Journal article
Impact of time zero designation on estimated COVID-19 antiviral effectiveness in observational studies
American journal of epidemiology, Vol.195(2), pp.562-568
02/05/2026
DOI: 10.1093/aje/kwaf221
PMID: 41078178
Abstract
In a well-designed clinical trial, time zero is when eligibility is determined, treatment is assigned, follow-up time begins, and each of these elements is aligned. Attaining this alignment can be challenging in observational studies, risking potential bias. We compared the impact of different time zero designations on the estimated effectiveness of nirmatrelvir-ritonavir for COVID-19. We identified US veterans who tested positive for SARS-CoV-2 from April 2022-March 2023 and compared nirmatrelvir-ritonavir versus no treatment using 5 time zero approaches: (1a) test-date (treated) versus test-date (untreated) allowing treatment on days 0-5 with matching, (1b) day 0 only with matching, or (1c) days 0-5 with a clone-censor-weight method; (2) treatment date versus test-date with matching; or (3) treatment date versus matched index date. Thirty-day incidence of hospitalization or death was lower in the nirmatrelvir-ritonavir group than the no treatment group for all time zero approaches. Estimated risk differences (95% CI) were larger for approaches 1a (-2.10% [-2.35 to -1.86]), 1b (-2.03% [-2.40 to -1.84]), and 2 (-2.26% [-2.47 to -2.02]); -1.80% (-1.89 to -1.45) for approach 3; and lowest for approach 1c (-0.95% [-1.11 to -0.75]). Different time zero designations can influence effect estimates and should be carefully considered when designing pharmacoepidemiology studies.
Details
- Title: Subtitle
- Impact of time zero designation on estimated COVID-19 antiviral effectiveness in observational studies
- Creators
- Kristina L Bajema - VA Portland Health Care SystemLei Yan - Yale UniversityKristin Berry - VA Puget Sound Health Care SystemDavid Bui - VA Portland Health Care SystemHung-Mo Lin - Yale UniversityYuan Huang - Yale UniversityYuli Li - Yale UniversityNallakkandi Rajeevan - Yale UniversityMatthew L Maciejewski - Durham VA Medical CenterValerie A Smith - Duke UniversityAmy S B Bohnert - University of MichiganDenise M Hynes - VA Portland Health Care SystemMihaela Aslan - VA Office of Research and DevelopmentGeorge N Ioannou - VA Puget Sound Health Care System
- Resource Type
- Journal article
- Publication Details
- American journal of epidemiology, Vol.195(2), pp.562-568
- DOI
- 10.1093/aje/kwaf221
- PMID
- 41078178
- NLM abbreviation
- Am J Epidemiol
- ISSN
- 1476-6256
- eISSN
- 1476-6256
- Publisher
- Oxford University Press
- Grant note
- US Department of Veterans Affairs Cooperative Studies ProgramDepartment of Health and Human Services, Biomedical Advanced Research and Development Authority: AAI21050 US Food and Drug Administration: 75F40121S30013 VA HSR funding: RCS 10-391, RCS 21-136
This study was supported by the US Department of Veterans Affairs Cooperative Studies Program and funded in part by the Department of Health and Human Services, Biomedical Advanced Research and Development Authority (interagency agreement No. AAI21050) and US Food and Drug Administration (interagency agreement No. 75F40121S30013). M.L.M. and D.N.H. were supported by VA HSR funding (RCS 10-391, RCS 21-136, respectively). These entities had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
- Language
- English
- Electronic publication date
- 10/13/2025
- Date published
- 02/05/2026
- Academic Unit
- Biostatistics
- Record Identifier
- 9985014893802771
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