Genetic Models for Long-Term Neurocognitive Outcomes in Pediatric Medulloblastoma and Traumatic Brain Injury

Background: Children who suffer from brain insults (i.e., traumatic brain injury (TBI), chemotherapy and radiation treatment for brain tumors) are susceptible to late-emerging cognitive sequelae. Even with similar neurological risk variables, variability in long-term cognitive outcomes remains an area of investigation for researchers of acquired brain injury. Given the potential for genetic factors to influence response to chemoradiation, researchers have examined associations between germline, inherited, single nucleotide polymorphisms (SNPs), and neurocognitive outcomes for cancer survivors. The study of TBI survivors’ genomic vulnerability is limited. This study aims to identify associations between genotype and long-term neurocognitive outcomes for acquired brain injury survivors by utilizing machine learning to uncover pathophysiological similarities and differences between groups. Methods: Fourteen brain tumor survivors, 139 traumatic brain injury, and 63 healthy, age-matched controls completed the Letter N-back task to obtain performances on core neurocognitive skills (attention, working memory, and processing speed). Ten targeted genotypes across five pathophysiological pathways were examined. Data were trained and tested utilizing three regression machine learning models. Mean squared error and R2 were generated for each neurocognitive outcome. Results: Genotype only accounted for a small amount of variance in cognitive outcomes when all clinical groups were combined. While the mean absolute error for the best-fitting models from Aim 1 decreased for Aim 2, the differences in model R2 values were not significant. The relationship between brain tumor survivors and processing speed was dependent on genotype, and two SNPs had positive feature importance at the interaction level (rs58225473 and rs1801394). These SNPs, located on the CACNB2 and MTR genes, are involved in neurotransmission and folate metabolism. Models of traumatic brain injury survivors did not explain positive variance and could not be examined for feature importance. Conclusions: Findings of the importance of two key SNPs, on MTR and CACNB2 genes align with recent systematic reviews. Models for TBI survivors were limited by the heterogeneity of the group and ceiling effects on performance. An understanding of genetic vulnerabilities influenced by treatment and injury-related factors in acquired brain injury will inform our understanding of the developing and recovering childhood brain