Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group

André Zugman¹, Anita Harrewijn¹, Elise M Cardinale¹, Hannah Zwiebel¹, Gabrielle F Freitag¹, Katy E Werwath¹, Janna M Bas-Hoogendam^{2

3

4}, Nynke A Groenewold⁵, Moji Aghajani^{6

7}, Kevin Hilbert⁸, Narcis Cardoner^{9

10

11}, Daniel Porta-Casteràs^{9

10

11}, Savannah Gosnell¹², Ramiro Salas¹², Karina S Blair¹³, James R Blair¹³, Mira Z Hammoud¹⁴, Mohammed Milad¹⁴, Katie Burkhouse¹⁵, K Luan Phan¹⁶, Heidi K Schroeder¹⁷, Jeffrey R Strawn¹⁷, Katja Beesdo-Baum¹⁸, Sophia I Thomopoulos¹⁹, Hans J Grabe^{20

21}, Sandra Van der Auwera^{20

21}, Katharina Wittfeld^{20

21}, Jared A Nielsen^{22

23}, Randy Buckner^{22

23

24}, Jordan W Smoller²⁴, Benson Mwangi²⁵, Jair C Soares²⁵, Mon-Ju Wu²⁵, Giovana B Zunta-Soares²⁵, Andrea P Jackowski²⁶, Pedro M Pan²⁶, Giovanni A Salum²⁷, Michal Assaf^{28

29}, Gretchen J Diefenbach^{30

31}, Paolo Brambilla³², Eleonora Maggioni³², David Hofmann³³, Thomas Straube³³, Carmen Andreescu³⁴, Rachel Berta³⁴, Erica Tamburo³⁴, Rebecca Price³⁵, Gisele G Manfro^{36

37}, Hugo D Critchley³⁸, Elena Makovac³⁹, Matteo Mancini³⁸, Frances Meeten⁴⁰, Cristina Ottaviani⁴¹, Federica Agosta^{42

43}, Elisa Canu⁴², Camilla Cividini⁴², Massimo Filippi^{42

43

44}, Milutin Kostić^{45

46}, Ana Munjiza⁴⁵, Courtney A Filippi¹, Ellen Leibenluft¹, Bianca A V Alberton⁴⁷, Nicholas L Balderston⁴⁸, Monique Ernst¹, Christian Grillon¹, Lilianne R Mujica-Parodi⁴⁹, Helena van Nieuwenhuizen⁵⁰, Gregory A Fonzo⁵¹, Martin P Paulus⁵², Murray B Stein⁵³, Raquel E Gur⁵⁴, Ruben C Gur⁵⁴, Antonia N Kaczkurkin⁵⁴, Bart Larsen⁵⁴, Theodore D Satterthwaite⁵⁴, Jennifer Harper⁵⁵, Michael Myers⁵⁵, Michael T Perino⁵⁵, Qiongru Yu⁵⁵, Chad M Sylvester⁵⁵, Dick J Veltman⁶, Ulrike Lueken⁸, Nic J A Van der Wee^{2

