Imputation and Missing Indicators for handling missing data in the development and implementation of clinical prediction models: a simulation study

Background: Existing guidelines for handling missing data are generally not consistent with the goals of prediction modelling, where missing data can occur at any stage of the model pipeline. Multiple imputation (MI), often heralded as the gold standard approach, can be challenging to apply in the clinic. Clearly, the outcome cannot be used to impute data at prediction time. Regression imputation (RI) may offer a pragmatic alternative in the prediction context, that is simpler to apply in the clinic. Moreover, the use of missing indicators can handle informative missingness, but it is currently unknown how well they perform within CPMs. Methods: We performed a simulation study where data were generated under various missing data mechanisms to compare the predictive performance of CPMs developed using both imputation methods. We consider deployment scenarios where missing data is permitted/prohibited, and develop models that use/omit the outcome during imputation and include/omit missing indicators. Results: When complete data must be available at deployment, our findings were in line with widely used recommendations; that the outcome should be used to impute development data under MI, yet omitted under RI. When imputation is applied at deployment, omitting the outcome from the imputation at development was preferred. Missing indicators improved model performance in some specific cases, but can be harmful when missingness is dependent on the outcome. Conclusion: We provide evidence that commonly taught principles of handling missing data via MI may not apply to CPMs, particularly when data can be missing at deployment. In such settings, RI and missing indicator methods can (marginally) outperform MI. As shown, the performance of the missing data handling method must be evaluated on a study-by-study basis, and should be based on whether missing data are allowed at deployment.