Robust FDR Control for Neuroimaging-based Classification via Knockoffs

Machine learning for medical image analysis has received unprecedented attention and success in the recent years. Yet, ensuring the reliability of discovered features for neuroimaging-based classification remains a challenge. In this study, we demonstrate the knockoff framework, a robust statistical approach that guarantees a theoretical bound on the False Discovery Rate (FDR), even under complex feature dependencies and model mis-specification. Unlike the Benjamini-Hochberg (BH) procedure, which assumes feature independence, knockoffs provide precise and provable FDR control for any feature correlation structure. We evaluate multiple knockoff construction methods on synthetic data for binary classification, observing near-perfect detection of true features and valid FDR control. We then apply the knockoff filter to fMRI data from the Human Connectome Project (HCP) to identify brain regions that contribute to an imaging-based classification model. The regions identified by the knockoff filter are found to be stable and reproducible across test-retest scans, indicating that they capture consistent task-related neural activation.