Training-Free Out-of-Distribution Detection for Pathology Whole-Slide Images

Safe deployment of AI methods in medicine requires robust guardrails that detect when input data deviate from the training distribution to ensure that models provide predictions only within their scope of expertise and abstain otherwise. Out-of-distribution (OOD) detection can provide such safeguards and is extensively studied in general computer vision. Yet, it remains underdeveloped in computational pathology, where gigapixel whole-slide images (WSIs), subtle differences between disease subtypes, and variability in tissue preparation pose unique challenges for conventional OOD methods. We propose ZIO, a training-free, multimodal OOD detector for pathology WSIs that leverages vision--language pathology foundation models (FMs). ZIO constructs text and visual prototypes of in-distribution classes and integrates their complementary information through a prototype shrinkage mechanism to derive OOD scores. We provide the ZIO formulation for both slide- and patch-level FMs. We evaluate ZIO across diverse clinically relevant domain shifts, including rare diseases and near-OOD settings. Extensive evaluation of over 14,700 WSIs from five independent consortia shows that ZIO consistently outperforms both unimodal prototypes and 40 state-of-the-art OOD methods. These results demonstrate the benefits of multimodal representation for OOD detection and pave the way towards safer AI deployment in clinical practice.

Calibrated Hybrid CNN-Transformer for Retinal OCT Classification

Deep models for retinal optical coherence tomography (OCT) classification report high accuracy but rarely report whether their confidence can be trusted -- a gap that matters when a wrong-but-confident reading delays sight-saving treatment. We pair a hybrid convolutional-Transformer encoder with a gradient-boosting (XGBoost) classification head and a three-part clinical safety layer: confidence calibration, out-of-distribution (OOD) rejection, and per-prediction uncertainty flagging. On four-class OCT (84,495 scans) the model reaches 95.4% accuracy while cutting calibration error twelve-fold (expected calibration error, ECE = 0.0024), so the confidence it reports tracks its true accuracy. To our knowledge this is the first OCT classifier to validate all three safety mechanisms jointly, with public weights and reproducible multi-seed evaluation.

MARVEL: Margin-Aware Robust von Mises-Fischer Expert Learning for Long-Tailed Out-of-Distribution Detection

For clinical deployment, it is essential that automated diagnostic systems remain reliable when confronted with previously unseen cases, yet deep models routinely misclassify out-of-distribution (OOD) inputs with high confidence, underscoring the need for more robust OOD detection methods. Although substantial effort has been devoted to improving model robustness, most of the existing literature assumes balanced datasets, evaluates OOD detection on coarse or non-clinical OOD sources, or lacks comprehensive assessment across diverse OOD scenarios. To address the gaps, we propose a novel methodology trained on diverse and imbalanced medical datasets and evaluated across a clinically reflective OOD spectrum. Our framework comprises three key components: (1) a Nonlinear von Mises-Fisher (NvMF) classifier capable of learning non-linear decision boundaries, with theoretical proof of its asymptotic connection to cosine classifiers; (2) a multi-expert framework in which margin-aware NvMF classifiers specialise in different regions of label distribution to better handle imbalance; and (3) an outlier expert trained explicitly to distinguish inlier from outlier data, thereby strengthening OOD detection. Evaluation on RFMiD, ISIC2019, and NCTCRC datasets demonstrates consistent improvements over state-of-the-art methods, achieving mean FPR95 reductions of 8.45%, 13.02%, and 36.90% respectively. These gains are further supported by comprehensive ablations that validated the contributions of each component. This enables reliable identification of unfamiliar cases for deferral to clinicians, supporting safer AI-assisted diagnosis in real-world workflows. Our code is available at https://github.com/redboxup/MARVEL.

MaRS: Robust Out-of-Distribution Detection via Mahalanobis Residual Scoring

Foundation models provide highly descriptive representations for medical images, yet their reliability degrades under distribution shifts arising from changes in patients, devices, or acquisition conditions. Reliable out-of-distribution (OOD) detection is therefore essential for safe deployment. Recent post-hoc detectors efficiently exploit frozen embeddings (e.g., kNN), whereas reconstruction-based OOD detection in latent feature space has seen limited adoption due to inconsistent performance. In this work, we show that the limitation of reconstruction-based methods in latent space does not stem from poor reconstruction quality, but from how reconstruction errors are scored. Standard L2 residual norms collapse the anisotropic residual structure, thereby suppressing informative deviations. To address this limitation, we introduce MaRS (Mahalanobis Residual Scoring), a label-free OOD detector that learns an in-distribution manifold using a lightweight autoencoder and measures deviation via a Mahalanobis distance on reconstruction residuals, yielding variance-aware OOD scores. Across three imaging modalities, multiple types of distribution shift, and different model families and scales, MaRS outperforms established confidence-, distance-, and reconstruction-based baselines, while remaining fully post-hoc and lightweight. The code is available at https://github.com/francescodisalvo05/mars.

