Imputation of Missing Data for Time-to-Event Endpoints Using Retrieved Dropouts.

Abstract

We have explored several statistical approaches to impute missing time-to-event data that arise from outcome trials with relatively long follow-up periods. Aligning with the primary estimand, such analyses evaluate the robustness of results by imposing an assumption different from censoring at random (CAR). Although there have been debates over which assumption and which method is more appropriate to be applied to the imputation, we propose to use the collection of retrieved dropouts as the basis of missing data imputation. As retrieved dropouts share a similar disposition, such as treatment discontinuation, with subjects who have missing data, they can reasonably be assumed to characterize the distribution of time-to-event among subjects with missing data. In terms of computational intensity and robustness to violation of underlying distributional assumption, we have compared parametric approaches via MCMC or MLE multivariate sampling procedures to a non-parametric bootstrap approach with respect to baseline hazard function. Each of these approaches follows a process of multiple imputation ("proper imputations"), analysis of complete datasets, and final combination. The type-I error, and power rates are examined under a wide range of scenarios to inform the performance characteristics. A subset of a real unblinded phase III CVOT is used to demonstrate the application of the proposed approaches, compared to the Cox proportional hazards model and jump-to-reference multiple imputation.