Sepsis Characterization in Kilimanjaro

项目总结 脓毒症是高收入国家住院死亡的主要原因之一，它同样会导致严重的 在低收入国家，严重脓毒症的住院死亡率可超过60%。 基于杜克大学在坦桑尼亚乞力马扎罗的强大协作临床研究平台，这些 研究将使用数据驱动的聚类方法和贝叶斯潜在类别模型来定义临床意义 感染性疾病流行病学和亚人群亚结构所特有的败血症亚型 撒哈拉非洲(SSA)。通过这样做，我们寻求推进改善检测、风险的长期目标 分层，并最终为资源有限的成年人中的脓毒症量身定做干预措施。这个 推动这个项目的基本原理是，脓毒症亚型特征对改善 SSA脓毒症的评估、处理和临床调查。来表现我们对成人的刻画 败血症亚型，我们将利用我们研究平台2016-2019年严重感染的现有样本和数据 发烧疾病队列通知一项为期两年的地区脓毒症入院前瞻性观察研究 乞力马扎罗山的医院。通过开发一种基于精确医学的方法来对关键的病理生理进行分类 SSA中败血症的亚型，该项目促进了美国国立卫生研究院发现新的 将为每个人带来更好健康的知识-在这种情况下，为世界上最严重的病人更好地健康 世界上败血症负担最重的地区。为了实现这一目标，该项目制定了具体目标 这将利用贝叶斯的临床生物信息学建立成人脓毒症的临床表型群 统计数据(目标1)以及基于宿主分子特征的免疫败血症群组 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，以便确定 乞力马扎罗山的强健和有临床意义的败血症亚型(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，以开发和完善统计和分析模型，以实现我们的目标。 这将为2-3年的预期脓毒症患者队列提供分析框架，这将是 为临床和分子败血症亚型分类的推导和验证奠定基础。临床部 在目标1和目标2中发现的团簇和分子特征也将与在 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。SSA败血症的疾病流行病学-晚期艾滋病毒感染的高流行率和 与欧洲和北方相比，脓毒症的病因更多样化，以及潜在的宿主遗传差异 美国脓毒症患者有必要对亚型鉴定进行专门的派生和验证 在SSA中的应用。该项目不仅将确定改进分类和量身定制的干预设计的子类型 对于SSA中的脓毒症-它还将建立一个框架，用于在一个最大的 在脓毒症的结局中确实可以取得最大的改善，这是需要的。

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.