The test-negative design: Opportunities, limitations and biases

The purpose of this paper is to investigate how to interpret the outcome of a test-negative design study. We does so by systematically reviewing the properties of the design in relation to its potential applications. We first argue that the application of the design does not depend on certain assumptions (as is sometimes articulated in the literature), which may open new opportunities for using the design. Then, we relate a number of limitations of the design. The design cannot be used for studying the mortality effects of vaccines and is problematic for studies into the effect on hospitalization. The vaccine's effectiveness on the transmission of viruses is also potentially problematic, depending very much on the characteristics of the tests. The implication of our findings is that the test-negative designs can, at best, be seen as an indication of effectiveness in highly idealized situations that are often far away from reality.