Validation of a Genomics Based Prognostic in Severe Trauma

描述（由申请人提供）：损伤仍然是总体死亡的第五大原因，也是美国45岁以下人群的主要死亡原因。多器官功能衰竭（MOF）和死亡在严重损伤患者中仍然是不可接受的常见现象。在我们最近的Glue Grant研究中，19%的严重创伤患者死亡，41%发展为MOF，平均恢复时间为16天。尽管对严重创伤及其后遗症的基本病理生理学有了更好的理解，但基本上没有生物反应调节剂在前瞻性随机临床试验中被证明是成功的。我们建议，在符合纳入标准的患者中， 严重受伤的患者不需要免疫调节治疗，并且不仅不可能从这种治疗中受益，而且还遭受直接毒性。与此相反，有一部分患者将有一个长期的临床过程，并将受益于生物反应调节剂的介入治疗。目前最重要的挑战是前瞻性地确定将有长期临床病程的患者亚组，并从生物反应调节剂的介入治疗中获益。我们相信我们已经开发出了这样一种前瞻性的基因组测试。因此，本提案的总体目标是前瞻性地验证在入院后的前24小时内从严重创伤患者的血液白细胞亚群中获得的快速基因组检测，该检测可用于区分那些具有复杂临床轨迹的患者，因此，这些患者是介入免疫调节治疗的良好候选者。基于我们的初步数据，我们已经开发了几种基于总白细胞和富集的血液中性粒细胞的基因组模型，这些模型可以回顾性地识别临床表现不佳的患者。 结果，并将受益于介入免疫治疗。在这里，我们建议验证这种方法在200名严重创伤患者在两个地理上不同的机构注册。将这些基因组检测的精度与标准解剖学和生理学评分系统以及基于血浆细胞因子浓度的模型进行比较。如果成功，这些研究将极大地改变未来在严重创伤患者中进行临床试验的方式。一个成功的，快速的，预后的基因组测试将减少规模，成本和时间所需的评估新药在这一人群中确定个人的风险，一个复杂的结果。“个性化医疗”将更接近现实。

DESCRIPTION (provided by applicant): Injuries continue to be the fifth leading cause of death overall and the leading cause of death for persons less than 45 years of age in the U.S. Multiorgan failure (MOF) and death remain unacceptably common in severely injured patients. In our recent Glue Grant study, 19% of severe trauma patients died, 41% developed MOF and the average time to recovery was 16 days. Despite an improved understanding of the basic pathophysiology of severe trauma and its sequelae, there are essentially no biological response modifiers that have proven successful in prospective, randomized clinical trials. We propose that a significant proportion of patients who would generally meet the inclusion criteria for a study of severely injured patients, are not in need of immunomodulatory therapy and are not only unlikely to benefit but also suffer direct toxicity from such therapies. In contrast, there exists subset of patients who are going to have a protracted clinical course, and would benefit from interventional therapies with biological-response modifiers. The most important challenge today is to identify prospectively the subset of patients who are going to have a protracted clinical course, and would benefit from interventional therapies with biological-response modifiers. We believe that we have developed such a prospective genomic test. Therefore, the overall goal of this proposal is to prospectively validate a rapid genomic test obtained from blood leukocyte subpopulations of severely traumatized patients in the first 24 hrs after admission that can be used to discriminate those patients who will have a complicated clinical trajectory and would, therefore, be good candidates for interventional, immunomodulatory therapies. Based on our preliminary data, we have developed several genomic models based on total leukocyte and enriched blood neutrophils that retrospectively can identify patients who will have a poor clinical outcome and would benefit from interventional immunological therapies. Here, we propose to validate this approach in 200 severely traumatized patients enrolled at two geographically-distinct institutions. These genomic tests will be compared for their precision to standard anatomical and physiological scoring systems, and models based on plasma cytokine concentrations. If successful, these studies would dramatically alter how clinical trials in severely traumatized patients would be conducted in the future. A successful, rapid, prognostic genomic test would reduce the size, cost and time required to evaluate new drugs in this population by identifying individuals at risk of a complicated outcome. Personalized medicine" would be one step closer to reality.