{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:08:17Z","timestamp":1791443297390,"version":"4.3.3"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012171","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T00:00:00Z","timestamp":1715212800000}}],"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T00:00:00Z","timestamp":1714348800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["#D18AC00031"],"award-info":[{"award-number":["#D18AC00031"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5T32 GM008185-33"],"award-info":[{"award-number":["5T32 GM008185-33"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCLA Office of the Vice Chancellor for Research","award":["3R Grant"],"award-info":[{"award-number":["3R Grant"]}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["DEB-1557022; DEB-2245631"],"award-info":[{"award-number":["DEB-1557022; DEB-2245631"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCLA AIDS Institute and Charity Treks"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Researchers and clinicians often rely on molecular assays like PCR to identify and monitor viral infections, instead of the resource-prohibitive gold standard of viral culture. However, it remains unclear when (if ever) PCR measurements of viral load are reliable indicators of replicating or infectious virus. The recent popularity of PCR protocols targeting subgenomic RNA for SARS-CoV-2 has caused further confusion, as the relationships between subgenomic RNA and standard total RNA assays are incompletely characterized and opinions differ on which RNA type better predicts culture outcomes. Here, we explore these issues by comparing total RNA, subgenomic RNA, and viral culture results from 24 studies of SARS-CoV-2 in non-human primates (including 2167 samples from 174 individuals) using custom-developed Bayesian statistical models. On out-of-sample data, our best models predict subgenomic RNA positivity from total RNA data with 91% accuracy, and they predict culture positivity with 85% accuracy. Further analyses of individual time series indicate that many apparent prediction errors may arise from issues with assay sensitivity or sample processing, suggesting true accuracy may be higher than these estimates. Total RNA and subgenomic RNA showed equivalent performance as predictors of culture positivity. Multiple cofactors (including exposure conditions, host traits, and assay protocols) influence culture predictions, yielding insights into biological and methodological sources of variation in assay outcomes\u2013and indicating that no single threshold value applies across study designs. We also show that our model can accurately predict when an individual is no longer infectious, illustrating the potential for future models trained on human data to guide clinical decisions on case isolation. Our work shows that meta-analysis of <jats:italic>in vivo<\/jats:italic> data can overcome longstanding challenges arising from limited sample sizes and can yield robust insights beyond those attainable from individual studies. Our analytical pipeline offers a framework to develop similar predictive tools in other virus-host systems, including models trained on human data, which could support laboratory analyses, medical decisions, and public health guidelines.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012171","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T17:36:28Z","timestamp":1714412188000},"page":"e1012171","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Predicting the presence of infectious virus from PCR data: A meta-analysis of SARS-CoV-2 in non-human primates"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-5614","authenticated-orcid":true,"given":"Celine E.","family":"Snedden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7941-502X","authenticated-orcid":true,"given":"James O.","family":"Lloyd-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"ppat.1012171.ref001","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3389\/fmicb.2017.00108","article-title":"A Basic Guide to Real Time PCR in Microbial Diagnostics: Definitions, Parameters, and Everything.","volume":"8","author":"P Kralik","year":"2017","journal-title":"Front Microbiol."},{"issue":"6","key":"ppat.1012171.ref002","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/S1473-3099(04)01044-8","article-title":"PCR-based diagnostics for infectious diseases: uses, limitations, and future applications in acute-care settings","volume":"4","author":"S Yang","year":"2004","journal-title":"Lancet Infect Dis"},{"key":"ppat.1012171.ref003","first-page":"1","volume-title":"Coronaviruses: Methods and Protocols [Internet]","author":"AR Fehr","year":"2015"},{"issue":"8","key":"ppat.1012171.ref004","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.3201\/eid2608.201246","article-title":"US CDC Real-Time Reverse Transcription PCR Panel for Detection of Severe Acute Respiratory Syndrome Coronavirus 2","volume":"26","author":"X Lu","year":"2020","journal-title":"Emerg Infect Dis"},{"issue":"14","key":"ppat.1012171.ref005","doi-asserted-by":"crossref","first-page":"7890","DOI":"10.1128\/JVI.77.14.7890-7902.2003","article-title":"Transmissible Gastroenteritis Coronavirus Packaging Signal Is Located at the 5\u2032 End of the Virus Genome","volume":"77","author":"D Escors","year":"2003","journal-title":"J Virol"},{"issue":"7809","key":"ppat.1012171.ref006","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/s41586-020-2196-x","article-title":"Virological assessment of hospitalized patients with COVID-2019.","volume":"581","author":"R W\u00f6lfel","year":"2020","journal-title":"Nature"},{"issue":"8","key":"ppat.1012171.ref007","article-title":"Comparison of Subgenomic and Total RNA in SARS-CoV-2-Challenged Rhesus Macaques.","volume":"95","author":"G Dagotto","year":"2021","journal-title":"J Virol [Internet]."