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Improving Assessment of Vaccine Effectiveness by Coupling Test-negative Design Studies with Survival Models

Year: 2026
Type: article
Abstract: The test-negative design (TND) has become a widely used observational study design for evaluating vaccine effectiveness, especially during the COVID-19 pandemic. Traditionally, TND has been viewed as a variant of the case-control study and largely limited to use with logistic regression models. In this paper, we first establish that TND can be framed as a special case of a cohort study, thereby opening the door to a wider range of analytical approaches. We then introduce the Prentice, Williams, and Peterson gap-time (PWP-GT) frailty model as a novel method for analyzing TND data, accounting for recurrent infections and time-dependent vaccination status. Through extensive simulation studies, we demonstrate that the proposed model outperforms conventional models commonly applied in TND-based vaccine effectiveness studies. Finally, we apply our method to data from the National COVID Cohort Collaborative, estimating the effectiveness of full and booster doses of Pfizer's COVID-19 vaccines against both initial infection and reinfection during the Omicron variant circulation period in a real-world setting.
Source: Epidemiology
DOI: 10.1097/ede.0000000000001972
Language: English
Open Access status: green
Funders: Bill and Melinda Gates Foundation, Yale University, University of Southern California, Children's Hospital of Philadelphia, University of Nebraska Medical Center, Vanderbilt University, University of Pennsylvania, Emory University, NYU Langone Medical Center, University of Wisconsin-Madison, Northwestern University, George Washington University, Wake Forest University, Cincinnati Children's Hospital Medical Center, Children's Hospital Colorado, Vanderbilt Institute for Clinical and Translational Research, Harvard Catalyst, Loyola University Chicago, University of Washington, Johns Hopkins University, University of Pittsburgh, University of Oklahoma, Institute for Translational Medicine and Therapeutics, Institute of Clinical and Translational Sciences, Georgetown University, University of Rochester, Dartmouth College, Pennsylvania State University, Rush University, University of South Carolina, Virginia Commonwealth University, Southern California Clinical and Translational Science Institute, West Virginia University, Montana State University, MedStar Health Research Institute, Georgetown-Howard Universities Center for Clinical and Translational Science, NorthShore University HealthSystem, Vanderbilt University Medical Center, Institute of Translational Health Sciences, Georgia Clinical and Translational Science Alliance, Penn State Clinical and Translational Science Institute, Children's National Hospital, Louisiana Clinical and Translational Science Center, Ochsner Health, West Virginia Clinical and Translational Science Institute, Stony Brook University, National Institutes of Health, Institute for Clinical and Translational Research, University of Wisconsin, Madison, University of California, Los Angeles, Weill Cornell Medical College, University of California, Davis, Oregon Clinical and Translational Research Institute, University of California, San Diego, University of Oklahoma Health Sciences Center, University of California, San Francisco, University of California, Irvine, Center for Clinical and Translational Research, School of Medicine, Indiana University, Center for Clinical and Translational Science, Mayo Clinic, Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston, Irving Medical Center, Columbia University, Translational Research Institute, University of Arkansas for Medical Sciences, South Carolina Clinical and Translational Research Institute, Medical University of South Carolina, Clinical and Translational Science Institute, University of Florida, Clinical and Translational Science Center, University of New Mexico, National Institute of General Medical Sciences, Institute for Integration of Medicine and Science, Colorado Clinical and Translational Sciences Institute, Institute for Clinical and Translational Science, University of California, Irvine, Wake Forest Clinical and Translational Science Institute, Wake Forest School of Medicine, Accelerated Innovation Research Initiative Turning Top Science and Ideas into High-Impact Values
