Impute-then-exclude versus exclude-then-impute: Lessons when imputing a variable used both in cohort creation and as an independent variable in the analysis model.

We examined the setting in which a variable that is subject to missingness is used both as an inclusion/exclusion criterion for creating the analytic sample and subsequently as the primary exposure in the analysis model that is of scientific interest. An example is cancer stage, where patients with stage IV cancer are often excluded from the analytic sample, and cancer stage (I to III) is an exposure variable in the analysis model. We considered two analytic strategies. The first strategy, referred to as "exclude-then-impute," excludes subjects for whom the observed value of the target variable is equal to the specified value and then uses multiple imputation to complete the data in the resultant sample. The second strategy, referred to as "impute-then-exclude," first uses multiple imputation to complete the data and then excludes subjects based on the observed or filled-in values in the completed samples. Monte Carlo simulations were used to compare five methods (one based on "exclude-then-impute" and four based on "impute-then-exclude") along with the use of a complete case analysis. We considered both missing completely at random and missing at random missing data mechanisms. We found that an impute-then-exclude strategy using substantive model compatible fully conditional specification tended to have superior performance across 72 different scenarios. We illustrated the application of these methods using empirical data on patients hospitalized with heart failure when heart failure subtype was used for cohort creation (excluding subjects with heart failure with preserved ejection fraction) and was also an exposure in the analysis model.