PT  - JOURNAL ARTICLE
AU  - Joseph A. Lewnard
AU  - Christine Tedijanto
AU  - Benjamin J. Cowling
AU  - Marc Lipsitch
TI  - Measurement of Vaccine Direct Effects under the Test-Negative Design
AID  - 10.1101/237503
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 237503
4099  - http://biorxiv.org/content/early/2018/07/30/237503.short
4100  - http://biorxiv.org/content/early/2018/07/30/237503.full
AB  - Test-negative designs are commonplace in assessments of influenza vaccination effectiveness, estimating this value from the exposure odds ratio (OR) of vaccination among individuals treated for acute respiratory illness who test positive for influenza virus infection. This approach is widely believed to recover the vaccine direct effect by correcting for differential healthcare-seeking behavior among vaccinated and unvaccinated persons. However, the relation of the measured OR to true vaccine effectiveness is poorly understood. We derive the OR under circumstances of real-world test-negative studies. The OR recovers the vaccine direct effect when two conditions are met: (1) individuals’ vaccination decisions are uncorrelated with exposure or susceptibility to the test-positive or test-negative conditions, and (2) vaccination confers “all-or-nothing” protection (whereby certain individuals have no protection while others are perfectly protected). Biased effect size estimates arise if either condition is unmet. Such bias may suggest misleading associations of vaccine effectiveness with time since vaccination or the force of infection of influenza. The test-negative design may also fail to correct for differential healthcare-seeking behavior among vaccinated and unvaccinated persons without stringent criteria for enrollment and testing. Our findings demonstrate a need to reassess how data from test-negative studies can inform policy decisions.AbbreviationsARI: Acute respiratory illnessDAG: Directed acyclic graphLAIV: Live attenuated influenza vaccineOR: Odds ratioVE: Vaccine effectiveness (used interchangeably with vaccine efficacy in this context as the estimand of both observational and randomized studies, and defined as the causal effect of the vaccine on susceptibility of individuals to infection and/or disease)