Classification of schizophrenia spectrum disorder using machine learning and functional connectivity: reconsidering...

Early identification of Schizophrenia Spectrum Disorder (SSD) is crucial for effective intervention and prognosis improvement. Previous neuroimaging-based classifications have primarily focused on chronic, medicated SSD cohorts. However, the question remains whether brain metrics identified in these populations can serve as trait biomarkers for early-stage SSD. This study investigates whether functional connectivity features identified in chronic, medicated SSD patients could be generalized to early-stage SSD.

Data were collected from 502 SSD patients and 575 healthy controls (HCs) across four medical institutions. Resting-state functional connectivity (FC) features were used to train a Support Vector Machine (SVM) classifier on individuals with medicated chronic SSD and HCs from three sites. The remaining site, comprising both chronic medicated and first-episode unmedicated SSD patients, was used for independent validation. A univariable analysis examined the association between medication dosage or illness duration and FC.

The classifier achieved 69% accuracy (p = 0.002), 63% sensitivity, 75% specificity, 0.75 area under the receiver operating characteristic curve, 69% F1-score, 72% positive predictive rate, and 67% negative predictive rate, when tested on an independent dataset. Subgroup analysis showed 71% sensitivity (p = 0.04) for chronic medicated SSD, but poor generalization to first-episode unmedicated SSD (sensitivity = 48%, p = 0.44). Univariable analysis revealed a significant association between FC and medication usage, but not disease duration.

Classifiers developed on chronic medicated SSD may predominantly capture state features of chronicity and medication, overshadowing potential SSD traits. This partially explains the current classifiers' non-generalizability across SSD patients with different clinical states, underscoring the need for models that can enhance the early detection of schizophrenia neural pathology.