Attributing Cohen's d: Training Data Attribution for Disease-Related Effects in Normative Age Biomarkers

Age dependent performance disparities in medical image classification often arise because age acts as a confounder, linking imaging morphology with disease prevalence. In practice, disparities can manifest as overdiagnosis at ages where disease prevalence is higher and underdiagnosis at ages where prevalence is lower, and can worsen under train test shifts in the age distribution. Conventional mitigation approaches that enforce strict age invariance may suppress diagnostically meaningful information encoded in age. We therefore propose a robust framework that mitigates the effects of age-dependent confounding by targeting spurious age linked trends rather than enforcing invariance. Following a warm-up phase, we characterize sample difficulty and model its age-dependent trends in a label-conditioned manner. We decorrelate age from dominant age difficulty trends using robust, Huber weighted affinity weights, attenuating confounding-driven shortcuts while preserving clinically meaningful, nonlinear age information. We further introduce an Age Coverage Score that scales the decorrelation penalty by minibatch age variance to ensure stable optimization under limited age diversity. Across two radiology datasets, our approach reduces age dependent true and false positive disparities with minimal AUC impact and remains robust to increasing train test age distribution shifts.

Aging clocks aim to estimate biological age, a measure of physiological state distinct from chronological age, from observable biomarkers, and are widely used for health assessment and disease analysis. DNA methylation is a particularly informative biomarker due to its stability and strong association with aging, and recent learning-based approaches have improved predictive performance. However, most existing methods treat CpG sites as independent features, overlooking the complex and heterogeneous biological relationships among them. We propose RelAge-GNN, a multi-relational graph neural network framework for DNA methylation-based age prediction. Our method constructs three complementary graphs capturing co-methylation patterns, genomic co-localization, and gene-level associations among CpG sites. Each graph is modeled by an independent GNN branch, and a learnable gating mechanism adaptively fuses the resulting representations. Experiments on large-scale datasets show that RelAge-GNN achieves competitive accuracy and stronger correlation with chronological age compared to state-of-the-art methods. Moreover, the model exhibits improved sensitivity in detecting age acceleration across diverse disease cohorts, highlighting its potential utility for disease characterization. Finally, through post hoc interpretability analyses, we quantify the contributions of different relational structures and CpG sites, providing biologically meaningful insights and suggesting potential directions for aging-related research. Our code is available at: https://anonymous.4open.science/r/RelAge-GNN-F1E3/.

Brain-age prediction models are commonly evaluated by predictive accuracy, yet accurate predictions alone do not establish that a model relies on reproducible or neurobiologically supported mechanisms. Post-hoc explanation methods can expose these mechanisms, but existing workflows typically stop at diagnosis or require correction targets to be specified before model analysis. We propose XAI-Refine, an automated explanation-knowledge loop for brain-age prediction from resting-state functional connectivity. At each iteration, XAI-Refine consolidates complementary post-hoc analyses across repeated training runs into reliable, structured model explanations. It converts each reliable explanation into a neutral neurobiological question, retrieves and verifies relevant literature, and compiles the verified evidence into an admissible set in the same typed explanation space. The target for refinement is defined as the minimal projection of the current model explanation onto the admissible set induced by applicable verified knowledge. This revised explanation is then translated into a differentiable constraint while preserving the originating model variable, measurement operator, and applicable scope. Candidate updates are promoted only when multi-seed validation confirms target-directed explanatory movement, predictive performance remains within a prespecified guardrail, and non-target explanatory drift remains bounded. Experiments on functional-connectivity-based brain-age prediction evaluate predictive performance, explanation reliability, literature alignment, and target-specific model revision, illustrating a structured route from post-hoc analysis to evidence-guided model refinement.