Evaluation of multiple imputation approaches for handling missing covariate information in a case-cohort study with a binary outcome

BACKGROUND: In case-cohort studies a random subcohort is selected from the inception cohort and acts as the sample of controls for several outcome investigations. Analysis is conducted using only the cases and the subcohort, with inverse probability weighting (IPW) used to account for the unequal sampling probabilities resulting from the study design. Like all epidemiological studies, case-cohort studies are susceptible to missing data. Multiple imputation (MI) has become increasingly popular for addressing missing data in epidemiological studies. It is currently unclear how best to incorporate the weights from a case-cohort analysis in MI procedures used to address missing covariate data. METHOD: A simulation study was conducted with missingness in two covariates, motivated by a case study within the Barwon Infant Study. MI methods considered were: using the outcome, a proxy for weights in the simple case-cohort design considered, as a predictor in the imputation model, with and without exposure and covariate interactions; imputing separately within each weight category; and using a weighted imputation model. These methods were compared to a complete case analysis (CCA) within the context of a standard IPW analysis model estimating either the risk or odds ratio. The strength of associations, missing data mechanism, proportion of observations with incomplete covariate data, and subcohort selection probability varied across the simulation scenarios. Methods were also applied to the case study. RESULTS: There was similar performance in terms of relative bias and precision with all MI methods across the scenarios considered, with expected improvements compared with the CCA. Slight underestimation of the standard error was seen throughout but the nominal level of coverage (95%) was generally achieved. All MI methods showed a similar increase in precision as the subcohort selection probability increased, irrespective of the scenario. A similar pattern of results was seen