Uncertainty-Aware Foundation Models for Clinical Data

Foundation models have achieved remarkable performance across medical question answering, imaging, and electronic health record (EHR) tasks, yet reliable clinical deployment remains challenging due to limited interpretability, vulnerability to distribution shift, and weak alignment with clinician reasoning. We argue that these limitations arise because existing approaches prioritize representation learning while treating patient comparison as an emergent property rather than a primary source of clinical evidence. To address this gap, we propose CAFM, a Cohort-Anchored Foundation Model framework that elevates patient cohorts to a first-class object throughout the learning pipeline. The framework consists of four stages: deviation-aware data curation, cohort-conditioned pretraining, multimodal cohort alignment, and clinician-in-the-loop refinement. Together, these stages improve data quality, organize representations around clinically meaningful cohort structure, preserve modality-specific relationships, and support auditable clinical decision-making. The framework is compositional and can augment existing EHR foundation models without modifying their underlying encoders. We illustrate CAFM through four clinical case studies spanning acute kidney injury prediction, cardiovascular risk stratification from electrocardiograms, optic neuropathy triage from orbital imaging, and electroretinogram-grounded report generation. We further present five empirically testable hypotheses and identify open challenges in data quality, irregular temporality, multimodal learning, distribution shift, and evaluation beyond predictive accuracy. We argue that explicitly anchoring foundation models to patient cohorts provides a principled path toward trustworthy clinical AI.

Accurate uncertainty estimation is essential for machine learning systems de- ployed in high-stakes domains such as medicine. Traditional approaches primarily rely on probability outputs from trained models (point predictions), which provide no formal guarantees on prediction coverage and often require additional calibra- tion techniques to improve reliability. In contrast, conformal prediction (region prediction) offers a principled alternative by generating prediction sets with finite- sample validity guarantees, ensuring that the ground truth is contained within the set at a specified confidence level. In this study, we explore the impact of pre-training approach, dataset scale and domain on both point and region-level uncertainty quantification, by studying domain-specific vision medical foundation models vs. general domain vision foundation models. We conduct a comprehensive evaluation across foundation models trained on retinal, histopathological, and Chest X-Rays data, applying various calibration techniques. Our results demonstrate that (1) pre-training on higher-quality domain-specific datasets along with self-supervised learning leads to better-calibrated point predictions than general domain pre-training, (2) stan- dard re-calibration methods alone cannot fully mitigate uncertainty discrepancies across models trained on different data sources, (3) domain-specific foundation model can lead to more efficient conformal prediction. These findings highlight the importance of careful model selection and the inte- gration of both point and region prediction to enhance the reliability and trust- worthiness of medical AI systems. Our work underscores the need for a holistic approach to uncertainty quantification in recent development of medical vision foundation model, ensuring robust and interpretable AI-driven decision-making.

Recent healthcare foundation models have achieved strong predictive performance through large scale self supervised learning, yet their latent representations frequently entangle physiologic severity, intervention intensity, observational structure, and institutional workflow into shared embedding directions. While effective for downstream prediction, such representations remain semantically opaque and unstable under contextual shift. We introduce AURORA, Adaptive Uncertainty aware Representations through Orthogonalized Relational Alignment, a new framework for healthcare representation learning based on contextual latent geometry. Rather than optimizing a single unified embedding manifold, AURORA decomposes representations into orthogonal semantic subspaces corresponding to distinct contextual factors and learns relational consistency objectives within each subspace. This induces latent spaces that are both semantically disentangled and geometrically interpretable. Across multiple clinical prediction and retrieval tasks, AURORA consistently outperforms reconstruction, contrastive, and self distillation baselines while substantially improving contextual disentanglement, neighborhood purity, and robustness under institutional distribution shift. Our results suggest that latent geometry itself constitutes an important axis of healthcare foundation model design and that explicitly structuring representation space according to contextual semantics provides a complementary direction beyond conventional predictive compression objectives.