{"doi":"10.1101/2020.07.17.20155937","title":"Probabilistic approaches for classifying highly variable anti-SARS-CoV-2 antibody responses","abstract":"Abstract Antibody responses vary widely between individuals 1 , complicating the correct classification of low-titer measurements using conventional assay cut-offs. We found all participants in a clinically diverse cohort of SARS-CoV-2 PCR+ individuals ( n =105) – and n= 33 PCR+ hospital staff – to have detectable IgG specific for pre-fusion-stabilized spike (S) glycoprotein trimers, while 98% of persons had IgG specific for the receptor-binding domain (RBD). However, anti-viral IgG levels differed by several orders of magnitude between individuals and were associated with disease severity, with critically ill patients displaying the highest anti-viral antibody titers and strongest in vitro neutralizing responses. Parallel analysis of random healthy blood donors and pregnant women ( n= 1,000) of unknown serostatus, further demonstrated highly variable IgG titers amongst seroconverters, although these were generally lower than in hospitalized patients and included several measurements that scored between the classical 3 and 6SD assay cut-offs. Since the correct classification of seropositivity is critical for individual- and population-level metrics, we compared different probabilistic algorithms for their ability to assign likelihood of past infection. To do this, we used tandem anti-S and -RBD IgG responses from our PCR+ individuals ( n= 138) and a large cohort of historical negative controls ( n= 595) as training data, and generated an equal-weighted learner from the output of support vector machines and linear discriminant analysis. Applied to test samples, this approach provided a more quantitative way to interpret anti-viral titers over a large continuum, scrutinizing measurements overlapping the negative control background more closely and offering a probability-based diagnosis with potential clinical utility. Especially as most SARS-CoV-2 infections result in asymptomatic or mild disease, these platform-independent approaches improve individual and epidemiological estimates of seropositivity, critical for effective management of the pandemic and monitoring the response to vaccination.","journal":"medRxiv","year":2020,"id":122437,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9596,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":559059,"name":"Leo Hanke","orcid":"0000-0001-5514-2418","position":1,"is_corresponding":false},{"id":559060,"name":"Daniel J. 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Grinberg","orcid":"0000-0002-2727-5130","position":5,"is_corresponding":false},{"id":564123,"name":"Mónika Ádori","orcid":null,"position":6,"is_corresponding":false},{"id":559058,"name":"Murray Christian","orcid":"0000-0001-8998-1367","position":7,"is_corresponding":false},{"id":563630,"name":"Laura Perez Vidakovics","orcid":"0000-0003-4283-812X","position":8,"is_corresponding":false},{"id":563631,"name":"Chang-Il Kim","orcid":"0000-0003-4977-4384","position":9,"is_corresponding":false},{"id":564124,"name":"Sharesta Khoenkhoen","orcid":null,"position":10,"is_corresponding":false},{"id":257572,"name":"Pradeepa Pushparaj","orcid":"0000-0002-4012-2198","position":11,"is_corresponding":false},{"id":563632,"name":"Ainhoa Moliner Morro","orcid":"0000-0001-8963-3063","position":12,"is_corresponding":false},{"id":563633,"name":"Marco Mandolesi","orcid":"0000-0003-2927-7831","position":13,"is_corresponding":false},{"id":563634,"name":"Marcus Ahl","orcid":"0000-0003-0034-1078","position":14,"is_corresponding":false},{"id":279515,"name":"Mattias N.E. Forsell","orcid":"0000-0001-6904-742X","position":15,"is_corresponding":false},{"id":563635,"name":"Jonathan M. Coquet","orcid":"0000-0002-5967-4857","position":16,"is_corresponding":false},{"id":482833,"name":"Martin Corcoran","orcid":"0000-0002-2774-0936","position":17,"is_corresponding":false},{"id":559062,"name":"Joanna Rorbach","orcid":"0000-0002-2891-2840","position":18,"is_corresponding":false},{"id":563636,"name":"Joakim Dillner","orcid":"0000-0001-8588-6506","position":19,"is_corresponding":false},{"id":104832,"name":"Gordana Bogdanović","orcid":"0000-0003-1563-8640","position":20,"is_corresponding":false},{"id":559064,"name":"Gerald M. 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