PROTON: Prototype-Based Test-Time Online OOD Detection for Medical VLMs

Medical vision-language models (VLMs) enable zero-shot clinical image classification, yet reliably detecting out-of-distribution (OOD) inputs at deployment remains an open problem. No static scoring method works across all shift types: Maximum Concept Matching (MCM) on FLAIR achieves 76.4% AUROC for far-OOD but only 42.4% for covariate shifts such as ultra-wide-field fundus images, effectively random. We trace this to a structural mismatch: covariate-shifted inputs are indistinguishable from in-distribution samples in softmax space, yet occupy distinct regions in the VLM embedding space. To exploit this untapped signal, we propose PROTON (PROtotype-based Test-time ONline OOD detection), a lightweight post-hoc module that maintains an online prototype bank from high-confidence test predictions and adaptively fuses prototype distance with MCM scoring via stream-level variance statistics, requiring no model modification, training data, or prompt engineering. On the ophthalmology benchmark FLAIR + FIVES, PROTON improves MCM by +23.9 AUROC on covariate shift, +8.8 on semantic shift, and +8.1 on far-OOD, making it the only zero-shot method to improve all three without hierarchical prompts or labeled data. Code is available at https://github.com/GenMI-Lab/PROTON, and the project page is available at https://genmi-lab.github.io/PROTON.

When Confidence Lacks Concepts: Interpretable OOD Detection via Representation Perturbations

Deep neural networks have achieved remarkable performance across medical imaging tasks, yet their tendency to overgeneralize under distributional shifts poses a major obstacle to safe clinical deployment. Out-of-Distribution (OOD) detection methods aim to mitigate this risk, but most existing approaches rely on opaque internal signals with poorly understood semantic meaning, limiting trust in safety-critical settings. In this work, we propose an interpretable OOD detection framework that probes the stability of model predictions under class-conditioned semantic perturbations. Leveraging sparse autoencoders (SAEs), we learn class-specific concept vectors from in-distribution data that disentangle dense intermediate representations into sparse, semantically meaningful components. At inference, we perturb deeper-layer representations using the concept vectors associated with the model's predicted class and measure the class logits stability. We hypothesize that in-distribution samples exhibit low sensitivity to such perturbations, as their representations align with class-specific semantic directions, whereas OOD samples show amplified deviations due to representational misalignment. By framing OOD detection as a concept conditioned stability analysis, our approach provides both a discriminative OOD signal and an interpretable lens into the internal mechanisms driving model uncertainty, making it particularly suitable for high stakes medical applications.

Wasserstein-Aligned Localisation for VLM-Based Distributional OOD Detection in Medical Imaging

Zero-shot anomaly localisation via vision-language models (VLMs) offers a compelling approach for rare pathology detection, yet its performance is fundamentally limited by the absence of healthy anatomical context. We reformulate zero-shot localisation as a comparative inference problem in which anomalies are identified through structured comparison against reference distributions of normal anatomy. We introduce WALDO, a training-free framework grounded in optimal transport theory that enables comparative reasoning through: (i) entropy-weighted Sliced Wasserstein distances for anatomically-aware reference selection from DINOv2 patch distributions, (ii) Goldilocks zone sampling exploiting the non-monotonic relationship between reference similarity and localisation accuracy, and (iii) self-consistency aggregation via weighted non-maximum suppression. We theoretically analyse the Goldilocks effect through distributional divergence, and show that references with moderate similarity minimize a bias-variance trade-off in comparative visual reasoning. On the NOVA brain MRI benchmark, WALDO with Qwen2.5-VL-72B achieves $43.5_{\pm1.6}\%$ mAP@30 (95\% CI: [40.4, 46.7]), representing a 19\% relative improvement over zero-shot baselines. Cross-model evaluation shows consistent gains: GPT-4o achieves $32.0_{\pm6.5}\%$ and Qwen3-VL-32B achieves $32.0_{\pm6.6}\%$ mAP@30. Paired McNemar tests confirm statistical significance ($p<0.01$). Source code is available at https://github.com/bkainz/WALDO_MICCAI26_demo .