AUTHOR=Vetter Clara S. , Bender Annika , Dwyer Dominic B. , Montembeault Max , Ruef Anne , Chisholm Katharine , Kambeitz-Ilankovic Lana , Antonucci Linda A. , Ruhrmann Stephan , Kambeitz Joseph , Rosen Marlene , Lichtenstein Theresa , Riecher-Rössler Anita , Upthegrove Rachel , Salokangas Raimo K. R. , Hietala Jarmo , Pantelis Christos , Lencer Rebekka , Meisenzahl Eva , Wood Stephen J. , Brambilla Paolo , Borgwardt Stefan , Falkai Peter , Bertolino Alessandro , Koutsouleris Nikolaos ,  PRONIA Consortium 

TITLE=Exploring the predictive value of structural covariance networks for the diagnosis of schizophrenia

JOURNAL=Frontiers in Psychiatry

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1570797

DOI=10.3389/fpsyt.2025.1570797

ISSN=1664-0640

ABSTRACT=IntroductionSchizophrenia is a psychiatric disorder hypothesized to result from disturbed brain connectivity. Structural covariance networks (SCN) describe the shared variation in morphological properties emerging from coordinated neurodevelopmental processes, This study evaluates the potential of SCNs as diagnostic biomarker for schizophrenia.MethodsWe compared the diagnostic value of two SCN computation methods derived from regional gray matter volume (GMV) in 154 patients with a diagnosis of first episode psychosis or recurrent schizophrenia (PAT) and 366 healthy control individuals (HC). The first method (REF-SCN) quantifies the contribution of an individual to a normative reference group’s SCN, and the second approach (KLS-SCN) uses a symmetric version of Kulback-Leibler divergence. Their diagnostic value compared to regional GMV was assessed in a stepwise analysis using a series of linear support vector machines within a nested cross-validation framework and stacked generalization, all models were externally validated in an independent sample (NPAT=71, NHC=74), SCN feature importance was assessed, and the derived risk scores were analyzed for differential relationships with clinical variables.ResultsWe found that models trained on SCNs were able to classify patients with schizophrenia and combining SCNs and regional GMV in a stacked model improved training (balanced accuracy (BAC)=69.96%) and external validation performance (BAC=67.10%). Among all unimodal models, the highest discovery sample performance was achieved by a model trained on REF-SCN (balanced accuracy (BAC=67.03%). All model decisions were driven by widespread structural covariance alterations involving the somato-motor, default mode, control, visual, and the ventral attention networks. Risk estimates derived from KLS-SCNs and regional GMV, but not REF-SCNs, could be predicted from clinical variables, especially driven by body mass index (BMI) and affect-related negative symptoms.DiscussionThese patterns of results show that different SCN computation approaches capture different aspects of the disease. While REF-SCNs contain valuable information for discriminating schizophrenia from healthy control individuals, KLS-SCNs may capture more nuanced symptom-level characteristics similar to those captured by PCA of regional GMV.