Dominic B Dwyer1,2, Madalina-Octavia Buciuman1,3, Anne Ruef1, Joseph Kambeitz4, Mark Sen Dong1, Caedyn Stinson5,6, Lana Kambeitz-Ilankovic1,4, Franziska Degenhardt7,8, Rachele Sanfelici1,9, Linda A Antonucci10, Paris Alexandros Lalousis11, Julian Wenzel4, Maria Fernanda Urquijo-Castro1, David Popovic1,3, Oemer Faruk Oeztuerk1,3, Shalaila S Haas12, Johanna Weiske1, Daniel Hauke13,14,15, Susanne Neufang16, Christian Schmidt-Kraepelin16, Stephan Ruhrmann4, Nora Penzel4, Theresa Lichtenstein4, Marlene Rosen4, Katharine Chisholm11,17, Anita Riecher-Rössler18, Laura Egloff13, André Schmidt13, Christina Andreou13, Jarmo Hietala19, Timo Schirmer20, Georg Romer21, Chantal Michel22, Wulf Rössler23, Carlo Maj24, Oleg Borisov24, Peter M Krawitz24, Peter Falkai1,9, Christos Pantelis25, Rebekka Lencer26,27, Alessandro Bertolino28, Stefan Borgwardt13,27, Markus Noethen7, Paolo Brambilla29,30, Frauke Schultze-Lutter16,22,31, Eva Meisenzahl32, Stephen J Wood2,33, Christos Davatzikos34,35, Rachel Upthegrove11,14, Raimo K R Salokangas19, Nikolaos Koutsouleris1,9,36. 1. Department of Psychiatry and Psychotherapy, Ludwig-Maximilian-University, Munich, Germany. 2. Centre for Youth Mental Health, University of Melbourne, Melbourne, Victoria, Australia. 3. International Max-Planck Research School for Translational Psychiatry, Munich, Germany. 4. Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital, University of Cologne, Cologne, Germany. 5. Max-Planck School of Cognition, Leipzig, Germany. 6. Center for Adaptive Rationality, Max Planck Institute for Human Development, Berlin, Germany. 7. Institute of Human Genetics, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. 8. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 9. Max-Planck Institute of Psychiatry, Munich, Germany. 10. Department of Education, Psychology, Communication, University of Bari Aldo Moro, Bari, Italy. 11. Institute for Mental Health and Centre for Brain Health, University of Birmingham, Birmingham, United Kingdom. 12. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York. 13. Department of Psychiatry (Psychiatric University Hospital, UPK), University of Basel, Basel, Switzerland. 14. Early Intervention Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, United Kingdom. 15. Department of Mathematics and Computer Science, University of Basel, Basel, Switzerland. 16. Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany. 17. Department of Psychology, Aston University, Birmingham, United Kingdom. 18. Faculty of Medicine, University of Basel, Basel, Switzerland. 19. Department of Psychiatry, University of Turku, Turku, Finland. 20. GE Healthcare GmbH (previously GE Global Research GmbH), Munich, Germany. 21. Department of Child and Adolescent Psychiatry, University of Münster, Münster, Germany. 22. University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland. 23. Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry Zurich, Zurich, Switzerland. 24. Institute of Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany. 25. Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Victoria, Australia. 26. Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany. 27. Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany. 28. Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy. 29. Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. 30. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. 31. Department of Psychology, Faculty of Psychology, Airlangga University, Surabaya, Indonesia. 32. Heinrich Heine University, Düsseldorf, Germany. 33. Orygen, the National Centre of Excellence for Youth Mental Health, Melbourne, Victoria, Australia. 34. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 35. Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 36. Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
Abstract
Importance: Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. Objective: To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. Design, Setting, and Participants: A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. Main Outcomes and Measures: A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. Results: There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample. Conclusions and Relevance: The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.
Importance: Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. Objective: To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. Design, Setting, and Participants: A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. Main Outcomes and Measures: A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. Results: There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample. Conclusions and Relevance: The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.