Awards: G1003362385, G1034546755, G1110702752, G112449207, G1133842343, Center for Clinical and Translational Sciences (CCTS), G1198907661, The OSU Center for Clinical and Translational Science: Advancing Today's Discoveries to Improve Health, G1576582908, University of Massachusetts Center for Clinical and Translational Science, G1699415014, G171052541, G1717162763, G1756254663, G1843193268, G1843992630, Wake Forest Clinical and Translational Science Award, Together: Transforming and Translating Discovery to Improve Health, Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS), G2008237588, Duke CTSA, G2101559773, G210617772, G2118698080, G213118816, G2152875133, G2190116832, G2191929784, G2202983096, G2228636686, G235420648, G237123860, G2508192175, G2529322290, G2592540264, G2610614086, G2615776415, G2635992203, G2714998049, G2761940466, Center for Clinical and Translational Science, G2922236389, G297095765, The Harvard Clinical and Translational Science Center, Stanford Center for Clinical & Translational Education and Research (Spectrum), G3015141988, G3075846822, G3137464953, G3187757946, UNM HSC Clinical and Translational Science Center, University of Minnesota Clinical and TranslationalmScience Institute (UMN CTSI), G3439874718, G3455473179, G3534013791, G3667826151, Institute for Clinical and Translational Science, Tufts Clinical and Translational Science Institute, G4091522973, G432001851, G4410787187, The integrated Translational Health Research Institute of Virginia (iTHRIV): Using Data to Improve Health, MSHS Translational Science Hub, A National Center for Digital Health Informatics Innovation, G476308836, Northwestern University Clinical and Translational Science Institute (NUCATS), G4823677270, G4851974581, G4950870472, G5031973872, Center for Clinical and Translational Research, G5086723997, G5258278944, Center for Clinical and Translational Science and Training, G536197267, G5409860367, G5430408733, G55941084, Miami Clinical and Translational Science Institute, G584478153, G5849810213, Expanding Translational Research in Arkansas, Utah Center for Clinical and Translational Science, G6036981074, G6090519289, G6107751520, G614564937, G625544220, G6292001676, American Indian - Alaska Native Clinical and Translational Research Center (AI-AN CTRC), G6576913434, Clinical and Translational Science Award, North Carolina Translational and Clinical Science Institute (NC TraCS), Sage Bionetworks - to evaluate the signs and symptoms of COVID-19 in a data-consortium approach to inform better clinical decision making for diagnosis, G6720719670, G6831857590, G687203789, G6979210571, Michigan Institute for Clinical and Health Research (MICHR), G707880362, Hispanic Alliance for Clinical and Translational Research (Alliance), G7406577712, G7473568262, Scripps Translational Science Institute, New Jersey Alliance for Clinical Translational Science: NJ ACTS, G761346317, Clinical and Translational Science Institute at Childrens National, G7695494419, G7707125228, The University of Rochester Clinical and Translational Science Award Hub, Indiana Clinical and Translational Sciences Institute, G7768549844, G7818101325, Clinical and Translational Science Award, Clinical and Translational Science Award, Johns Hopkins Institute for Clinical and Translational Research, The University of Iowa Clinical and Translational Science Award, University of Buffalo Clinical and Translational Science Institute, Institute for Integration of Medicine & Science: A Partnership to Improve Health, G8013765, G8021374757, Colorado Clinical and Transational Sciences Institute, G8241404708, South Carolina Clinical & Translational Research Institute (SCTR), Boston University Clinical and Translational Science Institute, G8536079613, Clinical and Translational Science Collaborative of Cleveland, UC San Diego Clinical and Translational Research Institute, G8908676624, Frontiers Clinical and Translational Science Institute at the University of Kansas, Clinical and Translational Science Collaborative of Northern Ohio, Catalyzing Linkages for Everyone's Health (CLE Health), Advance Clinical and Translational Research (Advance-CTR), Clinical and Translational Science Award, University of Pittsburgh Clinical and Translational Science Institute, UC Davis Clinical and Translational Science Center, Northern New England Clinical and Translational Research Network, University of Wisconsin Institute for Clinical and Translational Research, Clinical and Translational Science Center, Mayo Clinic Center for Clinical and Translational Science (CCaTS), West Virginia Clinical and Translational Science Institute: A Statewide Organization Building Research Excellence and Engaging Communities to Improve Health, Vanderbilt Institute for Clinical and Translational Research (VICTR), Oregon Clinical and Translational Research Institute, Clinical and Translational Science Award, Oklahoma Shared Clinical and Translational Resources, Great Plains IDeA-CTR, Delaware Clinical and Translational Research ACCEL Program, Penn State Clinical and Translational Science Institute, Southern California Clinical and Translational Science Institute, Institutional Clinical and Translational Science Award, Washington University Institute of Clinical and Translational Sciences, Mississippi Center for Clinical and Translational Research, The Institute for Translational Medicine, Georgia Clinical & Translational Science Alliance (Georgia CTSA), Institute of Translational Health Sciences, Louisiana Clinical and Translational Science Center, Yale Clinical and Translational Science Award, Kentucky Center for Clinical and Translational Science, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success, UCLA Clinical and Translational Science Institute, Clinical and Translational Science Institute, UTMB Clinical and Translational Science Award
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