seroincidence/0000755000176200001440000000000012640603670013070 5ustar liggesusersseroincidence/TODO0000644000176200001440000000000012640456126013550 0ustar liggesusersseroincidence/inst/0000755000176200001440000000000012640456126014047 5ustar liggesusersseroincidence/inst/CITATION0000644000176200001440000000107112640456126015203 0ustar liggesuserscitHeader("To cite package 'seroincidence' in publications use:") year <- sub(".*(2[[:digit:]]{3})-.*", "\\1", meta$Date, perl = TRUE) vers <- paste("R package version", meta$Version) url <- gsub("\n", "", meta$URL) citEntry(entry = "Manual", title = "seroincidence: Estimating Infection Rates from Serological Data", author = personList(as.person("Peter Teunis")), year = year, note = vers, url = url, textVersion = paste0("Peter Teunis (", year, "). Estimating Infection Rates from Serological Data. ", vers, "."), ) seroincidence/inst/doc/0000755000176200001440000000000012640456136014615 5ustar liggesusersseroincidence/inst/doc/installation.Rmd0000644000176200001440000001361712640456126017771 0ustar liggesusers--- vignette: > %\VignetteIndexEntry{Seroincidence package installation manual} %\VignetteEngine{knitr::rmarkdown} \usepackage[utf8]{inputenc} title: "Seroincidence package installation manual" author: "European Centre for Disease Prevention and Control (ECDC)" date: "`r Sys.Date()`" output: pdf_document: toc: yes header-includes: - \setkeys{Gin}{height=3.5in, keepaspectratio} --- ```{r, echo = FALSE} # Grab package version and date from DESCRIPTION file pkgVersion <- packageDescription("seroincidence")$Version pkgDate <- packageDescription("seroincidence")$Date pkgBaseFileName <- paste("seroincidence", pkgVersion, sep = "_") pkgUrl <- gsub("\n", "", packageDescription("seroincidence")$URL) pkgPath <- "http://ecdc.europa.eu/en/data-tools/seroincidence-calculator-tool/Documents" library("knitr") ``` # 1. Introduction Package **seroincidence** is written in programming language R and end user must have access to a working installation of R interpreter. This document describes the most common setup with R installed locally on the user's computer. The screenshots refer to the classical R interface, but the package can also be opened in other Graphical User Interfaces fo R like e.g. [RStudio](http://www.rstudio.com/products/RStudio/). # 2. Installation steps R is a free software and can be downloaded from [http://cran.r-project.org/](http://cran.r-project.org/). Latest version as of writing this document is **R 3.1.3**. Once the appropriate, operating system dependent, version is downloaded, install it on your computer following the standard procedure applicable to the operating system. For Windows the file to be downloaded is the so-called *base* distribution: [http://cran.r-project.org/bin/windows/base/](http://cran.r-project.org/bin/windows/base/). \pagebreak ## 2.1. Installing R Start the R installer and follow the presented steps: ![R installer - step 1](fig/setup1.png) It is advised to have R installed in folder that does not contain spaces, therefore please adjust the destination location accordingly: ![R installer - step 2](fig/setup2.png) \pagebreak The **seroincidence** package is compatible with both the 32-bit and the 64-bit version of R. Choose the preferred platform (or both). If unsure install the 32-bit version only, however on compatible platforms the 64-bit version may provide better performance: ![R installer - step 3](fig/setup3.png) It is advised to select *Registry entries* in the next step for best experience: ![R installer - step 4](fig/setup4.png) \pagebreak R interpreter, when installed on Windows, can be invoked from the start menu folder named **R**. ![Windows start menu](fig/startMenu.png) Start the preferred version of R (if both the 32-bit: *R i386* and the 64-bit: *x64* are installed). Graphical user interface for R interpreter will start in a new window: ![R Graphical User Interface - welcome screen](fig/RGui1.png) \pagebreak ## 2.2. Installing *seroincidence* package Since this is a new installation of R, the **seroincidence** package must be installed before first use. The package can be installed either through a menu option in the graphical user interface (GUI) or with a command executed in the R console. Both options are presented: ### 2.2.1. Package installation from the graphical user interface Download the seroincidence calculator package from ECDC website: [`r pkgUrl`](`r pkgUrl`). Two versions of the package are made available: * Windows binary package (seroincidence_[version].zip) * Source package (seroincidence_[version].tar.gz) If your operating system is Windows then it is best to download the Windows binary package. Go to menu *Packages* and select command *Install package(s) from local zip files...*: ![R GUI - install package menu](fig/RGui2.png) \pagebreak Select the package file and click "Open": ![R GUI - select package file](fig/RGui3.png) Post-installation message should appear: ![R GUI - welcome screen](fig/RGui4.png) The package is now installed in R. ### 2.2.2. Package installation from R console Alternatively, installation of the package can also be performed by executing one of the following commands in the *R console*: ```{r, include=FALSE, tidy=FALSE} chunkTemplate <- "```{r, eval = FALSE} # OPTION A # Install Windows binary package \"seroincidence\" directly from internet location: install.packages( pkgs = \"{{pkgPath}}/ {{pkgBaseFileName}}.zip\", repos = NULL, type = \"win.binary\") # OPTION B # Install source package directly from internet location: install.packages( pkgs = \"{{pkgPath}}/ {{pkgBaseFileName}}.tar.gz\", repos = NULL, type = \"source\") # OPTION C # Install Windows binary package from a local file: # install.packages(\"[PATH/TO/FILE/]seroincidence_[version].zip\", # repos = NULL, type = \"win.binary\") # For instance: install.packages(pkgs = \"C:/{{pkgBaseFileName}}.zip\", repos = NULL, type = \"win.binary\") # OPTION D # Install source package from a local file: install.packages(pkgs = \"C:/{{pkgBaseFileName}}.tar.gz\", repos = NULL, type = \"source\") ```" chunkSource <- knit_expand(text = chunkTemplate, pkgBaseFileName = pkgBaseFileName) ``` `r knit(text = chunkSource)` # 3. Post-installation Successful installation can be confirmed by loading the package into the workspace and exploring help files and manuals distributed with the package: ```{r, eval=FALSE} # Load package "seroincidence" library(seroincidence) # Show R help for the package ?seroincidence # Show tutorial for the package vignette(topic = "tutorial", package = "seroincidence") ``` Additionally, most package details can be found when executing the following commands: ```{r} # Description packageDescription("seroincidence") # Citation citation("seroincidence") ``` seroincidence/inst/doc/tutorial.pdf0000644000176200001440000025020012640456126017151 0ustar liggesusers%PDF-1.5 % 1 0 obj << /Type /ObjStm /Length 4275 /Filter /FlateDecode /N 88 /First 731 >> stream x[[s8~?o-_Rē$n"Ѷvd#љ5@Jɒj, FF7Iƙb1ͬ0',X2τ0&ńt /I F2T& LX&Dgx3Av3e5: /9׆sG_ޢ8lQ=ԝfmՆN]v\;ۦKzܚ|w8KCXrʂ=8P q~̓W'״drY^Z,'+׋.f\WbUuB&<:b\Fz嬨c*ɭg*7 )ZztsUvv]i]oQ*7\dr p8=؄5ntS"R6  5*EICbDAe"'//*yKb@zNjyYA:0thcѓpAR=k9+V,|-+I:1?YP__r1~W< %H>|؜l[$U*zF(~Xk~'䛑of3 jsA L ʕI3@AiÞt$ї<-oHۊ{Hjd- >$eVR[r#PC g T>tm<[(Ȝ$MD54A 釡|Ş8Dzi/vpUkgزqŵ8o߉ѨlT>!2eNa6 H5 \˸;Y}01 _}:Ӑ!_ݑ/L!o"_u|zcbΫ e[e kD b[E+n Ez.?Tؚӛ941c렳Ѽ0cf6Ԙp@!301D7`RE10FZ5dRGwD}?8!=f|3bʜR/BM휷5ۆ´@O~D@BM B: UqPb\MR -B2fFG|&ha4Uf\;:Sn:"L*QúgpF',Ld6h̄- k~ijj:VYwMB>T7wR:֢˼cF̸N'zVzӆYp uggH@Q s=$CCe፡0ģ]kr#2hWg_Τ:vEmPkei863NGሻx`Z!|tvч6{}'Ξ;iK2zpYb<grq=%/9mlb:O'|\G͌+csM'fVfן:, 1>I 2$oz a$t/Wߞ\uM|P?2Z1Dȟ~v_>[\Njt~|5܈;/ L5ܸXҫFG#HmA餼BThC!6k}O 1MUhI{ 8XdǣgⲮm Q>'y_|E~/2):R9jd6X^hأ:iA'YXp誸Ml:>_ ne$]Y\F[ 6'_ǕGi=ay' o(ߺ-5?#pq'viL^_+&gWș\tHᚠs '/)G;ϧ_%4Bp>krgyJK" E~>V#H쐒z׭yN>^>q-f}jziE+ЪaJ$,nÕ)-#s:kb>xZGN4Xϩ6WՊ-+qHM: &_y*?WF zA6׫`+`bRCrYʿwgL8lYpޅX fò}ŇOף.}mvkK߇7 W-:=O!q]Qn9Sm"7It)Ǡ# * hl'.-wOVN?s;ԓNЕ;ܵŲ݂z0ނO{+${sE[/7}ǧgQPֵݵ{ơt'xF>*0cIؘFW7k5 %2  hRv5yL'L9wO^~zTxuiUM%;D]vhZI zӓ! e0qЦĶ.oj&)>Ҥħ3ES{4|Raɣ?+h>Y {&L_WPm;S5^W60߽3.הt^b}c]݇ s5Nϧsjo՚wyoGn s{˷vQ?cCqϯ<3œ l~a gaO vRs})r%1ϬX63tz1}Tq^LעeˤFF6kVӠt[1Ϟ|ڌ[ǂ]-aCַۭk,{^wS&;}N?V=rb0K:߹J[.XzB;n`B\z? z@pq k79ԁ(Sb ?حS+endstream endobj 90 0 obj << /Subtype /XML /Type /Metadata /Length 1644 >> stream GPL Ghostscript 9.18 2015-12-29T10:49:50+01:00 2015-12-29T10:49:50+01:00 LaTeX with hyperref package Seroincidence package tutorialEuropean Centre for Disease Prevention and Control (ECDC) endstream endobj 91 0 obj << /Filter /FlateDecode /Length 4143 >> stream x[K_EG*b"8)xnvI3bV_~ nJRNjC FяV+r'VOw?I]?WHaWJ֪fuxSJzQ7ޯlֲwշ덨ΚjOx|55H UuSӪs մdO32-T #sNm֭צzrie=7hhLk΄F_+)isurlk߁^ǵiU 0I۪=krFi,ISGjiU/{)u]{`85v"Rj8dWo߯׸9\)ڋk=mR FjSkcyJ ؿdk-inW4jYer8Wzi@ W x8WMË7mnpXK*Xdr ŗ(&e|8(5/r@z~ m۟Dm@`͗(S .Ib}D͒o,I۲$zwm[Y}E4ZO5 jpA&Ӡ3Ѣվ.~K`{8}LAC-/ ˍp38]T;,5`O<]K vGqj`ҁϸswmnKU~N(j3_xOfSPA5*ǎ8Z,viP襖jH=9V R6]TE]p , q=$KSdL? 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------------------------------------------------------------------------ # Load package "seroincidence" library(seroincidence) ## ---- eval=FALSE--------------------------------------------------------- # # List all objects (functions and data) exposed by package "seroincidence" # ls("package:seroincidence") ## ---- echo=FALSE--------------------------------------------------------- ls("package:seroincidence") ## ------------------------------------------------------------------------ # Show first rows of "salmonellaSerologyData" data.frame head(salmonellaSerologyData) # Show first rows of "campylobacterSerologyData" data.frame head(campylobacterSerologyData) ## ------------------------------------------------------------------------ # Assign data.frame "salmonellaSerologyData" to object named "serologyData" serologyData <- salmonellaSerologyData ## ------------------------------------------------------------------------ # Assign output of function "simulateSerologyData" to object named "serologyData" serologyData <- simulateSerologyData(n = 300) # Show first rows of object "serologyData" head(serologyData) ## ---- eval=FALSE--------------------------------------------------------- # # Read content of file "c:\\cross-sectional-data.csv" into object named "serologyData" # serologyData <- read.csv(file = "c:\\cross-sectional-data.csv") ## ------------------------------------------------------------------------ # Show first rows of data.frame "A" in list "campylobacterResponseParams" head(campylobacterResponseParams$A) # Show first rows of data.frame "k" in list "campylobacterResponseParams" head(campylobacterResponseParams$k) ## ------------------------------------------------------------------------ responseParams <- campylobacterResponseParams ## ------------------------------------------------------------------------ responseParams <- simulateSalmonellaResponseParams() ## ----eval=FALSE---------------------------------------------------------- # AData <- read.csv(file = "A.csv") # kData <- read.csv(file = "k.csv") # # # Create a list named "responseData" containing objects named "A" and "k" # responseParams <- list(A = AData, k = kData) ## ---- eval=FALSE--------------------------------------------------------- # # Assign output of function "estimateSeroincidence" to object named "seroincidenceData" # serologyData <- salmonellaSerologyData # responseParams <- simulateSalmonellaResponseParams() # seroincidenceData <- estimateSeroincidence(data = serologyData, # antibodies = c("IgG", "IgM", "IgA"), # strata = "sex", # Ak = responseParams, # censorLimits = list(IgG = 0.25, IgM = 0.25, IgA = 0.25)) # # # Show content of the output variable # print(seroincidenceData) # # or simply type in the console: 'seroincidenceData' (without "'") and press ENTER ## ---- eval=FALSE--------------------------------------------------------- # censorLimits <- list(IgG = 0, IgM = 0, IgA = 0) ## ---- eval=FALSE--------------------------------------------------------- # summary(seroincidenceData) ## ---- eval=FALSE--------------------------------------------------------- # # Compute seroincidence summary and assign to object "seroincidenceSummary" # seroincidenceSummary <- summary(seroincidenceData) # # # Show the results # seroincidenceSummary$Results ## ---- eval=FALSE--------------------------------------------------------- # # Calculate seroincidence rates for Salmonella # # # 1. Define cross-sectional data # serologyData <- salmonellaSerologyData # # # 2. Define longitudinal response data (simulate 1000 observations) # responseParams <- simulateSalmonellaResponseParams(n = 1000) # # # 3. Define cut-offs # cutoffs <- list(IgG = 0.25, IgM = 0.25, IgA = 0.25) # # # 4a. Calculate seroincidence rates by age (triplet of titres)... # seroincidenceData <- estimateSeroincidence(data = serologyData, # antibodies = c("IgG", "IgM", "IgA"), # strata = "age", # Ak = responseParams, # censorLimits = cutoffs, # showProgress = TRUE) # # # 4b. ...or calculate a single seroincidence rate for all serum samples (triplet of titres)... # seroincidenceData <- estimateSeroincidence(data = serologyData, # antibodies = c("IgG", "IgM", "IgA"), # strata = "", # Ak = responseParams, # censorLimits = cutoffs) # # # 4c. ...or calculate a single seroincidence rate for a single serum sample (triplet of titres)... # seroincidenceData <- estimateSeroincidence(data = serologyData[1, ], # antibodies = c("IgG", "IgM", "IgA"), # strata = "", # Ak = responseParams, # censorLimits = cutoffs) # # # 4d. ...or calculate a single seroincidence rate for all serum samples (only IgG) # seroincidenceData <- estimateSeroincidence(data = serologyData, # antibodies = c("IgG"), # strata = "", # Ak = responseParams, # censorLimits = cutoffs) # # # 5a. Produce summary of the results with 2.5% and 97.5% bounds... # summary(seroincidenceData) # # # 5b. ...or produce summary of the results with 5% and 95% bounds, do not show convergence... # summary(seroincidenceData, quantiles = c(0.05, 0.95), showConvergence = FALSE) # # # 5c. ...or produce summary and assign to an object... # seroincidenceSummary <- summary(seroincidenceData) # # ...and work with the results object from now on (here: display the results). # seroincidenceSummary$Results seroincidence/inst/doc/cover.html0000644000176200001440000002340312640456126016622 0ustar liggesusers R Package - seroincidence

R package seroincidence allows translation of antibody levels measured in a (cross-sectional) population sample into an estimate of the frequency with which seroconversions (infections) occur in the sampled population.

