Genetic, demographic and clinical variables act synergistically to impact neurodevelopmental outcomes in children with single ventricle heart disease

Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetic data are complicated by the intrinsic severity of the CHD lesion and by interactions with conditionally dependent clinical variables. Here we apply Bayesian Networks, an explainable Artificial Intelligence solution, to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD. As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increased the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables acted synergistically to further increase the probability of a low MDI score by 10-fold. Likewise, genetic information was predictive of a favorable neurodevelopmental outcome. For example, the absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increased the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increased the probability of a good outcome by 59-fold. Our analyses suggest a modest genetic contribution to neurodevelopmental and growth outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography. ### Competing Interest Statement MY is a consultant to Fabric Genomics Inc. and has received consulting fees and stock grants from Fabric Genomics Inc. The remaining authors declare that they have no competing interests relevant to this project. ### Funding Statement The clinical data for this project was supported by National Heart, Lung, and Blood Institute (NHLBI) Pediatric Heart Network grants HL068269, HL068270, HL068279, HL068281, HL068285, HL068288, HL068290, HL068292, and HL085057. The genomic data for this project was supported by the NHLBI Pediatric Cardiac Genomics Consortium (UM1-HL098147, UM1-HL128761, UM1-HL098123, UM1-HL128711, UM1-HL098162, U01-HL131003, U01-HL098153, U01-HL098163), the National Center for Research Resources (U01-HL098153), and the National Institutes for Health (R01-GM104390, 1S10OD021644-01A1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Boards for all centers participating in the SVR and ISV trials gave ethical approval for the human subjects research in this work and written informed consent was obtained. Data Use Agreements between the PHN and the Pediatric Cardiac Genomics Consortium (PCGC) allowed for the de-identified sharing of genetic and limited clinical data between the two consortia. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The sequencing data used in this analysis may be downloaded, with committee-approved access, from the database of Genotypes and Phenotypes (dbGaP) \[www.ncbi.nlm.nih. gov/\] (accession numbers phs000571.v5.p2). Clinical data for this cohort is available as a public use dataset (https://www.pediatricheartnetwork.org/login/).