given sample size power.cc <- haplo.power.cc(hmat, hfreq, hbase, hbeta.cc, case.frac=.5, prevalence=.1, alpha=.05, sample.size=4566) power.cc @ \section{Haplotype Score Tests: {\sl haplo.score} \label{hapScore}} The {\sl haplo.score} routine is used to compute score statistics to test association between haplotypes and a wide variety of traits, including binary, ordinal, quantitative, and Poisson. This function provides several different global and haplotype-specific tests for association and allows for adjustment for non-genetic covariates. Haplotype effects can be specified as additive, dominant, or recessive. This method also has an option to compute permutation p-values, which may be needed for sparse data when distribution assumptions may not be met. Details on the background and theory of the score statistics can be found in Schaid et al.\cite{Schaid et al. 2002}. \subsection{Quantitative Trait Analysis} First, we assess a haplotype association with a quantitative trait in {\sl hla.demo} called {\sl resp}. To tell {\sl haplo.score} the trait is quantitative, specify the parameter {\sl trait.type="gaussian"} (a reminder that a gaussian distribution is assumed for the error terms). The other arguments, all set to default values, are explained in the help file. Note that rare haplotypes can result in unstable variance estimates, and hence unreliable test statistics for rare haplotypes. We restrict the analysis to get scores for haplotypes with a minimum sample count using {\sl min.count=5}. For more explanation on handling rare haplotypes, see section~\ref{freqmin}. Below is an example of running {\sl haplo.score} with a quantitative trait, then viewing the results using the {\sl print} method for the {\sl haplo.score} class. (again, output shortened by {\sl nlines}). <>= set.seed(seed) @ <>= # score statistics w/ Gaussian trait score.gaus.add <- haplo.score(resp, geno, trait.type="gaussian", min.count=5, locus.label=label, simulate=FALSE) print(score.gaus.add, nlines=10) @ \Explain First, the model effect chosen by {\sl haplo.effect} is printed across the top. The section {\sl Global Score Statistics} shows results for testing an overall association between haplotypes and the response. The {\sl global-stat} has an asymptotic $\chi^{2}$ distribution, with degrees of freedom ({\sl df}) and {\sl p-value} as indicated. Next, {\sl Haplotype-specific scores} are given in a table format. The column descriptions are as follows: \begin{itemize} \item{} The first column gives row numbers. \item{} The next columns (3 in this example) illustrate the alleles of the haplotypes. \item{} {\sl Hap-Freq} is the estimated frequency of the haplotype in the pool of all subjects. \item{} {\sl Hap-Score} is the score for the haplotype, the results are sorted by this value. Note, the score statistic should not be interpreted as a measure of the haplotype effect. \item{} {\sl p-val} is the asymptotic $\chi^{2}_1$ p-value, calculated from the square of the score statistic. \end{itemize} \subsection{Binary Trait Analysis} Let us assume that "low" responders are of primary interest, so we create a binary trait that has values of 1 when {\sl resp.cat} is "low", and 0 otherwise. Then in {\sl haplo.score} specify the parameter {\sl trait.type="binomial"}. <>= set.seed(seed) @ <>= # scores, binary trait y.bin <- 1*(resp.cat=="low") score.bin <- haplo.score(y.bin, geno, trait.type="binomial", x.adj = NA, min.count=5, haplo.effect="additive", locus.label=label, miss.val=0, simulate=FALSE) print(score.bin, nlines=10) @ \subsection{Ordinal Trait Analysis} To create an ordinal trait, here we convert {\sl resp.cat} (described above) to numeric values, {\sl y.ord} (with levels 1, 2, 3). For {\sl haplo.score}, use {\sl y.ord} as the response variable, and set the parameter {\sl trait.type = "ordinal"}. <>= set.seed(seed) @ <>= # scores w/ ordinal trait y.ord <- as.numeric(resp.cat) score.ord <- haplo.score(y.ord, geno, trait.type="ordinal", x.adj = NA, min.count=5, locus.label=label, miss.val=0, simulate=FALSE) print(score.ord, nlines=7) @ \noindent{\bf \large Warning for Ordinal Traits \vspace{.06in}\\} When analyzing an ordinal trait with adjustment for covariates (using the {\sl x.adj} option), the software requires the {\sl rms} package, distributed by Frank Harrell \cite{Harrell}. If the user does not have these packages installed, then it will not be possible to use the {\sl x.adj} option. However, the unadjusted scores for an ordinal trait (using the default option {\sl x.adj=NA}) do not require these pacakgeses. Check the list of your local packages in the list shown from entering {\sl library()}\ in your prompt. \subsection{Haplotype Scores, Adjusted for Covariates} To adjust for covariates in {\sl haplo.score}, first set up a matrix of covariates from the example data. For example, use a column for male (1 if male; 0 if female), and a second column for age. Then pass the matrix to {\sl haplo.score} using parameter {\sl x.adj}. The results change slightly in this example. <>= set.seed(seed) @ <>= # score w/gaussian, adjusted by covariates x.ma <- cbind(male, age) score.gaus.adj <- haplo.score(resp, geno, trait.type="gaussian", x.adj = x.ma, min.count=5, locus.label=label, simulate=FALSE) print(score.gaus.adj, nlines=10) @ \subsection{Plots and Haplotype Labels} A convenient way to view results from {\sl haplo.score} is a plot of the haplotype frequencies ({\sl Hap-Freq}) versus the haplotype score statistics ({\sl Hap-Score}). This plot, and the syntax for creating it, are shown in Figure~\ref{scorePlot}. Some points on the plot may be of interest. To identify individual points on the plot, use \mbox{\sl locator.haplo(score.gaus)}, which is similar to {\sl locator()}. Use the mouse to select points on the plot. After points are chosen, click on the middle mouse button, and the points are labeled with their haplotype labels. Note, in constructing Figure~\ref{scorePlot}, we had to define which points to label, and then assign labels in the same way as done within the {\sl locator.haplo} function. \begin{figure}[h] \begin{center} <>= ## plot score vs. frequency, gaussian response plot(score.gaus.add, pch="o") ## locate and label pts with their haplotypes ## works similar to locator() function #> pts.haplo <- locator.haplo(score.gaus) pts.haplo <- list(x.coord=c(0.05098, 0.03018, .100), y.coord=c(2.1582, 0.45725, -2.1566), hap.txt=c("62:2:7", "51:1:35", "21:3:8")) text(x=pts.haplo$x.coord, y=pts.haplo$y.coord, labels=pts.haplo$hap.txt) @ \caption{Haplotype Statistics: Score vs. Frequency, Quantitative Response} \label{scorePlot} \end{center} \end{figure} \clearpage \subsection{Skipping Rare Haplotypes\label{freqmin}} For the {\sl haplo.score}, the {\sl skip.haplo} and {\sl min.count} parameters control which rare haplotypes are pooled into a common group. The {\sl min.count} parameter is a recent addition to {\sl haplo.score}, yet it does the same task as {\sl skip.haplo} and is the same idea as {\sl haplo.min.count} used in {\sl haplo.glm.control} for {\sl haplo.glm}. As a guideline, you may wish to set {\sl min.count} to calculate scores for haplotypes with expected haplotype counts of $5$ or greater in the sample. We concentrate on this expected count because it adjusts to the size of the input data. If $N$ is the number of subjects and $f$ the haplotype frequency, then the expected haplotype count is \mbox{$count=2 \times N \times f$}. Alternatively, you can choose \mbox{$skip.haplo= \frac{count}{2 \times N}$}. In the following example we try a different cut-off than before, {\sl min.count=10}, which corresponds to {\sl skip.haplo} of $10 \div (2 \times 220) = .045$. In the output, see that the global statistic, degrees of freedom, and p-value change because of the fewer haplotypes, while the haplotype-specific scores do not change. <>= set.seed(seed) @ <>= # increase skip.haplo, expected hap counts = 10 score.gaus.min10 <- haplo.score(resp, geno, trait.type="gaussian", x.adj = NA, min.count=10, locus.label=label, simulate=FALSE) print(score.gaus.min10) @ \subsection{Score Statistic Dependencies: the {\sl eps.svd} parameter \label{scoreEPS}} The global score test is calculated using the vector of scores and the generalized inverse of their variance-covariance matrix, performed by the {\sl Ginv} function. This function determines the rank of the variance matrix by its singular value decomposition, and an epsilon value is used as the cut-off for small singular values. If all of the haplotypes in the sample are scored, then there is dependence between them and the variance matrix is not of full rank. However, it is more often the case that one or more rare haplotypes are not scored because of low frequency. It is not clear how strong the dependencies are between the remaining score statistics, and likewise, there is disparity in calculating the rank of the variance matrix. For these instances we give the user control over the epsilon parameter for {\sl haplo.score} with {\sl eps.svd}. We have seen instances where the global score test had a very significant p-value, but none of the haplotype-specific scores showed strong association. In such instances, we found the default epsilon value in {\sl Ginv} was incorrectly considering the variance matrix as having full rank, and the misleading global score test was corrected when we increased epsilon for {\sl Ginv}. We now set the default for {\sl eps.svd} at $1e-5$, which seems to perform better in the troublesome circumstances than the previous default of $1e-6$. \subsection{Haplotype Model Effect \label{scoreEffect} } A recent addition to {\sl haplo.score} is the ability to select non-additive effects to score haplotypes. The possible effects for haplotypes are additive, dominant, and recessive. Under recessive effects, fewer haplotypes may be scored, because subjects are required to be homozygous for haplotypes. Furthermore, there would have to be {\sl min.count} such persons in the sample to have the recessive effect scored. Therefore, a recessive model should only be used on samples with common haplotypes. In the example below with the gaussian response, set the haplotype effect to dominant using parameter {\sl haplo.effect = ''dominant''}. Notice the results change slightly compared to the {\sl score.gaus.add} results above. <>= set.seed(seed) @ <>= # score w/gaussian, dominant effect score.gaus.dom <- haplo.score(resp, geno, trait.type="gaussian", x.adj=NA, min.count=5, haplo.effect="dominant", locus.label=label, simulate=FALSE) print(score.gaus.dom, nlines=10) @ \subsection{Simulation p-values \label{scoreSim}} When {\sl simulate=TRUE}, {\sl haplo.score} gives simulated p-values. Simulated haplotype score statistics are the re-calculated score statistics from a permuted re-ordering of the trait and covariates and the original ordering of the genotype matrix. The simulated p-value for the global score statistic (\mbox{\sl Global sim. p-val}) is the number of times the simulated global score statistic exceeds the observed, divided by the total number of simulations. Likewise, simulated p-value for the maximum score statistic (\mbox{\sl Max-stat sim. p-val}) is the number of times the simulated maximum haplotype score statistic exceeds the observed maximum score statistic, divided by the total number of simulations. The maximum score statistic is the maximum of the square of the haplotype-specific score statistics, which has an unknown distribution, so its significance can only be given by the simulated p-value. Intuitively, if only one or two haplotypes are associated with the trait, the maximum score statistic should have greater power to detect association than the global statistic. The {\sl score.sim.control} function manages control parameters for simulations. The {\sl haplo.score} function employs the simulation p-value precision criteria of Besag and Clifford\cite{Besag and Clifford 1991}. These criteria ensure that the simulated p-values for both the global and the maximum score statistics are precise for small p-values. The algorithm performs a user-defined minimum number of permutations ({\sl min.sim}) to guarantee sufficient precision for the simulated p-values for score statistics of individual haplotypes. Permutations beyond this minimum are then conducted until the sample standard errors for simulated p-values for both the {\sl global-stat} and {\sl max-stat} score statistics are less than a threshold \mbox{({\sl p.threshold * p-value})}. The default value for \mbox{{\sl p.threshold= $\frac{1}{4}$}} provides a two-sided 95\% confidence interval for the p-value with a width that is approximately as wide as the p-value itself. Effectively, simulations are more precise for smaller p-values. The following example illustrates computation of simulation p-values with {\sl min.sim=1000}. <>= set.seed(seed) @ <>= # simulations when binary response score.bin.sim <- haplo.score(y.bin, geno, trait.type="binomial", x.adj = NA, locus.label=label, min.count=5, simulate=TRUE, sim.control = score.sim.control() ) print(score.bin.sim) @ \section{Regression Models: {\sl haplo.glm} \label{hapGLM}} The {\sl haplo.glm} function computes the regression of a trait on haplotypes, and possibly other covariates and their interactions with haplotypes. We currently support the gaussian, binomial, and Poisson families of traits with their canonical link functions. The effects of haplotypes on the link function can be modeled as either additive, dominant (heterozygotes and homozygotes for a particular haplotype assumed to have equivalent effects), or recessive (homozygotes of a particular haplotype considered to have an alternative effect on the trait). The basis of the algorithm is a two-step iteration process; the posterior probabilities of pairs of haplotypes per subject are used as weights to update the regression coefficients, and the regression coefficients are used to update the haplotype posterior probabilities. See Lake et al.\cite{Lake et al. 2003} for details. \subsection{New and Updated Methods for haplo.glm} We initially wrote {\sl haplo.glm} without much effort of making it work with R's glm class methods. We have now refined the {\sl haplo.glm} class to look and act as much like a glm object as possible with methods defined specifically for the {\sl haplo.glm} class. We provide print and summary methods that make use of the corresponding methods for glm and then add extra information for the haplotypes and their frequencies. Furthermore, we have defined for the {\sl haplo.glm} class some of the standard methods for regression fits, including residuals, fitted.values, vcov, and anova. We describe the challenges that haplotype regression presents with these methods in section~\ref{glmMethods}. \subsection{Preparing the {\sl data.frame} for {\sl haplo.glm} \label{glmSetup}} A critical distinction between {\sl haplo.glm} and all other functions in Haplo Stats is that the definition of the regression model follows the S/R formula standard (see {\sl lm} or {\sl glm}). So, a {\sl data.frame} must be defined, and this object must contain the trait and other optional covariates, plus a special kind of genotype matrix ({\sl geno.glm} for this example) that contains the genotypes of the marker loci. We require the genotype matrix to be prepared using {\sl setupGeno()}, which handles character, numeric, or factor alleles, and keeps the columns of the genotype matrix as a single unit when inserting into (and extracting from) a {\sl data.frame}. The {\sl setupGeno} function recodes all missing genotype value codes given by {\sl miss.val} to NA, and also recodes alleles to integer values. The original allele codes are preserved within an attribute of {\sl geno.glm}, and are utilized within {\sl haplo.glm}. The returned object has class {\sl model.matrix}, and it can be included in a {\sl data.frame} to be used in {\sl haplo.glm}. In the example below we prepare a genotype matrix, {\sl geno.glm}, and create a {\sl data.frame} object, {\sl glm.data}, for use in {\sl haplo.glm}. <>= # set up data for haplo.glm, include geno.glm, # covariates age and male, and responses resp and y.bin geno <- hla.demo[,c(17,18,21:24)] geno.glm <- setupGeno(geno, miss.val=c(0,NA), locus.label=label) attributes(geno.glm) y.bin <- 1*(resp.cat=="low") glm.data <- data.frame(geno.glm, age=age, male=male, y=resp, y.bin=y.bin) @ \subsection{Rare Haplotypes \label{rareHap}} The issue of deciding which haplotypes to use for association is critical in {\sl haplo.glm}. By default it will model a rare haplotype effect so that the effects of other haplotypes are in reference to the baseline effect of the one common happlotype. The rules for choosing haplotypes to be modeled in {\sl haplo.glm} are similar to the rules in {\sl haplo.score}: by a minimum frequency or a minimum expected count in the sample. Two control parameters in {\sl haplo.glm.control} may be used to control this setting: {\sl haplo.freq.min} may be set to a selected minimum haplotype frequency, and {\sl haplo.min.count} may be set to select the cut-off for minimum expected haplotype count in the sample. The default minimum frequency cut-off in {\sl haplo.glm} is set to $0.01$. More discussion on rare haplotypes takes place in section~\ref{controlRare}. \subsection{Regression for a Quantitative Trait \label{glmQuant}} The following illustrates how to fit a regression of a quantitative trait {\sl y} on the haplotypes estimated from the {\sl geno.glm} matrix, and the covariate {\sl male}. For {\sl na.action}, we use {\sl na.geno.keep}, which keeps a subject with missing values in the genotype matrix if they are not missing all alleles, but removes subjects with missing values ({\sl NA}) in either the response or covariate. <>= set.seed(seed) @ <>= # glm fit with haplotypes, additive gender covariate on gaussian response fit.gaus <- haplo.glm(y ~ male + geno.glm, family=gaussian, data=glm.data, na.action="na.geno.keep", locus.label = label, x=TRUE, control=haplo.glm.control(haplo.freq.min=.02)) summary(fit.gaus) @ \Explain The new summary function for {\sl haplo.glm} shows much the same information as summary for glm objects with the extra table for the haplotype frequencies. The above table for {\sl Coefficients} lists the estimated regression coefficients ({\sl coef}), standard errors ({\sl se}), the corresponding t-statistics ({\sl t.stat}), and p-values ({\sl pval}). The labels for haplotype coefficients are a concatenation of the name of the genotype matrix ({\sl geno.glm}) and unique haplotype codes assigned within {\sl haplo.glm}. The haplotypes corresponding to these haplotype codes are listed in the {\sl Haplotypes} table, along with the estimates of the haplotype frequencies ({\sl hap.freq}). The rare haplotypes, those with expected counts less than \mbox{\sl haplo.min.count=5} (equivalent to having frequencies less than \mbox{{\sl haplo.freq.min =} %.01136 \Sexpr{5/(2*nrow(glm.data))}}) in the above example), are pooled into a single category labeled {\sl geno.glm.rare}. The haplotype chosen as the baseline category for the design matrix (most frequent haplotype is the default) is labeled as {\sl haplo.base}; more information on the baseline may be found in section \ref{glmBaseline}. {\subsection{Fitting Haplotype x Covariate Interactions} Interactions are fit by the standard S-language model syntax, using a '$*$' in the model formula to indicate main effects and interactions. Some other formula constructs are not supported, so use the formula parameter with caution. Below is an example of modeling the interaction of {\sl male} and the haplotypes. Because more terms will be estimated in this case, we limit how many haplotypes will be included by increasing {\sl haplo.min.count} to 10. <>= set.seed(seed) @ <>= # glm fit haplotypes with covariate interaction fit.inter <- haplo.glm(formula = y ~ male * geno.glm, family = gaussian, data=glm.data, na.action="na.geno.keep", locus.label = label, control = haplo.glm.control(haplo.min.count = 10)) summary(fit.inter) @ \Explain The listed results are as explained under section~\ref{glmQuant}. The main difference is that the interaction coefficients are labeled as a concatenation of the covariate ({\sl male} in this example) and the name of the haplotype, as described above. In addition, estimates may differ because the model has changed. \subsection{Regression for a Binomial Trait \label{glmBinom}} Next we illustrate the fitting of a binomial trait with the same genotype matrix and covariate. <>= set.seed(seed) @ <>= # gender and haplotypes fit on binary response, # return model matrix fit.bin <- haplo.glm(y.bin ~ male + geno.glm, family = binomial, data=glm.data, na.action = "na.geno.keep", locus.label=label, control = haplo.glm.control(haplo.min.count=10)) summary(fit.bin) @ \Explain The underlying methods for {\sl haplo.glm} are based on a prospective likelihood. Normally, this type of likelihood works well for case-control studies with standard covariates. For ambiguous haplotypes, however, one needs to be careful when interpreting the results from fitting {\sl haplo.glm} to case-control data. Because cases are over-sampled, relative to the population prevalence (or incidence, for incident cases), haplotypes associated with disease will be over-represented in the case sample, and so estimates of haplotype frequencies will be biased. Positively associated haplotypes will have haplotype frequency estimates that are higher than the population haplotype frequency. To avoid this problem, one can weight each subject. The weights for the cases should be the population prevalence, and the weights for controls should be 1 (assuming the disease is rare in the population, and controls are representative of the general population). See Stram et al.\cite{Stram et al. 2003} for background on using weights, and see the help file for {\sl haplo.glm} for how to implement weights. The estimated regression coefficients for case-control studies can be biased by either a large amount of haplotype ambiguity and mis-specified weights, or by departures from Hardy-Weinberg Equilibrium of the haplotypes in the pool of cases and controls. Generally, the bias is small, but tends to be towards the null of no association. See Stram et al. \cite{Stram et al. 2003} and Epstein and Satten \cite{Epstein and Satten 2003} for further details. \subsubsection{Caution on Rare Haplotypes with Binomial Response \label{rarebinom}} If a rare haplotype occurs only in cases or only in controls, the fitted values would go to 0 or 1, where R would issue a warning. Also, the coefficient estimate for that haplotype would go to positive or negative infinity, If the default {\sl haplo.min.count=5} were used above, this warning would appear. To keep this from occuring in other model fits, increase the minimum count or minimum frequency. \subsection{Control Parameters \label{glmControl}} Additional parameters are handled using {\sl control}, which is a list of parameters providing additional functionality in {\sl haplo.glm}. This list is set up by the function {\sl haplo.glm.control}. See the help file ({\sl help(haplo.glm.control)}) for a full list of control parameters, with details of their usage. Some of the options are described here. \subsubsection{Controlling Genetic Models: {\sl haplo.effect}} The {\sl haplo.effect} control parameter for {\sl haplo.glm} instructs whether the haplotype effects are fit as additive, dominant, or recessive. That is, {\sl haplo.effect} determines whether the covariate ($x$) coding of haplotypes follows the values in Table 1 for each effect type. Heterozygous means a subject has one copy of a particular haplotype, and homozygous means a subject has two copies of a particular haplotype. \\ \\ \\ \\ \noindent {\bf Table 1:} Coding haplotype covariates in a model matrix\\ \begin{center} \begin{tabular}{|r|c|c|c|} \hline Hap - Pair & additive & dominant & recessive\\ \hline \hline Heterozygous & 1 & 1 & 0 \\ \hline Homozygous & 2 & 1 & 1 \\ \hline \end{tabular} \end{center} \noindent Note that in a recessive model, the haplotype effects are estimated only from subjects who are homozygous for a haplotype. Some of the haplotypes which meet the {\sl haplo.freq.min} and {\sl haplo.count.min} cut-offs may occur as homozygous in only a few of the subjects. As stated in \ref{scoreEffect}, recessive models should be used when the