Item Data
Version 1.0.5
Published 2015-10-12
Authors Peter Teunis peter.teunis@rivm.nl,
Author of the method and original code

Daniel Lewandowski daniel@nextpagesoft.net,
Creator of the R package

Chantal Quinten seroincidence@ecdc.europa.eu,
Project manager and the package maintainer
Maintainer Chantal Quinten seroincidence@ecdc.europa.eu
License GPL-3
Package source seroincidence_1.0.5.tar.gz
Windows binary seroincidence_1.0.5.zip
Installation manual installation.pdf
Tutorial tutorial.pdf
Appendix methodology.pdf
ECDC web site http://ecdc.europa.eu/en/data-tools/seroincidence-calculator-tool/Pages/default.aspx
seroincidence/inst/doc/methodology.Rmd0000644000176200001440000005531512640456126017623 0ustar liggesusers--- title: "Seroincidence package methodology" author: "European Centre for Disease Prevention and Control (ECDC)" date: '`r Sys.Date()`' output: pdf_document: toc: yes header-includes: - \usepackage{subfigure} - \usepackage[utf8]{inputenc} references: - DOI: 10.1002/sim.5322 author: - family: Teunis given: P. F. - family: van Eijkeren given: J. C. - family: Ang given: C. W. - family: van Duynhoven given: Y. T. - family: Simonsen given: J. B. - family: Strid given: M. A. - family: van Pelt given: W. container-title: Statistics in Medicine id: teunis2012 issue: 20 issued: month: 9 year: 2012 page: 2240-2248 title: 'Biomarker dynamics: estimating infection rates from serological data' type: article-journal volume: 31 - author: - family: Versteegh given: F. G. - family: Mertens given: P. L. - family: de Melker given: H. E. - family: Roord given: J. J. - family: Schellekens given: J. F. - family: Teunis given: P. F. container-title: Epidemiology and Infection id: versteegh2005 issue: 4 issued: month: 8 year: 2005 page: 737-748 title: Age-specific long-term course of IgG antibodies to pertussis toxin after symptomatic infection with Bordetella pertussis type: article-journal volume: 133 - DOI: 10.1002/sim.3592 author: - family: Simonsen given: J. - family: Mølbak given: K. - family: Falkenhorst given: G. - family: Krogfelt given: K. A. - family: Linneberg given: A. - family: Teunis given: P. F. container-title: Statistics in Medicine id: simonsen2009 issue: 14 issued: month: 6 year: 2009 page: 1882-1895 title: Estimation of incidences of infectious diseases based on antibody measurements type: article-journal volume: 28 - author: - family: Feller given: W. container-title: John Wiley & Sons id: feller1968 issued: year: 1968 title: An introduction to probability theory and its applications type: book volume: 2 - author: - family: Higgins given: P. M. container-title: 'London: Springer Verlag' id: higgins2008 issued: year: 2008 title: Number Story. From counting to cryptography type: book - author: - family: Scalia Tomba given: G. P. - family: Svenson given: Å. - family: Asikainen given: T. - family: Giesecke given: J. container-title: Mathematical Biosciences id: scalia2010 issue: 1 issued: year: 2010 page: 24-31 title: Some model based considerations on observing generation times for communicable diseases type: article-journal volume: 223 fontsize: 11pt --- # 1. Introduction The simplest possible model for serum antibody decay is an exponential decay function (see [Appendix](#method_longitudinal)). This is the default longitudinal model used in **seroincidence** package. Various modifications can be made, however, to allow for different interpretations of low antibody concentrations in cross-sectional data. The following three approaches are implemented in the current version of the package: 1. Exponential decay: seroconversion is instantaneous, and is followed by exponential decrease to zero (see [Appendix](#method_longitudinal) for more information). 2. Exponential decay with left censoring: seroconversion is instantaneous, and it is followed by exponential decay, but antibody concentrations below a given (fixed) level are treated as censored (see [Appendix](#censoring) for more information). This implies that observations below censoring level are considered to have been generated by seroconversions from at least a given time in the past (corresponding to the censoring level). In simple terms: for very low antibody concentrations we can only conclude that seroconversion occurred long ago, but not precisely how long. 3. Exponential decay with nonzero baseline: seroconversion is again instantaneous, and is again followed by exponential decay, but decay now is not towards zero but instead, approaches some baseline antibody concentration that may be different for any individual (see [Appendix](#baseline) for more information). Low antibody concentrations in the cross-sectional sample now may correspond to baseline levels, in which case seroconversion would have occurred an infinite period ago. Because of their different interpretations of low cross-sectional serum antibody concentrations, both alternatives (left censoring and decay to baseline) lead to decreased estimates of seroincidence, compared to the default model. Finally, note that the methods described in the [Appendix](#appendices) allow for arbitrary antibody decay patterns, so that adaptations can be made to accommodate any longitudinal model for the shape of the decaying arm of the seroresponse. # 2. Influence of censoring on seroincidence In case serum antibody data are known to be censored, a cutoff level can be defined in the seroincidence calculator script as a list, with separate values for each of the three antibody classes (IgG, IgM, and/or IgA). \begin{figure}[h!] \centering \mbox{ \subfigure[Same cutoff]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-campylobacter-1.png}} \subfigure[Different cutoffs]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-campylobacter-2.png}}} \caption{\label{censoring_campy}Influence of cutoff levels on seroincidence estimates for a cross-sectional sample of {\em Campylobacter} antibodies. (a) Identical cutoffs for all three antibody types; (b) Different cutoffs for IgG, IgM and IgA.} \end{figure} \begin{figure}[h!] \centering \mbox{ \subfigure[Same cutoff]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-salmonella-1.png}} \subfigure[Different cutoffs]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-salmonella-2.png}}} \caption{\label{censoring_salmo}Influence of cutoff levels on seroincidence estimates for a cross-sectional sample of {\em Salmonella} antibodies (mixed ELISA). (a) Identical cutoffs for all three antibody types; (b) Different cutoffs for IgG, IgM and IgA.} \end{figure} Figures \ref{censoring_campy} and \ref{censoring_salmo} show the change in seroincidence estimate, for a given set of cross-sectional antibody data (*Campylobacter* and *Salmonella*), with increasing cutoff levels. Cutoffs need not be identical for IgG, IgM and IgA antibodies, as illustrated in these graphs. # 3. Checks using the longitudinal data The longitudinal data may be used to obtain a crude estimate of bias in the estimated incidences (Figure \ref{verif}a, \ref{verif}e). \begin{figure}[h!] \centering \mbox{ \subfigure[Cutoff 0.0]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff0.png}} \subfigure[Cutoff 0.5]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff05.png}} \subfigure[Cutoff 1.0]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff1.png}} \subfigure[Cutoff 2.0]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff2.png}}} \mbox{ \subfigure[Cutoff 0.0]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff0.png}} \subfigure[Cutoff 0.5]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff05.png}} \subfigure[Cutoff 1.0]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff1.png}} \subfigure[Cutoff 2.0]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff2.png}}} \caption{\label{verif}Estimated incidences for longitudinal sera at different times since onset of illness symptoms. delta(incid) = difference between estimated incidence and 365/(time since onset). Top: Campylobacter, Delft ELISA, Bottom: Campylobacter, SSI ELISA.} \end{figure} It is seen that for samples taken 100--250 days post symptom onset, the estimated incidences appear unbiased (the 95\% interval includes 0). Increasing the cutoff (here applied identical values for all three antibody classes) causes underestimation of the incidence (Figures \ref{verif}b,c,d and \ref{verif}f,g,h). The high degree of variation in antibody levels in late samples (more than 100 days post symptom onset) renders estimation problematic. \newpage \newpage # Appendices {#appendices} This is a slightly modified description from [@teunis2012], extended with adaptations for censoring and elevated baseline levels. ## A.1. Characteristics of the serum antibody response {#method_longitudinal} The longitudinal model used for describing serum antibody responses has been published [@simonsen2009, @teunis2012]. As longitudinal data may include early samples taken shortly after infection, possibly during the initial increase in antibody concentrations (during seroconversion) the longitudinal model includes the rising phase of the seroresponse. This avoids misspecification of the peak antibody level, resulting in estimates for the (joint distribution of) peak levels, time to peak, and decay rates of the serum antibody concentration [@teunis2012, @versteegh2005]. However, seroconversion usually is rapid: the increase in antibody levels is orders of magnitude faster than the subsequent decrease. For seroconversion rate calculations we ignore the time to reach peak levels. For simplicity it will be assumed that the antibody response decays exponentially but this is not an essential assumption and it can be relaxed to any monotonically decreasing function of time. So, the antibody response $y$ to incidence at $t = 0$ is an instantaneous increase to peak level ($A$) followed by an exponential decrease (with rate $k$): $$ y = A \text{e}^{-kt} $$ ## A.2. Random sampling of randomly repeating responses {#A2} In a cross-sectional sample of responses, each subject will be sampled at a random time within its current inter-event interval $\Delta t$ (interval, for short). The within--interval sampling distribution is uniform: \begin{equation} \label{fundamental} u_{f}(\tau\vert\Delta t)=\frac{[0\le \tau < \Delta t]}{\Delta t} \end{equation} The subscript $f$ is introduced to show that this distribution is fundamental to sampling from the period between events that are separated by a constant time interval $\Delta t$. As the intervals $\Delta t$ generally will vary, the within--interval sampling distribution and the distribution of intervals combine to a population distribution of backward recurrence times. The backward recurrence time distribution can be translated into a corresponding distribution of response values (antibody concentrations), due to the monotonicity of the response. The intervals $\Delta t$ are supposed to vary randomly with distribution $p(\Delta t)$. This introduces a subtle question about the probability of sampling the response within an infinitesimal range of intervals $[\Delta t, \Delta t + \text{d}\Delta t]$. One would be inclined to assume that the probability is given only by the probability density $p(\Delta t)$, but one should keep in mind that responses with longer intervals are more likely to be sampled than those with shorter intervals. Obviously, the probability of the range of sampling intervals $[\Delta t, \Delta t + \text{d}\Delta t]$ should be proportional to the interval $\Delta t$ itself (size biased sampling, [@feller1968, @higgins2008, @scalia2010]). Then, the probability of sampling a response within an infinitesimal range of intervals $[\Delta t, \Delta t + \text{d}\Delta t]$ is $$ \frac{p(\Delta t)\Delta t}{\overline{\Delta t}_{p}}\text{d}\Delta t $$ Here $\overline{\Delta t}_{p}$ is the expected interval length from the distribution $p$. We define the incidence as its reciprocal $1/\overline{\Delta t}_{p}$. Combining this probability with the uniform distribution of sampling time within the interval $\Delta t$ leads to a population distribution of time since last event (backward recurrence time) \begin{eqnarray*} u(\tau) &=& \int_{\Delta t=0}^{\infty}u_{f}(\tau\vert\Delta t) \frac{p(\Delta t)\Delta t}{\overline{\Delta t}_{p}}\text{d}\Delta t\\ &=& \frac{1}{\overline{\Delta t}_{p}} \int_{\Delta t=\tau}^{\infty} p(\Delta t)\text{d}\Delta t = \frac{1-P(\tau)}{\overline{\Delta t}_{p}} \end{eqnarray*} where $P$ is the cumulative distribution of $p$. In going from the first to the second equality we used the fact that $\Delta t$ should exceed $\tau$ (equation (\ref{fundamental})). Note that the distribution $u(\tau)$ is monotonically non-increasing. ## A.3. Delta distribution {#A3} If $p(\Delta t)$ is the delta-distribution $p(\Delta t) = \delta(\Delta t-\Delta t^{\ast})$ representing identical intervals, then the uniform distribution $u_{f}(\tau\vert \Delta t^{\ast})$ is regained: for the delta distribution $p(\Delta t) = \delta(\Delta t -\Delta t^{\ast})$ the expected value is $\overline{\Delta t}_{p} = \Delta t^{\ast}$. It follows that $$ u(\tau\vert\Delta t^{\ast}) = \frac{1}{\Delta t^{\ast}} \int_{\tau}^{\infty} \delta (\Delta t-\Delta t^{\ast}) \text{d}\Delta t = \frac{\left[0\le \tau < \Delta t^{\ast}\right]}{\Delta t^{\ast}} $$ ## A.4. Distribution of response values given the distribution of backward recurrence times {#A4} Given incidence at $\tau = 0$, the response decays as $y(\tau) = A \text{e}^{-k\tau}$, with $\tau$ backward recurrence time. Consider \begin{eqnarray} P(y^{\prime}\le y) & = & P\left(A\text{e}^{-k\tau^{\prime}}\le A\text{e}^{-k\tau}\right) [y\le A] = P(\tau \le \tau^{\prime})[y\le A] \nonumber \\ & = & \left(1-U(\tau)\right)[y\le A] = \left(1-U(\log(A/y)/k)\right) [y\le A] \label{cumul_distr} \end{eqnarray} Differentiating this expression leads to \begin{eqnarray} \rho(y) & = & \frac{\text{d}}{\text{d}y} P(y^{\prime}\le y) = -u\left(\log(A/y)/k\right) \left(\frac{1}{k}\right) \left(\frac{-1}{y}\right)[y\le A] \nonumber\\ & = & \frac{[y\le A]}{ky}u\left(\log(A/y)/k\right)\label{distrib_y} \end{eqnarray} Given the antibody response $y$ with respect to time of incidence, $\rho(y)$ is the corresponding density for sampled response values. For the $n$th moment of the backward recurrence time one derives \begin{eqnarray*} E(\tau^{n}) & = & \int_{\tau = 0}^{\infty} \tau^{n} u(\tau)\text{d}\tau = \int_{\tau = 0}^{\infty}\left(\tau^{n}\frac{1}{\overline{\Delta t}_{p}} \int_{\Delta t = \tau}^{\infty} p(\Delta t)\text{d}\Delta t\right)\text{d}\tau \\ & = & \frac{1}{\overline{\Delta t}_{p}}\int_{\Delta t=0}^{\infty}p(\Delta t) \left(\int_{\tau = 0}^{\Delta t}\tau^{n}\text{d}\tau\right)\text{d}\Delta t \\ & = & \frac{1}{\overline{\Delta t}_{p}}\int_{\Delta t=0}^{\infty}p(\Delta t) \frac{(\Delta t)^{{n+1}}}{n+1}\text{d}\Delta t = \frac{\overline{(\Delta t)^{n+1}}_{p}}{(n+1)\overline{\Delta t}_{p}} \end{eqnarray*} ## A.5. Family of Gamma distributions {#A5} The distribution of intervals $p(\Delta t)$ may have any form. Let the family of $\Gamma(\lambda, m)$ distributions be given: $$ p_{m}(\Delta t\vert \lambda) = \frac{\lambda^{m+1}\Delta t^{m}}{m!}\text{e}^{-\lambda \Delta t} $$ From $$ \int_{x=0}^{\infty}x^{m+1}\text{e}^{-x}\text{d}x = (m+1)! $$ one easily derives that $\overline{\Delta t}_{p} = (m+1)/\lambda$. We shall need the cumulative distribution \begin{eqnarray} P_{m}(\tau\vert \lambda) & = & \int_{\Delta t=0}^{\tau} p_{m}(\Delta t\vert \lambda) \text{d}\Delta t = 1 - \int_{\Delta t=\tau}^{\infty}p_{m}(\Delta t\vert \lambda)d\Delta t \nonumber \\ & = & 1 - \frac{\Gamma(m+1,\lambda \tau)}{m!} \label{p_dist_gamma} \end{eqnarray} where $\Gamma(m + 1, \lambda\tau)$ denotes the (upper) incomplete gamma function (not to be confused with the gamma distribution). Note: working out the integral $$ P_{m}(\tau\vert\lambda) = \int_{\Delta t = 0}^{\tau} p_{m}(\Delta t\vert\lambda)\text{d}\Delta t, $$ it is straightforward to show that \begin{equation} \label{gamma_pj} \Gamma(m+1,\lambda\tau) = \frac{m!}{\lambda}\sum_{j=0}^{m}p_{j}(\tau\vert\lambda) \end{equation} For the distribution of backward recurrence times one finds \begin{equation} \label{u_dist_gamma} u_{m}(\tau\vert \lambda) = \frac{\lambda}{m+1} \int_{\Delta t=\tau}^{\infty}p_{m}(\Delta t\vert \lambda)\text{d}\Delta t = \frac{\lambda}{(m+1)!}\Gamma(m+1,\lambda\tau) \end{equation} when $m = 0$ $$ u_{0}(\tau\vert \lambda) = \lambda \Gamma(1,\lambda\tau) = p_{0}(\tau\vert \lambda), $$ the famous property of the Poisson process. ## A.6. Heterogeneity in serum antibody responses {#A6} Incorporation of responses that also vary in amplitude $A$ and decay rate $k$ can be easily described with a joint density $g(A, k)$. Of course, such heterogeneity changes the population based distribution of $y$ to $$ \rho(y) = \frac{1}{y}\int_{k=0}^{\infty}\int_{A=y}^{\infty} \frac{1}{k}u\left(\frac{\log(A/y)}{k}\right)g(A,k)\text{d}A\text{d}k $$ instead of corresponding equation (\ref{distrib_y}). Note that the factor $[y\le A]$ in equation ($\ref{distrib_y}$) forces the lower limit $y$ in the integration over $A$. In case the peak antibody levels $A$ and antibody decay rates $k$ are available as a Monte Carlo sample $\{A_{n},k_{n}\}$ of their joint distribution the integration can be approximated by \begin{equation} \label{mc_heterogeneity} \rho(y)=\frac{1}{y}\frac{1}{N}\sum_{n=1}^{N}\frac{1}{k_{n}} u\left(\frac{\log(A_{n}/y)}{k_{n}}\right)[y\le A_{n}] \end{equation} where $N$ is the size of the Monte-Carlo sample, maintaining any correlation between peak levels $A_{n}$ and decay rates $k_{n}$. Assuming e.g. that infections occur with Gamma distributed intervals with rate $\lambda$ and shape factor $m$: \begin{eqnarray*} \rho(y\vert \lambda, m) & = & \frac{1}{(m+1) N}\sum_{n=1}^{N}\left( \frac{\lambda}{k_{n}A_{n}} \left(\frac{y}{A_{n}}\right)^{-1+\lambda/k_{n}}\right.\\ &\times & \left.\sum_{j=0}^{m} \frac{\left(\lambda/k_{n} \log(A_{n}/y)\right)^{j}}{j!}[y\le A_{n}]\right) \end{eqnarray*} For a cross-sectional sample $\{Y_{1}, Y_{2},\dots , Y_{N_{c}}\}$ a likelihood $$ \ell (\lambda, m) = \prod_{i=1}^{N_{c}} \rho(Y_{i}\vert \lambda, m) $$ can be calculated to allow estimation of the parameters $(\lambda, m)$ of the process generating infections. The corresponding incidence is the average rate of infections $\lambda/(m+1)$. ## A.7. Censored observations {#censoring} In case observations are censored at $y_{c}$ such that an observed $Y = \text{max}(Y, y_{c})$, then for $y_{c} < Y$ the density $\rho(y)$ as in eq. ($\ref{distrib_y}$) holds, but the likelihood of any $Y \le y_{c}$ can be calculated $$ \ell(\lambda, m \vert y \le y_{c}) = \int_{z=0}^{y_{c}}\rho(z\vert \lambda,m)\text{d}z = R(y_{c}\vert \lambda,m) $$ and the likelihood function for a cross-sectional sample $\{Y_{1}, Y_{2}, \dots, Y_{N_{c}}\}$ becomes $$ \ell (\lambda, m) = \prod_{i=1}^{N_{c}} \left(\rho(Y_{i}\vert \lambda, m)[y_{c} < Y_{i}] \times R(y_{c}\vert \lambda,m)[Y_{i}\le y_{c}]\right) $$ We need the cumulative distribution $R(y)$ as given by eq. ($\ref{cumul_distr}$) \begin{equation} \label{r_cumul_def} R(y) = 1 - U\left(\frac{\log\left(\frac{A}{\min(y,A)}\right)}{k}\right) = 1 - U\left(\frac{\text{lm}(y,A)}{k}\right) \end{equation} with obvious definition of $\text{lm}(y, A)$. For the family of gamma distributions for the intervals $\Delta t$, eq. ($\ref{r_cumul_def}$) leads to $$ R_{m}(y) = 1 - U_{m}\left(\frac{\text{lm}(y,A)}{k}\vert \lambda\right) $$ Substituting eq. ($\ref{gamma_pj}$) into eq. ($\ref{u_dist_gamma}$), and using the cumulative distribution $P_{j}$ $$ R_{m}(y) = 1 - \frac{1}{m+1}\sum_{j=0}^{m}P_{j} \left(\frac{\text{lm}(y,A)}{k}\vert\lambda\right) $$ which can also be expressed in terms of incomplete Gamma functions, using eq. ($\ref{p_dist_gamma}$) $$ R_{m}(y) = 1 - \frac{1}{m+1}\sum_{j=0}^{m} 1 - \frac{\Gamma\left(j+1,\lambda\frac{\text{lm}(y,A)}{k}\right)}{j!} $$ or, expanding $\text{lm}$ $$ R(y) = \frac{1}{m+1}\sum_{j=0}^{m}\frac{1}{j!}\Gamma\left(j+1, \frac{\lambda}{k}\log\left(\frac{A}{\min(y,A)}\right)\right) $$ The latter form is useful for numeric calculations as there is a reliable and efficient implementation available in R. ## A.8. Nonzero baseline {#baseline} The procedure outlined in [@teunis2012] is valid for any monotonically non-increasing serum antibody response. If for instance, after seroconversion, antibody levels decrease to some baseline level greater than zero (however long ago seroconversion has occurred), the antibody response is $$ y = y_{0} + A \text{e}^{-kt} $$ Such responses have been assumed for back-calculations [@simonsen2009]. Now the distribution of response values given the distribution of the backward recurrence times becomes \begin{eqnarray*} P(y^{\prime}\le y) & = & P\left(y_{0}+A\text{e}^{-k\tau^{\prime}}\le y_{0}+A\text{e}^{-k\tau}\right)[y_{0} < y \le A] \\ & = & P(\tau \le \tau^{\prime})[y_{0} < y \le A] = \left(1 - U(\tau)\right)[y_{0} < y \le A] \\ & = & \left(1-U\left(\frac{1}{k}\log\left(\frac{A}{y-y_{0}}\right)\right)\right) [y_{0} < y \le A] \end{eqnarray*} Differentiation produces the density $$ \rho(y) = \frac{\text{d}}{\text{d}y} P(y^{\prime}\le y) = \frac{1}{k(y-y_{0})} u\left(\frac{1}{k}\log\left(\frac{A}{y-y_{0}}\right)\right) $$ Including heterogeneity in $A$, $k$ and $y_{0}$ via their joint distribution $$ \rho(y) = \int_{k=0}^{\infty}\int_{A=y}^{\infty}\int_{y_{0}=0}^y \frac{1}{k(y-y_{0})} u\left(\frac{1}{k}\log\left(\frac{A}{y-y_{0}}\right)\right) g(A,K,y_{0})\text{d}y_{0}\text{d}A\text{d}k $$ or, when a Monte-Carlo sample of $\{A_{n}, k_{n}, y_{0,n}\}$ triplets is available $$ \rho(y) = \frac{1}{N}\sum_{n=1}^{N}\frac{u\left(\frac{1}{k_{n}} \log\left(\frac{A_{n}}{y-y_{0,n}}\right)\right)}{k_{n}(y-y_{0,n})} [y_{0,n} < y < A_{n}] $$ For the gamma family of distributions for $\Delta t$, \begin{eqnarray*} \rho(y) & = & \frac{1}{N(m+1)}\sum_{n=1}^{N}\left(\frac{\lambda}{k_{n}A_{n}} \left(\frac{y-y_{0,n}}{A_{n}}\right)^{-1+\lambda/k_{n}}\right. \\ & \times & \left.