{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T07:10:50Z","timestamp":1773126650772,"version":"3.50.1"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 AI034533"],"award-info":[{"award-number":["P01 AI034533"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Military Infectious Disease Research Program"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AI175941-01"],"award-info":[{"award-number":["1R01AI175941-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM138361"],"award-info":[{"award-number":["R35 GM138361"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["804744"],"award-info":[{"award-number":["804744"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014989","name":"Chan Zuckerberg Initiative","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100014989","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Herchel Smith Postdoctoral Fellowship"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Dengue virus (DENV) is an increasingly important human pathogen, with already half of the globe\u2019s population living in environments with transmission potential. Since many cases are missed by direct detection methods (RT-PCR or antigen tests), serological assays play an important role in the diagnostic process. However, individual assays can suffer from low sensitivity and specificity and interpreting results from multiple assays remains challenging, particularly because interpretations from multiple assays may differ, creating uncertainty over how to generate finalized interpretations. We develop a Bayesian mixture model that can jointly model data from multiple paired serological assays, to infer infection events. We first test the performance of our model using simulated data. We then apply our model to 677 pairs of acute and convalescent serum collected as a part of illness and household investigations across two longitudinal cohort studies in Kamphaeng Phet, Thailand, including data from 232 RT-PCR confirmed infections (gold standard). We compare the classification of the new model to prior standard interpretations that independently utilize information from either the hemagglutination inhibition assay (HAI) or the enzyme-linked immunosorbent assay (EIA). We find that additional serological assays improve accuracy of infection detection for both simulated and real world data. Models incorporating paired IgG and IgM data as well as those incorporating IgG, IgM, and HAI data consistently have higher accuracy when using PCR confirmed infections as a gold standard (87\u201390% F1 scores, a combined metric of sensitivity and specificity) than currently implemented cut-point approaches (82\u201384% F1 scores). Our results provide a probabilistic framework through which multiple serological assays across different platforms can be leveraged across sequential serum samples to provide insight into whether individuals have recently experienced a DENV infection. These methods are applicable to other pathogen systems where multiple serological assays can be leveraged to quantify infection history.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013708","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T18:35:26Z","timestamp":1764095726000},"page":"e1013708","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Linking multiple serological assays to infer dengue virus infections from paired samples using mixture models"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3631-3637","authenticated-orcid":true,"given":"Marco","family":"Hamins-Pu\u00e9rtolas","sequence":"first","affiliation":[]},{"given":"Darunee","family":"Buddhari","sequence":"additional","affiliation":[]},{"given":"Henrik","family":"Salje","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9857-3506","authenticated-orcid":true,"given":"Angkana T.","family":"Huang","sequence":"additional","affiliation":[]},{"given":"Taweewun","family":"Hunsawong","sequence":"additional","affiliation":[]},{"given":"Derek A.T.","family":"Cummings","sequence":"additional","affiliation":[]},{"given":"Stefan","family":"Fernandez","sequence":"additional","affiliation":[]},{"given":"Aaron","family":"Farmer","sequence":"additional","affiliation":[]},{"given":"Surachai","family":"Kaewhiran","sequence":"additional","affiliation":[]},{"given":"Direk","family":"Khampaen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2423-8545","authenticated-orcid":true,"given":"Anon","family":"Srikiatkhachorn","sequence":"additional","affiliation":[]},{"given":"Sopon","family":"Iamsirithaworn","sequence":"additional","affiliation":[]},{"given":"Adam","family":"Waickman","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8368-7682","authenticated-orcid":true,"given":"Stephen