region has multiple common haplotypes. The default {\sl haplo.effect} is {\sl additive}, whereas the example below illustrates the fit of a {\sl dominant} effect of haplotypes for the gaussian trait with the gender covariate. <>= set.seed(seed) @ <>= # control dominant effect of haplotypes (haplo.effect) # by using haplo.glm.control fit.dom <- haplo.glm(y ~ male + geno.glm, family = gaussian, data = glm.data, na.action = "na.geno.keep", locus.label = label, control = haplo.glm.control(haplo.effect='dominant', haplo.min.count=8)) summary(fit.dom) @ \subsubsection{Selecting the Baseline Haplotype \label {glmBaseline} } The haplotype chosen for the baseline in the model is the one with the highest frequency. Sometimes the most frequent haplotype may be an at-risk haplotype, and so the measure of its effect is desired. To specify a more appropriate haplotype as the baseline in the binomial example, choose from the list of other common haplotypes, {\sl fit.bin\$haplo.common}. To specify an alternative baseline, such as haplotype 77, use the control parameter {\sl haplo.base} and haplotype code, as in the example below. <>= set.seed(seed) @ <>= # control baseline selection, perform the same exact run as fit.bin, # but different baseline by using haplo.base chosen from haplo.common fit.bin$haplo.common fit.bin$haplo.freq.init[fit.bin$haplo.common] fit.bin.base77 <- haplo.glm(y.bin ~ male + geno.glm, family = binomial, data = glm.data, na.action = "na.geno.keep", locus.label = label, control = haplo.glm.control(haplo.base=77, haplo.min.count=8)) summary(fit.bin.base77) @ \Explain The above model has the same haplotypes as {\sl fit.bin}, except haplotype $4$, the old baseline, now has an effect estimate while haplotype $77$ is the new baseline. Due to randomness in the starting values of the haplotype frequency estimation, different runs of {\sl haplo.glm} may result in a different set of haplotypes meeting the minimum counts requirement for being modeled. Therefore, once you have arrived at a suitable model, and you wish to modify it by changing baseline and/or effects, you can make results consistent by controlling the randomness using {\sl set.seed}, as described in section \ref{seed}. In this document, we use the same seed before making {\sl fit.bin} and {\sl fit.bin.base77}. \subsubsection{Rank of Information Matrix and eps.svd ({\bf NEW}) \label{glmSVD}} Similar to recent additions to {\sl haplo.score} in section~\ref{scoreEPS}, we give the user control over the epsilon parameter determining the number of singular values when determining the rank of the information matrix in {\sl haplo.glm}. Finding the generalized inverse of this matrix can be problematic when either the response variable or a covariate has a large variance and is not scaled before passed to {\sl haplo.glm}. The rank of the information matrix is determined by the number of non-zero singular values a small cutoff, epsilon. When the singular values for the coefficients are on a larger numeric scale than those for the haplotype frequencies, the generalized inverse may incorrectly determine the information matrix is not of full rank. Therefore, we allow the user to specify the epsilon as {\sl eps.svd} in the control parameters for {\sl haplo.glm}. A simpler fix, which we strongly suggest, is for the user to pre-scale any continuous responses or covariates with a large variance. Here we demonstrate what happens when we increase the variance of a gaussian response by $2500$. We see that the coefficients are all highly significant and the rank of the information matrix is much smaller than the scaled gaussian fit. <>= set.seed(seed) @ <>= glm.data$ybig <- glm.data$y*50 fit.gausbig <- haplo.glm(formula = ybig ~ male + geno.glm, family = gaussian, data = glm.data, na.action = "na.geno.keep", locus.label = label, control = haplo.glm.control(haplo.freq.min = 0.02), x = TRUE) summary(fit.gausbig) fit.gausbig$rank.info fit.gaus$rank.info @ Now we set a smaller value for the {\sl eps.svd} control parameter and find the fit matches the original Gaussian fit. <>= set.seed(seed) @ <>= fit.gausbig.eps <- haplo.glm(formula = ybig ~ male + geno.glm, family = gaussian, data = glm.data, na.action = "na.geno.keep", locus.label = label, control = haplo.glm.control(eps.svd=1e-10, haplo.freq.min = 0.02), x = TRUE) summary(fit.gausbig.eps) fit.gausbig.eps$rank.info @ \subsubsection{Rare Haplotypes and {\sl haplo.min.info} \label{controlRare}} Another notable control parameter is the minimum frequency for a rare haplotype to be included in the calculations for standard error (se) of the coefficients, or {\sl haplo.min.info}. The default value is $0.001$, which means that haplotypes with frequency less than that will be part of the rare haplotype coefficient estimate, but it will not be used in the standard error calculation. The following example demonstrates a possible result when dealing with the rare haplotype effect. We show with the hla genotype data one consequence for when this occurs. However, we make it happen by setting {\sl haplo.freq.min} equal to {\sl haplo.min.info}, which we advise strongly against in your analyses. <>= set.seed(seed) @ <>= ## set haplo.freq.min and haplo.min.info to same value to show how the ## rare coefficient may be modeled but standard error estimate is not ## calculated because all haps are below haplo.min.info fit.bin.rare02 <- haplo.glm(y.bin ~ geno.glm, family = binomial, data = glm.data, na.action = "na.geno.keep", locus.label = label, control = haplo.glm.control(haplo.freq.min=.02, haplo.min.info=.02)) summary(fit.bin.rare02) @ \Explain The above results show the standard error for the rare haplotype coefficient is ``NaN'', or ``Not a Number'' in R, which is a consequence of having most, or all, of the rare haplotypes discarded for the standard error estimate. In other datasets there may be only a few haplotypes between {\sl haplo.min.info} and {\sl haplo.freq.min}, and may yield misleading results for the rare haplotype coefficient. For this reason, we recommend that any inference made on the rare haplotypes be made with caution, if at all. \section{Methods for {\sl haplo.glm} {\bf (NEW)} \label{glmMethods}} The latest updates to \package\ is our work to make {\sl haplo.glm} to act similar to a glm object with methods to compare and assess model fits. In this section we describe the challenges and caveats of defining these methods for a {\sl haplo.glm} object and show how to use them. \subsection{fitted.values} A challenge when defining methods for {\sl haplo.glm} is that we account for the ambiguity in a persons haplotype pair. To handle this in the glm framework, the response and non-haplotype covariates are expanded for each person with a posterior probability of the haplotype given their genotype as a weight. The returned object from {\sl haplo.glm} looks somewhat like a regular glm, but the model matrix, response, and thus the fitted values, are all expanded. Users who want to work with the expanded versions of those items are welcome to access them from the returned object. We now provide a method to get the fitted values for each person, {\sl fitted.haplo.glm}. These collapsed fitted values are calculated by a weighted sum of the expanded fitted values for each person where the weights are the posterior probabilities of the person's expanded haplotype pairs. \subsection{residuals} The residuals within the {\sl haplo.glm} object are also expanded for the haplotype pairs for subjects. We provide {\sl residuals.haplo.glm} to get the collapsed deviance, pearson, working, and response residuals for each person. Because we have not implemented a predict method for {\sl haplo.glm}, the method does not calculate partial residuals. \subsection{vcov} We provide {\sl vcov.haplo.glm} as a method to get the variance-covariance matrix of model parameters in the {\sl haplo.glm} object. Unlike the standard glm object, this matrix is computed and retained in the returned object. We do this because the model parameters are the model coefficients and the haplotype frequencies, and it is computationally-intensive to compute. We