\sum_{j=0}^{m}\frac{1}{j!}\left(\frac{\lambda}{k_{n}} \log\left(\frac{A_{n}}{y-y_{0,n}}\right)\right)^{j} [y_{0,n} < y \le A_{n}]\right) \end{eqnarray*} For the Poisson process ($m = 0$) this reduces to $$ \rho(y) = \frac{1}{N}\sum_{n=1}^{N}\frac{\lambda}{k_{n}A_{n}} \left(\frac{y-y_{0,n}}{A_{n}}\right)^{-1+\lambda/k_{n}}[y_{0,n} < y \le A_{n}] $$ # References seroincidence/inst/doc/installation.pdf0000644000176200001440000064462012640456126020024 0ustar liggesusers%PDF-1.5 % 1 0 obj << /Type /ObjStm /Length 12014 /Filter /FlateDecode /N 90 /First 754 >> stream x}g[Wݽ{wewMT WkGEŰUPtP1gHXTa >^ڙp:R H`<cT Ȓ,s2_r@ᒮ ( MԀB\ p&C'Z@ 2t Jr : P VTCT `HDP`T t* g)d aª4*)U_M' 2#`ALFV*\Wg*CV9H$TBH 1k =*OYef=S @D\)Ԓ9:`t4`D+=sACk@ $&KPz hmniXy3 ?$:LT$&+@#Et*@=@#*@qERR  г@:\AnxB`Vr`M]ljX PG3jT D ۈh)N-N18f,; Ӡ~((0f"$8R:+I*$Es ~q$ .K@[sկK{.g:~e?a_q005 xny͛C8W# Q'0" =Ae Ȣ}'H77#&3Łŀâ" R@.TZ)#$'b]b9oɁőhU_ )fK+* 9qPs>F_V{1Ȓk_ITAG 5^8Xcl) GA'fBFŷ1'Eͫ δY6DSU*j?zYx+( $-:aS`J;` dlBR5"GJ, 29#' u'Ek>3`j(t9fL,"@Eр7dʲ7_1)&;'f)蹞 B$B`Z\+9: 8[$ ꓛg~|4y :7CYJ|=YGK)(Lpv.$D+| EfqpzYG%IY'X%NRpTOuq|c_Ÿ|:=(cH6yb< (oEKL8%ZgP) HGFXA> čLK}:~2L埋80fJ#*59?44! 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---- include=FALSE, tidy=FALSE------------------------------------------ chunkTemplate <- "```{r, eval = FALSE} # OPTION A # Install Windows binary package \"seroincidence\" directly from internet location: install.packages( pkgs = \"{{pkgPath}}/ {{pkgBaseFileName}}.zip\", repos = NULL, type = \"win.binary\") # OPTION B # Install source package directly from internet location: install.packages( pkgs = \"{{pkgPath}}/ {{pkgBaseFileName}}.tar.gz\", repos = NULL, type = \"source\") # OPTION C # Install Windows binary package from a local file: # install.packages(\"[PATH/TO/FILE/]seroincidence_[version].zip\", # repos = NULL, type = \"win.binary\") # For instance: install.packages(pkgs = \"C:/{{pkgBaseFileName}}.zip\", repos = NULL, type = \"win.binary\") # OPTION D # Install source package from a local file: install.packages(pkgs = \"C:/{{pkgBaseFileName}}.tar.gz\", repos = NULL, type = \"source\") ```" chunkSource <- knit_expand(text = chunkTemplate, pkgBaseFileName = pkgBaseFileName) ## ---- eval = FALSE------------------------------------------------------- # # OPTION A # # Install Windows binary package "seroincidence" directly from internet location: # install.packages( # pkgs = "http://ecdc.europa.eu/en/data-tools/seroincidence-calculator-tool/Documents/ # seroincidence_1.0.5.zip", # repos = NULL, type = "win.binary") # # # OPTION B # # Install source package directly from internet location: # install.packages( # pkgs = "http://ecdc.europa.eu/en/data-tools/seroincidence-calculator-tool/Documents/ # seroincidence_1.0.5.tar.gz", # repos = NULL, type = "source") # # # OPTION C # # Install Windows binary package from a local file: # # install.packages("[PATH/TO/FILE/]seroincidence_[version].zip", # # repos = NULL, type = "win.binary") # # For instance: # install.packages(pkgs = "C:/seroincidence_1.0.5.zip", repos = NULL, type = "win.binary") # # # OPTION D # # Install source package from a local file: # install.packages(pkgs = "C:/seroincidence_1.0.5.tar.gz", repos = NULL, type = "source") ## ---- eval=FALSE--------------------------------------------------------- # # Load package "seroincidence" # library(seroincidence) # # # Show R help for the package # ?seroincidence # # # Show tutorial for the package # vignette(topic = "tutorial", package = "seroincidence") ## ------------------------------------------------------------------------ # Description packageDescription("seroincidence") # Citation citation("seroincidence") seroincidence/inst/doc/tutorial.Rmd0000644000176200001440000006043412640456126017132 0ustar liggesusers--- vignette: | %\VignetteIndexEntry{Seroincidence package tutorial} %\VignetteEngine{knitr::rmarkdown} \usepackage[utf8]{inputenc} title: "Seroincidence package tutorial" author: "European Centre for Disease Prevention and Control (ECDC)" date: '`r Sys.Date()`' output: pdf_document: toc: yes references: - id: teunis2012 author: - family: Teunis given: P. F. - family: van Eijkeren given: J. C. - family: Ang given: C. W. - family: van Duynhoven given: Y. T. - family: Simonsen given: J. B. - family: Strid given: M. A. - family: van Pelt given: W. container-title: Statistics in Medicine DOI: 10.1002/sim.5322 issue: 20 issued: month: 9 year: 2012 page: 2240-2248 title: 'Biomarker dynamics: estimating infection rates from serological data' type: article-journal volume: 31 - id: feller1968 author: - family: Feller given: W. issued: year: 1968 title: An introduction to probability theory and its applications type: book volume: 2 container-title: John Wiley & Sons - id: strid2001 author: - family: Strid given: M. A. - family: Engberg given: J. - family: Larsen, given: L. B. - family: Begtrup given: K - family: Mølbak given: K - family: Krogfelt given: K. A. title: 'Antibody responses to Campylobacter infections determined by an enzyme--linked immunosorbent assay: 2-year follow-up study of 210 patients' container-title: Clinical and Vaccine Immunology issue: 8 volume: 2 page: 314-319 issued: year: 2001 month: 3 DOI: 10.1128/CDLI.8.2.314-319.2001 --- ```{r, echo = FALSE} pkgUrl <- gsub("\n", "", packageDescription("seroincidence")$URL) ``` # 1. Introduction Antibody levels measured by ELISA in a (cross-sectional) population sample can be translated into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. Formulated simply: the presence of many high titres indicates that many subjects likely experienced infection recently, while low titres indicate a low frequency of infections in the sampled population. More information about ELISA methods can be found at [ECDC web site](`r pkgUrl`). In order to thus interpret the measured cross-sectional antibody concentrations, characteristics of the time course of the serum antibody response must be known. For any antibody detected in the cross-sectional sample, a quantitative description of its dynamics following infection (seroconversion to an elevated concentration, followed by a gradual decrease) must be available. In published studies, this information on the time course of the serum antibody response has been obtained from follow-up data in subjects who had a symptomatic episode following infection. The onset of symptoms thus provided a proxy for the time that infection occurred. Care must be taken that longitudinal and cross-sectional measurements of antibody concentrations are calibrated on the same scale (or, preferably, expressed in identical units). The time course of the serum antibody response to infection is assumed generic: anyone infected by the same pathogen is expected to produce a response similar to those seen in the symptomatic cohort used for the follow-up study. Thus, the strategy is to set up a longitudinal model from a follow-up study once, and use the thus obtained information to analyze many different cross-sectional data sets. Note that it must be assumed that such variation among individuals as observed in the longitudinal cohort is the same as in the population where the cross-sectional sample was taken, where this variation cannot be observed. Analysis of longitudinal data and estimation of the required parameters is separated from the estimation of seroincidences, because (1) there are few longitudinal data sets available and they are difficult (and expensive) to obtain, (2) such longitudinal models may be considered "generic", presumably describing a physiological phenomenon that is similar in any infected individual, and (3) setting up and running the longitudinal model requires additional skills, not necessary for use of the sero-incidence estimator package. # 2. The seroincidence estimator Package **seroincidence** was designed to use the longitudinal response characteristics by means of a set of parameters characterizing the longitudinal response of the selected serum antibodies. These parameters are peak concentrations and decay rates (describing the maximum antibody concentration reached after seroconversion and the rate with which the antibody concentration decreases, assuming first order, or exponential, kinetics). Peak concentrations and decay rates may be provided as a set of parameters describing parametric distributions (a **gamma** distribution for the peak concentrations and an **inverse gamma** distribution for the decay rates, denoted by *A* and *k*, respectively), that characterize the heterogeneity of these response characteristics: peak concentrations and decay rates show considerable variation among individuals. This individual variation in antibody responses is accounted for by generating a Monte Carlo sample (default number of observations *n = 500*) from these parametric distributions and calculating the resulting incidence (as in vignette [methodology.pdf](methodology.pdf), equation (7)). Alternatively, these peak concentrations and decay rates may be provided as sets of Monte-Carlo samples, as can be obtained from longitudinal models (analyzed by *MCMC* methods). Note that, due to the limited number of parameter pairs, the generated incidence estimates will show minor variations: if the same calculation is run twice, the outcomes may differ slightly. If this variation should be undesired, the numbers of parameter pairs may be increased. This however will slow down the calculations. Given these longitudinal response characteristics, the R-scripts delivered for the ECDC project provide a rapid and computationally simple method for calculating seroconversion rates, as published in [@teunis2012]. Given these longitudinal response characteristics, this package provide a rapid and computationally simple method for calculating seroconversion rates, as published in [@feller1968]. The methods on which the seroincidence calculator is based were developed with publicly funded research. All procedures have been published and are open to the general public, including the core function on which the seroincidence calculator is based. To make the functionalities provided as broadly available as possible, R was chosen as the computing platform, because it is free and open source, and runs on any modern operating system. # 3. How to use *seroincidence* package This section provides step-by-step directions on the usage of the *seroincidence* package. ## 3.1. Loading the package Functionality of the *seroincidence* package is made available to the end user only once the library is loaded into the current workspace. Assuming the package is installed already (covered in [installation.pdf](installation.pdf)) loading it is achieved by running the following command in the R console (bear in mind that the text after character `#` is only a comment): ```{r} # Load package "seroincidence" library(seroincidence) ``` At this moment you should have all functions required to run the seroincidence calculation available. You can check that by running: ```{r, eval=FALSE} # List all objects (functions and data) exposed by package "seroincidence" ls("package:seroincidence") ``` Here is the resulting output: ```{r, echo=FALSE} ls("package:seroincidence") ``` We briefly describe the objects: [1] "campylobacterResponseParams": Monte Carlo sample of longitudinal response parameters `A` and `k` per antibody for Campylobacter collected with SSI ELISA procedure. Object class: `list`. [2] `campylobacterSerologyData`: Example antibody levels data measured in cross-sectional population sample for Campylobacter (Delft ELISA). Object class: `data.frame`. [3] `estimateSeroincidence`: Main function of the package. Estimates seroincidence based on supplied cross-section antibody levels data and longitudinal response parameters. Object class: `function`. [4] `salmonellaSerologyData`: Example antibody levels data measured in cross-sectional population sample for Salmonella (SSI Mixed ELISA). Object class: `data.frame`. [5] `simulateSalmonellaResponseParams`: Function to simulate the longitudinal response parameters `A` (peak level) and `k` (decay rate) per antibody for Salmonella. Object class: `function`. [6] `simulateSerologyData`: Function to simulate cross-sectional serology data for three antibodies: `IgG`, `IgM`, `IgA`. Object class: `function`. ## 3.2. Specifying input data There are two sets of inputs to the serology calculator that must always be specified: a) Antibody levels measured in cross-sectional population sample (see `salmonellaSerologyData`, `campylobacterSerologyData`, `simulateSerologyData` above). b) Longitudinal response characteristic as pair of peak concentrations and decay parameters `(A, k)` (see `simulateSalmonellaResponseParams`, `campylobacterResponseParams` above). We start with loading antibody levels measured in cross-sectional population sample. ### 3.2.1. Specifying cross-sectional antibody levels data The user has many options of providing this data to the calculator. Here are a few: **a) Using supplied sample data** Data sets `salmonellaSerologyData` and `campylobacterSerologyData` provide examples of cross-sectional antibody levels data for Salmonella and Campylobacter, respectively. They are loaded into the workspace as soon as the package is loaded, therefore they can be referenced right away. Here are small exempts from these data sets: ```{r} # Show first rows of "salmonellaSerologyData" data.frame head(salmonellaSerologyData) # Show first rows of "campylobacterSerologyData" data.frame head(campylobacterSerologyData) ``` Let us assign one of the sets to variable `serologyData`: ```{r} # Assign data.frame "salmonellaSerologyData" to object named "serologyData" serologyData <- salmonellaSerologyData ``` In this particular example `sex = 1` denotes "male" and `sex = 2` denotes "female". We shall pass this object later to the calculator. Of course, object `salmonellaSerologyData` can be used as an argument of the calculator directly as well. **b) Simulating data from parametric model** Another option is to generate cross-sectional data from the supplied Monte-Carlo simulation function `simulateSerologyData`. This function only exists for testing/training, the simulations do not represent outcomes of any seroconversion process. The underlying parametric models are log-Normal distributions with parameters: * IgG: `mu = 1.246, sd = 0.757` * IgM: `mu = -0.764, sd = 0.413` * IgA: `mu = -1.13, sd = 0.318` By default, 500 observations are generated if no argument `n` is supplied (`n`=number of observations). In the following example we override the default number of generated observations and set it to `300`: ```{r} # Assign output of function "simulateSerologyData" to object named "serologyData" serologyData <- simulateSerologyData(n = 300) # Show first rows of object "serologyData" head(serologyData) ``` **c) Loading from external files** Finally, user can load her/his own data into an R session. Details on loading specific file types can be found in online R manual on [R Data Import/Export] (http://cran.r-project.org/doc/manuals/r-release/R-data.html). It is important that the input data is in a tabular form with each column containing levels measured for a single antibody type. Column name should indicate name of the measured antibody. For instance, a comma separated file with the following content: ``` IgG, IgM, IgA 5.337300, 0.4414653, 0.3002395 3.534118, 0.3888226, 0.3543486 2.144549, 0.3320178, 0.3884205 2.957854, 0.4967764, 0.3472340 ``` is a valid cross-sectional data set. Suppose this file is named `c:\cross-sectional-data.csv`. Then it can be loaded into R like this: ```{r, eval=FALSE} # Read content of file "c:\\cross-sectional-data.csv" into object named "serologyData" serologyData <- read.csv(file = "c:\\cross-sectional-data.csv") ``` Please, note that the cross-sectional data set can include extra columns allowing performing the seroincidence calculations stratified per factors available in those data. For instance, data set `salmonellaSerologyData` includes factors `sex` and `age`. ### 3.2.2. Specifying longitudinal response parameters `(A, k)` The longitudinal response parameters set consists of two items: * `A` = antibody peak level (ELISA units) * `k` = antibody decay rate (1/days for the current longitudinal parameter sets) Please, refer to vignette [methodology.pdf](methodology.pdf) for more details on the underlying methodology. End user has three options for loading the response parameters into R session: **a) Using supplied data** For Campylobacter there is a data set provided by the package including Monte-Carlo sample of longitudinal response parameters, `campylobacterResponseParams`. This object is a list containing two data.frame objects named `A` and `k`. Let's have a pick into each of these two data sets separately (notice character `$` indicating a subobject of the parent object): ```{r} # Show first rows of data.frame "A" in list "campylobacterResponseParams" head(campylobacterResponseParams$A) # Show first rows of data.frame "k" in list "campylobacterResponseParams" head(campylobacterResponseParams$k) ``` Such data set is provided only for Campylobacter. Let us assign object `campylobacterResponseParams` to variable `responseParams`: ```{r} responseParams <- campylobacterResponseParams ``` **b) Simulating data from parametric model** Alternatively, for Salmonella an example of the `A` and `k` parameters can be generated using function `simulateSalmonellaResponseParams` provided by the package: ```{r} responseParams <- simulateSalmonellaResponseParams() ``` Similarly to function `simulateSerologyData` this function also accepts argument `n` specifying the number of observations to simulate. The default is `n = 500`. The underlying parametric models for peak levels `A` are Gamma distributions with parameters: * IgG: `shape = 1.1175, scale = 0.848` * IgM: `shape = 1.337, scale = 0.902` * IgA: `shape = 1.205, scale = 0.651` The underlying parametric models for decay rates `k` are Inverse Gamma distributions with parameters: * IgG: `shape = 0.869, scale = 1/728.5` * IgM: `shape = 0.731, scale = 1/514.6` * IgA: `shape = 1.759, scale = 1/132/5` **c) Loading from external files** Alternatively, this data can be loaded from an external file. Bear in mind, that most likely your data is organized into two files, separately for parameters `A` and `k`. Assuming that the data is saved into csv files named `A.csv` and `k.csv` the end user would run the following code in order to create a valid input to the calculator: ```{r,eval=FALSE} AData <- read.csv(file = "A.csv") kData <- read.csv(file = "k.csv") # Create a list named "responseData" containing objects named "A" and "k" responseParams <- list(A = AData, k = kData) ``` Note that object `responseParams` is a list with two dataframes named `A` and `k` as required. ## 3.3. Estimating seroincidence for human Salmonella and Campylobacter infections Main calculation function provided by package *seroincidence* is called `estimateSeroincidence`. It takes several arguments: - `data`: A data frame with the cross-sectional data. This may be the whole data set loaded from file, but can also be a subset, e.g. `data = serologyData[1, ]` to use only the first row. In this tutorial this is the data loaded into variable `serologyData`. It is a required input. - `antibodies`: A list of antibodies to be used. This can be a triplet (`antibodies = c("IgG", "IgM", "IgA")`) or any single antibody (`antibodies = c("IgG")`) or a combination of any two antibodies. It is a required input. - `strata`: A list of categories to stratify data. The column `age` in the example data set can be used as an example. If `strata = ""` the whole data set is treated as a single stratum; if each sample is assigned a unique identifier (e.g. `strata = "id"`) there are as many strata as there are samples and an incidence estimate is calculated for each sample. If not specified, then `strata` is initialized to `""`. - `Ak`: A list with the longitudinal parameters for all antibodies specified. In this tutorial this is the data loaded into variable `responseParams`. It is a required input. - `censorLimits`: A list of cutoff levels, one for each antibody used. It is a required input. - `showProgress`: A Boolean input indicating whether or not to show progress of the calculation. It is an optional input. If not specified then it is initialized to `FALSE`. Here is an example of the Salmonella seroincidence calculation for three antibodies measured, stratified per sex, and with measurements below 0.25 removed: ```{r, eval=FALSE} # Assign output of function "estimateSeroincidence" to object named "seroincidenceData" serologyData <- salmonellaSerologyData responseParams <- simulateSalmonellaResponseParams() seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = "sex", Ak = responseParams, censorLimits = list(IgG = 0.25, IgM = 0.25, IgA = 0.25)) # Show content of the output variable print(seroincidenceData) # or simply type in the console: 'seroincidenceData' (without "'") and press ENTER ``` The following text should be printed. ## Seroincidence object estimated given the following setup: ## a) Antibodies: IgG, IgM, IgA ## b) Strata: sex ## c) Censor limits: IgG = 0.25, IgM = 0.25, IgA = 0.25 ## ## This object is a list containing the following items: ## Fits - List of outputs of optim function per stratum. ## Antibodies - Input parameter antibodies of function estimateSeroincidence. ## Strata - Input parameter strata of function estimateSeroincidence. ## CensorLimits - Input parameter censorLimits of function estimateSeroincidence. ## ## Call