Multiple imputation methods for treatment noncompliance and nonresponse in randomized clinical trials

Biometrics. 2009 Mar;65(1):88-95. doi: 10.1111/j.1541-0420.2008.01023.x. Epub 2008 Apr 4.


Randomized clinical trials are a powerful tool for investigating causal treatment effects, but in human trials there are oftentimes problems of noncompliance which standard analyses, such as the intention-to-treat or as-treated analysis, either ignore or incorporate in such a way that the resulting estimand is no longer a causal effect. One alternative to these analyses is the complier average causal effect (CACE) which estimates the average causal treatment effect among a subpopulation that would comply under any treatment assigned. We focus on the setting of a randomized clinical trial with crossover treatment noncompliance (e.g., control subjects could receive the intervention and intervention subjects could receive the control) and outcome nonresponse. In this article, we develop estimators for the CACE using multiple imputation methods, which have been successfully applied to a wide variety of missing data problems, but have not yet been applied to the potential outcomes setting of causal inference. Using simulated data we investigate the finite sample properties of these estimators as well as of competing procedures in a simple setting. Finally we illustrate our methods using a real randomized encouragement design study on the effectiveness of the influenza vaccine.

MeSH terms

  • Causality
  • Cross-Over Studies
  • Humans
  • Influenza Vaccines / therapeutic use
  • Patient Compliance / statistics & numerical data*
  • Randomized Controlled Trials as Topic / statistics & numerical data*
  • Treatment Outcome


  • Influenza Vaccines