show how to get the variance matrix for all the parameters and for only the model coefficients. <>= varmat <- vcov(fit.gaus) dim(varmat) varmat <- vcov(fit.gaus, freq=FALSE) dim(varmat) print(varmat, digits=2) @ \subsection{anova and Model Comparison} We use the {\sl anova.glm} method as a framework for {\sl anova.haplo.glm} to allow comparisons of model fits. We limit the model comparisons to multiple nested model fits, which requires that each model to be compared is either a {\sl haplo.glm} or {\sl glm} fitted object. We eliminate the functionality of testing sub-models of a single fit because removal of a single covariate would require re-fitting of the reduced model to get updated coefficient and haplotype frequency estimates with a maximized log-likelihood. We decided to simplify the usage and require that all models to be compared are fully fitted. As with the {\sl anova.glm} method, it is difficult to check for truly nested models, so we pass the responsibility on to the user. We discuss some of the requirements. One type of two-model comparison is between models with haplotypes (expanded subjects) and a reduced model without haplotypes. We check for the same sample size in these models by comparing the collapsed sample size from a {\sl haplo.glm} fit to the sample size from the {\sl glm} fit, which we remind users is only a loose check of model comparability. The other comparison of two models in {\sl anova.haplo.glm} is to compare two models that contain the same genotypes, and inherently the same haplotypes. This is more tricky because a subject may not have the same expanded set of possible haplotype pairs across two fits of {\sl haplo.glm} unless the same seed is set before both fits. Even if a seed is the same, the other effects that are different between the two models will affect the haplotype frequency estimates, and may still result in a different expansion of haplotype pairs per subject. Our check of the collapsed sample size for the two models still applies with the same pitfalls, but a better assurance of model comparability is to use the same seed. In the {\sl haplo.glm} fit we provide the likelihood ratio test of the null model against the full model, which is the most appropriate test available for {\sl haplo.glm} objects, but it is difficult to compare the log-likeihood across two {\sl haplo.glm} fits. Therefore, we remain consistent with glm model comparison \cite{McCullaghNelder}, and use the difference in deviance to compare models. Furthermore, we restrict the asymptotic test for model comparison to be the $\chi^{2}$ test for goodness of fit. Below we show how to get the LRT from the {\sl fit.gaus} result, then show how to compare some of the nested models fit above, including a regular glm fit of $y \sim male$. The anova method requires the nested model to be given first, and any anova with a {\sl haplo.glm} object should explicitly call {\sl anova.haplo.glm}. <>= fit.gaus$lrt glmfit.gaus <- glm(y~male, family="gaussian", data=glm.data) anova.haplo.glm(glmfit.gaus, fit.gaus) anova.haplo.glm(fit.gaus, fit.inter) anova.haplo.glm(glmfit.gaus, fit.gaus, fit.inter) @ \section{Extended Applications} The following functions are designed to wrap the functionality of the major functions in Haplo Stats into other useful applications. \subsection{Combine Score and Group Results: {\sl haplo.score.merge}} When analyzing a qualitative trait, such as binary, it can be helpful to align the results from {\sl haplo.score} with {\sl haplo.group}. To do so, use the function {\sl haplo.score.merge}, as illustrated in the following example: <>= # merge haplo.score and haplo.group results merge.bin <- haplo.score.merge(score.bin, group.bin) print(merge.bin, nlines=10) @ \Explain The first column is a row index, the next columns (3 in this example) illustrate the haplotype, the {\sl Hap.Score} column is the score statistic and {\sl p.val} the corresponding $ \chi^{2} $ p-value. {\sl Hap.Freq} is the haplotype frequency for the total sample, and the remaining columns are the estimated haplotype frequencies for each of the group levels ({\sl y.bin} in this example). The default print method only prints results for haplotypes appearing in the {\sl haplo.score} output. To view all haplotypes, use the print option {\sl all.haps=TRUE}, which prints all haplotypes from the {\sl haplo.group} output. The output is ordered by the score statistic, but the {\sl order.by} parameter can specify ordering by haplotypes or by haplotype frequencyies. \subsection{Case-Control Haplotype Analysis: {\sl haplo.cc} \label{hapCC} } It is possible to combine the results of {\sl haplo.score}, {\sl haplo.group}, and {\sl haplo.glm} for case-control data, all performed within {\sl haplo.cc}. The function peforms a score test and a glm on the same haplotypes. The parameters that determine which haplotypes are used are {\sl haplo.min.count} and {\sl haplo.freq.min}, which are set in the {\sl control} parameter, as done for {\sl haplo.glm}. This is a change from previous versions, where {\sl haplo.min.count} was in the parameter list for {\sl haplo.cc}. Below we run {\sl haplo.cc} setting the minimum haplotype frequency at $0.02$. The print results are shown, in addition to the names of the objects stored in the {\sl cc.hla} result. <>= set.seed(seed) @ <>= # demo haplo.cc where haplo.min.count is specified # use geno, and this function prepares it for haplo.glm y.bin <- 1*(hla.demo$resp.cat=="low") cc.hla <- haplo.cc(y=y.bin, geno=geno, locus.label = label, control=haplo.glm.control(haplo.freq.min=.02)) ##, em.c=haplo.em.control(iseed=10))) perhaps not needed?? print(cc.hla, nlines=25, digits=2) names(cc.hla) @ \Explain First, from the names function we see that {\sl cc.hla} also contains {\sl score.lst} and {\sl fit.lst}, which are the {\sl haplo.score} and {\sl haplo.glm} objects, respectively. For the printed results of {\sl haplo.cc}, first are the global statistics from {\sl haplo.score}, followed by cell counts for cases and controls. The last portion of the output is a data frame containing combined results for individual haplotypes: \begin{itemize} \item{} {\bf Hap-Score:}{\ haplotype score statistic} \item{} {\bf p-val:}{\ haplotype score statistic p-value} \item{} {\bf sim p-val:}{\ (if simulations performed) simulated p-value for the haplotype score statistic} \item{} {\bf pool.hf:}{\ haplotype frequency for the pooled sample} \item{} {\bf control.hf:}{\ haplotype frequencies for the control sample only} \item{} {\bf case.hf:}{\ haplotype frequencies for the case sample only} \item{} {\bf glm.eff:}{\ one of three ways the haplotype appeared in the glm model: {\sl Eff}: modeled as an effect; {\sl Base}: part of the baseline; and {\sl R}: a rare haplotype, included in the effect of pooled rare haplotypes} \item{} {\bf OR.lower:}{\ Odds Ratio confidence interval lower limit} \item{} {\bf OR:}{\ Odds Ratio for each effect in the model} \item{} {\bf OR.upper:}{\ Odds Ratio confidence interval upper limit} \end{itemize} Significance levels are indicated by the p-values for the score statistics, and the odds ratio (OR) confidence intervals for the haplotype effects. Note that the Odds Ratios are effect sizes of haplotypes, assuming haplotype effects are multiplicative. Since this last table has many columns, lines are wrapped in the output in this manual. You can align wrapped lines by the haplotype code which appears on the far left. Alternatively, instruct the print function to only print {\sl digits} significant digits, and set the width settings for output in your session using the {\sl options()} function. \subsection{Score Tests on Sub-Haplotypes: {\sl haplo.score.slide}} To evaluate the association of sub-haplotypes (subsets of alleles from the full haplotype) with a trait, the user can evaluate a "window" of alleles by {\sl haplo.score}, and slide this window across the entire haplotype. This procedure is implemented by the function {\sl haplo.score.slide}. To illustrate this method, we use all 11 loci in the demo data, {\sl hla.demo}. First, make the geno matrix and the locus labels for the 11 loci. Then use {\sl