summary function to obtain output results. The most important output is subobject `Fits` containing raw results on the output incidence. Translation of these raw results is provided by a custom function `summary` explained in the following section. The cutoff argument is based on censoring of the observed serum antibody measurements [@strid2001]. Using different censoring levels will produce different results. Choosing higher cut-off causes the estimates of lambda to decrease. Results should be published together with the chosen cut-off values. Cut-off levels must always be specified when calling function `estimateSeroincidence` (argument `censorLimits`). Value `0` should be set for antibody measurements where no censoring is needed, for instance ```{r, eval=FALSE} censorLimits <- list(IgG = 0, IgM = 0, IgA = 0) ``` ## 3.4. Getting a summary of seroincidence Output of the calculator should be passed in to function `summary` calculating output results: ```{r, eval=FALSE} summary(seroincidenceData) ``` ## Seroincidence estimated given the following setup: ## a) Antibodies: IgG, IgM, IgA ## b) Strata: sex ## c) Censor limits: IgG = 0.25, IgM = 0.25, IgA = 0.25 ## d) Quantiles: 0.025, 0.975 ## e) Seroincidence estimates ## Lambda Lambda.lwr Lambda.upr Deviance Convergence Stratum ## 1 0.1218136 0.10788284 0.1375432 2144.977 0 1 ## 2 0.1063245 0.09367877 0.1206772 1908.507 0 2 The `summary` function returns a list of objects as well. It contains sub-objects `Antibodies`, `Strata`, `CensorLimits`, `Quantiles` and `Results`. The most important sub-object of the output of the `summary` functions is `Results`, containing estimates of `Lambda` (annual incidence) together with their lower and upper bounds (`Lambda.lwr` and `Lambda.upr`, respectively). The default lower bound is 2.5% and the upper bound is 97.5% of the distribution of `Lambda`. These values can be changed (see [Other examples](#other-examples)). In this particular example `lambda=0.12` for stratum `1` means that yearly 12% of people are infected based on the sample. Optionally, the summary function returns also `Deviance` (negative log likelihood at the estimated `Lambda`) and `Convergence` (indicator returned by function `optim`; value of 0 indicates convergence). It may be beneficial to assign output of this function to a variable for further analysis: ```{r, eval=FALSE} # Compute seroincidence summary and assign to object "seroincidenceSummary" seroincidenceSummary <- summary(seroincidenceData) # Show the results seroincidenceSummary$Results ``` ## Lambda Lambda.lwr Lambda.upr Deviance Convergence Stratum ## 1 0.1218136 0.10788284 0.1375432 2144.977 0 1 ## 2 0.1063245 0.09367877 0.1206772 1908.507 0 2 As one may note it is a dataframe with six columns that can be later post-processed with custom calculations. # 4. Other examples The following examples show the standard procedure for estimating seroincidence. ```{r, eval=FALSE} # Calculate seroincidence rates for Salmonella # 1. Define cross-sectional data serologyData <- salmonellaSerologyData # 2. Define longitudinal response data (simulate 1000 observations) responseParams <- simulateSalmonellaResponseParams(n = 1000) # 3. Define cut-offs cutoffs <- list(IgG = 0.25, IgM = 0.25, IgA = 0.25) # 4a. Calculate seroincidence rates by age (triplet of titres)... seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = "age", Ak = responseParams, censorLimits = cutoffs, showProgress = TRUE) # 4b. ...or calculate a single seroincidence rate for all serum samples (triplet of titres)... seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = "", Ak = responseParams, censorLimits = cutoffs) # 4c. ...or calculate a single seroincidence rate for a single serum sample (triplet of titres)... seroincidenceData <- estimateSeroincidence(data = serologyData[1, ], antibodies = c("IgG", "IgM", "IgA"), strata = "", Ak = responseParams, censorLimits = cutoffs) # 4d. ...or calculate a single seroincidence rate for all serum samples (only IgG) seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG"), strata = "", Ak = responseParams, censorLimits = cutoffs) # 5a. Produce summary of the results with 2.5% and 97.5% bounds... summary(seroincidenceData) # 5b. ...or produce summary of the results with 5% and 95% bounds, do not show convergence... summary(seroincidenceData, quantiles = c(0.05, 0.95), showConvergence = FALSE) # 5c. ...or produce summary and assign to an object... seroincidenceSummary <- summary(seroincidenceData) # ...and work with the results object from now on (here: display the results). seroincidenceSummary$Results ``` # Acknowledgements Project funded by European Centre for Disease Prevention and Control (ECDC). # References seroincidence/inst/doc/cover.R0000644000176200001440000000131112640456126016051 0ustar liggesusers## ---- echo = FALSE------------------------------------------------------- pkgVersion <- packageDescription("seroincidence")$Version pkgDate <- packageDescription("seroincidence")$Date authorsString <- gsub("^ *|(?<= ) |\n| *$", "", packageDescription("seroincidence")$Authors, perl = TRUE) authorList <- eval(parse(text = authorsString)) pkgAuthors <- paste(format(authorList, include = c("given", "family", "email", "comment"), braces = list(email = c("<", ">,
"), comment = c("", ""))), collapse = "

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"), comment = c("", ""))), collapse = "

") pkgMaintainer <- packageDescription("seroincidence")$Maintainer pkgBaseFileName <- paste("seroincidence", pkgVersion, sep = "_") pkgUrl <- packageDescription("seroincidence")$URL ``` R package **seroincidence** allows translation of antibody levels measured in a (cross-sectional) population sample into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. Item | Data ----- | ------ Version | `r pkgVersion` Published | `r pkgDate` Authors | `r pkgAuthors` Maintainer | `r pkgMaintainer` License | GPL-3 Package source | [`r pkgBaseFileName`.tar.gz](seroincidence_`r pkgVersion`.tar.gz) Windows binary | [`r pkgBaseFileName`.zip](seroincidence_`r pkgVersion`.zip) Installation manual | [installation.pdf](installation.pdf) Tutorial | [tutorial.pdf](tutorial.pdf) Appendix | [methodology.pdf](methodology.pdf) ECDC web site | `r pkgUrl` seroincidence/tests/0000755000176200001440000000000012640456126014234 5ustar liggesusersseroincidence/tests/testthat.R0000644000176200001440000000006012640456126016213 0ustar liggesuserslibrary(testthat) test_check("seroincidence") seroincidence/tests/testthat/0000755000176200001440000000000012640603670016072 5ustar liggesusersseroincidence/tests/testthat/test.simulateSerologyData.R0000644000176200001440000000033612640456126023340 0ustar liggesuserscontext("Simulation") test_that("simulateSerologyData produces samples", { expect_that(simulateSerologyData(n = 100), is_a("data.frame")) expect_that(nrow(simulateSerologyData(n = 100)), equals(100)) }) seroincidence/NAMESPACE0000644000176200001440000000037612640456126014317 0ustar liggesusers# Generated by roxygen2: do not edit by hand S3method(print,seroincidence) S3method(print,summary.seroincidence) S3method(summary,seroincidence) export(estimateSeroincidence) export(simulateSalmonellaResponseParams) export(simulateSerologyData) seroincidence/NEWS0000644000176200001440000000625212640456126013576 0ustar liggesusersseroincidence v.1.0.5 (Release date: 2015-12-29) ================ Changes: * Packages "stats" and "utils" listed in the "Imports" section of DESCRIPTION. Imported functions are called as "pkg::fun()". * Vignette "methodology.Rmd" made compatible with rmarkdown 0.9. Line "- \usepackage[pdftex]{graphicx}" removed. * Oxygen documentation made compatible with roxygen2 5.0.1. Values for tags "docType" and "news" put on the same line. seroincidence v.1.0.4 (Release date: 2015-05-22) ================ Changes: * URL for package location on ECDC website updated. seroincidence v.1.0.3 (Release date: 2015-04-10) ================ Changes: * LICENSE file removed, reference to that file removed from DESCRIPTION * NEWS updated * changed the version numbering from 1.0.2 to 1.0.3. seroincidence v.1.0.2 (Release date: 2015-04-09) ================ Changes: * manually corrected break line in URL in DESCRIPTION file in the source package "tar.gz" file (inserted there by the R build system). * ensured that all references to URL from DESCRIPTION (in citation, vignettes) have all break lines removed. * fixed one reference in the vignettes. * changed the version numbering from 1.0.1 to 1.0.2. seroincidence v.1.0.1 (Release date: 2015-03-31) ================ Changes: * All titles (package, functions, data sets) changed to title case * All S3 methods exported and registered * All exported functions/data sets are documented with examples including comments. Examples requiring time consuming calculations are put in \dontrun environment. seroincidence v.1.0.0 (Release date: 2015-03-18) ================ Changes: * Vignettes reformatted seroincidence v.0.9.9 (Release date: 2015-03-04) ================ Changes: * Vignette's content updated seroincidence v.0.9.8 (Release date: 2015-02-25) ================ Changes: * "Methodology" document extracted from the tutorial and converted to pdf. * Fixes of typos in the methodology document. * Fixes of typos, formatting, references, additional text in the tutorial. * Restructuring and additional text in the installation manual. * Acronym "GUI" expanded to "graphical user interface". * Description of parametric models in "simulateSerologyData.R", "simulateSalmonellaResponseParams" and the tutorial. * Description of response parameters added in the tutorial (section "Specifying longitudinal response parameters"). * Description of outputs of the summary function in the tutorial. * Spell check run on the installation, tutorial and methodology. seroincidence v.0.9.7 (Release date: 2015-01-30) ================ Changes: * Tutorial vignettes customized for pdf and html output * Sections "Antibody decay and seroincidence" of the tutorial vignettes include now subsections on censoring and checks. seroincidence v.0.9.6 (Release date: 2014-12-19) ================ Changes: * Fix intialization of variable "progressBarCreated" in "estimateSeroincidence". * Added URL to ECDC website * "estimateSeroincidence" and "summary.seroincidence" updated: operate on output of "optim" function. * printing functions added for outputs of "estimateSeroincidence" and "summary.seroincidence" seroincidence/data/0000755000176200001440000000000012640456126014003 5ustar liggesusersseroincidence/data/salmonellaSerologyData.RData0000644000176200001440000002270512640456126021373 0ustar liggesusers xՙǏþ@%a UZUQ[2]2ѱu6bR uAP[YTVqwo_$3>yIO+?SJRڥvC;k!k\ze,w+._p8{ޕRjUO;jR߯82MptݒR1DcD:V]GC4|_xI;tݦ]L'Hk7}> 5/UldRzL1Q?M#gh LsnѺRfkb54q"ѳ#5-{ jmOiɰSuZƱsoZ{ {[AώOc_h?)[S?N|i\5ى;N)>5NJ{kj:@.8D>.6)ܕP*A=/34Β,#88/A:J'zx.۵Գ_O=WJ_3 mҺSEb:'_$zR"?5jNKz=g9 %wt#4wh~UXݤ/Ѻբ3Xz4NV$&=;W?ޗ5nmAkj"ڍM8/Uosdjq/ҸXϿ+\Ju *tGt~$/%[oH w-ƽ]>~h^*~ۄŷ^xWsӄ/id;JXؤX[c@ $2)lu>Y*|>_}% Az~0\<ωs _+]:ƙ6G}>F$S(w%jZazdF%}giVE4_şflE8/iwEtx Ww4Γܹ\Sι]ոQ5hzƱi\&gַCGnٕwj'ܾ{o}(l~iwV{0BX:?ggK55u?iCɴCU=wzJ5=k0J48D:"ݐCeLT =xY"}*㕢59L{k}?_+M7H;$mZ9UlgӱSgi7\$ޮqfT#:$Z%=NZsp8DkznWyH^/q.ݧkݝSvJ[){xEt+m=%WD9S9t%ҿ)}vaN_8]+kºZ{'U/w461TkVؘF5z6BlK>vNqd*kD,5 D{ޓ՚l0/y'8=/EZN{1?GCu~Nzkt}Acm] .#ekD{rcfjtt;T6p,_Β IzwP\jǤo >w5HakY&9FLchX!o0x[2\xu|gi'syV/+_)YHᓫd&Ss4_Q!ًeUjt61;trX.7=uE"wr8Ds#xͫ((ߓkBɥ~BݠP>Rcq+[yl{s{U;!UXNsк[4nSDwh,\bkO3^U %q-z%\wgim'Cf  GW*˅[}?hOF|gxswP>-juqS4h~\Djs|mԨuI3d/s3M)%QO8k5oH|anu%r:D-dn979 Ywa #Z_\w?T 8]{кDsY*/s/9ט5ߑsy=U)/7W6a[Q{oF;npXl!%j{{`:ÓEZ[{?Oh/Kc'cǕN4T7Wݓ&w.MG^>~ʡw&܋>WcƯk:IGEud۠=?кBw>'46zs3VzL:TNܓoO5ssiNm=M|-'K!ϥǧ%&a}jki\+_Voy}ɟt^,SuGYQQ5JYҵ">uN}E>U^sg-.HS +.vT 'ޏvӳEbxS{;J#n"y I9S9Qs}o%SɶA+F{= HA_'sOo 5aEkn%7wuӧ^J-{.һJv#?zB:,Yݏnk>ˇE'[up_/7KeT.:*F%ӤCZ~^Pys.諒T oSy.7ľrd5BU*"㗷j6ȁC/xTuGU_g?Z>w˿Ao9wSWo/?%C5\>ݫp~ {n wUr}j ݫsCoIg+5v:_/_!;y?{Kr)>Z yG&#3l0yCGb:rA:K=q:f+J)pyn qSgv~k~qyL@~A,q N#Gv[ϣ;?lx!n͞F9wk/G!3d|'~b?9&1'|} ;ПA\S؟ coWN9=8-7؛HGŗ{W!33b B9xaG0x_Y>Ukk- Їy)YkxS?| _ ?уM\#"g?KYŏW==y{sZg둋~ }fw޻-l?ӇǏ\{w|N.6=]Yf|!>wcG9{y:;~sgvG—&ﯴEao;N ȏؕxXj\B8gag?+}4+ Z1>ȵG?2\|sSwKf- ǃN4>qm_OgC8 ,~a?rV=?54{-D9x`Fw?wK yp?oOϏЅ/DnhnR 'm})ؙ'QƲ6C>nF Uc~Ï&/v$]cw >޶5v؏?"?St'r ]o3lJzf[mzbgS=?zé"+=Ue~y#>|?Goo\;tџ+m~8p?o7Y?Y]?[~_}SF>r#}{q<כݼoN?_FyXiy xx7i?OSQωOk-zGy>yV?ߵo=v.|"ym)W/9O_?ƾ%W_z>%WSo^_9 ?yty]K;x<7?y_qO'>>? 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Additional arguments affecting the summary produced. #' #' @examples #' #' \dontrun{ #' #' # estimate seroincidence #' seroincidence <- estimateSeroincidence(...) #' #' # print the seroincidence object to the console #' print(seroincidence) #' #' # or simply type (appropriate print method will be invoked automatically) #' seroincidence #' } #' #' @export print.seroincidence <- function(x, ...) { cat("Seroincidence object estimated given the following setup:\n") cat(paste("a) Antibodies: ", paste(x[["Antibodies"]], collapse = ", ")), "\n") cat(paste("b) Strata: ", paste(x[["Strata"]], collapse = ", ")), "\n") censorLimits <- x[["CensorLimits"]] cat(paste("c) Censor limits: ", paste(sapply(names(censorLimits), FUN = function(name) {paste(name, censorLimits[name], sep = " = ")}), collapse = ", "), "\n")) cat("\n") cat("This object is a list containing the following items:\n") cat("Fits - List of outputs of optim function per stratum.\n") cat("Antibodies - Input parameter antibodies of function estimateSeroincidence.\n") cat("Strata - Input parameter strata of function estimateSeroincidence.\n") cat("CensorLimits - Input parameter censorLimits of function estimateSeroincidence.\n") cat("\n") cat("Call summary function to obtain output results.\n") } seroincidence/R/nllGamma.R0000644000176200001440000000062612640456126015152 0ustar liggesusers.nllGamma <- function(logLambda, y, m, A, k, censorLimit) { n <- length(A) lambda <- exp(logLambda) log.rho <- ifelse(y > censorLimit, sapply(X = y, FUN = .logRhoPdf, lambda = lambda, m = m, A = A, k = k, n = n), # uncensored sapply(X = y, FUN = .logRhoCdf, lambda = lambda, m = m, A = A, k = k, n = n)) # censored return(-sum(log.rho)) } seroincidence/R/simulateSerologyData.R0000644000176200001440000000231112640456126017554 0ustar liggesusers#' @title #' Simulate Cross-Sectional Serology Data #' #' @description #' Function to simulate cross-sectional serology data for three antibodies: IgG, IgM, IgA. #' The underlying parametric models are log-Normal distributions with parameters: #' \itemize{ #' \item{IgG: \code{mu} = 1.246, \code{sd} = 0.757} #' \item{IgM: \code{mu} = -0.764, \code{sd} = 0.413} #' \item{IgA: \code{mu} = -1.13, \code{sd} = 0.318} #' } #' #' @param #' n Number of simulations, default 500. #' #' @return #' A dataframe of simulated antibody data, with named columns IgG, IgM and IgA. #' #' @examples #' #' # simulate 500 observations of cross-sectional serology data #' simulateSerologyData() #' #' # simulate 10 observations of cross-sectional serology data #' simulateSerologyData(n = 10) #' #' @export simulateSerologyData <- function(n = 500) { simSerology <- function(n = 500, mu = 1, sd = 0.5) { return(exp(stats::rnorm(n = n, mean = mu, sd = sd))) } result <- data.frame( IgG = simSerology(n = n, mu = 1.246, sd = 0.757), IgM = simSerology(n = n, mu = -0.764, sd = 0.413), IgA = simSerology(n = n, mu = -1.13, sd = 0.318)) return(result) } seroincidence/R/logRhoCdf.R0000644000176200001440000000072712640456126015273 0ustar liggesusers.logRhoCdf <- function(y, lambda, m, A, k, n) { index <- (y <= A) A.i <- A[index] k.i <- k[index] term.j <- 0 for (j in 0:m) term.j <- term.j + stats::pgamma(q = log(A.i / y) * lambda / k.i, shape = j + 1, rate = 1, lower.tail = FALSE) term.i <- term.j / (m + 1) return(log((sum(term.i) / n))) } seroincidence/R/logRhoPdf.R0000644000176200001440000000062212640456126015302 0ustar liggesusers.logRhoPdf <- function(y, lambda, m, A, k, n) { index <- (y <= A) A.i <- A[index] k.i <- k[index] delta_t.p <- (m + 1)/lambda term.i <- stats::pgamma(q = log(A.i / y)/ k.i, shape = m + 1, rate = lambda, lower.tail = FALSE) / (k.i * delta_t.p) return(log((sum(term.i) / n) / y)) } seroincidence/R/salmonellaSerologyData.R0000644000176200001440000000224112640456126020062 0ustar liggesusers#' @docType data #' #' @name salmonellaSerologyData #' #' @title #' Salmonella Antibody Levels Data #' #' @description #' Antibody levels measured in cross-sectional population sample for Salmonella with SSI Mixed ELISA procedure. #' #' @usage #' data("salmonellaSerologyData") #' #' @format #' A data frame with 456 observations on the following 6 variables: #' \describe{ #' \item{\code{id}}{Observation id} #' \item{\code{IgG}}{Measured IgG antibody level} #' \item{\code{IgM}}{Measured IgM antibody level} #' \item{\code{IgA}}{Measured IgA antibody level} #' \item{\code{sex}}{Sex indicator (1 - Male, 2 - Female)} #' \item{\code{age}}{Age} #' } #' #' @source #' Dutch Pienter 1 serosurvey #' #' @references #' Teunis, P. F., van Eijkeren, J. C., Ang, C. W., van Duynhoven, Y. T., Simonsen, J. B., Strid, M. A., van Pelt W.\cr #' "Biomarker Dynamics: Estimating Infection Rates From Serological Data"\cr #' Statistics in Medicine 31, no. 20 (September 9, 2012): 2240--48. doi:10.1002/sim.5322. #' #' @examples #' #' # show first rows of the data #' head(salmonellaSerologyData) #' #' # plot the data #' plot(salmonellaSerologyData) #' NULL seroincidence/R/nll.R0000644000176200001440000000106512640456126014205 0ustar liggesusers.nll <- function(logLambda, y, m = 0, Ak, censorLimits) { # Start with zero total nllTotal <- 0 # Loop over antibodies for (i in names(y)) nllTotal <- nllTotal + .nllGamma(logLambda = logLambda, y = y[, i], m = m, A = Ak$A[, i], k = Ak$k[, i], censorLimit = censorLimits[i]) # Return total return(nllTotal) } seroincidence/R/estimateSeroincidence.R0000644000176200001440000001321512640456126017726 0ustar liggesusers#' @title #' Estimate Seroincidences #' #' @description #' Function to estimate seroincidences based on cross-section serology data and #' longitudinal response model. #' #' @param #' data Dataframe with cross-sectional serum antibody data. At least one #' antibody should be specified. Rows represent multiple antibody measurements #' in the same serum sample. Strata may be specified in additional columns. #' @param #' antibodies Character vector with names of antibodies to be included #' for incidence calculations. At least one antibody name must be specified, #' names must match with those in \code{data} and in \code{Ak}. #' @param #' strata Character vector with names of strata to be used, default ="". Names #' must match with data. #' @param #' Ak List with two dataframes containing longitudinal parameters named #' A (the peak serum antibody level) and k (the decay rate). Each dataframe #' contains sets of Monte Carlo samples, one for each antibody that is available. #' @param #' censorLimits List of cutoffs for each of the antibodies specified #' in 'antibodies'. Any cross-sectional observations below cutoff will be treated #' as censored at the cutoff level. #' @param #' showProgress Indicator whether or not to show text progress bar indicating progress of estimation. #' The setting is effective only if the number of levels per stratum if greater than 1. Default is \code{FALSE}. #' @param #' ... Additional arguments passed to function \code{\link{optim}}. #' #' @return #' A list with the following items: #' \describe{ #' \item{\code{Fits}}{Outputs of \code{\link{optim}} function per stratum.} #' \item{\code{Antibodies}}{Input parameter \code{antibodies} saved for \code{\link{summary}} function.} #' \item{\code{Strata}}{Input parameter \code{strata} saved for \code{\link{summary}} function.} #' \item{\code{CensorLimits}}{Input parameter \code{censorLimits} saved for \code{\link{summary}} function.} #' } #' #' @examples #' #' \dontrun{ #' estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), #' strata = c("age"), Ak = responseParams) #' } #' #' @export estimateSeroincidence <- function(data, antibodies, strata = "", Ak, censorLimits, showProgress = FALSE, ...) { # Check antibodies if (!is.character(antibodies)) stop("Argument \"antibodies\" is not a character vector.\nProvide a character vector with at least one antibody name") if (all(antibodies == "")) stop("Argument \"antibodies\" is empty.\nProvide a character vector with at least one antibody name") # Check data if (!is.data.frame(data)) stop("Argument \"data\" is not a dataframe.\nProvide a dataframe with cross-sectional serology data per antibody") if (!all(is.element(antibodies, names(data)))) stop("Antibody names in argument \"data\" and argument \"antibodies\" do not match") # Check strata if (!is.character(strata)) stop("Argument \"strata\" is not a character vector.\nProvide a character vector with strata names") if (!all(is.element(strata, c("", names(data))))) stop("Strata names in argument \"data\" and argument \"strata\" do not match") # Check AkSim if (!is.list(Ak) | length(Ak) != 2) stop("Argument \"Ak\" is not a list with two dataframes.\nProvide a list with two dataframes named A and k\nEach dataframe contains Monte Carlo simulations per antibody") if (!is.data.frame(Ak[[1]]) | !is.data.frame(Ak[[2]])) stop("Argument \"Ak\" does not contain two dataframes.\nProvide a list with two dataframes named A and k\nEach dataframe contains Monte Carlo simulations per antibody") if (!all(is.element(names(Ak), c("A", "k")))) stop("The two dataframes in argument \"Ak\" are not named A and k.