Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.
Competing Interests: Declaration of competing interest A. Kushki received grants from the National Science and Engineering Research Council during the conduct of the study and holds a patent for Anxiety Meter with royalties paid from Awake Labs. E. King reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Goldmuntz reported receiving grants from the NIH during the conduct of the study. T. A. Miller reported receiving grants from the NIH during the conduct of the study. N. H. Thomas reported receiving grants from the NIH, including the Clinical and Translational Science Awards Program, during the conduct of the study. J. F. Cnota reported receiving grants from the NIH during the conduct of the study and from Additional Ventures outside the submitted work. C. S. Goldberg reported receiving grants from the NIH related to work for the Pediatric Heart Network during the conduct of the study. P. McQuillen reported receiving grants from the NIH during the conduct of the study. G. A. Porter reported receiving grants from the University of Rochester Medical Center. A. E. Roberts reported receiving grants from the NIH during the conduct of the study. C. E. Seidman serves as a consultant for Maze Therapeutics and on the board of directors for Merck and the Burroughs Wellcome Fund; these companies had no role in the design, execution, or analyses of this study. J. W. Newburger has served as a consultant to and received grant funds from Pfizer: received honoraria from Daiichi-Sankyo for membership on a trial Steering Committee; and chaired Independent Clinical Events Committees for Bristol Myer Squibb, Pfizer, and Novartis. E. Anagnostou has received grants from Roche and Anavex, served as a consultant to Roche, Quadrant Therapeutics, Ono, and Impel Pharmaceuticals, has received in-kind support from AMO Pharma and CRA-Simons Foundation, holds a patent for the device, “Anxiety Meter”, has received royalties from APPI and Springer, and has received an editorial honorarium from Wiley. The remaining authors have reported no potential conflicts of interest.
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