Test-negative designs with various reasons for testing: statistical bias and solution

Test-negative designs are widely used for post-market evaluation of vaccine effectiveness. Different from classical test-negative designs where only healthcare-seekers with symptoms are included, recent test-negative designs have involved individuals with various reasons for testing, especially in an outbreak setting. While including these data can increase sample size and hence improve precision, concerns have been raised about whether they will introduce bias into the current framework of test-negative designs, thereby demanding a formal statistical examination of this modified design. In this article, using statistical derivations, causal graphs, and numerical simulations, we show that the standard odds ratio estimator may be biased if various reasons for testing are not accounted for. To eliminate this bias, we identify three categories of reasons for testing, including symptoms, disease-unrelated reasons, and case contact tracing, and characterize associated statistical properties and estimands. Based on our characterization, we propose stratified estimators that can incorporate multiple reasons for testing to achieve consistent estimation and improve precision by maximizing the use of data. The performance of our proposed method is demonstrated through simulation studies.