Interpretable Fundus Image Classification via Ring-Based Retinal Vasculature Features

Retinal fundus photography is widely used for screening and monitoring ocular diseases, but many modern classification pipelines rely on deep latent representations and provide limited interpretability. This study develops an interpretable fundus image classification framework based on a ring-structured representation of the retinal vasculature centered on the optic disc. The method quantifies vessel geometry, color appearance, oxygenation-related vascular appearance, and vessel--background entropy within concentric retinal regions. These physiologically motivated descriptors are derived from vessel masks, image intensities, and optical-density measurements and aggregated across rings to capture spatial variation in vascular properties. Using only quantitative vascular descriptors, the proposed method achieved strong classification performance across three public fundus datasets. On HRF, it achieved 91.1\% accuracy using automatically generated vessel masks, matching RETFound, a vision transformer pretrained on large-scale retinal fundus image data, under the same evaluation setting. Additional analyses suggest that pretrained image models are sensitive to acquisition-related spatial cues, including fundus scale and retinal position within the field of view, as well as broader non-vessel image characteristics. This framework may support interpretable disease classification, quantitative retinal phenotyping, and retinal biomarker discovery without requiring large task-specific training datasets.

EEG-PRISM: Physiologically-Grounded Interpretability of Predictions by EEG Foundation Models

Objective: Foundation models represent the next advancement in AI for EEG analysis; however current explainable AI techniques provide attribution scores in the time-channel input space, which is mismatched to clinical intuition about EEG. Thus, there is a critical need for a universal method that can extend the interpretability of any foundation model to alternative and physiologically relevant domains without modifying or retraining the underlying model. Methods: EEG-PRISM leverages linear transformations and established backpropagation rules to map time-channel attribution scores into alternative domains. We derive mappings to the frequency domain via an invertible DFT and to the source domain via an approximately invertible EEG generative model. We evaluate EEG-PRISM in simulated and real data, assessing recovery of ground-truth phenomena across domains with five foundation models and four AI explainers. Results: In simulation, EEG-PRISM achieves near-perfect spectral recovery and 69.2% spatial accuracy. In epilepsy, EEG-PRISM correctly determines that delta-theta activity is most salient and correctly localizes the seizure onset region with 50% accuracy. In autism, EEG-PRISM localizes the predictive delta-alpha biomarkers to frontal and temporal regions, consistent with prior work. Conclusion: EEG-PRISM is a theoretically-grounded post-hoc attribution method with accurate mapping into the spectral and spatial domains. It supports window-level analysis of transient events (e.g., seizures) and group-level identification of clinically relevant biomarkers (e.g., autism), thus advancing interpretable EEG foundation models. Significance: This work enables physiologically-grounded interpretation of EEG foundation models and supports clinically relevant insights such as event localization and biomarker identification.

Spatial proteomics guided by H&E-based AI reveals recurrence-risk niches in triple-negative breast cancer

Deep learning models can predict cancer recurrence from H&E stained slides, but the localized molecular states underlying these predictions remain largely obscured. Here, we developed an outcome informed spatial pathology framework in TNBC that integrates AI generated recurrence risk heatmaps with mass spectrometry based spatial proteomics. In a cohort of 156 patients, distribution based aggregation of high scoring patches achieved an AUC of 0.77 and a C-index of 0.77 in an independent test cohort. Bulk proteomics associated high image derived risk with cell cycle and genome maintenance programs and low risk with immune activation. High and low risk patches coexisted within the same tumor compartment and displayed distinct nuclear and architectural features, revealing intratumoral heterogeneity beyond tissue compartment identity. We then used the heatmaps as coordinate level guides to physically isolate and profile 46 AI defined tumor regions from two recurrence patients. Spatial proteomic profiling revealed a concordant molecular contrast across both patients: mitotic programs were enriched in high risk regions and immune and antigen presentation programs in low risk regions. A 13 protein composite derived from these spatial contrasts showed a trend toward poorer recurrence-free survival with increasing scores in an expanded cohort, while the corresponding transcript based composite stratified recurrence free survival in the independent METABRIC TNBC cohort. Integrating the protein composite with the H&E derived risk score improved the out of bag C-index from 0.679 to 0.739 and enhanced time dependent discrimination at 3 and 5 years. Together, these findings define a new role for outcome trained AI models as spatially explicit experimental guides that connect prognostic morphology with localized molecular states and advance biologically grounded, multiscale biomarker discovery in TNBC.