haplo.score.slide} for a window of 3 loci ({\sl n.slide=3}), which will slide along the haplotype for all 9 contiguous subsets of size 3, using the previously defined gaussian trait {\sl resp}. <>= set.seed(seed) @ <>= # haplo.score on 11 loci, slide on 3 consecutive loci at a time geno.11 <- hla.demo[,-c(1:4)] label.11 <- c("DPB","DPA","DMA","DMB","TAP1","TAP2","DQB","DQA","DRB","B","A") score.slide.gaus <- haplo.score.slide(hla.demo$resp, geno.11, trait.type = "gaussian", n.slide=3, min.count=5, locus.label=label.11) print(score.slide.gaus) @ \Explain The first column is the row index of the nine calls to {\sl haplo.score}, the second column is the number of the starting locus of the sub-haplotype, the third column is the global score statistic p-value for each call. The last two columns are the simulated p-values for the global and maximum score statistics, respectively. If you specify {\sl simulate=TRUE} in the function call, the simulated p-values would be present. \subsubsection{Plot Results from {\sl haplo.score.slide}} The results from {\sl haplo.score.slide} can be easily viewed in a plot shown in Figure~\ref{slidePlot} below. The x-axis has tick marks for each locus, and the y-axis is the $ -log_{10}(pval) $. To select which p-value to plot, use the parameter pval, with choices "{\sl global}", "{\sl global.sim}", and "{\sl max.sim}" corresponding to p-values described above. If the simulated p-values were not computed, the default is to plot the global p-values. For each p-value, a horizontal line is drawn at the height of $ -log_{10}(pval) $\ across the loci over which it was calculated. For example, the p-value {\sl score.global.p = 0.009963} for loci 8-10 is plotted as a horizontal line at $ y=2.002 $ spanning the $8^{th}$, $9^{th}$, and $10^{th}$ x-axis tick marks. \begin{figure}[ht] <>= # plot global p-values for sub-haplotypes from haplo.score.slide plot.haplo.score.slide(score.slide.gaus) @ \caption{Global p-values for sub-haplotypes; Gaussian Response} \label{slidePlot} \end{figure} \clearpage \subsection{Scanning Haplotypes Within a Fixed-Width Window: {\sl haplo.scan}} Another method to search for a candidate locus within a genome region is {\sl haplo.scan}, an implementation of the method proposed in Cheng et al. 2005 \cite{Cheng2005}. This method searches for a region for which the haplotypes have the strongest association with a binary trait by sliding a window of fixed width over each marker locus, and then scans over all haplotype lengths within each window. This latter step, scanning over all possible haplotype lengths within a window, distinguishes {\sl haplo.scan} from {\sl haplo.score.slide} (which considers only the maximum haplotype length within a window). To account for unknown linkage phase, the function {\sl haplo.em} is called prior to scanning, to create a list of haplotype pairs and posterior probabilities. To illustrate the scanning window, consider a 10-locus dataset. When placing a window of width 3 over locus 5, the possible haplotype lengths that contain locus 5 are three (loci 3-4-5, 4-5-6, and 5-6-7), two (loci 4-5 and 5-6) and one (locus 5). For each of these loci subsets a score statistic is computed, which is based on the difference between the mean vector of haplotype counts for cases and that for controls. The maximum of these score statistics, over all possible haplotype lengths within a window, is the locus-specific test statistic, or the locus scan statistic. The global test statistic is the maximum over all computed score statistics. To compute p-values, the case/control status is randomly permuted. Below we run {\sl haplo.scan} on the 11-locus HLA dataset with a binary response and a window width of $3$, but first we use the results of {\sl summaryGeno} to choose subjects with less than $50,000$ haplotype pairs to speed calculations with all $11$ polymorphic loci with many missing alleles. <>= set.seed(seed) @ <<>= geno.11 <- hla.demo[,-c(1:4)] y.bin <- 1*(hla.demo$resp.cat=="low") hla.summary <- summaryGeno(geno.11, miss.val=c(0,NA)) # track those subjects with too many possible haplotype pairs ( > 50,000) many.haps <- (1:length(y.bin))[hla.summary[,4] > 50000] # For speed, or even just so it will finish, make y.bin and geno.scan # for genotypes that don't have too many ambigous haplotypes geno.scan <- geno.11[-many.haps,] y.scan <- y.bin[-many.haps] # scan haplotypes for regions within width of 3 for each locus. # test statistic measures difference in haplotype counts in cases and controls # p-values are simulated for each locus and the maximum statistic, # we do 100 simuations here, should use default settings for analysis scan.hla <- haplo.scan(y.scan, geno.scan, width=3, sim.control=score.sim.control(min.sim=100, max.sim=100), em.control=haplo.em.control()) print(scan.hla) @ \Explain In the output we report the simulated p-values for each locus test statistic. Additionally, we report the loci (or locus) which provided the maximum observed test statistic, and the {\sl Max-Stat Simulated Global p-value} is the simulated p-value for that maximum statistic. We print the number of simulations, because they are performed until p-value precision criteria are met, as described in section~\ref{scoreSim}. We would typically allow simulations to run under default parameters rather than limiting to $100$ by the control parameters. \subsection{Sequential Haplotype Scan Methods: {\sl seqhap} \label{seqhap}} Another approach for choosing loci for haplotype associations is by {\sl seqhap}, as described in Yu and Schaid, 2007 \cite{Yu}. The {\sl seqhap} method performs three tests for association of a binary trait over a set of bi-allelic loci. When evaluating each locus, loci close to it are added in a sequential manner based on the Mantel-Haenszel test \cite{Mantel}. For each marker locus, three tests are provided: \begin{itemize} \item{\bf single locus}, the traditional single-locus $\chi^{2}_1$ test of association, \item{\bf sequential haplotype}, based on a haplotype test for sequentially chosen loci, \item{\bf sequential sum}, based on the sum of a series of conditional $\chi^{2}$ statistics. \end{itemize} All three tests are assessed for significance with permutation p-values, in addition to the asymptotic p-value. The point-wise p-value for a statistic at a locus is the fraction of times that the statistic for the permuted data is larger than that for the observed data. The regional p-value is the chance of observing a permuted test statistic, maximized over a region, that is greater than that for the observed data. Similar to the permutation p-values in {\sl haplo.score} as described in section \ref{scoreSim}, permutations are performed until a precision threshold is reached for the regional p-values. A minimum and maximum number of permutations specified in the {\sl sim.control} parameter list ensure a certain accuracy is met for every simulation p-value, yet having a limit to avoid infinite run-time. Below is an example of using {\sl seqhap} on data with case-control response for a chromosome region. First set up the binary response, y, with 0=control, 1=case, then a genotype matrix with two columns per locus, and a vector of chromosome positions. The genotype data is available in the {\sl seqhap.dat} dataset while the chromosome positions are in {\sl seqhap.pos}. The following example runs {\sl seqhap} with default settings for permutations and threshold parameters. <>= set.seed(seed) @ <>= # define binary response and genotype matrix data(seqhap.dat) data(seqhap.pos) y <- seqhap.dat$disease geno <- seqhap.dat[,-1] # get vector with chrom position pos <- seqhap.pos$pos seqhap.out <- seqhap(y=y, geno=geno, pos=pos, miss.val=c(0,NA), r2.threshold=.95, mh.threshold=3.84) seqhap.out$n.sim print(seqhap.out) @ \Explain The output from this example first shows {\sl n.sim}, the number of permutations needed for precision on the regional p-values. Next, in the printed results, the first section ({\sl Single-locus Chi-square Test}) shows a table with columns for single-locus tests. The table includes test statistics, permuted p-values, and asymptotic