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

NA methylation profiling has become a powerful approach for central nervous system (CNS) tumor classification, yet important challenges remain regarding cross-cohort transferability, methodological correctness, and robust multiclass evaluation. In this work, we propose a novel and methodologically rigorous machine-learning approach for methylation-based CNS tumor classification that combines Sparse Random Projection for dimensionality reduction with multinomial logistic regression for classification. We evaluate the proposed approach in the same general experimental setting established by a widely used reference classifier. On the 2,801-sample reference cohort, our method achieves a mean accuracy of 96% under stratified 3-fold cross-validation. On the independent 1,104-sample clinical evaluation cohort, it reaches 86% accuracy at the 91-class level and 93% when predictions are evaluated at the methylation class family level. These results improve upon the corresponding state-of-the-art reference figures of 82% class-level concordance and 88% family-level concordance, yielding absolute gains of approximately 4 and 5 percentage points, respectively. This improvement is clinically relevant: in a diagnostic setting, a 5-point increase in correct tumor classification can directly affect cancer subtype assignment and, in turn, influence treatment selection and downstream clinical decision-making. Our results show that the proposed model, grounded in stronger methodological practice in machine learning, consistently outperforms the previous state of the art across evaluation settings and can materially improve the reliability of CNS tumor classification.

Out-of-Distribution (OoD) detection aims to justify whether a given sample is from the training distribution of the classifier-under-protection, i.e., In-Distribution (InD), or from an unknown out distribution. Recent researches have leveraged Diffusion Models (DMs) for OoD detection due to their powerful distribution modeling capability. Given an input image, an InD-pretrained DM produces a corresponding InD-aligned counterpart, which serves as a generative reference for comparison. However, existing DM-based methods typically assess this underlying discrepancy through visual-level distances in the raw image space, which may be misaligned with the distributional discrepancy relevant to OoD detection. In this work, we investigate the fundamentals of discrepancy assessment in DM-based OoD detection, asking how the discrepancy between an input and its DM-generated counterpart should be formulated, and in which representation spaces and with which metrics it should be measured. To this end, we propose to assess the discrepancy in a classifier-relative manner by exploiting the representation spaces of the classifier-under-protection, whose training on InD data encodes rich task-relevant InD knowledge. In particular, we quantify two types of discrepancy: feature-level covariate discrepancy in deep feature representations and logit-level concept discrepancy in output logits, enabling effective differentiation between InD and OoD samples. Moreover, a subspace-based strategy is devised to refine representations of the DM generation to promote discrepancy assessment. Together, these designs form our novel detection framework, namely DDR. Extensive experiments on the challenging large-scale ImageNet-1K dataset demonstrate the superior detection performance of DDR over both DM-based and non-DM-based methods.

Out-of-distribution (OOD) detection is essential for reliable deployment of deep learning systems, yet the majority of existing methods are evaluated on small, visually homogeneous benchmarks. In this work, we study six OOD detection methods spanning post-hoc scoring, auxiliary objectives, energy-based models, and constrained optimization on the Plant Pathology 2021 dataset, a fine-grained task with natural distribution shifts. Energy-based fine-tuning performs best across OOD settings, improving detection over the softmax baseline while preserving in-distribution accuracy. Analysis shows these gains stem from both a restructuring of the embedding space alongside calibration of the scoring function. We further document practical training instabilities that arise when scaling constrained optimization methods to moderate-sized datasets, findings that are largely absent from existing literature. Our results demonstrate that principled OOD detection is achievable on real-world domain-specific data and that benchmark evaluations alone may not capture the challenges that emerge in practice.