A major hurdle to studying traumatic brain injury (TBI) has been disentangling the many complicating and compounding factors that influence outcome and recovery. While extensive efforts have been placed on delineating the impact of various environmental contributions (e.g., combat exposure, mechanism of injury, etc.) on TBI outcome, the literature pertaining to the neurobiological underpinnings of poor clinical outcome in the aftermath of TBI is comparatively limited. In particular, our understanding of the influence of genetic factors on outcome and recovery following TBI is incomplete. Notably, among the studies that have examined these relationships, findings are considerably disparate, likely due to inadequate sample sizes and therefore low power to detect meaningful differences in TBI samples. Additionally, existing genetics studies have largely adopted a ?candidate gene? approach, focusing on a specific gene of interest, thereby downplaying the possibility that genetic predisposition to complex traits is highly polygenic?that is, the individual contribution of a specific gene may be slight, but the effects of multiple genes could be quite significant. Thus, not only are adequately powered studies needed to better understand the influence of genetic markers on TBI clinical outcome, but a crucial next step is to apply the concept of polygenic risk to TBI and conceptualize post-injury clinical outcome as a complex polygenic phenotype. Moreover, there is accumulating evidence to suggest that the presence of neuroendocrine abnormalities may also contribute to the heterogeneous outcomes observed following TBI, yet these associations are also poorly understood. With this in mind, the present study is an observational cohort study proposing to use data available from the Million Veteran Program to examine the influence of genetic factors and neuroendocrine abnormalities on cognitive and psychiatric outcomes in Veterans with TBI histories in order to increase understanding of the extent to which neurobiological factors influence these important clinical outcomes post-TBI. Strengths of this proposal include (1) the use of large- scale genetic data to expand our understanding of neurobiological factors associated with TBI outcome, (2) the application of polygenic risk to TBI, and (3) a focus on the long-term health care outcomes of Veterans with TBI histories. Findings from this study may have particular relevance to treatments that are currently being developed and optimized within a precision medicine approach to target those most at risk of poor outcome. The applicant is currently a neuropsychology postdoctoral fellow completing the TBI/Polytrauma Fellowship at the VA San Diego Healthcare System. Successful completion of this VA Career Development Award-2 (CDA-2) will allow the candidate to advance toward a long-term career goal of being an independent clinical researcher within the VA, focused on the development of a TBI research program that serves to elucidate the acute and chronic effects of TBI across the lifespan by incorporating the tools and techniques of biological markers such as genetics and neuroendocrinology to study the processes that underlie TBI clinical outcome and recovery. To successfully develop an independent research program, the candidate would benefit from the additional training and experience that this CDA-2 will provide. Specific training goals are to: (1) acquire competencies in the integration of genetic data with clinically-relevant outcome measures (i.e., neurocognitive and psychiatric variables) while gaining familiarity with the methods of genome-wide association studies and the development and modeling of polygenic risk scores; (2) learn fundamental principles and applications of neuroendocrinology within the context of military TBI; (3) develop expertise in advanced biostatistics and big data, and receive training in navigating the VA Informatics & Computing Infrastructure; and (4) obtain mentorship related to scientific and professional development. Working collaboratively with a distinguished mentorship team, the candidate will receive the necessary training and preparation that will allow for advancement toward independence as a clinical researcher within the VA.
Neuropsychological and neurobehavioral outcomes following traumatic brain injury (TBI) are considerably heterogeneous, and despite there being an ?expected? recovery, there are many individual factors that can influence post-injury outcome. While extensive effort has been placed on delineating the impact of various environmental contributions on TBI outcome, the literature pertaining to neurobiological underpinnings of poor clinical outcome in the aftermath of TBI is comparatively limited. The proposed study seeks to use data from the Million Veteran Program?a very large genetic and clinical database?to examine the influence of genetic factors and neuroendocrine abnormalities on cognitive and psychiatric outcomes in Veterans with TBI histories. Determining the extent to which underlying neurobiological factors contribute to post-injury outcome would offer critical information to healthcare providers and patients, and findings could have profound relevance to treatments that are currently being developed and optimized using a personalized approach to medicine.
