COMPASS Ancillary NeuroDevelopmental Outcomes(CAN-DO) - PROJECT SUMMARY/ABSTRACT Neurodevelopmental (ND) impairment is the most common morbidity for individuals born with critical congenital heart disease (CHD) such as ductal-dependent pulmonary blood flow (DDPBF). This results in high individual, familial, and societal burden. Clinical and sociodemographic factors have been shown to impact ND outcome, and the interventional approach for cardiac repair may also play an important role. For neonates with DDPBF, recent preliminary studies have shown that using transcatheter ductal arterial stenting (DAS) in lieu of surgical systemic-to-pulmonary artery shunting (SPS) may result in improved survival and shorter length of stay but these studies have not examined differences in ND outcomes. These studies led to the COmparison of Methods of Pulmonary blood flow Augmentation in neonates: Shunt versus Stent (COMPASS) Trial, a multicenter randomized controlled trial currently being conducted through the Pediatric Heart Network, that will compare cardiac morbidities and mortality within the first 12 months of life in 300 neonates with DDPBF randomized to SPS or DAS intervention but does not include ND outcomes. The enclosed proposal is an ancillary prospective longitudinal ND study of COMPASS-eligible patients that will compare ND outcomes at 36-months of age between the SPS and DAS groups using a multivariable model to account for pre-procedural medical and sociodemographic risk factors for ND impairment. Candidate biomarkers of neural injury will be measured peri- operatively to evaluate for differences by intervention approach and assess their predictive utility for ND outcomes, while targeted biomarkers of neural development will be measured peri-operatively and at 36-months to determine their relationship to ND outcome. Broader multi-omics analyses will assess for interactions between the genome, proteome, and exposome (including medical exposures and social determinants of health) for predicting 36-month ND outcomes. We will test the following hypotheses: 1) After controlling for known pre- procedural risk factors for ND impairment (medical, sociodemographic, and genetic factors), children who underwent DAS will have better ND outcomes at 36-months of age compared to those who underwent SPS, 2) Perioperative candidate biomarkers of neural injury and longitudinal biomarkers of neural development will improve prediction of ND outcomes in both neonatal intervention groups, and 3). Proteomic, genomic, and exposomic risk factors will interact to further predict 36-month ND outcomes. Results from this proposal will contribute important ND outcome data for the COMPASS Trial and, more broadly, improve our understanding of the ND burden in this patient population through developing the most comprehensive predictive model to date for ND outcomes in children with critical CHD. Our ultimate goal is to identify interventional targets to improve ND outcomes in DDPBF and to inform precision medicine strategies for selecting the neonatal intervention approach based on patient-specific factors to optimize ND outcomes. Finally, this proposal will establish a robust framework for leveraging existing clinical registries to incorporate ND outcomes in future clinical trials in CHD.
