Sepsis Characterization in Kilimanjaro

乞力马扎罗山败血症特征

• 批准号: 10269012
• 负责人: Matthew P Rubach
• 金额: $ 59.27万
• 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/10269012
• 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; Foundations; 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; Institutes; Intervention; Investigation; Knowledge; Lead; 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; Resources; Sampling; Sepsis; Sepsis Syndrome; Septic Shock; Severities; Site; Stratification; Structure; Syndrome; Tanzania; Triage; Tuberculosis; United States National Institutes of Health; Universities; Validation; Virus Diseases; Whole Blood; Work; base; 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.

项目摘要 脓毒症是高收入国家住院死亡的主要原因，它同样会导致严重的疾病。 在低收入国家，严重脓毒症的住院死亡率可能超过60%。 基于杜克大学在坦桑尼亚基利曼哈罗强大的合作临床研究平台，这些 研究将使用数据驱动的聚类方法和贝叶斯潜在类模型来定义临床意义 脓毒症的亚型是特定的传染病流行病学和亚群的人口亚结构， 撒哈拉非洲。在这样做的过程中，我们寻求推进改善检测、风险 分层，并最终在资源有限的环境中对成人脓毒症采取量身定制的干预措施。的 驱动该项目的基本原理是脓毒症亚型表征对于改善 sSA中脓毒症的评估、管理和临床研究。来表现我们对成年人的描述 脓毒症亚型，我们将利用现有的样本和数据，从我们的研究平台的2016-2019年严重 发热性疾病队列为一项为期两年的前瞻性观察性研究提供信息， 基利曼哈罗的医院。通过开发一种基于精确医学的方法来分类关键的病理生理学 sSA中败血症的亚型，该项目促进了美国国立卫生研究院的使命， 知识，这将导致更好的健康为每个人-在这种情况下，更好的健康为最严重的疾病， 世界上脓毒症负担最高的地区。为实现这一目标，该项目制定了具体目标， 该研究将使用贝叶斯方法从临床生物信息学中得出成人脓毒症的临床表型簇， 统计学（目的1）以及基于宿主分子特征的免疫败血症集群 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 在基利曼哈罗的败血症的稳健和临床上有意义的亚型（Aim 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年前瞻性脓毒症患者队列的分析框架提供信息， 为临床和分子脓毒症亚型分类的推导和验证奠定了基础。临床 在目标1和目标2中发现的簇和分子表征也将与来自 描述欧洲败血症亚型的临床生物信息学和基因表达特征分析 和北美晚期HIV感染高患病率的SSA患者脓毒症的疾病流行病学研究 更多样化的败血症病因-以及潜在的宿主遗传差异相比，欧洲和北 美国脓毒症患者需要亚型鉴定是专门推导和验证， 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 它还将建立一个脓毒症研究的框架， 需要取得进展，并且确实可以在脓毒症结果方面取得最大的改善。