The healthy user effect in pharmacoepidemiology

The healthy user effect is a well-recognized bias in the field of pharmacoepidemiology and can be expected to overstate the effect of a preventive intervention when comparing long term users or "adherers" to non-users. Similar to the healthy worker effect observed in occupational epidemiology, the healthy user effect can be separated into a healthy initiator effect (baseline confounding) and a healthy adherer effect (selection bias). Restriction approaches and new user designs that implicitly condition on the indication and, similar healthy behaviors or health status can often mitigate the healthy initiator effect (confounding) or healthy adherer effect (selection bias) at the start of a study. Addressing the healthy adherer effect due to continued conditioning on adherence over the duration of a study is more challenging as methods to mitigate it require the ability to predict adherence, which is often difficult using databases common in pharmacoepidemiologic research. Here, we describe the healthy user effect, with supporting examples, and describe study design approaches available to pharmacoepidemiologists to mitigate the potential for bias.