Sepsis Characterization in Kilimanjaro

乞力马扎罗山败血症特征

• 批准号: 10686354
• 负责人: Matthew P Rubach
• 金额: $ 65.56万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686354
• 关键词: Admission activity; Adolescent; Adoption; Adult; Africa South of the Sahara; African; American; Automobile Driving; Award; Bayesian Analysis; Bayesian Modeling; Bioinformatics; Biological; Blood Circulation; Blood specimen; Caring; Cessation of life; Characteristics; Classification; Clinical; Clinical Data; Clinical Research; Cluster Analysis; Country; Cryptococcosis; Data; Data Collection; Derivation procedure; Detection; Disease; District Hospitals; Epidemiology; Etiology; Europe; European; Evaluation; Fever; Functional disorder; Future; Gene Expression Profile; Genetic; Genetic Transcription; Goals; HIV Infections; Health; Health system; High Prevalence; Hospital Mortality; Hospitals; Immune response; Immunologics; Income; Infection; Infectious Disease Epidemiology; Infrastructure; Intervention; Investigation; Knowledge; Mathematics; Methods; Mission; Modeling; Molecular; Morbidity - disease rate; North America; Observational Study; Outcome; Pathway interactions; Patients; Population; Positioning Attribute; Process; Protocols documentation; RNA analysis; Research; Research Personnel; Resource-limited setting; Sampling; Sepsis; Sepsis Syndrome; Septic Shock; Severities; Site; Stratification; Syndrome; Tanzania; Triage; Tuberculosis; United States National Institutes of Health; Universities; Validation; Virus Diseases; Whole Blood; Work; burden of illness; classifier algorithm; clinical investigation; clinical phenotype; clinical research site; clinically relevant; cohort; disability; improved; low income country; mortality; mortality risk; patient population; point of care; precision genomic medicine; precision medicine; prospective; randomized trial; risk stratification; sample collection; septic patients; therapy design; transcriptomics

PROJECT SUMMARY Sepsis is a leading cause of in-hospital death in high-income countries, and it likewise causes a formidable burden of disease in low-income countries, where in-hospital mortality for severe sepsis can exceed 60%. Building upon Duke University’s strong collaborative clinical research platform in Kilimanjaro, Tanzania, these studies will use data-driven clustering methods and Bayesian latent class models to define clinically meaningful subtypes of sepsis that are specific to the infectious disease epidemiology and population sub-structures of sub- Saharan Africa (sSA). In doing so, we seek to advance the long-term goal of improving detection, risk stratification and, eventually, tailored interventions for sepsis among adults in resource-limited settings. The rationale driving this project is that sepsis subtype characterization holds great promise for improving the evaluation, management and clinical investigation of sepsis in sSA. To perform our characterizations of adult sepsis subtypes, we will leverage existing samples and data from our research platform’s 2016-2019 severe febrile illness cohort to inform a two-year prospective observational study of sepsis admissions at district hospitals in Kilimanjaro. By developing a precision medicine-based approach to classify the key pathophysiologic subtypes of sepsis in sSA, this project promotes the US National Institutes of Health’s mission to uncover new knowledge that will lead to better health for everyone—in this case, better health for the most severely ill in the region with the highest burden of sepsis in the world. To achieve this, the project has set out SPECIFIC AIMS that will develop clinical phenotype clusters of adult sepsis derived from clinical bioinformatics using Bayesian statistics (Aim 1) as well as immunologic sepsis clusters based upon the molecular characterization of the host immune response to infection (Aim 2). We will integrate the approaches in Aim 1 and Aim 2 in order to identify robust and clinically meaningful subtypes of sepsis in Kilimanjaro (Aim 3). In Year 1, we will use the existing samples and data collected 2016-2019 to develop and refine the statistical and analytical models for our Aims. This will inform the analytical framework for the prospective sepsis patient cohort in Years 2-3, which will be the basis for both derivation and validation of the clinical and molecular sepsis subtype classifications. The clinical clusters and molecular characterizations discovered in Aim 1 and Aim 2 will also be compared to findings from clinical bioinformatic and gene expression signature analyses that have described sepsis subtypes in Europe and North America. The disease epidemiology of sepsis in sSA—high prevalence of advanced HIV infection and more diverse sepsis etiologies—as well as potential host genetic differences compared to European and North American sepsis patients necessitate that subtype identification be specifically derived and validated for application in sSA. Not only will this project identify subtypes that improve triage and tailored intervention design for sepsis in sSA—it will also establish a framework for sepsis research in a setting where the greatest gains are needed and where the greatest improvements in sepsis outcomes can indeed be made.

项目概要 脓毒症是高收入国家院内死亡的主要原因，它同样会造成巨大的损失。 低收入国家的疾病负担，严重败血症的院内死亡率可能超过 60%。 以杜克大学位于坦桑尼亚乞力马扎罗山的强大合作临床研究平台为基础，这些 研究将使用数据驱动的聚类方法和贝叶斯潜在类别模型来定义具有临床意义的 败血症的亚型，特定于传染病流行病学和亚型的人群亚结构 撒哈拉非洲 (sSA)。在此过程中，我们寻求推进改善检测、风险管理的长期目标。 对资源有限环境中的成年人进行分层，并最终针对脓毒症采取量身定制的干预措施。这 推动该项目的基本原理是脓毒症亚型表征对于改善脓毒症有很大希望 sSA 脓毒症的评估、管理和临床研究。来表现我们对成人的表征 脓毒症亚型，我们将利用我们研究平台 2016-2019 年严重脓毒症的现有样本和数据 发热性疾病队列为该地区败血症入院的两年前瞻性观察研究提供信息 乞力马扎罗山的医院。通过开发基于精准医学的方法对关键病理生理学进行分类 sSA 脓毒症亚型，该项目促进了美国国立卫生研究院发现新疾病的使命 这些知识将为每个人带来更好的健康——在本例中，是为世界上病情最严重的人带来更好的健康 世界上脓毒症负担最重的地区。为了实现这一目标，该项目制定了具体目标 将使用贝叶斯从临床生物信息学中开发成人脓毒症的临床表型簇 统计数据（目标 1）以及基于宿主分子特征的免疫败血症簇 对感染的免疫反应（目标 2）。我们将整合目标 1 和目标 2 中的方法，以确定 乞力马扎罗山败血症的稳健且有临床意义的亚型（目标 3）。在第一年，我们将使用现有的 2016-2019 年收集的样本和数据，用于开发和完善我们目标的统计和分析模型。 这将为第 2-3 年的前瞻性脓毒症患者队列的分析框架提供信息，该队列将是 临床和分子脓毒症亚型分类的推导和验证的基础。临床上 目标 1 和目标 2 中发现的簇和分子特征也将与来自 描述欧洲脓毒症亚型的临床生物信息和基因表达特征分析 和北美。 sSA 败血症的疾病流行病学——晚期 HIV 感染和感染的高患病率 与欧洲和北方相比，脓毒症病因更加多样化，以及潜在的宿主遗传差异 美国败血症患者需要专门进行亚型鉴定并对其进行验证 在 sSA 中的应用。该项目不仅将确定改善分诊和定制干预设计的亚型 针对 sSA 的脓毒症 — 它还将为脓毒症研究建立一个框架 需要取得进展，并且确实可以最大程度地改善败血症的结果。