Generalisable functional imaging classifiers of schizophrenia have multifunctionality as trait, state, and staging biomarkers

This study introduces a novel resting-state functional connectivity (rs-FC) magnetic resonance imaging (MRI) biomarker for diagnosing schizophrenia spectrum disorder (SSD), developed using customized machine learning on an anterogradely and retrogradely harmonized dataset from multiple sites, including 617 healthy controls and 116 patients with SSD. Unlike previous rs-FC MRI biomarkers, this new biomarker demonstrated a high accuracy rate of 77.3% in an independent validation cohort, including 404 healthy controls and 198 patients with SSD from seven different sites, while overcoming across-scan variability. It specifically identifies SSD, differentiating it from other psychiatric disorders. Our analysis identified 47 important FCs significant in SSD classification, many of which are involved in the pathophysiology of SSD. These FCs could be potential trait, state, and staging markers for effectively predicting delusional tendencies, specific symptoms, and disease stages. This research underscores the potential of rs-FC as a clinically applicable neural phenotype marker for SSD. ### Competing Interest Statement MK is an inventor of patents owned by the Advanced Telecommunications Research Institute International related to the present work (PCT/JP2014/061544 [WO2014178323] and JP2015-228970/6195329). AY and MK are inventors of a patent application submitted by the Advanced Telecommunications Research Institute International related to the present work (JP2018-192842). ### Funding Statement This study was supported by KAKENHI JP (23H04979) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, by AMED under Grant Numbers JP19dm0207069, JP18dm0307001, JP18dm0307004, JP18dm0307008, and JP18dm0307009, and by CREST (JPMJCR22P3) from the Japan Science and Technology Agency. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Kyoto University, Showa University, Hiroshima University, and University of Tokyo gave ethical approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.