Basic principles of test-negative design in evaluating influenza vaccine effectiveness

Based on the unique characteristics of influenza, the concept of “monitoring” influenza vaccine effectiveness (VE) across the seasons using the same observational study design has been developed. In recent years, there has been a growing number of influenza VE reports using the test-negative design, which can minimize both misclassification of diseases and confounding by health care-seeking behavior. Although the test-negative designs offer considerable advantages, there are some concerns that widespread use of the test-negative design without knowledge of the basic principles of epidemiology could produce invalid findings. In this article, we briefly review the basic concepts of the test-negative design with respect to classic study design such as cohort studies or case-control studies. We also mention selection bias, which may be of concern in some countries where rapid diagnostic testing is frequently used in routine clinical practices, as in Japan.