. 2024 Jun 1;45(8):e26682.

doi: 10.1002/hbm.26682.

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity

Sean R McWhinney¹, Jaroslav Hlinka^{2

3}, Eduard Bakstein^{3

4}, Lorielle M F Dietze^{1

5}, Emily L V Corkum¹, Christoph Abé⁶, Martin Alda^{1

3}, Nina Alexander⁷, Francesco Benedetti^{8

9}, Michael Berk¹⁰, Erlend Bøen¹¹, Linda M Bonnekoh^{12

13}, Birgitte Boye^{14

15}, Katharina Brosch^{7

16}, Erick J Canales-Rodríguez^{17

18}, Dara M Cannon¹⁹, Udo Dannlowski¹², Caroline Demro²⁰, Ana Diaz-Zuluaga²¹, Torbjørn Elvsåshagen^{15

22

23}, Lisa T Eyler^{24

25}, Lydia Fortea²⁶, Janice M Fullerton^{27

28}, Janik Goltermann¹², Ian H Gotlib²⁹, Dominik Grotegerd¹², Bartholomeus Haarman³⁰, Tim Hahn¹², Fleur M Howells^{31

32}, Hamidreza Jamalabadi⁷, Andreas Jansen^{7

33}, Tilo Kircher⁷, Anna Luisa Klahn³⁴, Rayus Kuplicki³⁵, Elijah Lahud²⁰, Mikael Landén^{34

36}, Elisabeth J Leehr¹², Carlos Lopez-Jaramillo²¹, Scott Mackey³⁷, Ulrik Malt^{11

38}, Fiona Martyn¹⁹, Elena Mazza^{8

9}, Colm McDonald¹⁹, Genevieve McPhilemy¹⁹, Sandra Meier¹, Susanne Meinert^{12

39}, Elisa Melloni^{8

9}, Philip B Mitchell⁴⁰, Leila Nabulsi¹⁹, Igor Nenadić⁷, Robert Nitsch³⁹, Nils Opel^{12

41

42}, Roel A Ophoff⁴³, Maria Ortuño⁴⁴, Bronwyn J Overs²⁷, Julian Pineda-Zapata⁴⁵, Edith Pomarol-Clotet^{17

18}, Joaquim Radua²⁶, Jonathan Repple^{12

46}, Gloria Roberts⁴⁰, Elena Rodriguez-Cano^{17

18}, Matthew D Sacchet⁴⁷, Raymond Salvador^{17

18}, Jonathan Savitz^{35

48}, Freda Scheffler^{31

32}, Peter R Schofield^{27

28}, Navid Schürmeyer¹², Chen Shen⁴⁹, Kang Sim^{50

51}, Scott R Sponheim^{20

52}, Dan J Stein^{31

32

53}, Frederike Stein⁷, Benjamin Straube⁷, Chao Suo⁵⁴, Henk Temmingh³², Lea Teutenberg⁷, Florian Thomas-Odenthal⁷, Sophia I Thomopoulos⁵⁵, Snezana Urosevic^{20

52}, Paula Usemann⁷, Neeltje E M van Haren^{56

57}, Cristian Vargas²¹, Eduard Vieta⁵⁸, Enric Vilajosana⁴⁴, Annabel Vreeker^{56

59}, Nils R Winter¹², Lakshmi N Yatham⁶⁰, Paul M Thompson⁵⁵, Ole A Andreassen²², Christopher R K Ching⁵⁵, Tomas Hajek^{1

