{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T09:22:43Z","timestamp":1766049763066,"version":"3.37.3"},"reference-count":89,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006955","name":"Office of Extramural Research, National Institutes of Health","doi-asserted-by":"publisher","award":["1R43AI069564-01"],"award-info":[{"award-number":["1R43AI069564-01"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Multiple different recombinant and peptide antigens are now available for serodiagnosis of Lyme disease (LD), but optimizing test utilization remains challenging. Since 1995 the Centers for Disease Control and Prevention (CDC) has recommended a 2-tiered serologic approach consisting of a first-tier whole-cell enzyme immunoassay (EIA) for polyvalent antibodies to<jats:italic>Borrelia burgdorferi<\/jats:italic>followed by confirmation of positive or equivocal results by IgG and IgM immunoblots [standard 2-tiered (STT) approach]. Newer modified 2-tiered (MTT) approaches employ a second-tier EIA to detect antibodies to<jats:italic>B<\/jats:italic>.<jats:italic>burgdorferi<\/jats:italic>rather than immunoblotting. We applied modern bioinformatic techniques to a large public database of recombinant and peptide antigen-based immunoassays to improve testing strategy. A retrospective CDC collection of 280 LD samples and 559 controls had been tested using the STT approach as well as kinetic-EIAs for VlsE1-IgG, C6-IgG, VlsE1-IgM, and pepC10-IgM antibodies. When used individually, the cutoff for each kinetic-EIA was set to generate 99% specificity. Utilizing logistic-likelihood regression analysis and receiver operating characteristic (ROC) techniques we determined that VlsE1-IgG, C6-IgG, and pepC10-IgM antibodies each contributed significant diagnostic information; a single-tier diagnostic score (DS) was generated for each sample using a weighted linear combination of antibody levels to these 3 antigens. DS performance was then compared to the STT and to MTT models employing different combinations of kinetic-EIAs. After setting the DS cutoff to match STT specificity (99%), the DS was 22.5% more sensitive than the STT for early-acute-phase disease (95% CI: 11.8% to 32.2%), 16.0% more sensitive for early-convalescent-phase disease (95% CI: 7.2% to 24.7%), and equivalent for detection of disseminated infection. The DS was also significantly more sensitive for early-acute-phase LD than MTT models whose specificity met or exceeded 99%. Prospective validation of this single-tier diagnostic score for Lyme disease will require larger studies using a broader range of potential cross-reacting conditions.<\/jats:p>","DOI":"10.1371\/journal.pone.0253514","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T17:51:23Z","timestamp":1631209883000},"page":"e0253514","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Optimizing use of multi-antibody assays for Lyme disease diagnosis: A bioinformatic approach"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4152-4383","authenticated-orcid":true,"given":"Richard","family":"Porwancher","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Landsberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"issue":"2","key":"pone.0253514.ref001","doi-asserted-by":"crossref","first-page":"616","DOI":"10.3201\/eid2702.202731","article-title":"Estimating the Frequency of Lyme Disease Diagnoses, United States, 2010\u20132018","volume":"27","author":"KJ Kugeler","year":"2021","journal-title":"Emerg Infect Dis"},{"issue":"22","key":"pone.0253514.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss6622a1","article-title":"Surveillance for Lyme Disease\u2014United States, 2008\u20132015","volume":"66","author":"AM Schwartz","year":"2017","journal-title":"MMWR Surveill Summ"},{"issue":"31","key":"pone.0253514.ref003","first-page":"590","article-title":"Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease","volume":"44","author":"Centers for Disease C, Prevention","year":"1995","journal-title":"MMWR Morb Mortal Wkly Rep"},{"issue":"10","key":"pone.0253514.ref004","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.1128\/JCM.01409-14","article-title":"Collection and characterization of samples for establishment of a serum repository for lyme disease diagnostic test development and evaluation","volume":"52","author":"CR Molins","year":"2014","journal-title":"J Clin Microbiol"},{"issue":"8","key":"pone.0253514.ref005","doi-asserted-by":"crossref","DOI":"10.1128\/JCM.00749-18","article-title":"Revisiting the Lyme Disease Serodiagnostic Algorithm: the Momentum Gathers","volume":"56","author":"AR Marques","year":"2018","journal-title":"J Clin Microbiol"},{"issue":"2","key":"pone.0253514.ref006","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1093\/infdis\/174.2.346","article-title":"Serodiagnosis of Lyme disease: accuracy of a two-step approach using a flagella-based ELISA and immunoblotting","volume":"174","author":"BJ Johnson","year":"1996","journal-title":"J Infect Dis"},{"issue":"2","key":"pone.0253514.ref007","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1128\/jcm.33.2.419-427.1995","article-title":"Immunoblot interpretation criteria for serodiagnosis of early Lyme disease","volume":"33","author":"SM Engstrom","year":"1995","journal-title":"J Clin Microbiol"},{"issue":"24","key":"pone.0253514.ref008","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1056\/NEJM200306123482423","article-title":"The presenting manifestations of Lyme disease and the outcomes of treatment","volume":"348","author":"AC Steere","year":"2003","journal-title":"N Engl J Med"},{"issue":"2","key":"pone.0253514.ref009","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.idc.2015.02.001","article-title":"Erythema migrans","volume":"29","author":"RB Nadelman","year":"2015","journal-title":"Infect Dis Clin North Am"},{"issue":"6","key":"pone.0253514.ref010","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1212\/WNL.0000000000011151","article-title":"Clinical Practice Guidelines by the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology: 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease","volume":"96","author":"PM Lantos","year":"2021","journal-title":"Neurology"},{"issue":"5","key":"pone.0253514.ref011","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1001\/archderm.140.5.620","article-title":"How accurate is a clinical diagnosis of erythema chronicum migrans? 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