\nProvide a list with two dataframes named A and k\nEach dataframe contains Monte Carlo simulations per antibody") if (nrow(Ak$A) != nrow(Ak$k)) stop("The two dataframes A and k in argument \"Ak\" are of different length") if (!all(is.element(antibodies, names(Ak$A)))) stop("Antibody names in argument \"antibodies\" and argument \"Ak\" do not match") # Make stratum variable (if needed) if (all(strata != "")) data <- within(data, stratum <- interaction(data[, strata])) else data <- within(data, stratum <- factor(1)) levelsStrata <- levels(data$stratum) numLevels <- nlevels(data$stratum) # Loop over levelsStrata progressBarCreated <- FALSE if (showProgress & numLevels > 1) { pb <- utils::txtProgressBar(min = 0, max = numLevels) progressBarCreated <- TRUE } fits <- list() for (i in seq_len(nlevels(data$stratum))) { # Make subset of data: per stratum, select antibodies y <- subset(data, subset = stratum == levelsStrata[i], select = antibodies) # Incidence can not be calculated if there are zero observations if (nrow(y) == 0) next # Estimate log.lambda, starting value = log(1/365.25) day^-1 fit <- stats::optim(par = log(1 / 365.25), fn = .nll, y = y, m = 0, Ak = Ak, censorLimits = censorLimits, method = "BFGS", hessian = TRUE, ...) # Collect results fits[[levelsStrata[i]]] <- fit if (progressBarCreated) utils::setTxtProgressBar(pb, i) } if (progressBarCreated) close(pb) incidenceData <- list(Fits = fits, Antibodies = antibodies, Strata = strata, CensorLimits = censorLimits) class(incidenceData) <- c("seroincidence", "list") # Return seroincidence object return(incidenceData) } seroincidence/R/campylobacterSerologyData.R0000644000176200001440000000125012640456126020557 0ustar liggesusers#' @docType data #' #' @name campylobacterSerologyData #' #' @title #' Campylobacter Antibody Levels Data #' #' @description #' Cross-sectional population sample of antibody levels data for Campylobacter. #' #' @usage #' campylobacterSerologyData #' #' @format #' A data frame with 258 observations on the following 3 variables: #' \describe{ #' \item{\code{IgG}}{Measured IgG antibody level} #' \item{\code{IgM}}{Measured IgM antibody level} #' \item{\code{IgA}}{Measured IgA antibody level} #' } #' #' @examples #' #' # show first rows of the data #' head(campylobacterSerologyData) #' #' # plot the data #' plot(campylobacterSerologyData) #' NULL seroincidence/R/seroincidence.R0000644000176200001440000001153712640456126016237 0ustar liggesusers#' @docType package #' #' @name seroincidence #' #' @title #' Estimating Infection Rates from Serological Data #' #' @description #' Translates antibody levels measured in a (cross-sectional) population sample into an #' estimate of the frequency with which seroconversions (infections) occur in the sampled population. #' #' @details #' For detailed documentation type the following in the R console:\cr #' #' \code{vignette("installation", package = "seroincidence")}\cr #' \code{vignette("tutorial", package = "seroincidence")}\cr #' \code{vignette("methodology", package = "seroincidence")} #' #' @author #' Author: Peter Teunis \email{}\cr #' Contributor: Daniel Lewandowski \email{}\cr #' Maintainer: Chantal Quinten \email{} #' #' @references #' #' \strong{\emph{Methods for estimating seroincidence}} #' #' \itemize{ #' \item Teunis, P. F., van Eijkeren, J. C., Ang, C. W., van Duynhoven, Y. T., Simonsen, J. B., Strid, M. A., van Pelt, W.\cr #' "Biomarker dynamics: estimating infection rates from serological data"\cr #' Statistics in Medicine 31, no. 20 (September 9, 2012): 2240--48. doi:10.1002/sim.5322. #' #' \item Simonsen, J., Molbak, K., Falkenhorst, G., Krogfelt, K. A., Linneberg, A., Teunis, P. F.\cr #' "Estimation of incidences of infectious diseases based on antibody measurements"\cr #' Statistics in Medicine 28, no. 14 (June 30, 2009): 1882--95. doi:10.1002/sim.3592. #' } #' #' \strong{\emph{Applications}} #' #' \itemize{ #' \item Kretzschmar, M., Teunis, P. F., Pebody, R. G.\cr #' "Incidence and reproduction numbers of pertussis: estimates from serological and social contact data in five European countries"\cr #' PLoS Medicine 7, no. 6 (June 1, 2010):e1000291. doi:10.1371/journal.pmed.1000291. #' #' \item Simonsen, J., Strid, M. A., Molbak, K., Krogfelt, K. A., Linneberg, A., Teunis, P.\cr #' "Sero-epidemiology as a tool to study the incidence of Salmonella infections in humans"\cr #' Epidemiology and Infection 136, no. 7 (July 1, 2008): 895--902. doi:10.1017/S0950268807009314 #' #' \item Simonsen, J., Teunis, P. F., van Pelt, W., van Duynhoven, Y., Krogfelt, K. A., Sadkowska-Todys, M., Molbak K.\cr #' "Usefulness of seroconversion rates for comparing infection pressures between countries"\cr #' Epidemiology and Infection, April 12, 2010, 1--8. doi:10.1017/S0950268810000750. #' #' \item Falkenhorst, G., Simonsen, J., Ceper, T. H., van Pelt, W., de Valk, H., Sadkowska-Todys, M., Zota, L., Kuusi, M., Jernberg, C., Rota, M. C., van Duynhoven, Y. T., Teunis, P. F., Krogfelt, K. A., Molbak, K.\cr #' "Serological cross-sectional studies on salmonella incidence in eight European countries: no correlation with incidence of reported cases"\cr #' BMC Public Health 12, no. 1 (July 15, 2012): 523--23. doi:10.1186/1471-2458-12-523. #' #' \item Teunis, P. F., Falkenhorst, G., Ang, C. W., Strid, M. A., De Valk, H., Sadkowska-Todys, M., Zota, L., Kuusi, M., Rota, M. C., Simonsen, J. B., Molbak, K., Van Duynhoven, Y. T., van Pelt, W.\cr #' "Campylobacter seroconversion rates in selected countries in the European Union"\cr #' Epidemiology and Infection 141, no. 10 (2013): 2051--57. doi:10.1017/S0950268812002774. #' #' \item de Melker, H. E., Versteegh, F. G., Schellekens, J. F., Teunis, P. F., Kretzschmar, M.\cr #' "The incidence of Bordetella pertussis infections estimated in the population from a combination of serological surveys"\cr #' The Journal of Infection 53, no. 2 (August 1, 2006): 106--13. doi:10.1016/j.jinf.2005.10.020 #' } #' #' \strong{\emph{Quantification of seroresponse}} #' #' \itemize{ #' \item de Graaf, W. F., Kretzschmar, M. E., Teunis, P. F., Diekmann, O.\cr #' "A two-phase within-host model for immune response and its application to serological profiles of pertussis"\cr #' Epidemics 9 (2014):1--7. doi:10.1016/j.epidem.2014.08.002. #' #' \item Berbers, G. A., van de Wetering, M. S., van Gageldonk, P. G., Schellekens, J. F., Versteegh, F. G., Teunis, P.F.\cr #' "A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens"\cr #' Vaccine 31, no. 36 (August 12, 2013): 3732--38. doi:10.1016/j.vaccine.2013.05.073. #' #' \item Versteegh, F. G., Mertens, P. L., de Melker, H. E., Roord, J. J., Schellekens, J. F., Teunis, P. F.\cr #' "Age-specific long-term course of IgG antibodies to pertussis toxin after symptomatic infection with Bordetella pertussis"\cr #' Epidemiology and Infection 133, no. 4 (August 1, 2005): 737--48. #' #' \item Teunis, P. F., van der Heijden, O. G., de Melker, H. E., Schellekens, J. F., Versteegh, F. G., Kretzschmar, M. E. #' "Kinetics of the IgG antibody response to pertussis toxin after infection with B. pertussis"\cr #' Epidemiology and Infection 129, no. 3 (December 10, 2002):479. doi:10.1017/S0950268802007896. #' } #' NULL seroincidence/R/rinvgamma.R0000644000176200001440000000015612640456126015401 0ustar liggesusers.rinvgamma <- function(n, shape = 1, scale = 1) { return(1 / stats::rgamma(n, shape, rate = scale)) } seroincidence/R/print.summary.seroincidence.R0000644000176200001440000000272012640456126021060 0ustar liggesusers#' @title #' Print Method for Seroincidence Summary Object #' #' @description #' Custom \code{\link{print}} function to show output of the seroincidence summary \code{\link{summary.seroincidence}}. #' #' @param #' x A list containing output of function \code{\link{summary.seroincidence}}. #' @param #' ... Additional arguments affecting the summary produced. #' #' @examples #' #' \dontrun{ #' #' # estimate seroincidence #' seroincidence <- estimateSeroincidence(...) #' #' # calculate summary statistics for the seroincidence object #' seroincidenceSummary <- summary(seroincidence) #' #' # print the summary of seroincidence object to the console #' print(seroincidenceSummary) #' #' # or simply type (appropriate print method will be invoked automatically) #' seroincidenceSummary #' } #' #' @export print.summary.seroincidence <- function(x, ...) { cat("Seroincidence estimated given the following setup:\n") cat(paste("a) Antibodies: ", paste(x[["Antibodies"]], collapse = ", ")), "\n") cat(paste("b) Strata: ", paste(x[["Strata"]], collapse = ", ")), "\n") censorLimits <- x[["CensorLimits"]] cat(paste("c) Censor limits: ", paste(sapply(names(censorLimits), FUN = function(name) {paste(name, censorLimits[name], sep = " = ")}), collapse = ", "), "\n")) cat(paste("d) Quantiles: ", paste(x[["Quantiles"]], collapse = ", ")), "\n") cat("\n Seroincidence estimates:\n") print(x[["Results"]]) } seroincidence/R/simulateSalmonellaResponseParams.R0000644000176200001440000000414612640456126022141 0ustar liggesusers#' @title #' Simulate Longitudinal Response Parameters for Salmonella #' #' @description #' Simulate longitudinal response parameters \code{A} and \code{k} per antibody #' for Salmonella (SSI Mixed ELISA). #' #' The underlying parametric models for peak levels \code{A} are Gamma distributions with parameters: #' \itemize{ #' \item{IgG: \code{shape} = 1.1175, \code{scale} = 0.848} #' \item{IgM: \code{shape} = 1.337, \code{scale} = 0.902} #' \item{IgA: \code{shape} = 1.205, \code{scale} = 0.651} #' } #' #' The underlying parametric models for decay rates \code{k} are Inverse Gamma distributions with parameters: #' \itemize{ #' \item{IgG: \code{shape} = 0.869, \code{scale} = 1/728.5} #' \item{IgM: \code{shape} = 0.731, \code{scale} = 1/514.6} #' \item{IgA: \code{shape} = 1.759, \code{scale} = 1/132/5} #' } #' #' @param #' n Number of Monte Carlo simulations per antibody, default 500. #' #' @return #' A list of two dataframes named \code{A} and \code{k}: #' \describe{ #' \item{\code{A}}{Dataframe containing peak levels (SSI mixed ELISA units/ml). Named #' columns contain estimated peak levels for IgG, IgM and IgA antibodies.} #' \item{\code{k}}{Dataframe containing decay rates (1/days). Named columns contain #' estimated decay rates for IgG, IgM and IgA antibodies.} #' } #' #' @examples #' #' # simulate 500 observations of longitudinal response data #' simulateSalmonellaResponseParams() #' #' # simulate 100 observations of longitudinal response data #' simulateSalmonellaResponseParams(n = 100) #' #' @export simulateSalmonellaResponseParams <- function(n = 500) { result <- list( A = data.frame( IgG = stats::rgamma(n = n, shape = 1.175, scale = 0.848), IgM = stats::rgamma(n = n, shape = 1.337, scale = 0.902), IgA = stats::rgamma(n = n, shape = 1.205, scale = 0.651)), k = data.frame( IgG = .rinvgamma(n = n, shape = 0.869, scale = 1/728.5), IgM = .rinvgamma(n = n, shape = 0.731, scale = 1/514.6), IgA = .rinvgamma(n = n, shape = 1.759, scale = 1/132.5))) return(result) } seroincidence/R/campylobacterResponseParams.R0000644000176200001440000000240412640456126021126 0ustar liggesusers#' @docType data #' #' @name campylobacterResponseParams #' #' @title #' Campylobacter Response Parameters Data #' #' @description #' Monte Carlo sample of longitudinal response parameters \code{A} (peak level) #' and \code{k} (decay rate) per antibody for Campylobacter collected with SSI ELISA procedure. #' #' @usage #' campylobacterResponseParams #' #' @format #' A list of two dataframes: #' \describe{ #' \item{\code{A}}{a dataframe containing 4000 peak levels (SSI ELISA units/ml). Named #' columns contain estimated peak levels for IgG, IgM and IgA antibodies.} #' \item{\code{k}}{a dataframe containing 4000 decay rates (1/days). Named columns #' contain estimated decay rates for IgG, IgM and IgA antibodies.} #' } #' #' @references #' Strid, M. A., Engberg, J., Larsen, L. B., Begtrup, K., Molbak, K., Krogfelt, K. A.\cr #' "Antibody responses to Campylobacter infections determined by an enzyme-linked immunosorbent assay: 2-year follow-up study of 210 patients"\cr #' Clinical and Diagnostic Laboratory Immunology 8, no. 2 (March 1, 2001): 314--19. doi:10.1128/CDLI.8.2.314-319.2001. #' #' @examples #' #' # show first rows of every dataframe contained in campylobacterResponseParams #' lapply(campylobacterResponseParams, head) #' NULL seroincidence/R/summary.seroincidence.R0000644000176200001440000000671612640456126017736 0ustar liggesusers#' @title #' Summary Method for Seroincidence Object #' #' @description #' Calculate seroincidence from output of the seroincidence calculator \code{\link{estimateSeroincidence}}. #' #' @param #' object A dataframe containing output of function \code{\link{estimateSeroincidence}}. #' @param #' ... Additional arguments affecting the summary produced. #' @param #' quantiles A vector of length 2 specifying quantiles for lower (first element) and upper (second element) bounds of \code{lambda}. Default \code{c(0.025, 0.975)}. #' @param #' showDeviance Logical flag (\code{FALSE}/\code{TRUE}) for reporting deviance (-2*log(likelihood) at estimated seroincidence. Default is \code{TRUE}. #' @param #' showConvergence Logical flag (\code{FALSE}/\code{TRUE}) for reporting convergence (see help for \code{\link{optim}} for details). Default is \code{TRUE}. #' #' @return #' A list with the following items: #' \describe{ #' \item{\code{Results}}{Dataframe with maximum likelihood estimate of \code{lambda} (the seroincidence) (column \code{Lambda}) and #' corresponding lower (\code{Lambda.lwr}) and upper (\code{Lambda.upr} bounds. #' Optionally \code{Deviance} (Negative log likelihood (NLL) at estimated (maximum likelhood) \code{lambda}) #' and \code{Covergence} (Convergence indicator returned by \code{\link{optim}}. Value of 0 indicates convergence) #' columns are included.} #' \item{\code{Antibodies}}{Character vector with names of input antibodies used in \code{\link{estimateSeroincidence}}.} #' \item{\code{Strata}}{Character with names of strata used in \code{\link{estimateSeroincidence}}.} #' \item{\code{CensorLimits}}{List of cutoffs for each of the antibodies used in \code{\link{estimateSeroincidence}}.} #' } #' #' @examples #' #' \dontrun{ #' #' # estimate seroincidence #' seroincidence <- estimateSeroincidence(...) #' #' # calculate summary statistics for the seroincidence object #' seroincidenceSummary <- summary(seroincidence) #' } #' #' @export summary.seroincidence <- function(object, ..., quantiles = c(0.025, 0.975), showDeviance = TRUE, showConvergence = TRUE) { if (length(quantiles) != 2 | any(quantiles < 0) | any(quantiles > 1)) stop("Incorrectly specified quantiles") if (quantiles[1] > quantiles[2]) stop("Quantile for upper bound of incidence estimate cannot be less than the lower bound") fits <- object[["Fits"]] results <- as.data.frame(t(sapply(fits, FUN = function(elem) { with(elem, c( Lambda = 365.25 * exp(par + qnorm(0.5) * sqrt(1 / hessian)), Lambda.lwr = 365.25 * exp(par + qnorm(quantiles[1]) * sqrt(1 / hessian)), Lambda.upr = 365.25 * exp(par + qnorm(quantiles[2]) * sqrt(1 / hessian)), Deviance = 2 * value, Convergence = convergence)) }))) results$Stratum <- rownames(results) rownames(results) <- NULL if (!showDeviance) results$Deviance <- NULL if (!showConvergence) results$Convergence <- NULL output <- list(Results = results, Antibodies = object[["Antibodies"]], Strata = object[["Strata"]], CensorLimits = object[["CensorLimits"]], Quantiles = quantiles) class(output) <- c("summary.seroincidence", "list") return(output) } seroincidence/vignettes/0000755000176200001440000000000012640456136015103 5ustar liggesusersseroincidence/vignettes/installation.Rmd0000644000176200001440000001361712640456126020257 0ustar liggesusers--- vignette: > %\VignetteIndexEntry{Seroincidence package installation manual} %\VignetteEngine{knitr::rmarkdown} \usepackage[utf8]{inputenc} title: "Seroincidence package installation manual" author: "European Centre for Disease Prevention and Control (ECDC)" date: "`r Sys.Date()`" output: pdf_document: toc: yes header-includes: - \setkeys{Gin}{height=3.5in, keepaspectratio} --- ```{r, echo = FALSE} # Grab package version and date from DESCRIPTION file pkgVersion <- packageDescription("seroincidence")$Version pkgDate <- packageDescription("seroincidence")$Date pkgBaseFileName <- paste("seroincidence", pkgVersion, sep = "_") pkgUrl <- gsub("\n", "", packageDescription("seroincidence")$URL) pkgPath <- "http://ecdc.europa.eu/en/data-tools/seroincidence-calculator-tool/Documents" library("knitr") ``` # 1. Introduction Package **seroincidence** is written in programming language R and end user must have access to a working installation of R interpreter. This document describes the most common setup with R installed locally on the user's computer. The screenshots refer to the classical R interface, but the package can also be opened in other Graphical User Interfaces fo R like e.g. [RStudio](http://www.rstudio.com/products/RStudio/). # 2. Installation steps R is a free software and can be downloaded from [http://cran.r-project.org/](http://cran.r-project.org/). Latest version as of writing this document is **R 3.1.3**. Once the appropriate, operating system dependent, version is downloaded, install it on your computer following the standard procedure applicable to the operating system. For Windows the file to be downloaded is the so-called *base* distribution: [http://cran.r-project.org/bin/windows/base/](http://cran.r-project.org/bin/windows/base/). \pagebreak ## 2.1. Installing R Start the R installer and follow the presented steps: ![R installer - step 1](fig/setup1.png) It is advised to have R installed in folder that does not contain spaces, therefore please adjust the destination location accordingly: ![R installer - step 2](fig/setup2.png) \pagebreak The **seroincidence** package is compatible with both the 32-bit and the 64-bit version of R. Choose the preferred platform (or both). If unsure install the 32-bit version only, however on compatible platforms the 64-bit version may provide better performance: ![R installer - step 3](fig/setup3.png) It is advised to select *Registry entries* in the next step for best experience: ![R installer - step 4](fig/setup4.png) \pagebreak R interpreter, when installed on Windows, can be invoked from the start menu folder named **R**. ![Windows start menu](fig/startMenu.png) Start the preferred version of R (if both the 32-bit: *R i386* and the 64-bit: *x64* are installed). Graphical user interface for R interpreter will start in a new window: ![R Graphical User Interface - welcome screen](fig/RGui1.png) \pagebreak ## 2.2. Installing *seroincidence* package Since this is a new installation of R, the **seroincidence** package must be installed before first use. The package can be installed either through a menu option in the graphical user interface (GUI) or with a command executed in the R console. Both options are presented: ### 2.2.1. Package installation from the graphical user interface Download the seroincidence calculator package from ECDC website: [`r pkgUrl`](`r pkgUrl`). Two versions of the package are made available: * Windows binary package (seroincidence_[version].zip) * Source package (seroincidence_[version].tar.gz) If your operating system is Windows then it is best to download the Windows binary package. Go to menu *Packages* and select command *Install package(s) from local zip files...*: ![R GUI - install package menu](fig/RGui2.png) \pagebreak Select the package file and click "Open": ![R GUI - select package file](fig/RGui3.png) Post-installation message should appear: ![R GUI - welcome screen](fig/RGui4.png) The package is now installed in R. ### 2.2.2. Package installation from R console Alternatively, installation of the package can also be performed by executing one of the following commands in the *R console*: ```{r, include=FALSE, tidy=FALSE} chunkTemplate <- "```{r, eval = FALSE} # OPTION A # Install Windows binary package \"seroincidence\" directly from internet location: install.packages( pkgs = \"{{pkgPath}}/ {{pkgBaseFileName}}.zip\", repos = NULL, type = \"win.binary\") # OPTION B # Install source package directly from internet location: install.packages( pkgs = \"{{pkgPath}}/ {{pkgBaseFileName}}.tar.gz\", repos = NULL, type = \"source\") # OPTION C # Install Windows binary package from a local file: # install.packages(\"[PATH/TO/FILE/]seroincidence_[version].zip\", # repos = NULL, type = \"win.binary\") # For instance: install.packages(pkgs = \"C:/{{pkgBaseFileName}}.zip\", repos = NULL, type = \"win.binary\") # OPTION D # Install source package from a local file: install.packages(pkgs = \"C:/{{pkgBaseFileName}}.tar.gz\", repos = NULL, type = \"source\") ```" chunkSource <- knit_expand(text = chunkTemplate, pkgBaseFileName = pkgBaseFileName) ``` `r knit(text = chunkSource)` # 3. Post-installation Successful installation can be confirmed by loading the package into the workspace and exploring help files and manuals distributed with the package: ```{r, eval=FALSE} # Load package "seroincidence" library(seroincidence) # Show R help for the package ?seroincidence # Show tutorial for the package vignette(topic = "tutorial", package = "seroincidence") ``` Additionally, most package details can be found when executing the following commands: ```{r} # Description packageDescription("seroincidence") # Citation citation("seroincidence") ``` seroincidence/vignettes/fig/0000755000176200001440000000000012640456126015647 5ustar liggesusersseroincidence/vignettes/fig/ssi-cutoff2.png0000644000176200001440000003007612640456126020527 0ustar liggesusersPNG  IHDR(9PLTE ӤlllUUU@@@...-/IDATxN@Ѯ( DXוs6է=Y6r9 `#q-uX?O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:O:d:\k>خ?Y`GӜ53l՟˜:{eϪS`ߪގ묿v쥎c9U=ˡd:<Wm3]iuC{{QGhU{U;Yu.Uj:9kKլ@gΪj9#63#NTo~]ν6 aLɗA&`7*R,=Աk>ke?u6H8tUǹj{ҽ#0w\NPG`}]Tԭ {g=u}svFq⎞ZUC(`S-KA~ #@:$#@:$#@:$#@:$#@:$#@:$#@:$#@:$#@S b[/0BAtppppppppppppppppppppppppppppppppppppppppppppppsGmAEwu ƄIkZ W,*PQG:Tu#@E*PQG:Tu#@E*PQG:T8Mz8q:m/u:eZ3"2 :%31&mu:]kd~zo/PSG:s۸r u:UihtC+TW_}n2LEjt8BEN@vQGNeJ㤎@'u:O꾳>#rom'u:p*3E>\yTG3z2ǹK=s9lcj{#Ћm\7b[5A'Xǜ۷!C1^'vQG:#^#@'ulKD|N@'x9Ddƺ2@'؆1>QNkru )1-w:(ĺswn.