J.","family":"Thomas","sequence":"additional","affiliation":[]},{"given":"Timothy","family":"Endy","sequence":"additional","affiliation":[]},{"given":"Alan L.","family":"Rothman","sequence":"additional","affiliation":[]},{"given":"Kathryn B.","family":"Anderson","sequence":"additional","affiliation":[]},{"given":"Isabel","family":"Rodriguez-Barraquer","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"issue":"7446","key":"pcbi.1013708.ref001","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nature12060","article-title":"The global distribution and burden of dengue","volume":"496","author":"S Bhatt","year":"2013","journal-title":"Nature"},{"issue":"528","key":"pcbi.1013708.ref002","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aax4144","article-title":"Mapping global variation in dengue transmission intensity","volume":"12","author":"L Cattarino","year":"2020","journal-title":"Sci Transl Med"},{"issue":"11","key":"pcbi.1013708.ref003","article-title":"The effects of weather and climate change on dengue","volume":"7","author":"FJ Col\u00f3n-Gonz\u00e1lez","year":"2013","journal-title":"PLoS Negl Trop Dis"},{"key":"pcbi.1013708.ref004","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1186\/1471-2334-14-167","article-title":"Climate change and dengue: a critical and systematic review of quantitative modelling approaches","volume":"14","author":"S Naish","year":"2014","journal-title":"BMC Infect Dis"},{"key":"pcbi.1013708.ref005","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.envres.2016.07.026","article-title":"Dengue in a changing climate","volume":"151","author":"KL Ebi","year":"2016","journal-title":"Environ Res"},{"key":"pcbi.1013708.ref006","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ijid.2023.07.010","article-title":"Global prevalence of asymptomatic dengue infections - a systematic review and meta-analysis","volume":"134","author":"PR Asish","year":"2023","journal-title":"Int J Infect Dis"},{"issue":"9","key":"pcbi.1013708.ref007","doi-asserted-by":"crossref","DOI":"10.1016\/j.heliyon.2023.e20069","article-title":"Asymptomatic dengue infection rate: A systematic literature review","volume":"9","author":"O De Santis","year":"2023","journal-title":"Heliyon"},{"issue":"1","key":"pcbi.1013708.ref008","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41564-023-01543-3","article-title":"Household immunity and individual risk of infection with dengue virus in a prospective, longitudinal cohort study","volume":"9","author":"M Hamins-Pu\u00e9rtolas","year":"2024","journal-title":"Nat Microbiol"},{"issue":"11","key":"pcbi.1013708.ref009","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1093\/trstmh\/trz068","article-title":"A review of dengue diagnostics and implications for surveillance and control","volume":"113","author":"N Raafat","year":"2019","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"1","key":"pcbi.1013708.ref010","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1186\/s12879-017-2525-3","article-title":"Assessing changes in knowledge, attitude and practices on dengue diagnosis and management among primary care physicians after the largest dengue epidemic in Singapore","volume":"17","author":"J Pang","year":"2017","journal-title":"BMC Infect Dis"},{"issue":"7","key":"pcbi.1013708.ref011","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3390\/bios11070206","article-title":"Dengue Detection: Advances in Diagnostic Tools from Conventional Technology to Point of Care","volume":"11","author":"MA Kabir","year":"2021","journal-title":"Biosensors (Basel)"},{"issue":"12","key":"pcbi.1013708.ref012","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1128\/JCM.00707-17","article-title":"Progress and Challenges towards Point-of-Care Diagnostic Development for Dengue","volume":"55","author":"J Pang","year":"2017","journal-title":"J Clin Microbiol"},{"key":"pcbi.1013708.ref013","article-title":"Laboratory diagnosis and diagnostic tests","volume-title":"Dengue: guidelines for diagnosis, treatment, prevention and control: new edition","year":"2009"},{"key":"pcbi.1013708.ref014","unstructured":"World Health Organization. Manual for the laboratory diagnosis and virological surveillance of influenza. 2011."