3}

Affiliations

¹ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
² Department of Complex Systems, Institute of Computer Science, Czech Academy of Sciences, Prague, Czech Republic.
³ National Institute of Mental Health, Klecany, Czech Republic.
⁴ Department of Cybernetics, Czech Technical University, Prague, Czech Republic.
⁵ Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
⁶ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁸ Vita-Salute San Raffaele University, Milan, Italy.
⁹ Division of Neuroscience, Psychiatry and Psychobiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
¹⁰ Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.
¹¹ Unit for Psychosomatics/CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹² Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹³ Department of Child Adolescent Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
¹⁴ Unit for Psychosomatics and C-L Psychiatry for Adults, Oslo University Hospital, Oslo, Norway.
¹⁵ Department of Behavioural Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
¹⁶ Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
¹⁷ FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
¹⁸ CIBERSAM, Instituto de Salud Carlos III, Barcelona, Spain.
¹⁹ Clinical Neuroimaging Laboratory, Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, University of Galway, Galway, Ireland.
²⁰ Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
²¹ Research Group in Psychiatry GIPSI, Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellin, Colombia.
²² Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²³ Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
²⁴ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.
²⁵ Desert-Pacific MIRECC, VA San Diego Healthcare, San Diego, California, USA.
²⁶ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain.
²⁷ Neuroscience Research Australia, Randwick, New South Wales, Australia.
²⁸ School of Biomedical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, Australia.
²⁹ Department of Psychology, Stanford University, Stanford, California, USA.
³⁰ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³¹ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³² Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
³³ Core-Facility Brainimaging, Faculty of Medicine, University of Marburg, Germany.
³⁴ Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
³⁵ Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.
³⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁷ Department of Psychiatry, University of Vermont College of Medicine, Burlington, Vermont, USA.
³⁸ Institute of Clinical Medicine, Department of Neurology, University of Oslo, Oslo, Norway.
³⁹ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁴⁰ Discipline of Psychiatry and Mental Health, School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, Australia.
⁴¹ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
⁴² German Center for Mental Health (DZPG), Site Jena-Magdeburg-Halle, Germany.
⁴³ UCLA Center for Neurobehavioral Genetics, Los Angeles, California, USA.
⁴⁴ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
⁴⁵ Research Group, Instituto de Alta Tecnología Médica, Ayudas diagnósticas SURA, Medellin, Colombia.
⁴⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
⁴⁷ Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴⁸ Oxley College of Health Sciences, The University of Tulsa, Tulsa, Oklahoma, USA.
⁴⁹ Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.
⁵⁰ West Region, Institute of Mental Health, Singapore, Singapore.
⁵¹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵² Minneapolis VA Health Care System, Minneapolis, Minnesota, USA.
⁵³ South African MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
⁵⁴ Turner Institute for Brain and Mental Health, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia.
⁵⁵ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
⁵⁶ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵⁷ Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵⁸ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Instituto de Salud Carlos III, Institute of Neuroscience, University of Barcelona, Hospital Clínic, Barcelona, Spain.
⁵⁹ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁶⁰ University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 38825977
PMCID: PMC11144951
DOI: 10.1002/hbm.26682

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity

Sean R McWhinney et al. Hum Brain Mapp. 2024.

. 2024 Jun 1;45(8):e26682.

doi: 10.1002/hbm.26682.