3}, Dan J Stein^{5

56}, Neda Jahanshad¹⁹, Paul M Thompson¹⁹, Daniel S Pine¹, Anderson M Winkler¹

Affiliations

¹ National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, Maryland, USA.
² Leiden University Medical Center, Department of Psychiatry, Leiden, The Netherlands.
³ Leiden Institute for Brain and Cognition (LIBC), Leiden, The Netherlands.
⁴ Leiden University, Institute of Psychology, Developmental and Educational Psychology, Leiden, The Netherlands.
⁵ Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁶ Department. of Psychiatry, Amsterdam UMC/VUMC, Amsterdam, The Netherlands.
⁷ GGZ InGeest, Department of Research & Innovation, Amsterdam, The Netherlands.
⁸ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁹ Department of Mental Health, University Hospital Parc Taulí-I3PT, Barcelona, Spain.
¹⁰ Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹¹ Centro de Investigación Biomédica en Red de Salud Mental, Carlos III Health Institute, Madrid, Spain.
¹² Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA.
¹³ Center for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, Nebraska, USA.
¹⁴ Department of Psychiatry, New York University, New York, New York, USA.
¹⁵ Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁶ Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, Ohio, USA.
¹⁷ Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁸ Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, California, USA.
²⁰ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
²¹ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
²² Department of Psychology, Harvard University, Cambridge, Massachusetts, USA.
²³ Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.
²⁴ Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁵ Center Of Excellence On Mood Disorders, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁶ LiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, São Paulo, Brazil.
²⁷ Section on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
²⁸ Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
²⁹ Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.
³⁰ Anxiety Disorders Center, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
³¹ Yale School of Medicine, New Haven, Connecticut, USA.
³² Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³³ Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
³⁴ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³⁵ Department of Psychiatry & Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³⁶ Anxiety Disorder Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
³⁷ Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
³⁸ Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.
³⁹ Centre for Neuroimaging Science, Kings College London, London, UK.
⁴⁰ School of Psychology, University of Sussex, Brighton, UK.
⁴¹ Department of Psychology, Sapienza University of Rome, Rome, Italy.
⁴² Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁴³ Vita-Salute San Raffaele University, Milan, Italy.
⁴⁴ Neurology and Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁴⁵ Institute of Mental Health, University of Belgrade, Belgrade, Serbia.
⁴⁶ Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁴⁷ Graduate Program in Electrical and Computer Engineering, Universidade Tecnológica Federal do Paraná, Curitiba, Puerto Rico, Brazil.
⁴⁸ Center for Neuromodulation in Depression and Stress, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁹ Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA.
⁵⁰ Department of Physics, Stony Brook University, Stony Brook, New York, USA.
⁵¹ Department of Psychiatry, The University of Texas at Austin Dell Medical School, Austin, Texas, USA.
⁵² Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.
⁵³ Department of Psychiatry & Family Medicine and Public Health, University of California, La Jolla, California, USA.
⁵⁴ Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵⁵ Department of Psychiatry, Washington University, St. Louis, Missouri, USA.
⁵⁶ SAMRC Unite on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

PMID: 32596977
PMCID: PMC8675407
DOI: 10.1002/hbm.25096

Review

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group

André Zugman et al. Hum Brain Mapp. 2022 Jan.

. 2022 Jan;43(1):255-277.

doi: 10.1002/hbm.25096. Epub 2020 Jun 29.