},{"issue":"4","key":"pcbi.1013708.ref015","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1017\/S0950268815001958","article-title":"Is it appropriate to use fixed assay cut-offs for estimating seroprevalence?","volume":"144","author":"G Kafatos","year":"2016","journal-title":"Epidemiol Infect"},{"key":"pcbi.1013708.ref016","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1186\/1743-422X-11-164","article-title":"Evaluation of four commercial real-time RT-PCR kits for the detection of dengue viruses in clinical samples","volume":"11","author":"F Najioullah","year":"2014","journal-title":"Virol J"},{"key":"pcbi.1013708.ref017","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jcv.2014.12.009","article-title":"Monitoring and improving the sensitivity of dengue nested RT-PCR used in longitudinal surveillance in Thailand","volume":"63","author":"C Klungthong","year":"2015","journal-title":"J Clin Virol"},{"key":"pcbi.1013708.ref018","doi-asserted-by":"crossref","first-page":"27663","DOI":"10.1038\/srep27663","article-title":"The Use of NS1 Rapid Diagnostic Test and qRT-PCR to Complement IgM ELISA for Improved Dengue Diagnosis from Single Specimen","volume":"6","author":"B-T Teoh","year":"2016","journal-title":"Sci Rep"},{"issue":"12","key":"pcbi.1013708.ref019","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1017\/S0950268808000393","article-title":"Analysis of rubella antibody distribution from newborn dried blood spots using finite mixture models","volume":"136","author":"P Hardelid","year":"2008","journal-title":"Epidemiol Infect"},{"issue":"2","key":"pcbi.1013708.ref020","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1017\/S0950268802008051","article-title":"Improving sensitivity of oral fluid testing in IgG prevalence studies: application of mixture models to a rubella antibody survey","volume":"130","author":"NJ Gay","year":"2003","journal-title":"Epidemiol Infect"},{"issue":"1","key":"pcbi.1013708.ref021","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/EDE.0000000000000196","article-title":"Estimating seroprevalence of human papillomavirus type 16 using a mixture model with smoothed age-dependent mixing proportions","volume":"26","author":"MA Vink","year":"2015","journal-title":"Epidemiology"},{"issue":"9","key":"pcbi.1013708.ref022","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1093\/aje\/kwad103","article-title":"A Mixture Model for Estimating SARS-CoV-2 Seroprevalence in Chennai, India","volume":"192","author":"MDT Hitchings","year":"2023","journal-title":"Am J Epidemiol"},{"issue":"4","key":"pcbi.1013708.ref023","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.prevetmed.2007.05.014","article-title":"Bayesian mixture models for within-herd prevalence estimates of bovine paratuberculosis based on a continuous ELISA response","volume":"81","author":"SS Nielsen","year":"2007","journal-title":"Prev Vet Med"},{"issue":"6","key":"pcbi.1013708.ref024","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1017\/S0950268806006340","article-title":"Interpreting serological surveys using mixture models: the seroepidemiology of measles, mumps and rubella in England and Wales at the beginning of the 21st century","volume":"134","author":"AJ Vyse","year":"2006","journal-title":"Epidemiol Infect"},{"issue":"6","key":"pcbi.1013708.ref025","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1017\/S0950268804003140","article-title":"Seroprevalence of antibody to varicella zoster virus in England and Wales in children and young adults","volume":"132","author":"AJ Vyse","year":"2004","journal-title":"Epidemiol Infect"},{"issue":"156","key":"pcbi.1013708.ref026","doi-asserted-by":"crossref","first-page":"20190207","DOI":"10.1098\/rsif.2019.0207","article-title":"Serological inference of past primary and secondary dengue infection: implications for vaccination","volume":"16","author":"HM Lam","year":"2019","journal-title":"J R Soc Interface"},{"issue":"1","key":"pcbi.1013708.ref027","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1186\/s12916-020-01833-1","article-title":"A serological framework to investigate acute primary and post-primary dengue cases reporting across the Philippines","volume":"18","author":"JR Biggs","year":"2020","journal-title":"BMC Med"},{"issue":"7","key":"pcbi.1013708.ref028","article-title":"Estimating dengue transmission intensity from serological data: A comparative analysis using mixture and catalytic models","volume":"16","author":"V Cox","year":"2022","journal-title":"PLoS Negl Trop Dis"},{"key":"pcbi.1013708.ref029","volume-title":"Monograph on Dengue\/Dengue Haemorrhagic Fever","author":"P Thongcharoen","year":"1993"},{"key":"pcbi.1013708.ref030","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-1-0716-1879-0_12","article-title":"Serological Diagnosis of Dengue","volume":"2409","author":"MRQ Lima","year":"2022","journal-title":"Methods Mol