Authors

Affiliations

¹ Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
² Department of Complex Systems, Institute of Computer Science, Czech Academy of Sciences, Prague, Czech Republic.
³ National Institute of Mental Health, Klecany, Czech Republic.
⁴ Department of Cybernetics, Czech Technical University, Prague, Czech Republic.
⁵ Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
⁶ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Marburg, Germany.
⁸ Vita-Salute San Raffaele University, Milan, Italy.
⁹ Division of Neuroscience, Psychiatry and Psychobiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
¹⁰ Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, Victoria, Australia.
¹¹ Unit for Psychosomatics/CL Outpatient Clinic for Adults, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹² Institute for Translational Psychiatry, University of Münster, Münster, Germany.
¹³ Department of Child Adolescent Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
¹⁴ Unit for Psychosomatics and C-L Psychiatry for Adults, Oslo University Hospital, Oslo, Norway.
¹⁵ Department of Behavioural Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
¹⁶ Institute of Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
¹⁷ FIDMAG Germanes Hospitalàries Research Foundation, Barcelona, Spain.
¹⁸ CIBERSAM, Instituto de Salud Carlos III, Barcelona, Spain.
¹⁹ Clinical Neuroimaging Laboratory, Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, University of Galway, Galway, Ireland.
²⁰ Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, Minnesota, USA.
²¹ Research Group in Psychiatry GIPSI, Department of Psychiatry, Faculty of Medicine, Universidad de Antioquia, Medellin, Colombia.
²² Institute of Clinical Medicine, Norwegian Centre for Mental Disorders Research (NORMENT), University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²³ Department of Neurology, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
²⁴ Department of Psychiatry, University of California San Diego, La Jolla, California, USA.
²⁵ Desert-Pacific MIRECC, VA San Diego Healthcare, San Diego, California, USA.
²⁶ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain.
²⁷ Neuroscience Research Australia, Randwick, New South Wales, Australia.
²⁸ School of Biomedical Sciences, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, Australia.
²⁹ Department of Psychology, Stanford University, Stanford, California, USA.
³⁰ Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
³¹ Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
³² Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
³³ Core-Facility Brainimaging, Faculty of Medicine, University of Marburg, Germany.
³⁴ Institute of Neuroscience and Physiology, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
³⁵ Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.
³⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
³⁷ Department of Psychiatry, University of Vermont College of Medicine, Burlington, Vermont, USA.
³⁸ Institute of Clinical Medicine, Department of Neurology, University of Oslo, Oslo, Norway.
³⁹ Institute for Translational Neuroscience, University of Münster, Münster, Germany.
⁴⁰ Discipline of Psychiatry and Mental Health, School of Clinical Medicine, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, Australia.
⁴¹ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
⁴² German Center for Mental Health (DZPG), Site Jena-Magdeburg-Halle, Germany.
⁴³ UCLA Center for Neurobehavioral Genetics, Los Angeles, California, USA.
⁴⁴ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
⁴⁵ Research Group, Instituto de Alta Tecnología Médica, Ayudas diagnósticas SURA, Medellin, Colombia.
⁴⁶ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
⁴⁷ Meditation Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁴⁸ Oxley College of Health Sciences, The University of Tulsa, Tulsa, Oklahoma, USA.
⁴⁹ Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.
⁵⁰ West Region, Institute of Mental Health, Singapore, Singapore.
⁵¹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵² Minneapolis VA Health Care System, Minneapolis, Minnesota, USA.
⁵³ South African MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa.
⁵⁴ Turner Institute for Brain and Mental Health, School of Psychological Sciences and Monash Biomedical Imaging, Monash University, Melbourne, Victoria, Australia.
⁵⁵ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
⁵⁶ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵⁷ Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
⁵⁸ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Instituto de Salud Carlos III, Institute of Neuroscience, University of Barcelona, Hospital Clínic, Barcelona, Spain.
⁵⁹ Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, The Netherlands.
⁶⁰ University of British Columbia, Vancouver, British Columbia, Canada.

PMID: 38825977
PMCID: PMC11144951
DOI: 10.1002/hbm.26682

Abstract

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.

Keywords: MRI; bipolar disorder; body mass index; obesity; principal component analysis; psychiatry.

PubMed Disclaimer

Conflict of interest statement

PMT & CRKC received a grant from Biogen, Inc., for research unrelated to this manuscript. DJS has received research grants and/or consultancy honoraria from Lundbeck and Sun. LNY has received speaking/consulting fees and/or research grants from Abbvie, Alkermes, Allergan, AstraZeneca, CANMAT, CIHR, Dainippon Sumitomo Pharma, Janssen, Lundbeck, Otsuka, Sunovion, and Teva. TE received speaker's honoraria from Lundbeck and Janssen Cilag and is a consultant to Sumitomo Pharma America. Thanks also for the support of the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing, and disease: Grant No 754907 and EU.3.1.3. Treating and managing disease: Grant No 945151). EV has received grants and served as consultant, advisor, or CME speaker for the following entities (unrelated to the present work): AB‐Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi‐Aventis, and Takeda. PMT and CRKC have received partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript. EV has received grants and served as consultant, advisor, or CME speaker for the following entities: AB‐Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer‐Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo‐Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi‐Aventis, Sunovion, Takeda, and Viatris, outside the submitted work. Yatham reports grants from Abbvie and Dainippon Sumitomo, and served as an advisor or consultant or speaker to JAMA Pharma, Intracellular Therapies, Merck, Allergan, GSK, Gedeon Richter, Sanofi, Sunovion, and Alkermes, outside the submitted work.

Figures

**FIGURE 1**
PCA results with variance explained by each component (left) and distribution of the first two components for cortical thickness and surface area (right). Cortical thickness distributions are broken out by research site.

**FIGURE 2**
Factor loadings of the first principal component for cortical thickness (top) and surface area (bottom).

See this image and copyright information in PMC

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Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity

Affiliations

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity

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Abstract

Conflict of interest statement

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