Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analyses are critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies and the pharmaceutical industry use sensitivity models such as return-to-baseline, control-based, and washout imputation, following the ICH E9(R1) guidance. Multiple imputation is popular in sensitivity analyses; however, it may be inefficient and result in an unsatisfying interval estimation by Rubin’s combining rule. We propose distributional imputation in sensitivity analysis, which imputes each missing value by samples from its target imputation model given the observed data. Drawn on the idea of Monte Carlo integration, the distributional imputation estimator solves the mean estimating equations of the imputed dataset. It is fully efficient with theoretical guarantees. Moreover, we propose weighted bootstrap to obtain a consistent variance estimator, taking into account the variabilities due to model parameter estimation and target parameter estimation. The superiority of the distributional imputation framework is validated in the simulation study and an antidepressant longitudinal clinical trial.
In causal inference problems, one is often tasked with estimating causal effects which are analytically intractable functionals of the data‐generating mechanism. Relevant settings include estimating intention‐to‐treat effects in longitudinal problems with missing data or computing direct and indirect effects in mediation analysis. One approach to computing these effects is to use the
- NSF-PAR ID:
- 10397038
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Biometrics
- Volume:
- 78
- Issue:
- 3
- ISSN:
- 0006-341X
- Format(s):
- Medium: X Size: p. 1001-1017
- Size(s):
- ["p. 1001-1017"]
- Sponsoring Org:
- National Science Foundation
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