p-values based on a $\chi^{2}_1$ distribution. The second section ({\sl Sequential Scan}) shows which loci are combined for association. In this example, the table shows the first locus is not combined with other loci, whereas the second locus is combined with loci 3, 4, and 5. The third section ({\sl Sequential Haplotype Test}), shows the test statistics for the sequential haplotype method with degrees of freedom and permuted and asymptotic p-values. The fourth section ({\sl Sequential Sum Test}) shows similar information for the sequential sum tests. \subsubsection{Plot Results from {\sl seqhap}} The results from {\sl seqhap} can be viewed in a useful plot shown in Figure~\ref{seqhapPlot}. The plot is similar to the plot for {\sl haplo.score.slide} results, with the x-axis having tick marks for all loci and the y-axis is the -log10() of p-value for the tests performed. For the sequential result for each locus, a horizontal line at the height of -log10(p-value) is drawn across the loci combined. The start locus is indicated by a filled triangle and other loci combined with the start locus are indicated by an asterisk or circle. The choices for pval include {\sl "hap"} (sequential haplotype asymptotic p-value), {\sl "hap.sim"} (sequential haplotype simulated p-value), {\sl "sum"} (sequential sum asymptotic p-value), and {\sl "sum.sim"} (sequential sum simulated p-value). The other parameter option is {\sl single}, indicating whether to plot a line for the single-locus tests. \begin{figure}[tpb] <>= # plot global p-values for sub-haplotypes from haplo.score.slide plot(seqhap.out, pval="hap", single=TRUE, las=2) @ \caption{Plot p-values for sequential haplotype scan and single-locus tests} \label{seqhapPlot} \end{figure} \clearpage \subsection{Creating Haplotype Effect Columns: {\sl haplo.design} \label{hapDesign}} In some instances, the desired model for haplotype effects is not possible with the methods given in {\sl haplo.glm}. Examples include modeling just one haplotype effect, or modeling an interaction of haplotypes from different chromosomes, or analyzing censored data. To circumvent these limitations, we provide a function called {\sl haplo.design}, which will set up an expected haplotype design matrix from a {\sl haplo.em} object, to create columns that can be used to model haplotype effects in other modeling functions. The function {\sl haplo.design} first creates a design marix for all pairs of haplotypes over all subjects, and then uses the posterior probabilities to create a weighted average contribution for each subject, so that the number of rows of the final design matrix is equal to the number of subjects. This is sometimes called the expectation-substitution method, as proposed by Zaykin et al. 2002 \cite{Zaykin}, and using this haplotype design matrix in a regression model is asymptotically equivalent to the score statistics from {\sl haplo.score} (Xie and Stram 2005 \cite{XieStram}). Although this provides much flexibility, by using the design matrix in any type of regression model, the estimated regression parameters can be biased toward zero (see Lin and Zeng, 2006 \cite{LinZeng} for concerns about the expectation-substitution method). In the first example below, using default parameters, the returned data.frame contains a column for each haplotype that meets a minimum count in the sample {\sl min.count}. The columns are named by the code they are assigned in {\sl haplo.em}. <>= # create a matrix of haplotype effect columns from haplo.em result hap.effect.frame <- haplo.design(save.em) names(hap.effect.frame) hap.effect.frame[1:10,1:8] @ Additionally, {\sl haplo.design} gives the user flexibility to make a more specific design matrix with the following parameters: \begin{itemize} \item{}{\bf hapcodes:\ }{codes assigned in the {\sl haplo.em} object, the only haplotypes to be made into effects} \item{}{\bf haplo.effect:\ }{the coding of haplotypes as additive, dominant, or recessive} \item{}{\bf haplo.base:\ }{code for the baseline haplotype} \item{}{\bf min.count:\ }{minimum haplotype count} \end{itemize} This second example below creates columns for specific haplotype codes that were most interesting in {\sl score.gaus.add}, haplotypes with alleles 21-3-8 and 62-2-7, corresponding to codes 4 and 138 in {\sl haplo.em}, respectively. Assume we want to test their individual effects when they are coded with {\sl haplo.effect=''dominant''}. <>= # create haplotype effect cols for haps 4 and 138 hap4.hap138.frame <- haplo.design(save.em, hapcodes=c(4,138), haplo.effect="dominant") hap4.hap138.frame[1:10,] dat.glm <- data.frame(resp, male, age, hap.4=hap4.hap138.frame$hap.4, hap.138=hap4.hap138.frame$hap.138) glm.hap4.hap138 <- glm(resp ~ male + age + hap.4 + hap.138, family="gaussian", data=dat.glm) summary(glm.hap4.hap138) @ \pagebreak \section{License and Warranty} \noindent License:\linebreak \noindent Copyright 2003 Mayo Foundation for Medical Education and Research. \linebreak \noindent This program is free software; you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation; either version 2 of the License, or (at your option) any later version.\\ \noindent This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. \\ \noindent You should have received a copy of the GNU General Public License along with this program; if not, write to \\ \noindent Free Software Foundation, Inc. \\ 59 Temple Place, Suite 330 \\ Boston, MA 02111-1307 USA \\ \noindent For other licensing arrangements, please contact Daniel J. Schaid.\\ Daniel J. Schaid, Ph.D.\\ Division of Biostatistics\\ Harwick Building - Room 775\\ Mayo Clinic\\ 200 First St., SW\\ Rochester, MN 55905\\ phone: 507-284-0639\\ fax:\ \ \ 507-284-9542\\ email: schaid@mayo.edu\\ \section{Acknowledgements} This research was supported by United States Public Health Services, National Institutes of Health; Contract grant numbers R01 DE13276, R01 GM 65450, N01 AI45240, and R01 2AI33144. The {\sl hla.demo} data is kindly provided by Gregory A. Poland, M.D. and the Mayo Vaccine Research Group for illustration only, and may not be used for publication. \pagebreak \appendix \noindent{\large {\bf Appendix}} \section{Counting Haplotype Pairs When Marker Phenotypes Have Missing Alleles} The following describes the process for counting the number of haplotype pairs that are consistent with a subject's observed marker phenotypes, allowing for some loci with missing data. Note that we refer to marker phenotypes, but our algorithm is oriented towards typical markers that have a one-to-one correspondence with their genotypes. We first describe how to count when none of the loci have missing alleles, and then generalize to allow loci to have either one or two missing alleles. When there are no missing alleles, note that homozygous loci are not ambiguous with respect to the underlying haplotypes, because at these loci the underlying haplotypes will not differ if we interchange alleles between haplotypes. In contrast, heterozygous loci are ambiguous, because we do not know the haplotype origin of the distinguishable alleles (i.e., unknown linkage phase). However, if there is only one heterozygous locus, then it doesn't matter if we interchange alleles, because the pair of haplotypes will be the same. In this situation, if parental origin of alleles were known, then interchanging alleles would switch parental origin of haplotypes, but not the composition of the haplotypes. Hence, ambiguity arises only when there are at least two heterozygous loci. For each heterozygous locus beyond the first one, the number of possible haplotypes increases by a factor of 2, because we interchange the two alleles at each heterozygous locus to create all possible pairs of haplotypes. Hence, the number of possible haplotype pairs can be expressed as $2^{x}$, where $x = H-1$, if $H$\ (the number of heterozygous loci) is at least 2, otherwise $x = 0$. Now consider a locus with missing alleles. The possible alleles at a given locus are considered to be those that are actually observed in the data. Let $a_{i}$\ denote the number of distinguishable alleles at the locus. To count