Enhancing Clinical Classifier Robustness with Deep Representation Learning Based OOD Detection on DNA Methylation Data

DNA methylation (DNAM) array-based tumor classification is a powerful clinical diagnostic tool, but models trained on fixed reference cohorts can produce faulty predictions for tumor types not represented in the training distribution. We propose an end-to-end deep representation learning-based out-of-distribution (OOD) detection framework for DNAm array data. Deep neural network (DNN) classifiers were trained on public sarcoma (SARC) (GSE140686) and brain tumor (BT) (GSE90496) cohorts, and feature vectors were extracted from bottleneck layers. Five OOD methods, including 1dimension (1D)-Subspace Analysis (1D-SSA), K-Nearest Neighbors (KNN), Ridge Regression, Mahalanobis Distance (MD), and Sum of Squared Distances (SSD), were explored with 200 and 500-dimensional embeddings. Spectral discrepancy was used to discriminate in-distribution (IND) from OOD samples. Performance was measured via cross-validation, holdout samples, and an independent clinical dataset. 1D-SSA was the most effective approach. In the sarcoma-IND/brain tumor-OOD setting, the framework achieved an AUROC of 0.975 and True Negative Rate (TNR)@95TPR of 0.930, and an AUROC of 0.9569 and TNR@95TPR of 0.8660 for the brain tumor-IND/sarcoma-OOD setting. On the independent clinical test set, the method yielded a mean AUROC of 0.976, a DE of 0.032, an FPR@95TPR of 0.065, and a TNR@95TPR of 0.935. These results show deep representation-based OOD detection as a practical quality-control layer for clinical-grade methylation-based tumor classification systems.