Authors: Daniel J Brat; Roel G W Verhaak; Kenneth D Aldape; W K Alfred Yung; Sofie R Salama; Lee A D Cooper; Esther Rheinbay; C Ryan Miller; Mark Vitucci; Olena Morozova; A Gordon Robertson; Houtan Noushmehr; Peter W Laird; Andrew D Cherniack; Rehan Akbani; Jason T Huse; Giovanni Ciriello; Laila M Poisson; Jill S Barnholtz-Sloan; Mitchel S Berger; Cameron Brennan; Rivka R Colen; Howard Colman; Adam E Flanders; Caterina Giannini; Mia Grifford; Antonio Iavarone; Rajan Jain; Isaac Joseph; Jaegil Kim; Katayoon Kasaian; Tom Mikkelsen; Bradley A Murray; Brian Patrick O'Neill; Lior Pachter; Donald W Parsons; Carrie Sougnez; Erik P Sulman; Scott R Vandenberg; Erwin G Van Meir; Andreas von Deimling; Hailei Zhang; Daniel Crain; Kevin Lau; David Mallery; Scott Morris; Joseph Paulauskis; Robert Penny; Troy Shelton; Mark Sherman; Peggy Yena; Aaron Black; Jay Bowen; Katie Dicostanzo; Julie Gastier-Foster; Kristen M Leraas; Tara M Lichtenberg; Christopher R Pierson; Nilsa C Ramirez; Cynthia Taylor; Stephanie Weaver; Lisa Wise; Erik Zmuda; Tanja Davidsen; John A Demchok; Greg Eley; Martin L Ferguson; Carolyn M Hutter; Kenna R Mills Shaw; Bradley A Ozenberger; Margi Sheth; Heidi J Sofia; Roy Tarnuzzer; Zhining Wang; Liming Yang; Jean Claude Zenklusen; Brenda Ayala; Julien Baboud; Sudha Chudamani; Mark A Jensen; Jia Liu; Todd Pihl; Rohini Raman; Yunhu Wan; Ye Wu; Adrian Ally; J Todd Auman; Miruna Balasundaram; Saianand Balu; Stephen B Baylin; Rameen Beroukhim; Moiz S Bootwalla; Reanne Bowlby; Christopher A Bristow; Denise Brooks; Yaron Butterfield; Rebecca Carlsen; Scott Carter; Lynda Chin; Andy Chu; Eric Chuah; Kristian Cibulskis; Amanda Clarke; Simon G Coetzee; Noreen Dhalla; Tim Fennell; Sheila Fisher; Stacey Gabriel; Gad Getz; Richard Gibbs; Ranabir Guin; Angela Hadjipanayis; D Neil Hayes; Toshinori Hinoue; Katherine Hoadley; Robert A Holt; Alan P Hoyle; Stuart R Jefferys; Steven Jones; Corbin D Jones; Raju Kucherlapati; Phillip H Lai; Eric Lander; Semin Lee; Lee Lichtenstein; Yussanne Ma; Dennis T Maglinte; Harshad S Mahadeshwar; Marco A Marra; Michael Mayo; Shaowu Meng; Matthew L Meyerson; Piotr A Mieczkowski; Richard A Moore; Lisle E Mose; Andrew J Mungall; Angeliki Pantazi; Michael Parfenov; Peter J Park; Joel S Parker; Charles M Perou; Alexei Protopopov; Xiaojia Ren; Jeffrey Roach; Thaís S Sabedot; Jacqueline Schein; Steven E Schumacher; Jonathan G Seidman; Sahil Seth; Hui Shen; Janae V Simons; Payal Sipahimalani; Matthew G Soloway; Xingzhi Song; Huandong Sun; Barbara Tabak; Angela Tam; Donghui Tan; Jiabin Tang; Nina Thiessen; Timothy Triche; David J Van Den Berg; Umadevi Veluvolu; Scot Waring; Daniel J Weisenberger; Matthew D Wilkerson; Tina Wong; Junyuan Wu; Liu Xi; Andrew W Xu; Lixing Yang; Travis I Zack; Jianhua Zhang; B Arman Aksoy; Harindra Arachchi; Chris Benz; Brady Bernard; Daniel Carlin; Juok Cho; Daniel DiCara; Scott Frazer; Gregory N Fuller; JianJiong Gao; Nils Gehlenborg; David Haussler; David I Heiman; Lisa Iype; Anders Jacobsen; Zhenlin Ju; Sol Katzman; Hoon Kim; Theo Knijnenburg; Richard Bailey Kreisberg; Michael S Lawrence; William Lee; Kalle Leinonen; Pei Lin; Shiyun Ling; Wenbin Liu; Yingchun Liu; Yuexin Liu; Yiling Lu; Gordon Mills; Sam Ng; Michael S Noble; Evan Paull; Arvind Rao; Sheila Reynolds; Gordon Saksena; Zack Sanborn; Chris Sander; Nikolaus Schultz; Yasin Senbabaoglu; Ronglai Shen; Ilya Shmulevich; Rileen Sinha; Josh Stuart; S Onur Sumer; Yichao Sun; Natalie Tasman; Barry S Taylor; Doug Voet; Nils Weinhold; John N Weinstein; Da Yang; Kosuke Yoshihara; Siyuan Zheng; Wei Zhang; Lihua Zou; Ty Abel; Sara Sadeghi; Mark L Cohen; Jenny Eschbacher; Eyas M Hattab; Aditya Raghunathan; Matthew J Schniederjan; Dina Aziz; Gene Barnett; Wendi Barrett; Darell D Bigner; Lori Boice; Cathy Brewer; Chiara Calatozzolo; Benito Campos; Carlos Gilberto Carlotti; Timothy A Chan; Lucia Cuppini; Erin Curley; Stefania Cuzzubbo; Karen Devine; Francesco DiMeco; Rebecca Duell; J Bradley Elder; Ashley Fehrenbach; Gaetano Finocchiaro; William Friedman; Jordonna Fulop; Johanna Gardner; Beth Hermes; Christel Herold-Mende; Christine Jungk; Ady Kendler; Norman L Lehman; Eric Lipp; Ouida Liu; Randy Mandt; Mary McGraw; Roger Mclendon; Christopher McPherson; Luciano Neder; Phuong Nguyen; Ardene Noss; Raffaele Nunziata; Quinn T Ostrom; Cheryl Palmer; Alessandro Perin; Bianca Pollo; Alexander Potapov; Olga Potapova; W Kimryn Rathmell; Daniil Rotin; Lisa Scarpace; Cathy Schilero; Kelly Senecal; Kristen Shimmel; Vsevolod Shurkhay; Suzanne Sifri; Rosy Singh; Andrew E Sloan; Kathy Smolenski; Susan M Staugaitis; Ruth Steele; Leigh Thorne; Daniela P C Tirapelli; Andreas Unterberg; Mahitha Vallurupalli; Yun Wang; Ronald Warnick; Felicia Williams; Yingli Wolinsky; Sue Bell; Mara Rosenberg; Chip Stewart; Franklin Huang; Jonna L Grimsby; Amie J Radenbaugh; Jianan Zhang Journal: N Engl J Med Date: 2015-06-10 Impact factor: 91.245
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