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: 9061719
• 负责人: LYLE L MOLDAWER
• 金额: $ 44.93万
• 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/9061719
• 关键词: Admission activity; Age-Years; Appearance; Benchmarking; 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; Interferon Type II; Intervention; Kinetics; Leukocytes; Lymphocyte; 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; Trauma patient; Treatment-related toxicity; Validation; Variant; base; beta-Glucans; clinical predictors; cost; cytokine; design; genome-wide; genomic data; immunoregulation; improved; improved outcome; inclusion criteria; injured; intervention effect; meetings; monocyte; mortality; neutrophil; novel; novel therapeutics; patient subsets; personalized genomic medicine; personalized medicine; 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）：损伤仍然是总体死亡的第五大原因，也是美国45岁以下人群死亡的主要原因。在严重损伤患者中，多器官衰竭（MOF）和死亡仍然是不可接受的。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的了解有所提高，但在前瞻性随机临床试验中，基本上没有生物反应调节剂被证明是成功的。我们建议有相当比例的患者通常符合研究的纳入标准