Missing Data in OHCA Registries: How Multiple Imputation Methods Affect Research Conclusions—Paper II

<b>Background/Objectives:</b> Missing data in clinical observational studies, such as out-of-hospital cardiac arrest (OHCA) registries, can compromise statistical validity. Single imputation methods are simple alternatives to complete-case analysis (CCA) but do not account for imputation uncertainty. Multiple imputation (MI) is the standard for handling missing-at-random (MAR) data, yet its implementation remains challenging. This study evaluated the performance of MI in association analysis compared with CCA and single imputation methods. <b>Methods:</b> Using a simulation framework with real-world Singapore OHCA registry data (N = 13,274 complete cases), we artificially introduced 20%, 30%, and 40% missingness under MAR. MI was implemented using predictive mean matching (PMM), random forest (RF), and classification and regression trees (CART) algorithms, with 5-20 imputations. Performance was assessed based on bias and precision in a logistic regression model evaluating the association between alert issuance and bystander CPR. <b>Results:</b> CART outperformed PMM, providing more accurate <i>β</i> coefficients and stable CIs across missingness levels. Although K-Nearest Neighbours (KNN) produced similar point estimates, it underestimated imputation uncertainty. PMM showed larger bias, wider and less stable CIs, and in some settings performed similarly to CCA. MI methods produced wider CIs than single imputation, appropriately capturing imputation uncertainty. Increasing the number of imputations had minimal impact on point estimates but modestly narrowed CIs. <b>Conclusions:</b> MI performance depends strongly on the chosen algorithm. CART and RF methods offered the most robust and consistent results for OHCA data, whereas PMM may not be optimal and should be selected with caution. MI using tree-based methods (CART/RF) remains the preferred strategy for generating reliable conclusions in OHCA research.