Reproducible brain-wide association studies require thousands of individuals

Scott Marek, Brenden Tervo-Clemmens, Finnegan J. Calabro, David F. Montez, Benjamin P. Kay, Alexander S. Hatoum, Meghan Rose Donohue, William Foran, Ryland L. Miller, Timothy J. Hendrickson, Stephen M. Malone, Sridhar Kandala, Eric Feczko, Oscar Miranda-Dominguez, Alice M. Graham, Eric A. Earl, Anders J. Perrone, Michaela Cordova, Olivia Doyle, Lucille A. MooreGregory M. Conan, Johnny Uriarte, Kathy Snider, Benjamin J. Lynch, James C. Wilgenbusch, Thomas Pengo, Angela Tam, Jianzhong Chen, Dillan J. Newbold, Annie Zheng, Nicole A. Seider, Andrew N. Van, Athanasia Metoki, Roselyne J. Chauvin, Timothy O. Laumann, Deanna J. Greene, Steven E. Petersen, Hugh Garavan, Wesley K. Thompson, Thomas E. Nichols, B. T.Thomas Yeo, Deanna M. Barch, Beatriz Luna, Damien A. Fair, Nico U.F. Dosenbach

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals.

Original languageEnglish (US)
Pages (from-to)654-660
Number of pages7
JournalNature
Volume603
Issue number7902
DOIs
StatePublished - Mar 24 2022

Bibliographical note

Funding Information:
We thank A. M. Dale, T. L. Jernigan, W. Zhao, C. Makowski, C. C. Fan and C. Palmer for their thoughtful comments on the manuscript. This work was supported by NIH grants MH100019 (S.M., N.A.S., A.M. and T.O.L.,), MH121518 (S.M.), DA007261 (D.F.M.), NS090978 (B.P.K.), DA007261 (A.S.H.), MH125023 (M.R.D), NS110332 (D.J.N.), NS115672 (A.Z.), MH112473 (T.O.L.), MH104592 (D.J.G.), AA02969 (S.M.M.), DA041148 (D.A.F.), DA04112 (D.A.F.), MH115357 (D.A.F.), MH096773 (D.A.F. and N.U.F.D.), MH122066 (D.A.F. and N.U.F.D.), MH121276 (D.A.F. and N.U.F.D.), MH124567 (D.A.F. and N.U.F.D.), NS088590 (N.U.F.D.), and the Andrew Mellon Predoctoral Fellowship (B.T.-C.), Lynne and Andrew Redleaf Foundation (D.A.F.), Kiwanis Neuroscience Research Foundation (N.U.F.D.) and the Jacobs Foundation grant 2016121703 (N.U.F.D.). ABCD Study: data used in the preparation of this article, in part, were obtained from the ABCD Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9?10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147, U01DA041093 and U01DA041025. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/scientists/workgroups/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. HCP Study: data were provided, in part, by the Human Connectome Project, WU-Minn Consortium (U54 MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. UK Biobank study: this research has been conducted, in part, using data from UK Biobank (www.ukbiobank.ac.uk). UK Biobank is generously supported by its founding funders the Wellcome Trust and UK Medical Research Council, as well as the Department of Health, Scottish Government, the Northwest Regional Development Agency, British Heart Foundation and Cancer Research UK. XSEDE and Pittsburgh Supercomputing Center: this work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. Specifically, it used the Bridges system, which is supported by NSF award number ACI-1445606, at the Pittsburgh Supercomputing Center (PSC TG-IBN200009). MIDB, NGDR and MSI: this work used the storage and computational resources provided by the Masonic Institute for the Developing Brain (MIDB) the Neuroimaging Genomics Data Resource (NGDR) and the Minnesota Supercomputing Institute (MSI). NGDR is supported by the University of Minnesota Informatics Institute through the MnDRIVE initiative in coordination with the College of Liberal Arts, Medical School and College of Education and Human Development at the University of Minnesota. Daenerys NCCR: this work used the storage and computational resources provided by the Daenerys Neuroimaging Community Computing Resource (NCCR). The Daenerys NCCR is supported by the McDonnell Center for Systems Neuroscience at Washington University, the Intellectual and Developmental Disabilities Research Center (IDDRC; P50 HD103525) at Washington University School of Medicine and the Institute of Clinical and Translational Sciences (ICTS; UL1 TR002345) at Washington University School of Medicine.