䡎 ~ɁPG;m#x(GBq^:؇Yᬳu_Gi$Avl:sx@6O=)$P)_G:Ժw|G@B i~uت(wY!YD?r0Fۀ#ɒe )eB6hA˳ХXQ?Wǐt]:X:֝YNK]skrǴ`v*>;*v`U-$VQu-dwݍnxBO4 ?Tǰdk5F[zxKYz3kOݳK^OO`SRwc`،:$O>QrzsM\}G84m޽,| m2u u]caS.ɇb%F+4s:\Ya#wןջط. ub9v?|f_uRG^XssuN' cN0``M~ u X`#cT&F|Yy&F,W_.5-8ք:؈:.k'j.oֆ:؈:R*9X`#܃ey9?֊:؄:v^(HG u:*ى+ɬPGq]Y}$qcIbGɓUݜYO|,W*ֆ:؄,s$yg 5]ѢYKs:X`#u(Ywuq(w|FFܝ`VyWu|9]]vioք:؈:oeevi^Gz4Y$$i&F>YxM}'C4xd:m>3V#<βc\6FwX{i(Bj'v1TL^.>؉:kA-upvUou &PGe~]J V:؉atwIɒv"cܥZZGYpPYGwB%8u{=X̆PGct%3 R:Ra]YXƎfu|eȋ-;.u^"NqpV:؇MBo/Ǝde#}XױcXƎ!JY8u-$XK uY- i{BNu]g.:fSp78#pvN84-$ۆ4e@7>9kR:%vv;v(ЌgxvBlspνf@UoaS ׬C#Cs =r{L2Vi}+Dku6d;VR@co7'OVw/x9.L:cG^NPյNmnm[ozZʼnZKA.wJ[[VeVӨC%%+Cck]mP=y-v(k]ڐjSv]l%B8QWc*c\\.q ]n,t/!QG>w iSG$׻w<[dQG[<{ w6ens:W#am =tHkbbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbGbG|,ˎp;im*;Bx#`GaGbGbGbGbGbGbGbGbGbGةA P##############################################cAJEQ~jMj1"Riso>#@QGE:u(P#@QGE:u(P#@QGE:u(P#@QGE:u(P#@QGE:u(P}XUs82?eFs8ۼ<^U8|,M92{f#p2Gmf{bfVuo`i è;4$KX`f,QF9xݧa$3[D?gd#˨:"n25rxh2SOb#ɨ:~%bQG Qu,Zoq/: cx4uVDzEԈѹ?#Ÿ:ǯ:]D:q֩, L;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;NF|,u ɎmGaG`GbGbGbGbGbGbGbGbGbGbGbG{m(;4)3BrKwA%dLPG8Bu#PG8Bu}^u>G/G̴SjzZӨ5wmD@ȦM@c)'ci!dӂ{k BN1cfڻ'Q+2uQz3Ӟ8:^i:Ɲ[݈#:.?qd2 +}ZwD@}e{ֱHo,]A]mu͘l:*@0&,c g@8/ӆ#u2T#ui5u2ioJb^Ш-:z1\::zyG 2u<~bȵ>Y,CB]L;fv+-c,̦U3/J:)dj yM,?DE_7L);%QQnYu967@X)Ό1@`A4  @\Af wo9PE9y?Nw)W"@̨cy%??u vd@j1j#u u?Cn:j@Z1TՁk /jXZcvp)uyp /jс -htԮ )Ԩck֋@V1ؽOܨc{eI $Gݸ" :Fk@~1Z_zMjcj=~SH:j/c1wfi u3/R^:FYlIE50fL\F@c\<1{@ct@Cm  u #0ꇭȎ:]G 3@v1@/6cVؕ#uѭo {@~1jLP 7[Our_6ςcQ۶,_u Z`1HU/B?>6j`(Sֳ~k0u@#5]˦CXu_g-FC?LgdPǏs.7N 00qm&]nr>ҬECu̴72d-`:&:Vء&pDSi\QT}10E3-2uTآ5GuL4/[Աc ~ OKԱ%x:c[W5/OcCu9EՀ/a}1*[1u5:7}5`:67GpE[OԱQwր)Z [ԱwԱ70Ez̻Dۊ'?:u:G'Zulntآ O=c1CQ&P֨c37`pG:;cL:N6?uػݸa : _hSA!;,:8CwS:fL:#w[:tܵ%;7tM: jz&*'3If?1[C;ZHDž<@;N"qӞTﺯ2lr{߬G@W~M6cGP+1KG.MǴNm!5x83 uǗe@ʌv! 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Introduction The simplest possible model for serum antibody decay is an exponential decay function (see [Appendix](#method_longitudinal)). This is the default longitudinal model used in **seroincidence** package. Various modifications can be made, however, to allow for different interpretations of low antibody concentrations in cross-sectional data. The following three approaches are implemented in the current version of the package: 1. Exponential decay: seroconversion is instantaneous, and is followed by exponential decrease to zero (see [Appendix](#method_longitudinal) for more information). 2. Exponential decay with left censoring: seroconversion is instantaneous, and it is followed by exponential decay, but antibody concentrations below a given (fixed) level are treated as censored (see [Appendix](#censoring) for more information). This implies that observations below censoring level are considered to have been generated by seroconversions from at least a given time in the past (corresponding to the censoring level). In simple terms: for very low antibody concentrations we can only conclude that seroconversion occurred long ago, but not precisely how long. 3. Exponential decay with nonzero baseline: seroconversion is again instantaneous, and is again followed by exponential decay, but decay now is not towards zero but instead, approaches some baseline antibody concentration that may be different for any individual (see [Appendix](#baseline) for more information). Low antibody concentrations in the cross-sectional sample now may correspond to baseline levels, in which case seroconversion would have occurred an infinite period ago. Because of their different interpretations of low cross-sectional serum antibody concentrations, both alternatives (left censoring and decay to baseline) lead to decreased estimates of seroincidence, compared to the default model. Finally, note that the methods described in the [Appendix](#appendices) allow for arbitrary antibody decay patterns, so that adaptations can be made to accommodate any longitudinal model for the shape of the decaying arm of the seroresponse. # 2. Influence of censoring on seroincidence In case serum antibody data are known to be censored, a cutoff level can be defined in the seroincidence calculator script as a list, with separate values for each of the three antibody classes (IgG, IgM, and/or IgA). \begin{figure}[h!] \centering \mbox{ \subfigure[Same cutoff]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-campylobacter-1.png}} \subfigure[Different cutoffs]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-campylobacter-2.png}}} \caption{\label{censoring_campy}Influence of cutoff levels on seroincidence estimates for a cross-sectional sample of {\em Campylobacter} antibodies. (a) Identical cutoffs for all three antibody types; (b) Different cutoffs for IgG, IgM and IgA.} \end{figure} \begin{figure}[h!] \centering \mbox{ \subfigure[Same cutoff]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-salmonella-1.png}} \subfigure[Different cutoffs]{ \includegraphics[width=0.48\linewidth]{./fig/cutoff-salmonella-2.png}}} \caption{\label{censoring_salmo}Influence of cutoff levels on seroincidence estimates for a cross-sectional sample of {\em Salmonella} antibodies (mixed ELISA). (a) Identical cutoffs for all three antibody types; (b) Different cutoffs for IgG, IgM and IgA.} \end{figure} Figures \ref{censoring_campy} and \ref{censoring_salmo} show the change in seroincidence estimate, for a given set of cross-sectional antibody data (*Campylobacter* and *Salmonella*), with increasing cutoff levels. Cutoffs need not be identical for IgG, IgM and IgA antibodies, as illustrated in these graphs. # 3. Checks using the longitudinal data The longitudinal data may be used to obtain a crude estimate of bias in the estimated incidences (Figure \ref{verif}a, \ref{verif}e). \begin{figure}[h!] \centering \mbox{ \subfigure[Cutoff 0.0]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff0.png}} \subfigure[Cutoff 0.5]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff05.png}} \subfigure[Cutoff 1.0]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff1.png}} \subfigure[Cutoff 2.0]{ \includegraphics[width=0.24\linewidth]{./fig/delft-cutoff2.png}}} \mbox{ \subfigure[Cutoff 0.0]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff0.png}} \subfigure[Cutoff 0.5]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff05.png}} \subfigure[Cutoff 1.0]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff1.png}} \subfigure[Cutoff 2.0]{ \includegraphics[width=0.24\linewidth]{./fig/ssi-cutoff2.png}}} \caption{\label{verif}Estimated incidences for longitudinal sera at different times since onset of illness symptoms. delta(incid) = difference between estimated incidence and 365/(time since onset). Top: Campylobacter, Delft ELISA, Bottom: Campylobacter, SSI ELISA.} \end{figure} It is seen that for samples taken 100--250 days post symptom onset, the estimated incidences appear unbiased (the 95\% interval includes 0). Increasing the cutoff (here applied identical values for all three antibody classes) causes underestimation of the incidence (Figures \ref{verif}b,c,d and \ref{verif}f,g,h). The high degree of variation in antibody levels in late samples (more than 100 days post symptom onset) renders estimation problematic. \newpage \newpage # Appendices {#appendices} This is a slightly modified description from [@teunis2012], extended with adaptations for censoring and elevated baseline levels. ## A.1. Characteristics of the serum antibody response {#method_longitudinal} The longitudinal model used for describing serum antibody responses has been published [@simonsen2009, @teunis2012]. As longitudinal data may include early samples taken shortly after infection, possibly during the initial increase in antibody concentrations (during seroconversion) the longitudinal model includes the rising phase of the seroresponse. This avoids misspecification of the peak antibody level, resulting in estimates for the (joint distribution of) peak levels, time to peak, and decay rates of the serum antibody concentration [@teunis2012, @versteegh2005]. However, seroconversion usually is rapid: the increase in antibody levels is orders of magnitude faster than the subsequent decrease. For seroconversion rate calculations we ignore the time to reach peak levels. For simplicity it will be assumed that the antibody response decays exponentially but this is not an essential assumption and it can be relaxed to any monotonically decreasing function of time. So, the antibody response $y$ to incidence at $t = 0$ is an instantaneous increase to peak level ($A$) followed by an exponential decrease (with rate $k$): $$ y = A \text{e}^{-kt} $$ ## A.2. Random sampling of randomly repeating responses {#A2} In a cross-sectional sample of responses, each subject will be sampled at a random time within its current inter-event interval $\Delta t$ (interval, for short). The within--interval sampling distribution is uniform: \begin{equation} \label{fundamental} u_{f}(\tau\vert\Delta t)=\frac{[0\le \tau < \Delta t]}{\Delta t} \end{equation} The subscript $f$ is introduced to show that this distribution is fundamental to sampling from the period between events that are separated by a constant time interval $\Delta t$. As the intervals $\Delta t$ generally will vary, the within--interval sampling distribution and the distribution of intervals combine to a population distribution of backward recurrence times. The backward recurrence time distribution can be translated into a corresponding distribution of response values (antibody concentrations), due to the monotonicity of the response. The intervals $\Delta t$ are supposed to vary randomly with distribution $p(\Delta t)$. This introduces a subtle question about the probability of sampling the response within an infinitesimal range of intervals $[\Delta t, \Delta t + \text{d}\Delta t]$. One would be inclined to assume that the probability is given only by the probability density $p(\Delta t)$, but one should keep in mind that responses with longer intervals are more likely to be sampled than those with shorter intervals. Obviously, the probability of the range of sampling intervals $[\Delta t, \Delta t + \text{d}\Delta t]$ should be proportional to the interval $\Delta t$ itself (size biased sampling, [@feller1968, @higgins2008, @scalia2010]). Then, the probability of sampling a response within an infinitesimal range of intervals $[\Delta t, \Delta t + \text{d}\Delta t]$ is $$ \frac{p(\Delta t)\Delta t}{\overline{\Delta t}_{p}}\text{d}\Delta t $$ Here $\overline{\Delta t}_{p}$ is the expected interval length from the distribution $p$. We define the incidence as its reciprocal $1/\overline{\Delta t}_{p}$. Combining this probability with the uniform distribution of sampling time within the interval $\Delta t$ leads to a population distribution of time since last event (backward recurrence time) \begin{eqnarray*} u(\tau) &=& \int_{\Delta t=0}^{\infty}u_{f}(\tau\vert\Delta t) \frac{p(\Delta t)\Delta t}{\overline{\Delta t}_{p}}\text{d}\Delta t\\ &=& \frac{1}{\overline{\Delta t}_{p}} \int_{\Delta t=\tau}^{\infty} p(\Delta t)\text{d}\Delta t = \frac{1-P(\tau)}{\overline{\Delta t}_{p}} \end{eqnarray*} where $P$ is the cumulative distribution of $p$. In going from the first to the second equality we used the fact that $\Delta t$ should exceed $\tau$ (equation (\ref{fundamental})). Note that the distribution $u(\tau)$ is monotonically non-increasing. ## A.3. Delta distribution {#A3} If $p(\Delta t)$ is the delta-distribution $p(\Delta t) = \delta(\Delta t-\Delta t^{\ast})$ representing identical intervals, then the uniform distribution $u_{f}(\tau\vert \Delta t^{\ast})$ is regained: for the delta distribution $p(\Delta t) = \delta(\Delta t -\Delta t^{\ast})$ the expected value is $\overline{\Delta t}_{p} = \Delta t^{\ast}$. It follows that $$ u(\tau\vert\Delta t^{\ast}) = \frac{1}{\Delta t^{\ast}} \int_{\tau}^{\infty} \delta (\Delta t-\Delta t^{\ast}) \text{d}\Delta t = \frac{\left[0\le \tau < \Delta t^{\ast}\right]}{\Delta t^{\ast}} $$ ## A.4. Distribution of response values given the distribution of backward recurrence times {#A4} Given incidence at $\tau = 0$, the response decays as $y(\tau) = A \text{e}^{-k\tau}$, with $\tau$ backward recurrence time. Consider \begin{eqnarray} P(y^{\prime}\le y) & = & P\left(A\text{e}^{-k\tau^{\prime}}\le A\text{e}^{-k\tau}\right) [y\le A] = P(\tau \le \tau^{\prime})[y\le A] \nonumber \\ & = & \left(1-U(\tau)\right)[y\le A] = \left(1-U(\log(A/y)/k)\right) [y\le A] \label{cumul_distr} \end{eqnarray} Differentiating this expression leads to \begin{eqnarray} \rho(y) & = & \frac{\text{d}}{\text{d}y} P(y^{\prime}\le y) = -u\left(\log(A/y)/k\right) \left(\frac{1}{k}\right) \left(\frac{-1}{y}\right)[y\le A] \nonumber\\ & = & \frac{[y\le A]}{ky}u\left(\log(A/y)/k\right)\label{distrib_y} \end{eqnarray} Given the antibody response $y$ with respect to time of incidence, $\rho(y)$ is the corresponding density for sampled response values. For the $n$th moment of the backward recurrence time one derives \begin{eqnarray*} E(\tau^{n}) & = & \int_{\tau = 0}^{\infty} \tau^{n} u(\tau)\text{d}\tau = \int_{\tau = 0}^{\infty}\left(\tau^{n}\frac{1}{\overline{\Delta t}_{p}} \int_{\Delta t = \tau}^{\infty} p(\Delta t)\text{d}\Delta t\right)\text{d}\tau \\ & = & \frac{1}{\overline{\Delta t}_{p}}\int_{\Delta t=0}^{\infty}p(\Delta t) \left(\int_{\tau = 0}^{\Delta t}\tau^{n}\text{d}\tau\right)\text{d}\Delta t \\ & = & \frac{1}{\overline{\Delta t}_{p}}\int_{\Delta t=0}^{\infty}p(\Delta t) \frac{(\Delta t)^{{n+1}}}{n+1}\text{d}\Delta t = \frac{\overline{(\Delta t)^{n+1}}_{p}}{(n+1)\overline{\Delta t}_{p}} \end{eqnarray*} ## A.5. Family of Gamma distributions {#A5} The distribution of intervals $p(\Delta t)$ may have any form. Let the family of $\Gamma(\lambda, m)$ distributions be given: $$ p_{m}(\Delta t\vert \lambda) = \frac{\lambda^{m+1}\Delta t^{m}}{m!}\text{e}^{-\lambda \Delta t} $$ From $$ \int_{x=0}^{\infty}x^{m+1}\text{e}^{-x}\text{d}x = (m+1)! $$ one easily derives that $\overline{\Delta t}_{p} = (m+1)/\lambda$. We shall need the cumulative distribution \begin{eqnarray} P_{m}(\tau\vert \lambda) & = & \int_{\Delta t=0}^{\tau} p_{m}(\Delta t\vert \lambda) \text{d}\Delta t = 1 - \int_{\Delta t=\tau}^{\infty}p_{m}(\Delta t\vert \lambda)d\Delta t \nonumber \\ & = & 1 - \frac{\Gamma(m+1,\lambda \tau)}{m!} \label{p_dist_gamma} \end{eqnarray} where $\Gamma(m + 1, \lambda\tau)$ denotes the (upper) incomplete gamma function (not to be confused with the gamma distribution). Note: working out the integral $$ P_{m}(\tau\vert\lambda) = \int_{\Delta t = 0}^{\tau} p_{m}(\Delta t\vert\lambda)\text{d}\Delta t, $$ it is straightforward to show that \begin{equation} \label{gamma_pj} \Gamma(m+1,\lambda\tau) = \frac{m!}{\lambda}\sum_{j=0}^{m}p_{j}(\tau\vert\lambda) \end{equation} For the distribution of backward recurrence times one finds \begin{equation} \label{u_dist_gamma} u_{m}(\tau\vert \lambda) = \frac{\lambda}{m+1} \int_{\Delta t=\tau}^{\infty}p_{m}(\Delta t\vert \lambda)\text{d}\Delta t = \frac{\lambda}{(m+1)!}\Gamma(m+1,\lambda\tau) \end{equation} when $m = 0$ $$ u_{0}(\tau\vert \lambda) = \lambda \Gamma(1,\lambda\tau) = p_{0}(\tau\vert \lambda), $$ the famous property of the Poisson process. ## A.6. Heterogeneity in serum antibody responses {#A6} Incorporation of responses that also vary in amplitude $A$ and decay rate $k$ can be easily described with a joint density $g(A, k)$. Of course, such heterogeneity changes the population based distribution of $y$ to $$ \rho(y) = \frac{1}{y}\int_{k=0}^{\infty}\int_{A=y}^{\infty} \frac{1}{k}u\left(\frac{\log(A/y)}{k}\right)g(A,k)\text{d}A\text{d}k $$ instead of corresponding equation (\ref{distrib_y}). Note that the factor $[y\le A]$ in equation ($\ref{distrib_y}$) forces the lower limit $y$ in the integration over $A$. In case the peak antibody levels $A$ and antibody decay rates $k$ are available as a Monte Carlo sample $\{A_{n},k_{n}\}$ of their joint distribution the integration can be approximated by \begin{equation} \label{mc_heterogeneity} \rho(y)=\frac{1}{y}\frac{1}{N}\sum_{n=1}^{N}\frac{1}{k_{n}} u\left(\frac{\log(A_{n}/y)}{k_{n}}\right)[y\le A_{n}] \end{equation} where $N$ is the size of the Monte-Carlo sample, maintaining any correlation between peak levels $A_{n}$ and decay rates $k_{n}$. Assuming e.g. that infections occur with Gamma distributed intervals with rate $\lambda$ and shape factor $m$: \begin{eqnarray*} \rho(y\vert \lambda, m) & = & \frac{1}{(m+1) N}\sum_{n=1}^{N}\left( \frac{\lambda}{k_{n}A_{n}} \left(\frac{y}{A_{n}}\right)^{-1+\lambda/k_{n}}\right.\\ &\times & \left.\sum_{j=0}^{m} \frac{\left(\lambda/k_{n} \log(A_{n}/y)\right)^{j}}{j!}[y\le A_{n}]\right) \end{eqnarray*} For a cross-sectional sample $\{Y_{1}, Y_{2},\dots , Y_{N_{c}}\}$ a likelihood $$ \ell (\lambda, m) = \prod_{i=1}^{N_{c}} \rho(Y_{i}\vert \lambda, m) $$ can be calculated to allow estimation of the parameters $(\lambda, m)$ of the process generating infections. The corresponding incidence is the average rate of infections $\lambda/(m+1)$. ## A.7. Censored observations {#censoring} In case observations are censored at $y_{c}$ such that an observed $Y = \text{max}(Y, y_{c})$, then for $y_{c} < Y$ the density $\rho(y)$ as in eq. ($\ref{distrib_y}$) holds, but the likelihood of any $Y \le y_{c}$ can be calculated $$ \ell(\lambda, m \vert y \le y_{c}) = \int_{z=0}^{y_{c}}\rho(z\vert \lambda,m)\text{d}z = R(y_{c}\vert \lambda,m) $$ and the likelihood function for a cross-sectional sample $\{Y_{1}, Y_{2}, \dots, Y_{N_{c}}\}$ becomes $$ \ell (\lambda, m) = \prod_{i=1}^{N_{c}} \left(\rho(Y_{i}\vert \lambda, m)[y_{c} < Y_{i}] \times R(y_{c}\vert \lambda,m)[Y_{i}\le y_{c}]\right) $$ We need the cumulative distribution $R(y)$ as given by eq. ($\ref{cumul_distr}$) \begin{equation} \label{r_cumul_def} R(y) = 1 - U\left(\frac{\log\left(\frac{A}{\min(y,A)}\right)}{k}\right) = 1 - U\left(\frac{\text{lm}(y,A)}{k}\right) \end{equation} with obvious definition of $\text{lm}(y, A)$. For the family of gamma distributions for the intervals $\Delta t$, eq. ($\ref{r_cumul_def}$) leads to $$ R_{m}(y) = 1 - U_{m}\left(\frac{\text{lm}(y,A)}{k}\vert \lambda\right) $$ Substituting eq. ($\ref{gamma_pj}$) into eq. ($\ref{u_dist_gamma}$), and using the cumulative distribution $P_{j}$ $$ R_{m}(y) = 1 - \frac{1}{m+1}\sum_{j=0}^{m}P_{j} \left(\frac{\text{lm}(y,A)}{k}\vert\lambda\right) $$ which can also be expressed in terms of incomplete Gamma functions, using eq. ($\ref{p_dist_gamma}$) $$ R_{m}(y) = 1 - \frac{1}{m+1}\sum_{j=0}^{m} 1 - \frac{\Gamma\left(j+1,\lambda\frac{\text{lm}(y,A)}{k}\right)}{j!} $$ or, expanding $\text{lm}$ $$ R(y) = \frac{1}{m+1}\sum_{j=0}^{m}\frac{1}{j!}\Gamma\left(j+1, \frac{\lambda}{k}\log\left(\frac{A}{\min(y,A)}\right)\right) $$ The latter form is useful for numeric calculations as there is a reliable and efficient implementation available in R. ## A.8. Nonzero baseline {#baseline} The procedure outlined in [@teunis2012] is valid for any monotonically non-increasing serum antibody response. If for instance, after seroconversion, antibody levels decrease to some baseline level greater than zero (however long ago seroconversion has occurred), the antibody response is $$ y = y_{0} + A \text{e}^{-kt} $$ Such responses have been assumed for back-calculations [@simonsen2009]. Now the distribution of response values given the distribution of the backward recurrence times becomes \begin{eqnarray*} P(y^{\prime}\le y) & = & P\left(y_{0}+A\text{e}^{-k\tau^{\prime}}\le y_{0}+A\text{e}^{-k\tau}\right)[y_{0} < y \le A] \\ & = & P(\tau \le \tau^{\prime})[y_{0} < y \le A] = \left(1 - U(\tau)\right)[y_{0} < y \le A] \\ & = & \left(1-U\left(\frac{1}{k}\log\left(\frac{A}{y-y_{0}}\right)\right)\right) [y_{0} < y \le A] \end{eqnarray*} Differentiation produces the density $$ \rho(y) = \frac{\text{d}}{\text{d}y} P(y^{\prime}\le y) = \frac{1}{k(y-y_{0})} u\left(\frac{1}{k}\log\left(\frac{A}{y-y_{0}}\right)\right) $$ Including heterogeneity in $A$, $k$ and $y_{0}$ via their joint distribution $$ \rho(y) = \int_{k=0}^{\infty}\int_{A=y}^{\infty}\int_{y_{0}=0}^y \frac{1}{k(y-y_{0})} u\left(\frac{1}{k}\log\left(\frac{A}{y-y_{0}}\right)\right) g(A,K,y_{0})\text{d}y_{0}\text{d}A\text{d}k $$ or, when a Monte-Carlo sample of $\{A_{n}, k_{n}, y_{0,n}\}$ triplets is available $$ \rho(y) = \frac{1}{N}\sum_{n=1}^{N}\frac{u\left(\frac{1}{k_{n}} \log\left(\frac{A_{n}}{y-y_{0,n}}\right)\right)}{k_{n}(y-y_{0,n})} [y_{0,n} < y < A_{n}] $$ For the gamma family of distributions for $\Delta t$, \begin{eqnarray*} \rho(y) & = & \frac{1}{N(m+1)}\sum_{n=1}^{N}\left(\frac{\lambda}{k_{n}A_{n}} \left(\frac{y-y_{0,n}}{A_{n}}\right)^{-1+\lambda/k_{n}}\right. \\ & \times & \left.\sum_{j=0}^{m}\frac{1}{j!