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Here, we sought to identify key clinical and neurobiological factors that relate to symptom organization in established schizophrenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A symptom comorbidity network was mapped for a broad constellation of symptoms measured in 642 individuals with a schizophrenia-spectrum disorder. Centrality analyses were used to identify hub symptoms. The extent to which each patient\u2019s symptoms formed clusters in the comorbidity network was quantified with cluster analysis and used to predict (1) clinical features, including illness duration and psychosis (positive symptom) severity and (2) brain white matter microstructure, indexed by the fractional anisotropy (FA), in a subset (n = 296) of individuals with diffusion-weighted imaging (DWI) data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Global functioning, substance use, and blunted affect were the most central symptoms within the symptom comorbidity network. Symptom profiles for some patients formed highly interconnected clusters, whereas other patients displayed unrelated and disconnected symptoms. Stronger clustering among an individual\u2019s symptoms was significantly associated with shorter illness duration (t = 2.7; P = .0074), greater psychosis severity (ie, positive symptoms expression) (t = \u22125.5; P &amp;lt; 0.0001) and lower fractional anisotropy in fibers traversing the cortico-cerebellar-thalamic-cortical circuit (r = .59, P &amp;lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Symptom network structure varies over the course of schizophrenia: symptom interactions weaken with increasing illness duration and strengthen during periods of high positive symptom expression. Reduced white matter coherence relates to stronger symptom clustering, and thus, may underlie symptom cascades and global symptomatic burden in individuals with schizophrenia.<\/jats:p><\/jats:sec>","DOI":"10.1093\/schbul\/sbab015","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T12:18:36Z","timestamp":1611749916000},"page":"1156-1167","source":"Crossref","is-referenced-by-count":19,"title":["Network Analysis of Symptom Comorbidity in Schizophrenia: Relationship to Illness Course and Brain White Matter Microstructure"],"prefix":"10.1093","volume":"47","author":[{"given":"Hua","family":"Ye","sequence":"first","affiliation":[{"name":"Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Zalesky","sequence":"additional","affiliation":[{"name":"Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia"},{"name":"Melbourne School of Engineering, The University of Melbourne, Parkville, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinglei","family":"Lv","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering & Brain and Mind Centre, The University of Sydney, Camperdown, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha M","family":"Loi","sequence":"additional","affiliation":[{"name":"Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suheyla","family":"Cetin-Karayumak","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogesh","family":"Rathi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"},{"name":"Department of Radiology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Tian","sequence":"additional","affiliation":[{"name":"Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9565-0238","authenticated-orcid":false,"given":"Christos","family":"Pantelis","sequence":"additional","affiliation":[{"name":"Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7100-651X","authenticated-orcid":false,"given":"Maria A","family":"Di Biase","sequence":"additional","affiliation":[{"name":"Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia"},{"name":"Department of Psychiatry, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,8]]},"reference":[{"issue":"1","key":"2021070901551071000_CIT0001","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1093\/schbul\/sbw095","article-title":"A transdiagnostic network approach to psychosis","volume":"43","author":"Wigman","year":"2017","journal-title":"Schizophr 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