Disproportionality Analysis and Causal Inference in Drug Safety.

Disproportionality analysis is a method of safety signal detection based on quantitative analysis of spontaneous reports of adverse events. Disproportionality findings are often presented in medical publications as real-world evidence on drug safety. In this paper, we review theoretical properties of disproportionality analysis in the framework of causal inference theory. We show that measures of disproportionality can approximate the causal rate ratio for a specific drug-event combination when the study drug and the set of comparator drugs satisfy all of the following conditions: (1) there is no uncontrolled confounding for the drug-event association of interest, (2) under-reporting for the event of interest is either absent or has the same relative magnitude for the study drug and for the comparator drugs, and (3) reporting rates for all adverse events combined are the same for the study drug and for the comparator drug set. Because these conditions are typically not even approximately satisfied in practice, the overwhelming majority of disproportionality hits represent statistical noise rather than causal associations. Researchers choosing to report disproportionality findings in publications should explicitly acknowledge all key assumptions and the exploratory nature of this data-mining technique.