Explainable Artificial Intelligence Unravels the Possible Distinct Roles of VKORC1 and CYP2C9 in Predicting Warfarin Anticoagulation Control

<b>Background:</b> Warfarin pharmacogenomics is critical due to its narrow therapeutic index and significant interpatient variability. While machine learning (ML) can predict anticoagulation control status (ACS), its "black-box" nature limits clinical translatability. Explainable Artificial Intelligence (XAI) addresses this by providing interpretable insights. This study applied ML and XAI to a warfarin pharmacogenomic dataset to predict poor ACS and explain model decisions. <b>Methods:</b> A post hoc analysis was conducted on a cross-sectional dataset of 232 patients receiving warfarin for ≥6 months. Data included age, gender, interacting drugs, SAMe-TT2R2 score, and genotypes for CYP2C9, VKORC1, and CYP4F2. Poor ACS was defined as time in therapeutic range (TTR) < 70%. The dataset was split into training (70%) and testing (30%) cohorts. Three models, Random Forest, XGBoost, and Logistic Regression, were developed and evaluated using AUC-ROC, sensitivity, and specificity. XAI techniques, including permutation importance and SHapley Additive exPlanations (SHAP), were employed for global and local interpretability. <b>Results:</b> Of 232 patients, 141 (60.8%) had poor ACS. XGBoost and Random Forest demonstrated comparable predictive accuracy (AUC-ROC: 0.67), outperforming Logistic Regression. Sensitivity was 0.83 and 0.79 for XGBoost and Random Forest, respectively. However, specificity was modest for both ensemble methods (Random Forest: 0.48; XGBoost: 0.41) and extremely low for Logistic Regression (0.04), indicating poor discrimination, particularly for identifying patients with adequate anticoagulation control. Globally, important predictors included the age, SAMe-TT2R2 score, CYP2C9 (*2/*2), female gender, and VKORC1 (C/T). XAI revealed predictions were primarily driven by VKORC1, CYP4F2, SAMe-TT2R2 scores, and drug interactions. Concordance between XAI predictions and actual ACS was 78% for adequate and 88.6% for poor ACS. SHAP analysis showed VKORC1 provided a stable risk signal (mean absolute SHAP: 1.44 ± 0.49 in concordant cases), while CYP2C9 was a high-variance, high-impact driver of discordance (mean SHAP: 3.44 ± 3.79 in discordant cases). <b>Conclusions:</b> ML models, particularly ensemble methods, show modest ability to predict poor warfarin control with limited ability to correctly identify patients with adequate control from our dataset. XAI transforms these models into interpretable tools, with SHAP analysis attributing predictions to specific genetic and clinical features. While predictive accuracy remains modest, this approach enhances transparency and provides a foundation for generating hypotheses that may ultimately support clinical decision-making in pharmacogenomic-guided warfarin therapy.