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）：在美国多机器人失败（MOF）和死亡人数不到45岁的患者中，伤害仍然是第五大死亡原因，并且在严重受伤的患者中仍然是不可接受的。在我们最近的胶水赠款研究中，有19％的严重创伤患者死亡，41％的MOF发展，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改进的了解，但基本上没有证明在前瞻性，随机临床试验中成功的生物反应修饰剂。我们建议，很大一部分患者通常符合纳入标准以进行研究 严重受伤的患者不需要免疫调节疗法，不仅不太可能受益，而且还受到这种疗法的直接毒性。相比之下，存在将持久临床病程的患者子集，并将受益于具有生物反应修饰剂的介入疗法。当今最重要的挑战是前瞻性地确定要持久临床病程的患者的子集，并将受益于具有生物反应修饰剂的介入疗法。我们认为我们已经开发了这种前瞻性基因组检验。因此，该提案的总体目标是前瞻性地验证从血清白细胞亚群中获得的快速基因组检验，该测试在入院后的头24小时内严重创伤了患者，该测试可用于区分那些将具有复杂的临床轨迹的患者，因此将成为良好的候选者，以供干预性，免疫，免疫，免疫疗法。根据我们的初步数据，我们基于总白细胞和富集血液中性粒细胞开发了几种基因组模型，回顾性地可以鉴定出临床较差的患者 结果，将受益于介入的免疫疗法。在这里，我们建议在两个地理位置上的机构招收的200名严重创伤的患者中验证这种方法。这些基因组检验的精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严重创伤患者的临床试验。成功，快速，预后的基因组检验将通过识别出患有复杂结果的个体来评估该人群中新药所需的大小，成本和时间。个性化医学“将更接近现实。