Reuter-Rice and Co-PI Ashley-Koch Submit NIH R01 Proposal

Kudos to Karin Reuter-Rice and  her Co-PI, Allison Ashley-Koch (SoM) and their entire team for the submission of their NIH R01 proposal entitled "Genetic and Genomic Predictors of Child Health Outcomes after mTBI." This proposal requests funding for a five-year period with a start date of July 1, 2019.

Pediatric mild traumatic brain injury (mTBI) impacts child health outcomes. Recent studies have found that mTBI-related emergency department visits increased by 47% (2007-2013) and that in 20% of children subtle cognitive, functional, and/or behavioral (neurologic) impact persist at 3-months post-injury, making mTBI a “silent epidemic”. Therefore, early identification of the child who is at risk for neurologic outcomes would radically impact the timing, evaluation and effectiveness of treatment strategies for mTBI, and thereby lead to improved child health outcomes. Prognostic genetic/genomic biomarkers of neurologic outcomes in pediatric mTBI do not yet exist; however, we have preliminary evidence of novel genetic markers that may objectively reflect underlying risk for poor health outcomes in children with mTBI. In a genome wide association study (GWAS); using available data from dbGaP, we identified genome-wide significant evidence for a SNP (rs2165255) associated with cognitive delay in a cohort of 1,200 children (mean age 14.8 years) with reported history of TBI (FDR q-value=0.04; b=3.681). The dbGaP study, however, was not designed to specifically examine pediatric mTBI who present to the emergency department, and thus lacks rich clinical data such as comprehensive measures over multiple time-points to assess cognitive, functional, and behavioral outcomes after mTBI. The goal of this first-of-its-kind study is to address the following aims.

Aim 1: Prospectively ascertain 1,200 children (aged Birth-17 years) with mTBI, collecting saliva for genomic and transcriptomic data generation, deeply phenotyping for cognitive, functional, and behavioral outcome scores at time of TBI evaluation (t1), as well as at 1 month post-injury (t2) and 3-month post-injury (t3). We will also collect outcome measures at 3 months post-injury to provide further evaluation of recovery.

Aim 2: Identify novel genes through GWAS that are associated with poor neurologic outcomes in children with mTBI as measured by cognitive, functional, and behavioral outcome scores over the 3-time points. We will also replicate and meta-analyze discovery GWAS significant hits for cognitive delay in the dbGaP cohort.

Aim 3: Perform transcriptomic analysis in the prospective cohort of 1,200 children with mTBI to identify transcriptomic signatures at t2 that are associated with poor in cognitive, functional, and behavioral outcomes collected at t2 and t3. This study will be the first to examine novel transcription signatures of transient biological effects across time in mTBI. Results will vertically advance our understanding of biological contributions to differences in three dimensions of pediatric health outcomes that could lead to innovations in personalized medicine and treatments for mTBI.

This project will also be the first to contribute well-powered pediatric mTBI GWAS, RNA-seq, and repeated measures outcome data to the NIH’s shared repositories to inform future hypotheses. Our approaches may also be transferable to investigations of other brain injury populations.