A Post-Hoc Interpretable Ensemble Model to Feature Effect Analysis in Warfarin Dose Prediction for Chinese Patients

To interprete the importance of clinical features and genotypes for warfarin daily dose prediction, we developed a post-hoc interpretable framework based on an ensemble predictive model. This framework includes permutation importance for global interpretation and local interpretable model-agnostic explanation (LIME) and shapley additive explanations (SHAP) for local explanation. The permutation importance globally ranks the importance of features on the whole data set. This can guide us to build a predictive model with less variables and the complexity of final predictive model can be reduced. LIME and SHAP together explain how the predictive model give the predicted dosage for specific samples. This help clinicians prescribe accurate doses to patients using more effective clinical variables. Results showed that both the permutation importance and SHAP demonstrated that VKORC1, age, serum creatinine (SCr), left atrium (LA) size, CYP2C9 and weight were the most important features on the whole data set. In specific samples, both SHAP and LIME discovered that in Chinese patients, wild-type VKORC1-AA, mutant-type CYP2C9*3, age over 60, abnormal LA size, SCr within the normal range, and using amiodarone definitely required dosage reduction, whereas mutant-type VKORC1-AG/GG, small age, SCr out of normal range, normal LA size, diabetes and heavy weight required dosage enhancementt.