},{"issue":"578","key":"ppat.1012171.ref008","article-title":"Single-cell RNA sequencing reveals SARS-CoV-2 infection dynamics in lungs of African green monkeys.","volume":"13","author":"E Speranza","year":"2021","journal-title":"Sci Transl Med [Internet]."},{"issue":"1","key":"ppat.1012171.ref009","first-page":"e01609","article-title":"Viral Culture Confirmed SARS-CoV-2 Subgenomic RNA Value as a Good Surrogate Marker of Infectivity","volume":"60","author":"MS Bravo","year":"2022","journal-title":"J Clin Microbiol"},{"issue":"11","key":"ppat.1012171.ref010","first-page":"2701","volume":"26","author":"RAPM Perera","year":"2020","journal-title":"SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease\u2014Volume 26, Number 11\u2014November 2020\u2014Emerging Infectious Diseases journal\u2014CDC."},{"issue":"5","key":"ppat.1012171.ref011","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1093\/infdis\/jiab039","article-title":"Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Replication and Tropism in the Lungs, Airways, and Vascular Endothelium of Patients With Fatal Coronavirus Disease 2019: An Autopsy Case Series.","volume":"223","author":"J Bhatnagar","year":"2021","journal-title":"J Infect Dis"},{"issue":"2","key":"ppat.1012171.ref012","doi-asserted-by":"crossref","first-page":"e02277","DOI":"10.1128\/JCM.02277-20","article-title":"Inference of Active Viral 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Infect Dis"},{"issue":"10","key":"ppat.1012171.ref015","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1093\/cid\/ciac282","article-title":"Surveillance and Correlation of Severe Acute Respiratory Syndrome Coronavirus 2 Viral RNA, Antigen, Virus Isolation, and Self-Reported Symptoms in a Longitudinal Study With Daily Sampling","volume":"75","author":"G Bonenfant","year":"2022","journal-title":"Clin Infect Dis"},{"issue":"1","key":"ppat.1012171.ref016","doi-asserted-by":"crossref","first-page":"6059","DOI":"10.1038\/s41467-020-19883-7","article-title":"SARS-CoV-2 genomic and subgenomic RNAs in diagnostic samples are not an indicator of active replication.","volume":"11","author":"S Alexandersen","year":"2020","journal-title":"Nat Commun."},{"issue":"8","key":"ppat.1012171.ref017","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1093\/infdis\/jiab215","article-title":"Severe Acute Respiratory Syndrome Coronavirus 2 Total and Subgenomic RNA Viral Load in Hospitalized 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Salguero","year":"2021","journal-title":"Nat Commun."},{"issue":"2","key":"ppat.1012171.ref021","doi-asserted-by":"crossref","first-page":"e15290","DOI":"10.15252\/emmm.202115290","article-title":"Predicting infectivity: comparing four PCR-based assays to detect culturable SARS-CoV-2 in clinical samples","volume":"14","author":"EA Bruce","year":"2022","journal-title":"EMBO Mol Med"},{"issue":"10","key":"ppat.1012171.ref022","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1093\/cid\/ciaa638","article-title":"Predicting Infectious Severe Acute Respiratory Syndrome Coronavirus 2 From Diagnostic Samples","volume":"71","author":"J Bullard","year":"2020","journal-title":"Clin Infect Dis"},{"issue":"4","key":"ppat.1012171.ref023","doi-asserted-by":"crossref","first-page":"e860","DOI":"10.1093\/cid\/ciaa1616","article-title":"Repeated Coronavirus Disease 2019 Molecular Testing: Correlation of Severe Acute Respiratory Syndrome Coronavirus 2 Culture With Molecular Assays and Cycle 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Gender-Based Differences in the Host Immune Response to Coronaviruses","volume":"11","author":"N Gadi","year":"2020","journal-title":"Front Immunol [Internet]."},{"key":"ppat.1012171.ref026","article-title":"Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections?","volume":"11","author":"V Bajaj","year":"2021","journal-title":"Front Physiol [Internet]."},{"issue":"1","key":"ppat.1012171.ref027","doi-asserted-by":"crossref","first-page":"5493","DOI":"10.1038\/s41467-020-19057-5","article-title":"SARS-CoV-2 viral load is associated with increased disease severity and mortality.","volume":"11","author":"J Fajnzylber","year":"2020","journal-title":"Nat Commun."},{"issue":"6551","key":"ppat.1012171.ref028","doi-asserted-by":"crossref","first-page":"eabi5273","DOI":"10.1126\/science.abi5273","article-title":"Estimating infectiousness throughout SARS-CoV-2 infection course","volume":"373","author":"TC 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virus shedding even after seroconversion in a patient with COVID-19.","volume":"81","author":"WD Liu","year":"2020","journal-title":"J Infect."