Estimating direct effects in cohort and case-control studies.

Estimating the effect of an exposure on an outcome, other than through some given mediator, requires adjustment for all risk factors of the mediator that are also associated with the outcome. When these risk factors are themselves affected by the exposure, then standard regression methods do not apply. In this article, I review methods for accommodating this and discuss their limitations for estimating the controlled direct effect (ie, the exposure effect when controlling the mediator at a specified level uniformly in the population). In addition, I propose a powerful and easy-to-apply alternative that uses G-estimation in structural nested models to address these limitations both for cohort and case-control studies.