LAUSR

In the test negative design, routine testing at healthcare facilities is leveraged to estimate the effectiveness of an intervention such as a vaccine. The odds of vaccination for individuals who test positive for a target pathogen is compared to the odds of vaccination for individuals who test negative for that pathogen, adjusting for key confounders. The design is rapidly growing in popularity, but many open questions remain about its properties. In this paper, we examine temporal confounding by generalizing derivations to allow for time-varying vaccine status, including out of season controls, and open populations. We confirm that calendar time is an important confounder when vaccine status varies during the study. We demonstrate that, where time is not a confounder, including out of season controls can improve precision. We generalize these results to open populations. We use our theoretical findings to interpret three recent papers utilizing the test negative design. Through careful examination of the theoretical properties of this study design, we provide key insights that can directly inform the implementation and analysis of future test negative studies.