000865283 001__ 865283 000865283 005__ 20220930130219.0 000865283 0247_ $$2doi$$a10.1016/j.biopsych.2019.08.031 000865283 0247_ $$2ISSN$$a0006-3223 000865283 0247_ $$2ISSN$$a1873-2402 000865283 0247_ $$2Handle$$a2128/23815 000865283 0247_ $$2altmetric$$aaltmetric:67027073 000865283 0247_ $$2pmid$$apmid:31748126 000865283 0247_ $$2WOS$$aWOS:000505773200013 000865283 037__ $$aFZJ-2019-04803 000865283 082__ $$a610 000865283 1001_ $$0P:(DE-Juel1)171414$$aChen, Ji$$b0$$ufzj 000865283 245__ $$aNeurobiological divergence of the positive and negative schizophrenia subtypes identified upon a new factor-structure of psychopathology using non-negative factorization: An international machine-learning study 000865283 260__ $$aAmsterdam [u.a.]$$bElsevier Science$$c2020 000865283 3367_ $$2DRIVER$$aarticle 000865283 3367_ $$2DataCite$$aOutput Types/Journal article 000865283 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1578641980_24601 000865283 3367_ $$2BibTeX$$aARTICLE 000865283 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000865283 3367_ $$00$$2EndNote$$aJournal Article 000865283 500__ $$aThis study was supported by the Deutsche Forschungsgemeinschaft (DFG, EI 816/4-1), the National Institute of Mental Health (R01-MH074457), the Helmholtz Portfolio Theme "Supercomputing and Modeling for the Human Brain", and the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 720270 (HBP SGA1) and 785907 (HBP SGA2). Ji Chen has received a Ph.D fellowship from the Chinese Scholarship Council. Also, acknowledgment goes to Asadur Chowdury, PhD (Brain Imaging Research Division, Wayne State University School of Medicine, Detroit, Michigan), who contributed to the early arrangement and communication of the Wayne-State dataset. 000865283 520__ $$aObjectiveDisentangling psychopathological heterogeneity in schizophrenia is challenging and previous results remain inconclusive. We employed advanced machine-learning to identify a stable and generalizable factorization of the “Positive and Negative Syndrome Scale (PANSS)”, and used it to identify psychopathological subtypes as well as their neurobiological differentiations.MethodsPANSS data from the Pharmacotherapy Monitoring and Outcome Survey cohort (1545 patients, 586 followed up after 1.35±0.70 years) were used for learning the factor-structure by an orthonormal projective non-negative factorization. An international sample, pooled from nine medical centers across Europe, USA, and Asia (490 patients), was used for validation. Patients were clustered into psychopathological subtypes based on the identified factor-structure, and the neurobiological divergence between the subtypes was assessed by classification analysis on functional MRI connectivity patterns.ResultsA four-factor structure representing negative, positive, affective, and cognitive symptoms was identified as the most stable and generalizable representation of psychopathology. It showed higher internal consistency than the original PANSS subscales and previously proposed factor-models. Based on this representation, the positive-negative dichotomy was confirmed as the (only) robust psychopathological subtypes, and these subtypes were longitudinally stable in about 80% of the repeatedly assessed patients. Finally, the individual subtype could be predicted with good accuracy from functional connectivity profiles of the ventro-medial frontal cortex, temporoparietal junction, and precuneus.ConclusionsMachine-learning applied to multi-site data with cross-validation yielded a factorization generalizable across populations and medical systems. Together with subtyping and the demonstrated ability to predict subtype membership from neuroimaging data, this work further disentangles the heterogeneity in schizophrenia. 000865283 536__ $$0G:(DE-HGF)POF3-572$$a572 - (Dys-)function and Plasticity (POF3-572)$$cPOF3-572$$fPOF III$$x0 000865283 536__ $$0G:(DE-Juel1)HGF-SMHB-2013-2017$$aSMHB - Supercomputing and Modelling for the Human Brain (HGF-SMHB-2013-2017)$$cHGF-SMHB-2013-2017$$fSMHB$$x1 000865283 536__ $$0G:(EU-Grant)785907$$aHBP SGA2 - Human Brain Project Specific Grant Agreement 2 (785907)$$c785907$$fH2020-SGA-FETFLAG-HBP-2017$$x2 000865283 588__ $$aDataset connected to CrossRef 000865283 7001_ $$0P:(DE-Juel1)172843$$aPatil, Kaustubh R.$$b1$$ufzj 000865283 7001_ $$0P:(DE-Juel1)172811$$aWeis, Susanne$$b2 000865283 7001_ $$aSim, Kang$$b3 000865283 7001_ $$aNickl-Jockschat, Thomas$$b4 000865283 7001_ $$00000-0002-0180-8648$$aZhou, Juan$$b5 000865283 7001_ $$aAleman, André$$b6 000865283 7001_ $$aSommer, Iris E.$$b7 000865283 7001_ $$aLiemburg, Edith J.$$b8 000865283 7001_ $$0P:(DE-Juel1)131684$$aHoffstaedter, Felix$$b9 000865283 7001_ $$0P:(DE-Juel1)172840$$aHabel, Ute$$b10 000865283 7001_ $$aDerntl, Birgit$$b11 000865283 7001_ $$aLiu, Xiaojin$$b12 000865283 7001_ $$aKogler, Lydia$$b13 000865283 7001_ $$aRegenbogen, Christina$$b14 000865283 7001_ $$aDiwadkar, Vaibhav A.$$b15 000865283 7001_ $$aStanley, Jeffrey A.$$b16 000865283 7001_ $$aRiedl, Valentin$$b17 000865283 7001_ $$00000-0003-4596-1502$$aJardri, Renaud$$b18 000865283 7001_ $$aGruber, Oliver$$b19 000865283 7001_ $$00000-0003-0795-8820$$aSotiras, Aristeidis$$b20 000865283 7001_ $$aDavatzikos, Christos$$b21 000865283 7001_ $$0P:(DE-Juel1)131678$$aEickhoff, Simon$$b22$$eCorresponding author 000865283 773__ $$0PERI:(DE-600)1499907-9$$a10.1016/j.biopsych.2019.08.031$$gp. 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