}\left(\frac{\lambda}{k_{n}} \log\left(\frac{A_{n}}{y-y_{0,n}}\right)\right)^{j} [y_{0,n} < y \le A_{n}]\right) \end{eqnarray*} For the Poisson process ($m = 0$) this reduces to $$ \rho(y) = \frac{1}{N}\sum_{n=1}^{N}\frac{\lambda}{k_{n}A_{n}} \left(\frac{y-y_{0,n}}{A_{n}}\right)^{-1+\lambda/k_{n}}[y_{0,n} < y \le A_{n}] $$ # References seroincidence/vignettes/tutorial.Rmd0000644000176200001440000006043412640456126017420 0ustar liggesusers--- vignette: | %\VignetteIndexEntry{Seroincidence package tutorial} %\VignetteEngine{knitr::rmarkdown} \usepackage[utf8]{inputenc} title: "Seroincidence package tutorial" author: "European Centre for Disease Prevention and Control (ECDC)" date: '`r Sys.Date()`' output: pdf_document: toc: yes references: - id: teunis2012 author: - family: Teunis given: P. F. - family: van Eijkeren given: J. C. - family: Ang given: C. W. - family: van Duynhoven given: Y. T. - family: Simonsen given: J. B. - family: Strid given: M. A. - family: van Pelt given: W. container-title: Statistics in Medicine DOI: 10.1002/sim.5322 issue: 20 issued: month: 9 year: 2012 page: 2240-2248 title: 'Biomarker dynamics: estimating infection rates from serological data' type: article-journal volume: 31 - id: feller1968 author: - family: Feller given: W. issued: year: 1968 title: An introduction to probability theory and its applications type: book volume: 2 container-title: John Wiley & Sons - id: strid2001 author: - family: Strid given: M. A. - family: Engberg given: J. - family: Larsen, given: L. B. - family: Begtrup given: K - family: Mølbak given: K - family: Krogfelt given: K. A. title: 'Antibody responses to Campylobacter infections determined by an enzyme--linked immunosorbent assay: 2-year follow-up study of 210 patients' container-title: Clinical and Vaccine Immunology issue: 8 volume: 2 page: 314-319 issued: year: 2001 month: 3 DOI: 10.1128/CDLI.8.2.314-319.2001 --- ```{r, echo = FALSE} pkgUrl <- gsub("\n", "", packageDescription("seroincidence")$URL) ``` # 1. Introduction Antibody levels measured by ELISA in a (cross-sectional) population sample can be translated into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. Formulated simply: the presence of many high titres indicates that many subjects likely experienced infection recently, while low titres indicate a low frequency of infections in the sampled population. More information about ELISA methods can be found at [ECDC web site](`r pkgUrl`). In order to thus interpret the measured cross-sectional antibody concentrations, characteristics of the time course of the serum antibody response must be known. For any antibody detected in the cross-sectional sample, a quantitative description of its dynamics following infection (seroconversion to an elevated concentration, followed by a gradual decrease) must be available. In published studies, this information on the time course of the serum antibody response has been obtained from follow-up data in subjects who had a symptomatic episode following infection. The onset of symptoms thus provided a proxy for the time that infection occurred. Care must be taken that longitudinal and cross-sectional measurements of antibody concentrations are calibrated on the same scale (or, preferably, expressed in identical units). The time course of the serum antibody response to infection is assumed generic: anyone infected by the same pathogen is expected to produce a response similar to those seen in the symptomatic cohort used for the follow-up study. Thus, the strategy is to set up a longitudinal model from a follow-up study once, and use the thus obtained information to analyze many different cross-sectional data sets. Note that it must be assumed that such variation among individuals as observed in the longitudinal cohort is the same as in the population where the cross-sectional sample was taken, where this variation cannot be observed. Analysis of longitudinal data and estimation of the required parameters is separated from the estimation of seroincidences, because (1) there are few longitudinal data sets available and they are difficult (and expensive) to obtain, (2) such longitudinal models may be considered "generic", presumably describing a physiological phenomenon that is similar in any infected individual, and (3) setting up and running the longitudinal model requires additional skills, not necessary for use of the sero-incidence estimator package. # 2. The seroincidence estimator Package **seroincidence** was designed to use the longitudinal response characteristics by means of a set of parameters characterizing the longitudinal response of the selected serum antibodies. These parameters are peak concentrations and decay rates (describing the maximum antibody concentration reached after seroconversion and the rate with which the antibody concentration decreases, assuming first order, or exponential, kinetics). Peak concentrations and decay rates may be provided as a set of parameters describing parametric distributions (a **gamma** distribution for the peak concentrations and an **inverse gamma** distribution for the decay rates, denoted by *A* and *k*, respectively), that characterize the heterogeneity of these response characteristics: peak concentrations and decay rates show considerable variation among individuals. This individual variation in antibody responses is accounted for by generating a Monte Carlo sample (default number of observations *n = 500*) from these parametric distributions and calculating the resulting incidence (as in vignette [methodology.pdf](methodology.pdf), equation (7)). Alternatively, these peak concentrations and decay rates may be provided as sets of Monte-Carlo samples, as can be obtained from longitudinal models (analyzed by *MCMC* methods). Note that, due to the limited number of parameter pairs, the generated incidence estimates will show minor variations: if the same calculation is run twice, the outcomes may differ slightly. If this variation should be undesired, the numbers of parameter pairs may be increased. This however will slow down the calculations. Given these longitudinal response characteristics, the R-scripts delivered for the ECDC project provide a rapid and computationally simple method for calculating seroconversion rates, as published in [@teunis2012]. Given these longitudinal response characteristics, this package provide a rapid and computationally simple method for calculating seroconversion rates, as published in [@feller1968]. The methods on which the seroincidence calculator is based were developed with publicly funded research. All procedures have been published and are open to the general public, including the core function on which the seroincidence calculator is based. To make the functionalities provided as broadly available as possible, R was chosen as the computing platform, because it is free and open source, and runs on any modern operating system. # 3. How to use *seroincidence* package This section provides step-by-step directions on the usage of the *seroincidence* package. ## 3.1. Loading the package Functionality of the *seroincidence* package is made available to the end user only once the library is loaded into the current workspace. Assuming the package is installed already (covered in [installation.pdf](installation.pdf)) loading it is achieved by running the following command in the R console (bear in mind that the text after character `#` is only a comment): ```{r} # Load package "seroincidence" library(seroincidence) ``` At this moment you should have all functions required to run the seroincidence calculation available. You can check that by running: ```{r, eval=FALSE} # List all objects (functions and data) exposed by package "seroincidence" ls("package:seroincidence") ``` Here is the resulting output: ```{r, echo=FALSE} ls("package:seroincidence") ``` We briefly describe the objects: [1] "campylobacterResponseParams": Monte Carlo sample of longitudinal response parameters `A` and `k` per antibody for Campylobacter collected with SSI ELISA procedure. Object class: `list`. [2] `campylobacterSerologyData`: Example antibody levels data measured in cross-sectional population sample for Campylobacter (Delft ELISA). Object class: `data.frame`. [3] `estimateSeroincidence`: Main function of the package. Estimates seroincidence based on supplied cross-section antibody levels data and longitudinal response parameters. Object class: `function`. [4] `salmonellaSerologyData`: Example antibody levels data measured in cross-sectional population sample for Salmonella (SSI Mixed ELISA). Object class: `data.frame`. [5] `simulateSalmonellaResponseParams`: Function to simulate the longitudinal response parameters `A` (peak level) and `k` (decay rate) per antibody for Salmonella. Object class: `function`. [6] `simulateSerologyData`: Function to simulate cross-sectional serology data for three antibodies: `IgG`, `IgM`, `IgA`. Object class: `function`. ## 3.2. Specifying input data There are two sets of inputs to the serology calculator that must always be specified: a) Antibody levels measured in cross-sectional population sample (see `salmonellaSerologyData`, `campylobacterSerologyData`, `simulateSerologyData` above). b) Longitudinal response characteristic as pair of peak concentrations and decay parameters `(A, k)` (see `simulateSalmonellaResponseParams`, `campylobacterResponseParams` above). We start with loading antibody levels measured in cross-sectional population sample. ### 3.2.1. Specifying cross-sectional antibody levels data The user has many options of providing this data to the calculator. Here are a few: **a) Using supplied sample data** Data sets `salmonellaSerologyData` and `campylobacterSerologyData` provide examples of cross-sectional antibody levels data for Salmonella and Campylobacter, respectively. They are loaded into the workspace as soon as the package is loaded, therefore they can be referenced right away. Here are small exempts from these data sets: ```{r} # Show first rows of "salmonellaSerologyData" data.frame head(salmonellaSerologyData) # Show first rows of "campylobacterSerologyData" data.frame head(campylobacterSerologyData) ``` Let us assign one of the sets to variable `serologyData`: ```{r} # Assign data.frame "salmonellaSerologyData" to object named "serologyData" serologyData <- salmonellaSerologyData ``` In this particular example `sex = 1` denotes "male" and `sex = 2` denotes "female". We shall pass this object later to the calculator. Of course, object `salmonellaSerologyData` can be used as an argument of the calculator directly as well. **b) Simulating data from parametric model** Another option is to generate cross-sectional data from the supplied Monte-Carlo simulation function `simulateSerologyData`. This function only exists for testing/training, the simulations do not represent outcomes of any seroconversion process. The underlying parametric models are log-Normal distributions with parameters: * IgG: `mu = 1.246, sd = 0.757` * IgM: `mu = -0.764, sd = 0.413` * IgA: `mu = -1.13, sd = 0.318` By default, 500 observations are generated if no argument `n` is supplied (`n`=number of observations). In the following example we override the default number of generated observations and set it to `300`: ```{r} # Assign output of function "simulateSerologyData" to object named "serologyData" serologyData <- simulateSerologyData(n = 300) # Show first rows of object "serologyData" head(serologyData) ``` **c) Loading from external files** Finally, user can load her/his own data into an R session. Details on loading specific file types can be found in online R manual on [R Data Import/Export] (http://cran.r-project.org/doc/manuals/r-release/R-data.html). It is important that the input data is in a tabular form with each column containing levels measured for a single antibody type. Column name should indicate name of the measured antibody. For instance, a comma separated file with the following content: ``` IgG, IgM, IgA 5.337300, 0.4414653, 0.3002395 3.534118, 0.3888226, 0.3543486 2.144549, 0.3320178, 0.3884205 2.957854, 0.4967764, 0.3472340 ``` is a valid cross-sectional data set. Suppose this file is named `c:\cross-sectional-data.csv`. Then it can be loaded into R like this: ```{r, eval=FALSE} # Read content of file "c:\\cross-sectional-data.csv" into object named "serologyData" serologyData <- read.csv(file = "c:\\cross-sectional-data.csv") ``` Please, note that the cross-sectional data set can include extra columns allowing performing the seroincidence calculations stratified per factors available in those data. For instance, data set `salmonellaSerologyData` includes factors `sex` and `age`. ### 3.2.2. Specifying longitudinal response parameters `(A, k)` The longitudinal response parameters set consists of two items: * `A` = antibody peak level (ELISA units) * `k` = antibody decay rate (1/days for the current longitudinal parameter sets) Please, refer to vignette [methodology.pdf](methodology.pdf) for more details on the underlying methodology. End user has three options for loading the response parameters into R session: **a) Using supplied data** For Campylobacter there is a data set provided by the package including Monte-Carlo sample of longitudinal response parameters, `campylobacterResponseParams`. This object is a list containing two data.frame objects named `A` and `k`. Let's have a pick into each of these two data sets separately (notice character `$` indicating a subobject of the parent object): ```{r} # Show first rows of data.frame "A" in list "campylobacterResponseParams" head(campylobacterResponseParams$A) # Show first rows of data.frame "k" in list "campylobacterResponseParams" head(campylobacterResponseParams$k) ``` Such data set is provided only for Campylobacter. Let us assign object `campylobacterResponseParams` to variable `responseParams`: ```{r} responseParams <- campylobacterResponseParams ``` **b) Simulating data from parametric model** Alternatively, for Salmonella an example of the `A` and `k` parameters can be generated using function `simulateSalmonellaResponseParams` provided by the package: ```{r} responseParams <- simulateSalmonellaResponseParams() ``` Similarly to function `simulateSerologyData` this function also accepts argument `n` specifying the number of observations to simulate. The default is `n = 500`. The underlying parametric models for peak levels `A` are Gamma distributions with parameters: * IgG: `shape = 1.1175, scale = 0.848` * IgM: `shape = 1.337, scale = 0.902` * IgA: `shape = 1.205, scale = 0.651` The underlying parametric models for decay rates `k` are Inverse Gamma distributions with parameters: * IgG: `shape = 0.869, scale = 1/728.5` * IgM: `shape = 0.731, scale = 1/514.6` * IgA: `shape = 1.759, scale = 1/132/5` **c) Loading from external files** Alternatively, this data can be loaded from an external file. Bear in mind, that most likely your data is organized into two files, separately for parameters `A` and `k`. Assuming that the data is saved into csv files named `A.csv` and `k.csv` the end user would run the following code in order to create a valid input to the calculator: ```{r,eval=FALSE} AData <- read.csv(file = "A.csv") kData <- read.csv(file = "k.csv") # Create a list named "responseData" containing objects named "A" and "k" responseParams <- list(A = AData, k = kData) ``` Note that object `responseParams` is a list with two dataframes named `A` and `k` as required. ## 3.3. Estimating seroincidence for human Salmonella and Campylobacter infections Main calculation function provided by package *seroincidence* is called `estimateSeroincidence`. It takes several arguments: - `data`: A data frame with the cross-sectional data. This may be the whole data set loaded from file, but can also be a subset, e.g. `data = serologyData[1, ]` to use only the first row. In this tutorial this is the data loaded into variable `serologyData`. It is a required input. - `antibodies`: A list of antibodies to be used. This can be a triplet (`antibodies = c("IgG", "IgM", "IgA")`) or any single antibody (`antibodies = c("IgG")`) or a combination of any two antibodies. It is a required input. - `strata`: A list of categories to stratify data. The column `age` in the example data set can be used as an example. If `strata = ""` the whole data set is treated as a single stratum; if each sample is assigned a unique identifier (e.g. `strata = "id"`) there are as many strata as there are samples and an incidence estimate is calculated for each sample. If not specified, then `strata` is initialized to `""`. - `Ak`: A list with the longitudinal parameters for all antibodies specified. In this tutorial this is the data loaded into variable `responseParams`. It is a required input. - `censorLimits`: A list of cutoff levels, one for each antibody used. It is a required input. - `showProgress`: A Boolean input indicating whether or not to show progress of the calculation. It is an optional input. If not specified then it is initialized to `FALSE`. Here is an example of the Salmonella seroincidence calculation for three antibodies measured, stratified per sex, and with measurements below 0.25 removed: ```{r, eval=FALSE} # Assign output of function "estimateSeroincidence" to object named "seroincidenceData" serologyData <- salmonellaSerologyData responseParams <- simulateSalmonellaResponseParams() seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = "sex", Ak = responseParams, censorLimits = list(IgG = 0.25, IgM = 0.25, IgA = 0.25)) # Show content of the output variable print(seroincidenceData) # or simply type in the console: 'seroincidenceData' (without "'") and press ENTER ``` The following text should be printed. ## Seroincidence object estimated given the following setup: ## a) Antibodies: IgG, IgM, IgA ## b) Strata: sex ## c) Censor limits: IgG = 0.25, IgM = 0.25, IgA = 0.25 ## ## This object is a list containing the following items: ## Fits - List of outputs of optim function per stratum. ## Antibodies - Input parameter antibodies of function estimateSeroincidence. ## Strata - Input parameter strata of function estimateSeroincidence. ## CensorLimits - Input parameter censorLimits of function estimateSeroincidence. ## ## Call summary function to obtain output results. The most important output is subobject `Fits` containing raw results on the output incidence. Translation of these raw results is provided by a custom function `summary` explained in the following section. The cutoff argument is based on censoring of the observed serum antibody measurements [@strid2001]. Using different censoring levels will produce different results. Choosing higher cut-off causes the estimates of lambda to decrease. Results should be published together with the chosen cut-off values. Cut-off levels must always be specified when calling function `estimateSeroincidence` (argument `censorLimits`). Value `0` should be set for antibody measurements where no censoring is needed, for instance ```{r, eval=FALSE} censorLimits <- list(IgG = 0, IgM = 0, IgA = 0) ``` ## 3.4. Getting a summary of seroincidence Output of the calculator should be passed in to function `summary` calculating output results: ```{r, eval=FALSE} summary(seroincidenceData) ``` ## Seroincidence estimated given the following setup: ## a) Antibodies: IgG, IgM, IgA ## b) Strata: sex ## c) Censor limits: IgG = 0.25, IgM = 0.25, IgA = 0.25 ## d) Quantiles: 0.025, 0.975 ## e) Seroincidence estimates ## Lambda Lambda.lwr Lambda.upr Deviance Convergence Stratum ## 1 0.1218136 0.10788284 0.1375432 2144.977 0 1 ## 2 0.1063245 0.09367877 0.1206772 1908.507 0 2 The `summary` function returns a list of objects as well. It contains sub-objects `Antibodies`, `Strata`, `CensorLimits`, `Quantiles` and `Results`. The most important sub-object of the output of the `summary` functions is `Results`, containing estimates of `Lambda` (annual incidence) together with their lower and upper bounds (`Lambda.lwr` and `Lambda.upr`, respectively). The default lower bound is 2.5% and the upper bound is 97.5% of the distribution of `Lambda`. These values can be changed (see [Other examples](#other-examples)). In this particular example `lambda=0.12` for stratum `1` means that yearly 12% of people are infected based on the sample. Optionally, the summary function returns also `Deviance` (negative log likelihood at the estimated `Lambda`) and `Convergence` (indicator returned by function `optim`; value of 0 indicates convergence). It may be beneficial to assign output of this function to a variable for further analysis: ```{r, eval=FALSE} # Compute seroincidence summary and assign to object "seroincidenceSummary" seroincidenceSummary <- summary(seroincidenceData) # Show the results seroincidenceSummary$Results ``` ## Lambda Lambda.lwr Lambda.upr Deviance Convergence Stratum ## 1 0.1218136 0.10788284 0.1375432 2144.977 0 1 ## 2 0.1063245 0.09367877 0.1206772 1908.507 0 2 As one may note it is a dataframe with six columns that can be later post-processed with custom calculations. # 4. Other examples The following examples show the standard procedure for estimating seroincidence. ```{r, eval=FALSE} # Calculate seroincidence rates for Salmonella # 1. Define cross-sectional data serologyData <- salmonellaSerologyData # 2. Define longitudinal response data (simulate 1000 observations) responseParams <- simulateSalmonellaResponseParams(n = 1000) # 3. Define cut-offs cutoffs <- list(IgG = 0.25, IgM = 0.25, IgA = 0.25) # 4a. Calculate seroincidence rates by age (triplet of titres)... seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = "age", Ak = responseParams, censorLimits = cutoffs, showProgress = TRUE) # 4b. ...or calculate a single seroincidence rate for all serum samples (triplet of titres)... seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = "", Ak = responseParams, censorLimits = cutoffs) # 4c. ...or calculate a single seroincidence rate for a single serum sample (triplet of titres)... seroincidenceData <- estimateSeroincidence(data = serologyData[1, ], antibodies = c("IgG", "IgM", "IgA"), strata = "", Ak = responseParams, censorLimits = cutoffs) # 4d. ...or calculate a single seroincidence rate for all serum samples (only IgG) seroincidenceData <- estimateSeroincidence(data = serologyData, antibodies = c("IgG"), strata = "", Ak = responseParams, censorLimits = cutoffs) # 5a. Produce summary of the results with 2.5% and 97.5% bounds... summary(seroincidenceData) # 5b. ...or produce summary of the results with 5% and 95% bounds, do not show convergence... summary(seroincidenceData, quantiles = c(0.05, 0.95), showConvergence = FALSE) # 5c. ...or produce summary and assign to an object... seroincidenceSummary <- summary(seroincidenceData) # ...and work with the results object from now on (here: display the results). seroincidenceSummary$Results ``` # Acknowledgements Project funded by European Centre for Disease Prevention and Control (ECDC). # References seroincidence/vignettes/cover.Rmd0000644000176200001440000000323612640456126016670 0ustar liggesusers--- title: "R Package - seroincidence" author: "European Centre for Disease Prevention and Control (ECDC)" output: rmarkdown::html_vignette: toc: yes vignette: > %\VignetteIndexEntry{R Package - seroincidence} %\VignetteEngine{knitr::rmarkdown} %\usepackage[utf8]{inputenc} --- ```{r, echo = FALSE} pkgVersion <- packageDescription("seroincidence")$Version pkgDate <- packageDescription("seroincidence")$Date authorsString <- gsub("^ *|(?<= ) |\n| *$", "", packageDescription("seroincidence")$Authors, perl = TRUE) authorList <- eval(parse(text = authorsString)) pkgAuthors <- paste(format(authorList, include = c("given", "family", "email", "comment"), braces = list(email = c("<", ">,
