Automatic Discovery of Disease Subgroups by Contrasting with Healthy Controls

We study the problem of understanding where two populations differ within a feature space, which we formalize in the concept of a differential subgroup: a subset of individuals from both populations who, despite sharing similar characteristics, exhibit exceptional differences in a target outcome. Differential subgroups reveal the regions of the feature space where population-level gaps are most pronounced and can help practitioners identify the covariate combinations that are structurally responsible for these differences, e.g.~in clinical analysis, model diagnostics, or treatment-effect studies. We introduce a general optimization objective for discovering differential subgroups and establish conditions under which the resulting subgroups admit a causal interpretation of population differences. We propose DiffSub, a gradient-based approach that discovers interpretable differential subgroups in tabular data. Across synthetic benchmarks, medical case studies, model-error analyses, and treatment-effect settings, DiffSub identifies informative subgroups that reveal where population differences arise and why.

Medical imaging models are often deployed without the demographic, acquisition, and quality metadata needed for subgroup auditing. Once those metadata disappear, clinically critical failure modes can be masked by strong aggregate performance, and many robust-learning methods lose the group structure they rely on. We present CAPRA, a calibrated proxy-axis framework for hidden subgroup analysis under missing metadata. CAPRA predicts image-derived semantic axes, calibrates axis posteriors on a small metadata-labeled split via patient-level cross-fitting, and organizes those posteriors into a calibrated subgroup interface that supports both deployment-time failure analysis and downstream robust learning without requiring subgroup labels at deployment. Across fundus, dermoscopy, and chest radiography, CAPRA reveals disparity patterns missed by metadata-only slicing, remains informative under dataset shift, and produces subgroup partitions that align more closely with explicit failure axes than image-only or latent-slice baselines. The same interface can also be reused by downstream robust learners, although those gains are domain-dependent. Overall, CAPRA turns hidden subgroup analysis under missing metadata into a calibrated, interpretable, and reusable subgroup interface for deployment-time analysis and robust transfer.

Learning unsupervised representations of medical imaging cohorts can reveal anatomically meaningful prototypes without expert labels, which are often noisy and fail to capture true pathological heterogeneity. However, existing deep latent-variable models estimate Gaussian mixture priors via Euclidean averaging, producing prototypes that drift off the curved data manifold and degenerate as the number of sub-populations grows. We propose a manifold-anchored variational framework built on a geometry-aware Expectation-Maximization (EM) algorithm, whose M-step selects each sub-population prototype as the graph medoid with the highest diffusion centrality on a heat-kernel-weighted latent graph, ensuring that every prototype remains on-manifold. A Dirichlet energy regularizer enforces geometric smoothness of the latent space, and a per-sub-population uncertainty score enables label-free quality assessment. The manifold-anchored EM is a general-purpose geometric tool that extends standard EM and applies readily to other latent-variable models beyond this setting. On cardiac scar and brain MRI benchmarks, our framework attains the highest accuracy among all compared methods, produces the sharpest prototypes reported to date, and remains stable at large sub-population counts where all baselines degenerate. Code and implementation details are available at https://github.com/jr-xing/On-Manifold-Variational-Learning-with-Heat-Kernel-Priors.