Beyond Single Biomarkers: A Graph Neural Network Framework for Multivariable Prediction of Clinical Outcomes from Brain Imaging

Understanding brain-behavior relationships requires models capturing the distributed, interactive, and multiscale nature of neural systems. Traditional univariate approaches and single-biomarker models are inherently limited in this context, as they fail to represent dependencies across regions and the hierarchical organization of brain networks. In this study, we propose a graph-based multivariable framework for brain imaging analysis that integrates key organizational principles of brain function-including segregation, integration, modularity, and temporal dynamics-within a unified graph neural network architecture. The framework represents brain data as hierarchical graphs, where node features encode regional activation and temporal variability, and graph structure captures interactions within and between functional modules. The proposed approach is evaluated using functional near-infrared spectroscopy (fNIRS) data as a case study, where subject-specific brain graphs are constructed from task-based recordings acquired shortly after cochlear implant activation to predict speech understanding outcomes one year later. Under leave-one-subject-out validation, the model demonstrates strong predictive performance (R = 0.73, p < 0.001), outperforming previously reported single-biomarker approaches. Perturbation-based analyses further show that predictions are driven by distributed patterns of activity and interaction across regions and modalities, rather than isolated features. These results illustrate the capability of the proposed framework to capture complex brain organization and highlight its potential as a generalizable platform for multivariable analysis and prediction in neuroimaging applications beyond the specific clinical use case considered here.