Authors

Affiliations

¹ National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, Maryland, USA.
² Leiden University Medical Center, Department of Psychiatry, Leiden, The Netherlands.
³ Leiden Institute for Brain and Cognition (LIBC), Leiden, The Netherlands.
⁴ Leiden University, Institute of Psychology, Developmental and Educational Psychology, Leiden, The Netherlands.
⁵ Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
⁶ Department. of Psychiatry, Amsterdam UMC/VUMC, Amsterdam, The Netherlands.
⁷ GGZ InGeest, Department of Research & Innovation, Amsterdam, The Netherlands.
⁸ Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany.
⁹ Department of Mental Health, University Hospital Parc Taulí-I3PT, Barcelona, Spain.
¹⁰ Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
¹¹ Centro de Investigación Biomédica en Red de Salud Mental, Carlos III Health Institute, Madrid, Spain.
¹² Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA.
¹³ Center for Neurobehavioral Research, Boys Town National Research Hospital, Boys Town, Nebraska, USA.
¹⁴ Department of Psychiatry, New York University, New York, New York, USA.
¹⁵ Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
¹⁶ Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, Ohio, USA.
¹⁷ Department of Psychiatry & Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁸ Behavioral Epidemiology, Institute of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Marina del Rey, California, USA.
²⁰ Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
²¹ German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany.
²² Department of Psychology, Harvard University, Cambridge, Massachusetts, USA.
²³ Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.
²⁴ Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁵ Center Of Excellence On Mood Disorders, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
²⁶ LiNC, Department of Psychiatry, Federal University of São Paulo, São Paulo, São Paulo, Brazil.
²⁷ Section on Negative Affect and Social Processes, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
²⁸ Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
²⁹ Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, USA.
³⁰ Anxiety Disorders Center, Institute of Living, Hartford Hospital, Hartford, Connecticut, USA.
³¹ Yale School of Medicine, New Haven, Connecticut, USA.
³² Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³³ Institute of Medical Psychology and Systems Neuroscience, University of Muenster, Muenster, Germany.
³⁴ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³⁵ Department of Psychiatry & Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
³⁶ Anxiety Disorder Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.
³⁷ Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
³⁸ Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton, UK.
³⁹ Centre for Neuroimaging Science, Kings College London, London, UK.
⁴⁰ School of Psychology, University of Sussex, Brighton, UK.
⁴¹ Department of Psychology, Sapienza University of Rome, Rome, Italy.
⁴² Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁴³ Vita-Salute San Raffaele University, Milan, Italy.
⁴⁴ Neurology and Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁴⁵ Institute of Mental Health, University of Belgrade, Belgrade, Serbia.
⁴⁶ Department of Psychiatry, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁴⁷ Graduate Program in Electrical and Computer Engineering, Universidade Tecnológica Federal do Paraná, Curitiba, Puerto Rico, Brazil.
⁴⁸ Center for Neuromodulation in Depression and Stress, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴⁹ Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA.
⁵⁰ Department of Physics, Stony Brook University, Stony Brook, New York, USA.
⁵¹ Department of Psychiatry, The University of Texas at Austin Dell Medical School, Austin, Texas, USA.
⁵² Laureate Institute for Brain Research, Tulsa, Oklahoma, USA.
⁵³ Department of Psychiatry & Family Medicine and Public Health, University of California, La Jolla, California, USA.
⁵⁴ Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁵⁵ Department of Psychiatry, Washington University, St. Louis, Missouri, USA.
⁵⁶ SAMRC Unite on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

PMID: 32596977
PMCID: PMC8675407
DOI: 10.1002/hbm.25096

Abstract

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Keywords: data sharing; generalized anxiety disorder; mega-analyses; meta-analyses; neuroimaging.

PubMed Disclaimer

Figures

**FIGURE 1**
Differences between classical, literature‐based meta‐analyses, conducted without access to individual participant data (IPD) (upper panel) versus approaches used by different ENIGMA working groups, in which researchers, collectively, have access to IPD (lower panel). The latter encompasses three main approaches (top) data are processed using common methods at each site, then summary statistics are computed and sent to a coordinating facility which then conducts a meta‐analysis; (middle) data are processed using common methods at each site, then sent to the coordinating facility which then conducts a mega‐analysis; and (bottom) raw data are sent to the coordinating facility which then processes the data in batch and conducts a mega‐analysis, while taking site‐specific effects into account

**FIGURE 2**
Example screenshot of a report of image quality for the subjects of one site. Box plots of various metrics are shown. The report is produced by the tool MRIQC, available, along with documentation that details all the metrics (many more than shown in the figure), at https://mriqc.readthedocs.io

**FIGURE 3**
Surface reconstructions of the cortex of the right hemisphere based on different resolutions of a recursively subdivided icosahedron. The default in FreeSurfer uses n = 7 recursions, resulting in a total of 163,842 vertices. Considerable computational savings can be obtained with lower resolutions (such as with n = 4 or 5) without substantial losses in localizing power. V, number of vertices; E, number of edges; F, number of triangular faces

**FIGURE 4**
Example report pages with multiple views of the cortical surfaces (front) and slices of subcortical volumes (back). Pial surfaces are shown, but inspection can use white and inflated; slices with subcortical volumes can be complemented with surface overlays. The script that generates these pages uses FreeSurfer scripting to automate the operation of the tools “tkmedit” and “tksurfer,” and is available at https://brainder.org

See this image and copyright information in PMC

References

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Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group

Affiliations

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous