Abstract:Out-of-distribution (OOD) detection is crucial in AI-driven medical imaging to ensure reliability and safety by identifying inputs outside a model's training distribution. Existing methods often require retraining or modifications to pre-trained models, which is impractical for clinical applications. This study introduces a post-hoc normalizing flow-based approach that seamlessly integrates with pre-trained models. By leveraging normalizing flows, it estimates the likelihood of feature vectors extracted from pre-trained models, capturing semantically meaningful representations without relying on pixel-level statistics. The method was evaluated using the MedMNIST benchmark and a newly curated MedOOD dataset simulating clinically relevant distributional shifts. Performance was measured using standard OOD detection metrics (e.g., AUROC, FPR@95, AUPR_IN, AUPR_OUT), with statistical analyses comparing it against ten baseline methods. On MedMNIST, the proposed model achieved an AUROC of 93.80%, outperforming state-of-the-art methods. On MedOOD, it achieved an AUROC of 84.61%, demonstrating superior performance against other methods. Its post-hoc nature ensures compatibility with existing clinical workflows, addressing the limitations of previous approaches. The model and code to build OOD datasets are available at https://github.com/dlotfi/MedOODFlow.