"), comment = c("", ""))), collapse = "

") pkgMaintainer <- packageDescription("seroincidence")$Maintainer pkgBaseFileName <- paste("seroincidence", pkgVersion, sep = "_") pkgUrl <- packageDescription("seroincidence")$URL ``` R package **seroincidence** allows translation of antibody levels measured in a (cross-sectional) population sample into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. Item | Data ----- | ------ Version | `r pkgVersion` Published | `r pkgDate` Authors | `r pkgAuthors` Maintainer | `r pkgMaintainer` License | GPL-3 Package source | [`r pkgBaseFileName`.tar.gz](seroincidence_`r pkgVersion`.tar.gz) Windows binary | [`r pkgBaseFileName`.zip](seroincidence_`r pkgVersion`.zip) Installation manual | [installation.pdf](installation.pdf) Tutorial | [tutorial.pdf](tutorial.pdf) Appendix | [methodology.pdf](methodology.pdf) ECDC web site | `r pkgUrl` seroincidence/README.md0000644000176200001440000000171412640456126014354 0ustar liggesusersseroincidence package ===================== ------------------------------------------------------------------------ Antibody levels measured in a (cross--sectional) population sample can be translated into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. Formulated simply: the presence of many high titres indicates that many subjects likely experienced infection recently, while low titres indicate a low frequency of infections in the sampled population. The seroincidence calculator script was designed to use the longitudinal response characteristics by means of a set of parameters characterizing the longitudinal response of the selected serum antibodies. 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liggesusersRn04$<ĩ{hqz]:v"nk]g&M3,0c`i12)l9KJF7\F͡A߸3V:qd lD3Ʌ<6ɤ⦂$E iT8.bg.W.|BM.9L/+D4=quaS6 4䢤C"ÅT ޤ`9_kkE!4/ _ao,Ț}e Jȓ1b?_K $seroincidence/DESCRIPTION0000644000176200001440000000264012640603670014600 0ustar liggesusersPackage: seroincidence Type: Package Title: Estimating Infection Rates from Serological Data Version: 1.0.5 Date: 2015-10-12 Authors@R: c(person(given = "Peter", family = "Teunis", email = "peter.teunis@rivm.nl", role = c("aut"), comment = "Author of the method and original code"), person(given = "Daniel", family = "Lewandowski", email = "daniel@nextpagesoft.net", role = c("com", "ctb"), comment = "Creator of the R package"), person(given = "Chantal", family = "Quinten", email = "seroincidence@ecdc.europa.eu", role = c("ctb", "cre"), comment = "Project manager and the package maintainer")) Maintainer: Chantal Quinten Description: Translates antibody levels measured in a (cross-sectional) population sample into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. License: GPL-3 Imports: stats, utils Suggests: testthat, knitr VignetteBuilder: knitr LazyData: true Encoding: UTF-8 URL: http://ecdc.europa.eu/en/data-tools/seroincidence-calculator-tool/Pages/default.aspx RoxygenNote: 5.0.1 NeedsCompilation: no Packaged: 2015-12-29 10:11:42 UTC; Daniel Author: Peter Teunis [aut] (Author of the method and original code), Daniel Lewandowski [com, ctb] (Creator of the R package), Chantal Quinten [ctb, cre] (Project manager and the package maintainer) Repository: CRAN Date/Publication: 2015-12-29 23:22:48 seroincidence/man/0000755000176200001440000000000012640456126013645 5ustar liggesusersseroincidence/man/campylobacterResponseParams.Rd0000644000176200001440000000247512640456126021654 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/campylobacterResponseParams.R \docType{data} \name{campylobacterResponseParams} \alias{campylobacterResponseParams} \title{Campylobacter Response Parameters Data} \format{A list of two dataframes: \describe{ \item{\code{A}}{a dataframe containing 4000 peak levels (SSI ELISA units/ml). Named columns contain estimated peak levels for IgG, IgM and IgA antibodies.} \item{\code{k}}{a dataframe containing 4000 decay rates (1/days). Named columns contain estimated decay rates for IgG, IgM and IgA antibodies.} }} \usage{ campylobacterResponseParams } \description{ Monte Carlo sample of longitudinal response parameters \code{A} (peak level) and \code{k} (decay rate) per antibody for Campylobacter collected with SSI ELISA procedure. } \examples{ # show first rows of every dataframe contained in campylobacterResponseParams lapply(campylobacterResponseParams, head) } \references{ Strid, M. A., Engberg, J., Larsen, L. B., Begtrup, K., Molbak, K., Krogfelt, K. A.\cr "Antibody responses to Campylobacter infections determined by an enzyme-linked immunosorbent assay: 2-year follow-up study of 210 patients"\cr Clinical and Diagnostic Laboratory Immunology 8, no. 2 (March 1, 2001): 314--19. doi:10.1128/CDLI.8.2.314-319.2001. } seroincidence/man/print.seroincidence.Rd0000644000176200001440000000150612640456126020103 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/print.seroincidence.R \name{print.seroincidence} \alias{print.seroincidence} \title{Print Method for Seroincidence Object} \usage{ \method{print}{seroincidence}(x, ...) } \arguments{ \item{x}{A list containing output of function \code{\link{estimateSeroincidence}}.} \item{...}{Additional arguments affecting the summary produced.} } \description{ Custom \code{\link{print}} function to show output of the seroincidence calculator \code{\link{estimateSeroincidence}}. } \examples{ \dontrun{ # estimate seroincidence seroincidence <- estimateSeroincidence(...) # print the seroincidence object to the console print(seroincidence) # or simply type (appropriate print method will be invoked automatically) seroincidence } } seroincidence/man/simulateSerologyData.Rd0000644000176200001440000000167612640456126020307 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/simulateSerologyData.R \name{simulateSerologyData} \alias{simulateSerologyData} \title{Simulate Cross-Sectional Serology Data} \usage{ simulateSerologyData(n = 500) } \arguments{ \item{n}{Number of simulations, default 500.} } \value{ A dataframe of simulated antibody data, with named columns IgG, IgM and IgA. } \description{ Function to simulate cross-sectional serology data for three antibodies: IgG, IgM, IgA. The underlying parametric models are log-Normal distributions with parameters: \itemize{ \item{IgG: \code{mu} = 1.246, \code{sd} = 0.757} \item{IgM: \code{mu} = -0.764, \code{sd} = 0.413} \item{IgA: \code{mu} = -1.13, \code{sd} = 0.318} } } \examples{ # simulate 500 observations of cross-sectional serology data simulateSerologyData() # simulate 10 observations of cross-sectional serology data simulateSerologyData(n = 10) } seroincidence/man/campylobacterSerologyData.Rd0000644000176200001440000000134712640456126021304 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/campylobacterSerologyData.R \docType{data} \name{campylobacterSerologyData} \alias{campylobacterSerologyData} \title{Campylobacter Antibody Levels Data} \format{A data frame with 258 observations on the following 3 variables: \describe{ \item{\code{IgG}}{Measured IgG antibody level} \item{\code{IgM}}{Measured IgM antibody level} \item{\code{IgA}}{Measured IgA antibody level} }} \usage{ campylobacterSerologyData } \description{ Cross-sectional population sample of antibody levels data for Campylobacter. } \examples{ # show first rows of the data head(campylobacterSerologyData) # plot the data plot(campylobacterSerologyData) } seroincidence/man/print.summary.seroincidence.Rd0000644000176200001440000000176312640456126021604 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/print.summary.seroincidence.R \name{print.summary.seroincidence} \alias{print.summary.seroincidence} \title{Print Method for Seroincidence Summary Object} \usage{ \method{print}{summary.seroincidence}(x, ...) } \arguments{ \item{x}{A list containing output of function \code{\link{summary.seroincidence}}.} \item{...}{Additional arguments affecting the summary produced.} } \description{ Custom \code{\link{print}} function to show output of the seroincidence summary \code{\link{summary.seroincidence}}. } \examples{ \dontrun{ # estimate seroincidence seroincidence <- estimateSeroincidence(...) # calculate summary statistics for the seroincidence object seroincidenceSummary <- summary(seroincidence) # print the summary of seroincidence object to the console print(seroincidenceSummary) # or simply type (appropriate print method will be invoked automatically) seroincidenceSummary } } seroincidence/man/summary.seroincidence.Rd0000644000176200001440000000441512640456126020446 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/summary.seroincidence.R \name{summary.seroincidence} \alias{summary.seroincidence} \title{Summary Method for Seroincidence Object} \usage{ \method{summary}{seroincidence}(object, ..., quantiles = c(0.025, 0.975), showDeviance = TRUE, showConvergence = TRUE) } \arguments{ \item{object}{A dataframe containing output of function \code{\link{estimateSeroincidence}}.} \item{...}{Additional arguments affecting the summary produced.} \item{quantiles}{A vector of length 2 specifying quantiles for lower (first element) and upper (second element) bounds of \code{lambda}. Default \code{c(0.025, 0.975)}.} \item{showDeviance}{Logical flag (\code{FALSE}/\code{TRUE}) for reporting deviance (-2*log(likelihood) at estimated seroincidence. Default is \code{TRUE}.} \item{showConvergence}{Logical flag (\code{FALSE}/\code{TRUE}) for reporting convergence (see help for \code{\link{optim}} for details). Default is \code{TRUE}.} } \value{ A list with the following items: \describe{ \item{\code{Results}}{Dataframe with maximum likelihood estimate of \code{lambda} (the seroincidence) (column \code{Lambda}) and corresponding lower (\code{Lambda.lwr}) and upper (\code{Lambda.upr} bounds. Optionally \code{Deviance} (Negative log likelihood (NLL) at estimated (maximum likelhood) \code{lambda}) and \code{Covergence} (Convergence indicator returned by \code{\link{optim}}. Value of 0 indicates convergence) columns are included.} \item{\code{Antibodies}}{Character vector with names of input antibodies used in \code{\link{estimateSeroincidence}}.} \item{\code{Strata}}{Character with names of strata used in \code{\link{estimateSeroincidence}}.} \item{\code{CensorLimits}}{List of cutoffs for each of the antibodies used in \code{\link{estimateSeroincidence}}.} } } \description{ Calculate seroincidence from output of the seroincidence calculator \code{\link{estimateSeroincidence}}. } \examples{ \dontrun{ # estimate seroincidence seroincidence <- estimateSeroincidence(...) # calculate summary statistics for the seroincidence object seroincidenceSummary <- summary(seroincidence) } } seroincidence/man/estimateSeroincidence.Rd0000644000176200001440000000446212640456126020450 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/estimateSeroincidence.R \name{estimateSeroincidence} \alias{estimateSeroincidence} \title{Estimate Seroincidences} \usage{ estimateSeroincidence(data, antibodies, strata = "", Ak, censorLimits, showProgress = FALSE, ...) } \arguments{ \item{data}{Dataframe with cross-sectional serum antibody data. At least one antibody should be specified. Rows represent multiple antibody measurements in the same serum sample. Strata may be specified in additional columns.} \item{antibodies}{Character vector with names of antibodies to be included for incidence calculations. At least one antibody name must be specified, names must match with those in \code{data} and in \code{Ak}.} \item{strata}{Character vector with names of strata to be used, default ="". Names must match with data.} \item{Ak}{List with two dataframes containing longitudinal parameters named A (the peak serum antibody level) and k (the decay rate). Each dataframe contains sets of Monte Carlo samples, one for each antibody that is available.} \item{censorLimits}{List of cutoffs for each of the antibodies specified in 'antibodies'. Any cross-sectional observations below cutoff will be treated as censored at the cutoff level.} \item{showProgress}{Indicator whether or not to show text progress bar indicating progress of estimation. The setting is effective only if the number of levels per stratum if greater than 1. Default is \code{FALSE}.} \item{...}{Additional arguments passed to function \code{\link{optim}}.} } \value{ A list with the following items: \describe{ \item{\code{Fits}}{Outputs of \code{\link{optim}} function per stratum.} \item{\code{Antibodies}}{Input parameter \code{antibodies} saved for \code{\link{summary}} function.} \item{\code{Strata}}{Input parameter \code{strata} saved for \code{\link{summary}} function.} \item{\code{CensorLimits}}{Input parameter \code{censorLimits} saved for \code{\link{summary}} function.} } } \description{ Function to estimate seroincidences based on cross-section serology data and longitudinal response model. } \examples{ \dontrun{ estimateSeroincidence(data = serologyData, antibodies = c("IgG", "IgM", "IgA"), strata = c("age"), Ak = responseParams) } } seroincidence/man/salmonellaSerologyData.Rd0000644000176200001440000000227712640456126020611 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/salmonellaSerologyData.R \docType{data} \name{salmonellaSerologyData} \alias{salmonellaSerologyData} \title{Salmonella Antibody Levels Data} \format{A data frame with 456 observations on the following 6 variables: \describe{ \item{\code{id}}{Observation id} \item{\code{IgG}}{Measured IgG antibody level} \item{\code{IgM}}{Measured IgM antibody level} \item{\code{IgA}}{Measured IgA antibody level} \item{\code{sex}}{Sex indicator (1 - Male, 2 - Female)} \item{\code{age}}{Age} }} \source{ Dutch Pienter 1 serosurvey } \usage{ data("salmonellaSerologyData") } \description{ Antibody levels measured in cross-sectional population sample for Salmonella with SSI Mixed ELISA procedure. } \examples{ # show first rows of the data head(salmonellaSerologyData) # plot the data plot(salmonellaSerologyData) } \references{ Teunis, P. F., van Eijkeren, J. C., Ang, C. W., van Duynhoven, Y. T., Simonsen, J. B., Strid, M. A., van Pelt W.\cr "Biomarker Dynamics: Estimating Infection Rates From Serological Data"\cr Statistics in Medicine 31, no. 20 (September 9, 2012): 2240--48. doi:10.1002/sim.5322. } seroincidence/man/simulateSalmonellaResponseParams.Rd0000644000176200001440000000326712640456126022662 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/simulateSalmonellaResponseParams.R \name{simulateSalmonellaResponseParams} \alias{simulateSalmonellaResponseParams} \title{Simulate Longitudinal Response Parameters for Salmonella} \usage{ simulateSalmonellaResponseParams(n = 500) } \arguments{ \item{n}{Number of Monte Carlo simulations per antibody, default 500.} } \value{ A list of two dataframes named \code{A} and \code{k}: \describe{ \item{\code{A}}{Dataframe containing peak levels (SSI mixed ELISA units/ml). Named columns contain estimated peak levels for IgG, IgM and IgA antibodies.} \item{\code{k}}{Dataframe containing decay rates (1/days). Named columns contain estimated decay rates for IgG, IgM and IgA antibodies.} } } \description{ Simulate longitudinal response parameters \code{A} and \code{k} per antibody for Salmonella (SSI Mixed ELISA). The underlying parametric models for peak levels \code{A} are Gamma distributions with parameters: \itemize{ \item{IgG: \code{shape} = 1.1175, \code{scale} = 0.848} \item{IgM: \code{shape} = 1.337, \code{scale} = 0.902} \item{IgA: \code{shape} = 1.205, \code{scale} = 0.651} } The underlying parametric models for decay rates \code{k} are Inverse Gamma distributions with parameters: \itemize{ \item{IgG: \code{shape} = 0.869, \code{scale} = 1/728.5} \item{IgM: \code{shape} = 0.731, \code{scale} = 1/514.6} \item{IgA: \code{shape} = 1.759, \code{scale} = 1/132/5} } } \examples{ # simulate 500 observations of longitudinal response data simulateSalmonellaResponseParams() # simulate 100 observations of longitudinal response data simulateSalmonellaResponseParams(n = 100) } seroincidence/man/seroincidence.Rd0000644000176200001440000001141012640456126016743 0ustar liggesusers% Generated by roxygen2: do not edit by hand % Please edit documentation in R/seroincidence.R \docType{package} \name{seroincidence} \alias{seroincidence} \alias{seroincidence-package} \title{Estimating Infection Rates from Serological Data} \description{ Translates antibody levels measured in a (cross-sectional) population sample into an estimate of the frequency with which seroconversions (infections) occur in the sampled population. } \details{ For detailed documentation type the following in the R console:\cr \code{vignette("installation", package = "seroincidence")}\cr \code{vignette("tutorial", package = "seroincidence")}\cr \code{vignette("methodology", package = "seroincidence")} } \author{ Author: Peter Teunis \email{}\cr Contributor: Daniel Lewandowski \email{}\cr Maintainer: Chantal Quinten \email{} } \references{ \strong{\emph{Methods for estimating seroincidence}} \itemize{ \item Teunis, P. F., van Eijkeren, J. C., Ang, C. W., van Duynhoven, Y. T., Simonsen, J. B., Strid, M. A., van Pelt, W.\cr "Biomarker dynamics: estimating infection rates from serological data"\cr Statistics in Medicine 31, no. 20 (September 9, 2012): 2240--48. doi:10.1002/sim.5322. \item Simonsen, J., Molbak, K., Falkenhorst, G., Krogfelt, K. A., Linneberg, A., Teunis, P. F.\cr "Estimation of incidences of infectious diseases based on antibody measurements"\cr Statistics in Medicine 28, no. 14 (June 30, 2009): 1882--95. doi:10.1002/sim.3592. } \strong{\emph{Applications}} \itemize{ \item Kretzschmar, M., Teunis, P. F., Pebody, R. G.\cr "Incidence and reproduction numbers of pertussis: estimates from serological and social contact data in five European countries"\cr PLoS Medicine 7, no. 6 (June 1, 2010):e1000291. doi:10.1371/journal.pmed.1000291. \item Simonsen, J., Strid, M. A., Molbak, K., Krogfelt, K. A., Linneberg, A., Teunis, P.\cr "Sero-epidemiology as a tool to study the incidence of Salmonella infections in humans"\cr Epidemiology and Infection 136, no. 7 (July 1, 2008): 895--902. doi:10.1017/S0950268807009314 \item Simonsen, J., Teunis, P. F., van Pelt, W., van Duynhoven, Y., Krogfelt, K. A., Sadkowska-Todys, M., Molbak K.\cr "Usefulness of seroconversion rates for comparing infection pressures between countries"\cr Epidemiology and Infection, April 12, 2010, 1--8. doi:10.1017/S0950268810000750. \item Falkenhorst, G., Simonsen, J., Ceper, T. H., van Pelt, W., de Valk, H., Sadkowska-Todys, M., Zota, L., Kuusi, M., Jernberg, C., Rota, M. C., van Duynhoven, Y. T., Teunis, P. F., Krogfelt, K. A., Molbak, K.\cr "Serological cross-sectional studies on salmonella incidence in eight European countries: no correlation with incidence of reported cases"\cr BMC Public Health 12, no. 1 (July 15, 2012): 523--23. doi:10.1186/1471-2458-12-523. \item Teunis, P. F., Falkenhorst, G., Ang, C. W., Strid, M. A., De Valk, H., Sadkowska-Todys, M., Zota, L., Kuusi, M., Rota, M. C., Simonsen, J. B., Molbak, K., Van Duynhoven, Y. T., van Pelt, W.\cr "Campylobacter seroconversion rates in selected countries in the European Union"\cr Epidemiology and Infection 141, no. 10 (2013): 2051--57. doi:10.1017/S0950268812002774. \item de Melker, H. E., Versteegh, F. G., Schellekens, J. F., Teunis, P. F., Kretzschmar, M.\cr "The incidence of Bordetella pertussis infections estimated in the population from a combination of serological surveys"\cr The Journal of Infection 53, no. 2 (August 1, 2006): 106--13. doi:10.1016/j.jinf.2005.10.020 } \strong{\emph{Quantification of seroresponse}} \itemize{ \item de Graaf, W. F., Kretzschmar, M. E., Teunis, P. F., Diekmann, O.\cr "A two-phase within-host model for immune response and its application to serological profiles of pertussis"\cr Epidemics 9 (2014):1--7. doi:10.1016/j.epidem.2014.08.002. \item Berbers, G. A., van de Wetering, M. S., van Gageldonk, P. G., Schellekens, J. F., Versteegh, F. G., Teunis, P.F.\cr "A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens"\cr Vaccine 31, no. 36 (August 12, 2013): 3732--38. doi:10.1016/j.vaccine.2013.05.073. \item Versteegh, F. G., Mertens, P. L., de Melker, H. E., Roord, J. J., Schellekens, J. F., Teunis, P. F.\cr "Age-specific long-term course of IgG antibodies to pertussis toxin after symptomatic infection with Bordetella pertussis"\cr Epidemiology and Infection 133, no. 4 (August 1, 2005): 737--48. \item Teunis, P. F., van der Heijden, O. G., de Melker, H. E., Schellekens, J. F., Versteegh, F. G., Kretzschmar, M. E. "Kinetics of the IgG antibody response to pertussis toxin after infection with B. pertussis"\cr Epidemiology and Infection 129, no. 3 (December 10, 2002):479. doi:10.1017/S0950268802007896. } }