Biol"},{"issue":"6","key":"pcbi.1013708.ref031","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1586\/eri.11.51","article-title":"Serologic assays for influenza surveillance, diagnosis and vaccine evaluation","volume":"9","author":"JM Katz","year":"2011","journal-title":"Expert Rev Anti Infect Ther"},{"issue":"12","key":"pcbi.1013708.ref032","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1003061","article-title":"Influenza infection rates, measurement errors and the interpretation of paired serology","volume":"8","author":"S Cauchemez","year":"2012","journal-title":"PLoS Pathog"},{"issue":"8","key":"pcbi.1013708.ref033","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0000811","article-title":"Multi-country evaluation of the sensitivity and specificity of two commercially-available NS1 ELISA assays for dengue diagnosis","volume":"4","author":"MG Guzman","year":"2010","journal-title":"PLoS Negl Trop Dis"},{"issue":"6","key":"pcbi.1013708.ref034","article-title":"The diagnostic sensitivity of dengue rapid test assays is significantly enhanced by using a combined antigen and antibody testing approach","volume":"5","author":"SR Fry","year":"2011","journal-title":"PLoS Negl Trop Dis"},{"key":"pcbi.1013708.ref035","doi-asserted-by":"crossref","DOI":"10.1093\/infdis\/jiw649","article-title":"Clinical and Laboratory Diagnosis of Dengue Virus Infection","volume":"215","author":"DA Muller","year":"2017","journal-title":"J Infect Dis"},{"issue":"1","key":"pcbi.1013708.ref036","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.trstmh.2010.09.007","article-title":"A prospective evaluation of diagnostic methodologies for the acute diagnosis of dengue virus infection on the Thailand-Myanmar border","volume":"105","author":"W Watthanaworawit","year":"2011","journal-title":"Trans R Soc Trop Med Hyg"},{"issue":"6","key":"pcbi.1013708.ref037","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pntd.0009457","article-title":"Determining seropositivity-A review of approaches to define population seroprevalence when using multiplex bead assays to assess burden of tropical diseases","volume":"15","author":"Y Chan","year":"2021","journal-title":"PLoS Negl Trop Dis"},{"issue":"8","key":"pcbi.1013708.ref038","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1011384","article-title":"serosim: An R package for simulating serological data arising from vaccination, epidemiological and antibody kinetics processes","volume":"19","author":"A Menezes","year":"2023","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1013708.ref039","volume-title":"R: A Language and Environment for Statistical Computing","author":"R C, Team","year":"2023"},{"issue":"1","key":"pcbi.1013708.ref040","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1093\/aje\/kwf006","article-title":"Spatial and temporal circulation of dengue virus serotypes: a prospective study of primary school children in Kamphaeng Phet, Thailand","volume":"156","author":"TP Endy","year":"2002","journal-title":"Am J Epidemiol"},{"issue":"1","key":"pcbi.1013708.ref041","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1093\/aje\/kwf005","article-title":"Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand","volume":"156","author":"TP Endy","year":"2002","journal-title":"Am J Epidemiol"},{"key":"pcbi.1013708.ref042","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1093\/aje\/kwaa008","article-title":"An innovative, prospective, hybrid cohort-cluster study design to characterize dengue virus transmission in multigenerational households in Kamphaeng Phet, Thailand","volume":"189","author":"KB Anderson","year":"2020","journal-title":"Am J Epidemiol"},{"key":"pcbi.1013708.ref043","unstructured":"Stan Development Team. Stan Reference Manual. 2024."},{"key":"pcbi.1013708.ref044","unstructured":"Gabry J, \u010ce\u0161novar R, Johnson A, Bronder S. cmdstanr: R Interface to \u2018CmdStan\u2019. 2025."},{"issue":"5","key":"pcbi.1013708.ref045","doi-asserted-by":"crossref","first-page":"561","DOI":"10.4269\/ajtmh.1958.7.561","article-title":"Techniques for hemagglutination and hemagglutination-inhibition with arthropod-borne viruses","volume":"7","author":"DH Clarke","year":"1958","journal-title":"Am J Trop Med Hyg"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013708","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T18:35:38Z","timestamp":1764095738000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013708"}},"subtitle":[],"editor":[{"given":"Roger Dimitri","family":"Kouyos","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,11,25]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013708","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,25]]}}}