855Multiple Imputation in the Context of Case-Cohort Studies: Simulation and Case Study

Abstract Background Multiple imputation (MI) is commonly used to address missing data in epidemiological studies, but valid use requires compatibility between the imputation and analysis models. Case-cohort studies use unequal sampling probabilities for cases and controls which are often accounted for during analyses through inverse probability weighting (IPW). It is unclear how to apply MI for missing covariates while achieving compatibility in this setting. Methods A simulation study was conducted with missingness in two covariates, motivated by a case-cohort investigation within the Barwon Infant Study. MI methods considered involved including interactions between the outcome (as a proxy for weights) and analysis variables, stratification by weights, and ignoring weights, within the context of an IPW analysis. Factors such as the target estimand, proportion of incomplete observations, missing data mechanism and subcohort selection probabilities were varied to assess performance of MI methods. Results There was similar performance in terms of bias and efficiency across the MI methods, with expected improvements compared to IPW applied to the complete cases. Precision tended to decrease as the subcohort selection probability decreased. Similar results were observed irrespective of the proportion of incomplete cases. Conclusions Our results suggest that it makes little difference how weights are incorporated in the MI model in the analysis of case-cohort studies, potentially due to only two weight classes in this setting. Key messages If and how the weights are incorporated in the imputation model may have little impact in the analysis of case-cohort studies with incomplete covariates