},{"issue":"6","key":"ppat.1012171.ref033","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/s41577-018-0005-7","article-title":"Nonhuman primate models of human viral infections","volume":"18","author":"JD Estes","year":"2018","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"ppat.1012171.ref034","doi-asserted-by":"crossref","first-page":"264","DOI":"10.7326\/0003-4819-151-4-200908180-00135","article-title":"Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement","volume":"151","author":"D Moher","year":"2009","journal-title":"Ann Intern Med"},{"issue":"6520","key":"ppat.1012171.ref035","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1126\/science.abe2402","article-title":"REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters","volume":"370","author":"A Baum","year":"2020","journal-title":"Science"},{"key":"ppat.1012171.ref036","first-page":"eabc4776","article-title":"SARS-CoV-2 infection protects against rechallenge in rhesus macaques","author":"A Chandrashekar","year":"2020","journal-title":"Science"},{"key":"ppat.1012171.ref037","first-page":"NEJMoa2024671","article-title":"Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates","author":"KS Corbett","year":"2020","journal-title":"N Engl J Med"},{"issue":"1","key":"ppat.1012171.ref038","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/s12985-020-01396-w","article-title":"Intranasal exposure of African green monkeys to SARS-CoV-2 results in acute phase pneumonia with shedding and lung injury still present in the early convalescence phase","volume":"17","author":"RW Cross","year":"2020","journal-title":"Virol J"},{"issue":"1","key":"ppat.1012171.ref039","doi-asserted-by":"crossref","first-page":"4400","DOI":"10.1038\/s41467-020-18149-6","article-title":"Ocular conjunctival inoculation of SARS-CoV-2 can cause mild COVID-19 in rhesus macaques.","volume":"11","author":"W Deng","year":"2020","journal-title":"Nat Commun."},{"key":"ppat.1012171.ref040","article-title":"Dual-Antigen COVID-19 Vaccine Subcutaneous Prime Delivery With Oral Boosts Protects NHP Against SARS-CoV-2 Challenge.","volume":"12","author":"E Gabitzsch","year":"2021","journal-title":"Front Immunol [Internet]."},{"issue":"5","key":"ppat.1012171.ref041","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1053\/j.gastro.2020.12.001","article-title":"The Gastrointestinal Tract Is an Alternative Route for SARS-CoV-2 Infection in a Nonhuman Primate Model","volume":"160","author":"L Jiao","year":"2021","journal-title":"Gastroenterology"},{"key":"ppat.1012171.ref042","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.virol.2020.12.013","article-title":"Neutralizing antibody-dependent and -independent immune responses against SARS-CoV-2 in cynomolgus macaques","volume":"554","author":"H Ishigaki","year":"2021","journal-title":"Virology"},{"issue":"2","key":"ppat.1012171.ref043","doi-asserted-by":"crossref","first-page":"e0246366","DOI":"10.1371\/journal.pone.0246366","article-title":"Development of a coronavirus disease 2019 nonhuman primate model using airborne exposure.","volume":"16","author":"SC Johnston","year":"2021","journal-title":"PLOS ONE."},{"issue":"593","key":"ppat.1012171.ref044","doi-asserted-by":"crossref","first-page":"eabf1906","DOI":"10.1126\/scitranslmed.abf1906","article-title":"The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates.","volume":"13","author":"BE 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pneumonia severity in cynomolgus monkeys experimentally infected with severe acute respiratory syndrome coronavirus 2 [Internet].","author":"N Nagata","year":"2021"},{"issue":"10","key":"ppat.1012171.ref049","doi-asserted-by":"crossref","first-page":"100420","DOI":"10.1016\/j.xcrm.2021.100420","article-title":"Intradermal-delivered DNA vaccine induces durable immunity mediating a reduction in viral load in a rhesus macaque SARS-CoV-2 challenge model.","volume":"2","author":"A Patel","year":"2021","journal-title":"Cell Rep Med."},{"key":"ppat.1012171.ref050","first-page":"1","article-title":"Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques.","author":"C Shan","year":"2020","journal-title":"Cell Res"},{"issue":"1","key":"ppat.1012171.ref051","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41564-020-00841-4","article-title":"Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets.","volume":"6","author":"DK Singh","year":"2021","journal-title":"Nat Microbiol."},{"key":"ppat.1012171.ref052","first-page":"1","article-title":"Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2","author":"BN Williamson","year":"2020","journal-title":"Nature"},{"key":"ppat.1012171.ref053","first-page":"eabc6284","article-title":"DNA vaccine protection against SARS-CoV-2 in rhesus macaques","author":"J Yu","year":"2020","journal-title":"Science"},{"issue":"1","key":"ppat.1012171.ref054","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41590-020-00835-8","article-title":"Establishment of an African green monkey model for COVID-19 and protection against re-infection","volume":"22","author":"C Woolsey","year":"2021","journal-title":"Nat Immunol"},{"key":"ppat.1012171.ref055","first-page":"1","article-title":"ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques","author":"N van 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