Background In cluster randomized trials, patients are typically recruited after clusters are randomized, and the recruiters and patients may not be blinded to the assignment. This often leads to differential recruitment and consequently systematic differences in baseline characteristics of the recruited patients between intervention and control arms, inducing post-randomization selection bias. We aim to rigorously define causal estimands in the presence of selection bias. We elucidate the conditions under which standard covariate adjustment methods can validly estimate these estimands. We further discuss the additional data and assumptions necessary for estimating causal effects when such conditions are not met. Methods Adopting the principal stratification framework in causal inference, we clarify there are two average treatment effect (ATE) estimands in cluster randomized trials: one for the overall population and one for the recruited population. We derive analytical formula of the two estimands in terms of principal-stratum-specific causal effects. Furthermore, using simulation studies, we assess the empirical performance of the multivariable regression adjustment method under different data generating processes leading to selection bias. Results When treatment effects are heterogeneous across principal strata, the average treatment effect on the overall population generally differs from the average treatment effect on the recruited population. A naïve intention-to-treat analysis of the recruited sample leads to biased estimates of both average treatment effects. In the presence of post-randomization selection and without additional data on the non-recruited subjects, the average treatment effect on the recruited population is estimable only when the treatment effects are homogeneous between principal strata, and the average treatment effect on the overall population is generally not estimable. The extent to which covariate adjustment can remove selection bias depends on the degree of effect heterogeneity across principal strata. Conclusion There is a need and opportunity to improve the analysis of cluster randomized trials that are subject to post-randomization selection bias. For studies prone to selection bias, it is important to explicitly specify the target population that the causal estimands are defined on and adopt design and estimation strategies accordingly. To draw valid inferences about treatment effects, investigators should (1) assess the possibility of heterogeneous treatment effects, and (2) consider collecting data on covariates that are predictive of the recruitment process, and on the non-recruited population from external sources such as electronic health records.
Generalizability of Randomized Trial Results to Target Populations