the number of underlying haplotypes that are consistent with the observed and missing marker data, we need to enumerate all possible genotypes for the loci with missing data, and consider whether the imputed genotypes are heterozygous or homozygous. To develop our method, first consider how to count the number of genotypes at a locus, say the $i^{th}$ locus, when either one or two alleles are missing. This locus could have either a homozygous or heterozygous genotype, and both possibilities must be considered for our counting method. If the locus is considered as homozygous, and there is one allele missing, then there is only one possible genotype; if there are two alleles missing, then there are $a_{i}$ possible genotypes. A function to perform this counting for homozygous loci is denoted $f(a_{i})$. If the locus is considered as heterozygous, and there is one allele missing, then there are $ a_{i}-1$\ possible genotypes; if there are two alleles missing, then there are $\frac{a_{i}(a_{i}-1)}{2}$\ possible genotypes. A function to perform this counting for heterozygous loci is denoted $g(a_{i})$ These functions and counts are summarized in Table A.1. \\ \noindent {\bf Table A.1:} Factors for when a locus having missing allele(s) is counted as homozygous($f()$) or heterozygous($g()$)\\ \begin{table}[h] \begin{center} \begin{tabular}{|r|c|c|} \hline Number of & Homozygous & Heterozygous \\ missing alleles & function $f(a_{i})$ & function $g(a_{i})$ \\ \hline \hline 1 & 1 & $a_{i} - 1$ \\ \hline 2 & $ a_{i}$ & $\frac{a_{i}(a_{i}-1)}{2}$ \\ \hline \end{tabular} \end{center} \end{table} Now, to use these genotype counting functions to determine the number of possible haplotype pairs, first consider a simple case where only one locus, say the $i^{th}$ locus, has two missing alleles. Suppose that the phenotype has H heterozygous loci (H is the count of heterozygous loci among those without missing data). We consider whether the locus with missing data is either homozygous or heterozygous, to give the count of possible haplotype pairs as \begin{equation} a_{i}2^{x} + \left[{\frac{a_{i}(a_{i}-1)}{2}}\right]2^{x+1} \end{equation} \noindent where again $x = H-1$\ if H is at least 2, otherwise x = 0. This special case can be represented by our more general genotype counting functions as \begin{equation} f(a_{i})\,2^{x} + g(a_{i})\,2^{x+1} \end{equation} When multiple loci have missing data, we need to sum over all possible combinations of heterozygous and homozygous genotypes for the incomplete loci. The rows of Table A.2 below present these combinations for up to $m=3$\ loci with missing data. Note that as the number of heterozygous loci increases (across the columns of Table A.2), so too does the exponent of 2. To calculate the total number of pairs of haplotypes, given observed and possibly missing genotypes, we need to sum the terms in Table A.2 across the appropriate row. For example, with $m=3$, there are eight terms to sum over. The general formulation for this counting method can be expressed as \begin{equation} Total Pairs = \sum_{j=0}^{m} \sum_{combo} C(combo,j) \end{equation} \noindent where combo is a particular pattern of heterozygous and homozygous loci among the loci with missing values (e.g., for $m = 3$, one combination is the first locus heterozygous and the $2^{nd}$\ and $3^{rd}$\ third as homozygous), and $C(combo,j)$\ is the corresponding count for this pattern when there are $i$\ loci that are heterozygous (e.g., for $m = 3$\ and $j = 1$\, , as illustrated in Table A.2). \noindent {\bf Table A.2:} Genotype counting terms when $m$ loci have missing \\ alleles, grouped by number of heterozygous loci (out of $m$)\\ \begin{table}[h] \begin{center} \begin{tabular}{|r||r|r|r|r|} \hline $m$ & $j=0\,of\, m$ & $j=1\, of\, m$ &$j=2\, of\, m$ & $j=3\, of\, m$ \\ \hline \hline $0$ & $2^{x}$ & & & \\ \hline $1$ & $f(a_{1})2^{x}$ & $g(a_{1})2^{x+1}$ & & \\ \hline $2$ & $f(a_{1})f(a_{2})2^{x}$ & $g(a_{1})f(a_{2})2^{x+1}$ &$g(a_{1})g(a_{2})2^{x+1}$ & \\ & & $f(a_{1})g(a_{2})2^{x+1}$ & & \\ \hline $3$ & $f(a_{1})f(a_{2})f(a_{3})2^{x}$&$g(a_{1})f(a_{2})f(a_{3})2^{x+1}$&$g(a_{1})g(a_{2})f(a_{3})2^{x+2}$& $g(a_{1})g(a_{2})g(a_{3})2^{x+2}$ \\ & &$f(a_{1})g(a_{2})f(a_{3})2^{x+1}$&$g(a_{1})f(a_{2})g(a_{3})2^{x+2}$& \\ & &$f(a_{1})f(a_{2})g(a_{3})2^{x+1}$&$f(a_{1})g(a_{2})g(a_{3})2^{x+2}$& \\ \hline \end{tabular} \end{center} \end{table} \pagebreak \begin{thebibliography}{} %% using AMA, listed in order of appearance \bibitem{Clayton} Clayton, David. Personal web page, software list. \mbox{.} Accessed April 1, 2004. \bibitem{Schaid 2005} Schaid DJ. Power and Sample Size for Testing Associations of Haplotypes with Complex Traits. {\em Annals of Human Genetics} 2005;70:116-130. \bibitem{Schaid et al. 2002} Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA. Score tests for association between traits and haplotypes when linkage phase is ambiguous. {\em Am J Hum Genet} 2002;70:425-34. \bibitem{Zaykin} Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG. Testing Association of Statistically Inferred Haplotypes with Discreet and Continuous Traits in Samples of Unrelated Individuals. {\em Human Heredity} 2002;53:79-91. \bibitem{Harrell} Harrell, FE. {\em Regression Modeling Strategies.} New York: Springer-Verlag; 2001. \bibitem{Besag and Clifford 1991} Besag J, Clifford P. Sequential Monte Carlo p-Values. {\em Biometrika} 1991;78:301-304. \bibitem{Lake et al. 2003} Lake S, Lyon H, Silverman E, Weiss S, Laird N, Schaid D. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. {\em Human Heredity} 2003;55:56-65. \bibitem{Stram et al. 2003} Stram D, Pearce C, Bretsky P, Freedman M, Hirschhorn J, Altshuler D, Kolonel L, Henderson B, Thomas D. Modeling and E-M estimation of haplotype-specific relative risks from genotype data for case-control study of unrelated individuals. {\em Hum Hered} 2003;55:179-190. \bibitem{Epstein and Satten 2003} Epstein MP, Satten GA. Inference on haplotype effects in case-control studies using unphased genotype data. {\em Am J Hum Genet} 2003;73:1316-1329. \bibitem{McCullaghNelder} McCullagh P, Nelder JA. {\em Generalized Linear Models, Second Edition}. Boca Raton, FL: Chapman and Hall. 1989:35-36. %\bibitem{Cheng2003} % Cheng R, Ma JZ, Wright FA, Lin S, Gau X, Wang D, Elston RC, Li % MD. Nonparametric disequilibrium mapping of functional sites using % haplotypes of multiple tightly linked single-nucleotide polymorphism markers. % {\em Genetics} 2003;164:1175-1187. \bibitem{Cheng2005} Cheng R, Ma JZ, Elston RC, Li MD. Fine Mapping Functional Sites or Regions from Case-Control Data Using Haplotypes of Multiple Linked SNPs. {\em Annals of Human Genetics} 2005;69: 102-112. \bibitem{Yu} Yu Z, Schaid DJ. Sequential haplotype scan methods for association analysis. {\em Gen Epi} 2007;31:553-564. \bibitem{Mantel} Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. {\em J Nat Cancer Inst} 1959;22:719-48. \bibitem{XieStram} Xie R, Stram DO. Asymptotic equivalence between two score tests for haplotype-specific risk in general linear models. {\em Gen Epi} 2005;29:166-170. \bibitem{LinZeng} Lin DY, Zeng D. Likelihood-based inference on haplotype effects in genetic association studies. {\em J Am Stat Assoc} 2006;101:473. \end{thebibliography} \end{document} haplo.stats/DESCRIPTION0000644000176000001440000000152012075717237014261 0ustar ripleyusersPackage: haplo.stats Version: 1.6.3 Date: 2013-1-16 Title: Statistical Analysis of Haplotypes with Traits and Covariates when Linkage Phase is Ambiguous Author: Sinnwell JP, Schaid DJ Maintainer: Jason P. Sinnwell Description: A suite of R routines for the analysis of indirectly measured haplotypes. The statistical methods assume that all subjects are unrelated and that haplotypes are ambiguous (due to unknown linkage phase of the genetic markers). The main functions are: haplo.em, haplo.glm, haplo.score, haplo.power, and seqhap. License: GPL-2 | file LICENSE Depends: R (>= 2.15.0) Suggests: rms URL: http://mayoresearch.mayo.edu/mayo/research/schaid_lab/software.cfm Packaged: 2013-01-16 21:22:38 UTC; sinnwell Repository: CRAN Date/Publication: 2013-01-17 07:47:59