Connectome-based spatial statistics enabling large-scale population analyses of human connectome across cohorts

Large-scale population analyses of structural connectome organization remain challenging because of cross-subject alignment, pathway interpretability and computational burden. No widely adopted standard exists for systematic evaluation across processing methods. We developed connectome-based spatial statistics (CBSS), a scalable framework for anatomically aligned and functionally informed quantification of white-matter microstructure that yields atlas-defined pathways organized into 13 functional networks. Using data from 56,510 UK Biobank participants together with five independent lifespan cohorts, we evaluated the streamline-, voxel– and network-level measures in the aspects of reliability, heritability, structure–function coupling, cognitive and behavioral prediction, brain aging patterns and lifespan trajectories across cohorts. The systematic evaluation workflow compares population-level white-matter representations across methods, spatial scales, tasks and datasets. The results support CBSS as a common connectome reference for large-scale, cross-cohort diffusion MRI studies.