Elucidating some common biases in randomized controlled trials using directed acyclic graphs.

Although the ideal randomized clinical trial is the gold standard for causal inference, real randomized trials often suffer from imperfections that may hamper causal effect estimation. Stating the estimand of interest can help reduce confusion about what is being estimated, but it is often difficult to determine what is and is not identifiable given a trial's specific imperfections. We demonstrate how directed acyclic graphs can be used to elucidate the consequences of common imperfections, such as noncompliance, unblinding, and drop-out, for the identification of the intention-to-treat effect, the total treatment effect and the physiological treatment effect. We assert that the physiological treatment effect is not identifiable outside a trial with perfect compliance and no dropout, where blinding is perfectly maintained.