Funding Information:
We thank A. M. Dale, T. L. Jernigan, W. Zhao, C. Makowski, C. C. Fan and C. Palmer for their thoughtful comments on the manuscript. This work was supported by NIH grants MH100019 (S.M., N.A.S., A.M. and T.O.L.,), MH121518 (S.M.), DA007261 (D.F.M.), NS090978 (B.P.K.), DA007261 (A.S.H.), MH125023 (M.R.D), NS110332 (D.J.N.), NS115672 (A.Z.), MH112473 (T.O.L.), MH104592 (D.J.G.), AA02969 (S.M.M.), DA041148 (D.A.F.), DA04112 (D.A.F.), MH115357 (D.A.F.), MH096773 (D.A.F. and N.U.F.D.), MH122066 (D.A.F. and N.U.F.D.), MH121276 (D.A.F. and N.U.F.D.), MH124567 (D.A.F. and N.U.F.D.), NS088590 (N.U.F.D.), and the Andrew Mellon Predoctoral Fellowship (B.T.-C.), Lynne and Andrew Redleaf Foundation (D.A.F.), Kiwanis Neuroscience Research Foundation (N.U.F.D.) and the Jacobs Foundation grant 2016121703 (N.U.F.D.). ABCD Study: data used in the preparation of this article, in part, were obtained from the ABCD Study ( https://abcdstudy.org ), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10,000 children aged 9–10 and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041022, U01DA041028, U01DA041048, U01DA041089, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147, U01DA041093 and U01DA041025. A full list of supporters is available at https://abcdstudy.org/federal-partners.html . A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/scientists/workgroups/ . ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators. HCP Study: data were provided, in part, by the Human Connectome Project, WU-Minn Consortium (U54 MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. UK Biobank study: this research has been conducted, in part, using data from UK Biobank ( www.ukbiobank.ac.uk ). UK Biobank is generously supported by its founding funders the Wellcome Trust and UK Medical Research Council, as well as the Department of Health, Scottish Government, the Northwest Regional Development Agency, British Heart Foundation and Cancer Research UK. XSEDE and Pittsburgh Supercomputing Center: this work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. Specifically, it used the Bridges system, which is supported by NSF award number ACI-1445606, at the Pittsburgh Supercomputing Center (PSC TG-IBN200009). MIDB, NGDR and MSI: this work used the storage and computational resources provided by the Masonic Institute for the Developing Brain (MIDB) the Neuroimaging Genomics Data Resource (NGDR) and the Minnesota Supercomputing Institute (MSI). NGDR is supported by the University of Minnesota Informatics Institute through the MnDRIVE initiative in coordination with the College of Liberal Arts, Medical School and College of Education and Human Development at the University of Minnesota. Daenerys NCCR: this work used the storage and computational resources provided by the Daenerys Neuroimaging Community Computing Resource (NCCR). The Daenerys NCCR is supported by the McDonnell Center for Systems Neuroscience at Washington University, the Intellectual and Developmental Disabilities Research Center (IDDRC; P50 HD103525) at Washington University School of Medicine and the Institute of Clinical and Translational Sciences (ICTS; UL1 TR002345) at Washington University School of Medicine.

Funding Information:
Participant level data from all datasets (ABCD, HCP, UKB) are openly available pursuant to individual consortium-level data access rules. The ABCD data repository grows and changes over time ( https://nda.nih.gov/abcd ). The ABCD data used in this report came from ABCD collection 3165 and the Annual Release 2.0 ( https://doi.org/10.15154/1503209 ). The UK Biobank is a large-scale biomedical database and research resource containing genetic, lifestyle and health information from half a million UK participants ( www.ukbiobank.ac.uk ). UK Biobank’s database, which includes blood samples, heart and brain scans and genetic data of the 500,000 volunteer participants, is globally accessible to approved researchers who are undertaking health-related research that is in the public interest. Data were provided, in part, by the Human Connectome Project, WU-Minn Consortium (principal investigators: D. Van Essen and K. Ugurbil; 1U54MH091657) funded by the 16 NIH institutes and centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. Some data used in the present study are available for download from the Human Connectome Project ( www.humanconnectome.org ). Users must agree to data use terms for the HCP before being allowed access to the data and ConnectomeDB; details are provided at https://www.humanconnectome.org/study/hcp-young-adult/data-use-terms . are provided with this paper.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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