Dataset Properties Shape the Success of Neuroimaging-Based Patient Stratification: A Benchmarking Analysis Across Clustering Algorithms

Abstract: Background: Data driven stratification of patients into biologically informed subtypes holds promise for precision neuropsychiatry, yet neuroimaging-based clustering methods often fail to generalize across cohorts. While algorithmic innovations have focused on model complexity, the role of underlying dataset characteristics remains underexplored. We hypothesized that cluster separation, size imbalance, noise, and the direction and magnitude of disease-related effects in the input data critically determine both within-algorithm accuracy and reproducibility. Methods: We evaluated 4 widely used stratification algorithms, HYDRA, SuStaIn, SmileGAN, and SurrealGAN, on a suite of synthetic brain-morphometry cohorts derived from the Human Connectome Project Young Adult dataset. Three global transformation patterns were applied to 600 pseudo-patients against 508 controls, followed by 4 within-dataset variations varying cluster count (k=2-6), overlap, and effect magnitude. Algorithm performance was quantified by accuracy in recovering the known ground-truth clusters. Results: Across 122 synthetic scenarios, data complexity consistently outweighed algorithm choice in predicting stratification success. Well-separated clusters yielded high accuracy for all methods, whereas overlapping, unequal-sized, or subtle effects reduced accuracy by up to 50%. SuStaIn could not scale beyond 17 features, HYDRA's accuracy varied unpredictably with data heterogeneity. SmileGAN and SurrealGAN maintained robust pattern detection but did not assign discrete cluster labels to individuals. Conclusions: The study results demonstrate the impact of statistical properties of input data across algorithms and highlight the need for using realistic dataset distributions when new algorithms are being developed and suggest greater focus on data-centric strategies that actively shape and standardize the input distributions.