Validation of a Genomics Based Prognostic in Severe Trauma

严重创伤中基于基因组学的预后验证

• 批准号: 8427852
• 负责人: LYLE L MOLDAWER
• 金额: $ 46.58万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427852
• 关键词: Admission activity; Age-Years; Appearance; Benchmarking; Biological; Biological Models; Biological Response Modifiers; Blood Transfusion; Blunt Trauma; Caring; Cause of Death; Cessation of life; Clinical; Clinical Trials; Critical Illness; Data; Databases; Enrollment; Failure; Frequencies; Functional disorder; Future; Gene Expression Profile; Genomics; Glucans; Glues; Goals; Grant; Health; Hospitalization; Hour; Immune response; Immunoglobulins; Individual; Inflammation; Injury; Institution; Interferons; Intervention; Kinetics; Leukocytes; Lymphocyte; Medicine; Meta-Analysis; Modeling; Multiple Organ Failure; Nosocomial Infections; One-Step dentin bonding system; Organ; Organ failure; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Physiological; Plasma; Population; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recommendation; Recovery; Research; Risk; Secondary to; Sensitivity and Specificity; Sepsis; Technology; Testing; Therapeutic Intervention; Time; Toxic effect; Trauma; Validation; Variant; base; cost; cytokine; design; genome-wide; immunoregulation; improved; inclusion criteria; injured; intervention effect; meetings; monocyte; mortality; neutrophil; novel; prognostic; programs; prospective; response; response to injury; secondary infection; success; systematic review

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.

描述(由申请人提供)：在美国，伤害仍然是第五大死因，也是45岁以下人群的主要死因。在严重受伤的患者中，多器官衰竭(MOF)和死亡仍然是不可接受的常见情况。在我们最近的Glue Grant研究中，19%的严重创伤患者死亡，41%发生多器官功能衰竭，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了解，但基本上还没有在前瞻性随机临床试验中被证明成功的生物反应调节剂。我们建议，相当大比例的患者通常符合纳入标准的研究 严重受伤的患者不需要免疫调节治疗，不仅不太可能从这种治疗中受益，而且还会遭受直接毒性。相比之下，有一部分患者将有长期的临床病程，并将从使用生物反应调节剂的介入治疗中受益。当今最重要的挑战是前瞻性地确定哪些患者将具有长期的临床病程，并将从具有生物反应调节剂的介入治疗中受益。我们相信，我们已经开发出了这样一种预期的基因组测试。因此，这项建议的总体目标是前瞻性地验证在入院后24小时内从严重创伤患者的血白细胞亚群中获得的快速基因组测试，该测试可用于区分哪些患者将具有复杂的临床轨迹，因此将成为介入和免疫调节治疗的良好候选者。基于我们的初步数据，我们已经开发了几个基于总白细胞和浓缩的血液中性粒细胞的基因组模型，这些模型可以回溯性地识别临床表现不佳的患者。 结果，并将受益于介入性免疫疗法。在这里，我们建议在两个地理位置不同的机构登记的200名严重创伤患者中验证这种方法。这些基因组测试的精确度将与标准的解剖和生理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对严重创伤患者进行临床试验的方式。一种成功的、快速的、具有预测意义的基因组测试将通过识别面临复杂结果风险的个体，减少在这一人群中评估新药所需的规模、成本和时间。个性化医疗“将离现实更近一步。