Wavelet Scattering Transform for Interpretable Schizophrenia Biomarker Discovery and Classification from Resting-State EEG

Schizophrenia is a debilitating neuropsychiatric disorder characterized by profound cortical network dysregulation, for which objective, clinically translatable EEG based biomarkers remain underdeveloped. Existing automated classification pipelines rely predominantly on static power spectral density features inherently blind to amplitude modulation dynamics and cross-frequency coupling, phenomena central to schizophrenia pathophysiology, while adopting epoch level cross validation strategies that introduce temporal data leakage, artificially inflate reported performance. This study introduces a mathematically principled diagnostic framework integrating the multi-order Wavelet Scattering Transform(WST), strict Leave One Subject Out (LOSO) cross-validation, and SHAP explainability for simultaneous EEG classification and biomarker discovery. Hierarchical WST coefficients capturing multi-scale amplitude modulation structure were extracted from resting state multichannel EEG. Subject-level ANOVA with Benjamini Hochberg false discovery rate correction identified significant biomarkers, with Random Forest and SVM classifiers evaluated under strict LOSO cross validation and subject-level majority voting. Second-order scattering coefficients encoding cross frequency coupling dominated the discriminative biomarker set, with gamma-band features most prevalent, demonstrating that temporal amplitude modulation constitutes the primary electrophysiological signature of schizophrenia. Electrode P3 was identified as the single most discriminative site. Under rigorous subject independent evaluation, the Random Forest achieved 90.48% accuracy (AUC = 0.9339; sensitivity = 95.56%). The proposed WST framework establishes a rigorous, interpretable standard for EEG-driven psychiatric biomarker discovery that can also be applicable in the detection of schizophrenia subtypes in the future.

CALM: Interpretable Cross-Modal Alignment for Biomarker Discovery from Unpaired Data

The interaction between brain structure and genetic influences is key to understanding neuropsychiatric disorders. However, most large-scale datasets are unimodal, providing either neuroimaging or genetics data. We propose CALM, a framework that learns interpretable associations between brain ROIs and genetic pathways from completely disjoint populations. CALM aligns the two modalities in a shared latent space via linear projections that simultaneously match the class-conditional latent distributions and ensure group separability. These projections provide interpretable pathway--ROI associations. When trained on unimodal imaging and genetics datasets, CALM generalizes to an unseen paired dataset, outperforming several state-of-the-art methods and ablation baselines. We also demonstrate stability of the learned associations against a paired baseline. Our experiments on autism spectrum disorder reveal immune and metabolic pathways linked to specific cortical regions and are consistent with established literature. Thus, CALM opens the door to leveraging large unimodal repositories for studying cross-modal interactions in brain disorders across disparate datasets.

Robust and Clinically Reliable EEG Biomarkers: A Cross Population Framework for Generalizable Parkinson's Disease Detection

Developing robust and clinically reliable EEG biomarkers requires evaluation frameworks that explicitly address cross population generalization in multi site settings such as Parkinsons disease (PD) detection. Models trained under i.i.d. assumptions often capture population specific artifacts rather than disease relevant neural structure, leading to poor generalization across clinical cohorts. EEG further amplifies this challenge due to low signal to noise ratio and heterogeneous acquisition conditions. We propose a population aware evaluation framework to assess the robustness and clinical reliability of EEG biomarkers under distribution shift. Using an n gram expansion strategy, we enumerate all cross population train test configurations across five independent cohorts, resulting in 75 directional evaluations. A nested cross validation design with integrated channel selection ensures prospective biomarker identification without population leakage. Results show that cross population transfer is asymmetric and that both accuracy and biomarker stability improve with increasing training population diversity, achieving up to 94.1% accuracy on held out cohorts. A theoretical analysis based on mixture risk optimization and hypothesis space contraction explains these trends, showing that multi population training promotes population robust representations. This work establishes a principled framework for learning robust, generalizable, and clinically reliable EEG biomarkers for multi site biomedical applications.