Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

CIBERSAM Instituto de Salud Carlos 3 Barcelona Spain

Clinical Neuroimaging Laboratory Galway Neuroscience Centre College of Medicine Nursing and Health Sciences University of Galway Galway Ireland

Core Facility Brainimaging Faculty of Medicine University of Marburg Germany

Department of Behavioural Medicine Institute of Basic Medical Sciences University of Oslo Oslo Norway

Department of Child Adolescent Psychiatry and Psychotherapy University of Münster Münster Germany

Department of Child and Adolescent Psychiatry Psychology Erasmus University Medical Center Rotterdam The Netherlands

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Complex Systems Institute of Computer Science Czech Academy of Sciences Prague Czech Republic

Department of Cybernetics Czech Technical University Prague Czech Republic

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Neuroscience Dalhousie University Halifax Nova Scotia Canada

Department of Neurology Division of Clinical Neuroscience Oslo University Hospital Oslo Norway

Department of Psychiatry and Behavioral Sciences University of Minnesota Minneapolis Minnesota USA

Department of Psychiatry and Mental Health University of Cape Town Cape Town South Africa

Department of Psychiatry and Psychotherapy Jena University Hospital Jena Germany

Department of Psychiatry and Psychotherapy Philipps University Marburg Marburg Germany

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Psychosomatic Medicine and Psychotherapy Goethe University Frankfurt University Hospital Frankfurt Germany

Department of Psychiatry University Medical Center Groningen University of Groningen Groningen The Netherlands

Department of Psychiatry University Medical Center Utrecht Utrecht The Netherlands

Department of Psychiatry University of California San Diego La Jolla California USA

Department of Psychiatry University of Vermont College of Medicine Burlington Vermont USA

Department of Psychology Education and Child Studies Erasmus University Rotterdam Rotterdam The Netherlands

Department of Psychology Stanford University Stanford California USA

Department of Psychology University of Minnesota Minneapolis Minnesota USA

Desert Pacific MIRECC VA San Diego Healthcare San Diego California USA

Discipline of Psychiatry and Mental Health School of Clinical Medicine Faculty of Medicine and Health University of New South Wales Sydney New South Wales Australia

Division of Neuroscience Psychiatry and Psychobiology Unit IRCCS San Raffaele Scientific Institute Milan Italy

FIDMAG Germanes Hospitalàries Research Foundation Barcelona Spain

German Center for Mental Health Site Jena Magdeburg Halle Germany

Imaging Genetics Center Mark and Mary Stevens Neuroimaging and Informatics Institute Keck School of Medicine University of Southern California Marina del Rey California USA

Institut d'Investigacions Biomèdiques August Pi i Sunyer Barcelona Spain

Institut d'Investigacions Biomèdiques August Pi i Sunyer CIBERSAM Instituto de Salud Carlos 3 Institute of Neuroscience University of Barcelona Hospital Clínic Barcelona Spain

Institut d'Investigacions Biomèdiques August Pi i Sunyer CIBERSAM Instituto de Salud Carlos 3 University of Barcelona Barcelona Spain

Institute for Mental and Physical Health and Clinical Translation School of Medicine Barwon Health Deakin University Geelong Victoria Australia

Institute for Translational Neuroscience University of Münster Münster Germany

Institute for Translational Psychiatry University of Münster Münster Germany

Institute of Behavioral Science Feinstein Institutes for Medical Research Manhasset New York USA

Institute of Clinical Medicine Department of Neurology University of Oslo Oslo Norway

Institute of Clinical Medicine Norwegian Centre for Mental Disorders Research University of Oslo and Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Institute of Neuroscience and Physiology Sahlgrenska Academy at Gothenburg University Gothenburg Sweden

Laureate Institute for Brain Research Tulsa Oklahoma USA

Meditation Research Program Department of Psychiatry Massachusetts General Hospital Harvard Medical School Boston Massachusetts USA

Minneapolis VA Health Care System Minneapolis Minnesota USA

National Institute of Mental Health Klecany Czech Republic

Neuroscience Institute University of Cape Town Cape Town South Africa

Neuroscience Research Australia Randwick New South Wales Australia

Oxley College of Health Sciences The University of Tulsa Tulsa Oklahoma USA

Research Group in Psychiatry GIPSI Department of Psychiatry Faculty of Medicine Universidad de Antioquia Medellin Colombia

Research Group Instituto de Alta Tecnología Médica Ayudas diagnósticas SURA Medellin Colombia

School of Biomedical Sciences Faculty of Medicine and Health University of New South Wales Sydney New South Wales Australia

South African MRC Unit on Risk and Resilience in Mental Disorders University of Cape Town Cape Town South Africa

Turner Institute for Brain and Mental Health School of Psychological Sciences and Monash Biomedical Imaging Monash University Melbourne Victoria Australia

UCLA Center for Neurobehavioral Genetics Los Angeles California USA

Unit for Psychosomatics and C L Psychiatry for Adults Oslo University Hospital Oslo Norway

Unit for Psychosomatics CL Outpatient Clinic for Adults Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

University of British Columbia Vancouver British Columbia Canada

Vita Salute San Raffaele University Milan Italy

West Region Institute of Mental Health Singapore Singapore

Yong Loo Lin School of Medicine National University of Singapore Singapore Singapore

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