Abstract
<jats:p>Background: Genome wide association studies (GWAS) often fail to identify higher-order epistatic interactions that contribute to complex inheritance patterns of traits and diseases. While machine learning (ML) can capture nonlinear relationships, extracting interpretable insights from these models remains a challenge. We propose a novel tree-based feature engineering framework that uses Classification and Regression Trees (CART) to explicitly encode high order interaction decision paths as dummy variables. We investigate three path-based encoding strategies: (i) all decision paths, (ii) leaf node paths only, and (iii) internal-node paths only. This approach aims to transform complex decision boundaries into discrete features that capture nonlinear interactions that are not readily captured by traditional association models. Results: The framework was evaluated using genetic data for ANCA associated vasculitis (AAV). To manage the high dimensionality of the engineered feature space, we applied a comprehensive suite of ML methods across three tasks: (1) Ensemble Learning (Random Forest, XGBoost, and Gradient Boosting Machine); (2) Decision Tree Analysis (CART); and (3) Regression and Classification Tasks (Regularized Linear Regression/LASSO, Support Vector Machine, and Logistic Regression). Stepwise feature selection and regularization were employed to isolate the most informative interaction patterns. Results indicate that incorporating CART-derived interaction paths, particularly those from high-impact regions of the tree, significantly improves classification accuracy and model interpretability compared to using the original feature space alone. Conclusions: The proposed framework provides a robust, scalable methodology for identifying high-order genetic interactions. By bridging the gap between the predictive power of ensemble ML and the necessity for mechanistic insight, this approach offers a clearer mapping of the combinatorial genetic processes underlying complex diseases. While applied here to AAV, the method is highly adaptable for exploring the genetic architecture of diverse populations and complex traits.</jats:p>