Phenotyping ARDS, Pneumonia, and Sepsis over time to elucidate shared and distinct trajectories ofillness and recovery

这项建议是为了支持招募患有急性呼吸窘迫综合征的受试者的强大的人类队列 (ARDS)、肺炎或败血症(统称为APS)，作为APS联盟的一部分，并确定临床 以及更好地预测、分层和解释以下器官衰竭、死亡率和残疾的分子特征 APS。我们假设不同的和可重复的分子亚型是常见的，并且在所有 3 APS综合征，我们将确定最大限度地导致器官衰竭和 通过这个强大的分子队列的复苏轨迹。作为财团范围纵向计划的一部分 在队列研究中，我们建议开发新的工具，用于风险评估、分层和从APS中恢复。在……里面 目的1a，我们将使用联合建模来集成炎症、血管调节失调、 骨质疏松症和神经损伤以确定与器官衰竭最相关的组合，推断 血浆中间体可能导致器官衰竭，并确定死亡风险的比例。 由特定的器官衰竭引起。在目标1b中，我们专注于更好地预测APS后的长期残疾， 测试Katz和Lawson知晓的功能状态特征预测持续性残疾和 询问是否通过增加炎症、血管损伤、 或者神经肌肉损伤。我们的中心特定目标使用新的分子表型来更好地解释器官 失败、死亡和APS后的残疾。在目标2a中，我们测试特定的假设驱动的候选标记 作为潜在器官衰竭标志物的免疫失调。目标2b确定宿主免疫健康的模式 应用高维流式细胞术了解恢复期外周血宿主免疫功能 回答，并询问免疫细胞轨迹是否与残疾或康复有关。Aim 2c专注于 血管损伤标记物，并询问血管损伤的哪些组成部分与特定器官衰竭相关 以及APS后的残疾。在目标3中，我们集成了多个生物数据流，并确定了 在恢复过程中，使用机器学习来选择信息最丰富的选项 用于联合建模的特征，并测试模型在不同的急性或长期残疾情况下的性能 APS状态。我们的网站将为APS联盟做出持久的贡献，我们完成的目标将 推进ARDS、肺炎、败血症的预防和个体化治疗，全面提高 健康。

This proposal is to support a robust human cohort enrolling subjects with acute respiratory distress syndrome (ARDS), pneumonia, or sepsis (collectively termed APS) as part of the APS Consortium, and to identify clinical and molecular features that better predict, stratify, and explain organ failure, mortality, and disability following APS. We hypothesize that distinct and reproducible molecular subtypes are common and detectable across all 3 APS syndromes, and that we will identify the pathways that maximally contribute to organ failure and recovery trajectory through this well-powered molecular cohort. As part of the Consortium-Wide Longitudinal Cohort study, we propose to develop new tools for risk assessment, stratification, and recovery from APS. In aim 1a, we will use joint modeling to integrate multiple plasma markers of inflammation, vascular dysregulation, sarcopenia, and neural injury to identify the combinations most associated with organ failure, infer which plasma intermediates might contribute causally to organ failures, and identify the proportion of mortality risk mediated by specific organ failures. In aim 1b we focus on better prediction of long term disability post-APS, testing the ability of Katz- and Lawson-informed functional status features to predict persistent disability and asking whether prediction of disability is enhanced by added plasma markers of inflammation, vascular injury, or neuromuscular injury. Our Center-specific aims employ novel molecular phenotyping to better explain organ failure, death, and disability post-APS. In aim 2a we test specific hypothesis-driven candidate markers of immune dysregulation as potential organ failure markers. Aim 2b identifies patterns of host immune health during recovery using high dimensional flow cytometry to understand the peripheral blood host immune response, and asks whether immune cell trajectory associates with disability or recovery. Aim 2c focuses on vascular injury markers, and asks which components of vascular injury associate with specific organ failures and with post-APS disabilities. In aim 3, we integrate multiple streams of biologic data and identify patterns of response across APS acutely and during recovery, use machine learning to select the most informative features for joint modeling, and test the performance of the model of acute or long term disability in different APS states. Our site will make a lasting contribution to the APS Consortium and our completed aims will advance the prevention and personalized treatment of ARDS, pneumonia, and sepsis to improve overall health.