Examination of Biological Markers Associated with Neurobehavioral and Neuropsychological Outcomes in Military Veterans with a History of Traumatic Brain Injury

研究创伤性脑损伤(TBI)的一个主要障碍是解开许多复杂的 以及影响结果和恢复的复合因素。虽然已经做出了广泛的努力， 描述各种环境贡献的影响(例如，战斗暴露、伤害机制、 等)关于颅脑损伤的结果，与临床预后不良的神经生物学基础有关的文献 创伤性脑损伤的后果相对有限。特别是，我们对遗传因素的影响的理解 关于颅脑损伤后的结果和恢复是不完整的。值得注意的是，在研究这些问题的研究中 关系，结果是相当不同的，可能是由于样本量不足，因此低 检测TBI样本中有意义的差异的能力。此外，现有的遗传学研究在很大程度上 采用了“候选基因”的方法，专注于感兴趣的特定基因，从而淡化了 复杂性状的遗传易感性是高度多基因的可能性--也就是，个体对 一个特定的基因可能很轻微，但多个基因的影响可能相当显著。因此，不仅是 需要充足的研究来更好地了解遗传标记对脑外伤临床的影响 结果，但关键的下一步是将多基因风险的概念应用于脑外伤并概念化损伤后 临床结果表现为复杂的多基因表型。此外，越来越多的证据表明， 神经内分泌异常的存在也可能是观察到的不同结果的原因。 然而，在脑外伤之后，人们对这些联系也知之甚少。考虑到这一点，本研究是一项 观察性队列研究建议使用百万退伍军人计划提供的数据来检查 遗传因素和神经内分泌异常对认知和精神结局的影响 有脑外伤病史的退伍军人，以增加对神经生物学因素在多大程度上的了解 影响颅脑损伤后这些重要的临床结果。这项提议的优点包括：(1)使用大型- 衡量遗传数据，以扩大我们对与脑外伤预后相关的神经生物学因素的理解，(2) 多基因风险在脑外伤中的应用，以及(3)关注退伍军人脑外伤患者的长期保健结果 历史。这项研究的发现可能对目前正在进行的治疗具有特别的相关性 在精准医学方法内开发和优化，以瞄准那些面临不良结果风险最大的人。 申请人目前是神经心理学博士后，正在攻读脑损伤/多发性创伤。 退伍军人事务部圣地亚哥医疗系统研究员。顺利完成退伍军人管理局的职业发展 奖项2(CDA-2)将允许候选人朝着成为一名独立人士的长期职业目标前进 退伍军人事务部的临床研究人员，专注于脑损伤研究计划的开发，该计划服务于 通过整合以下工具和技术，阐明脑外伤对生命周期的急性和慢性影响 生物学标记物，如遗传学和神经内分泌学，用于研究脑外伤临床基础过程 结果和恢复。为了成功地开发一个独立的研究计划，候选人将 受益于CDA-2将提供的额外培训和经验。具体的培训目标是： (1)获得将遗传数据与临床相关的结果衡量标准相结合的能力(即， 神经认知和精神病学变量)，同时熟悉全基因组的方法 关联性研究和多基因风险评分的开发和建模；(2)学习基础知识 在军事脑外伤背景下的神经内分泌学原理和应用；(3)在以下方面发展专门知识 高级生物统计学和大数据，并接受退伍军人信息学和计算导航培训 基础设施；以及(4)获得与科学和专业发展有关的指导。劳作 与杰出的指导团队合作，应聘者将接受必要的培训和 作为退伍军人事务部的一名临床研究人员，这一准备工作将使其走向独立。

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.