A stacked approach for chained equations multiple imputation incorporating the substantive model.

Multiple imputation by chained equations (MICE) has emerged as a popular approach for handling missing data. A central challenge for applying MICE is determining how to incorporate outcome information into covariate imputation models, particularly for complicated outcomes. Often, we have a particular analysis model in mind, and we would like to ensure congeniality between the imputation and analysis models. We propose a novel strategy for directly incorporating the analysis model into the handling of missing data. In our proposed approach, multiple imputations of missing covariates are obtained without using outcome information. We then utilize the strategy of imputation stacking, where multiple imputations are stacked on top of each other to create a large data set. The analysis model is then incorporated through weights. Instead of applying Rubin's combining rules, we obtain parameter estimates by fitting a weighted version of the analysis model on the stacked data set. We propose a novel estimator for obtaining standard errors for this stacked and weighted analysis. Our estimator is based on the observed data information principle in Louis' work and can be applied for analyzing stacked multiple imputations more generally. Our approach for analyzing stacked multiple imputations is the first method that can be easily applied (using R package StackImpute) for a wide variety of standard analysis models and missing data settings.

Multiple imputation for cause-specific Cox models: Assessing methods for estimation and prediction.

In studies analyzing competing time-to-event outcomes, interest often lies in both estimating the effects of baseline covariates on the cause-specific hazards and predicting cumulative incidence functions. When missing values occur in these baseline covariates, they may be discarded as part of a complete-case analysis or multiply imputed. In the latter case, the imputations may be performed either compatibly with a substantive model pre-specified as a cause-specific Cox model [substantive model compatible fully conditional specification (SMC-FCS)], or approximately so [multivariate imputation by chained equations (MICE)]. In a large simulation study, we assessed the performance of these three different methods in terms of estimating cause-specific regression coefficients and predicting cumulative incidence functions. Concerning regression coefficients, results provide further support for use of SMC-FCS over MICE, particularly when covariate effects are large and the baseline hazards of the competing events are substantially different. Complete-case analysis also shows adequate performance in settings where missingness is not outcome dependent. With regard to cumulative incidence prediction, SMC-FCS and MICE are performed more similarly, as also evidenced in the illustrative analysis of competing outcomes following a hematopoietic stem cell transplantation. The findings are discussed alongside recommendations for practising statisticians.