Confounding due to changing background risk in adaptively randomized trials

Abstract

Background While adaptive trials tend to improve efficiency, they are also subject to some unique biases. Purpose We address a bias that arises from adaptive randomization in the setting of a time trend in disease incidence. Methods We use a potential-outcome model and directed acyclic graphs to illustrate the bias that arises from a changing subject allocation ratio with a concurrent change in background risk. Results In a trial that uses adaptive randomization, time trends in risk can bias the crude effect estimate obtained by naively combining the data from the different stages of the trial. We illustrate how the bias arises from an interplay of departures from exchangeability among groups and the changing randomization proportions. Limitations We focus on risk-ratio and risk-difference analysis. Conclusions Analysis of trials using adaptive randomization should involve attention to or adjustment for possible trends in background risk. Numerous modeling strategies are available for that purpose, including stratification, trend modeling, inverse-probability-of-treatment weighting, and hierarchical regression.