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

随着时间的推移对 ARDS、肺炎和脓毒症进行表型分析，以阐明共同和不同的疾病和康复轨迹

• 批准号: 10649194
• 负责人: Michael Oscar Harhay
• 金额: $ 15.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649194
• 关键词: 2019-nCoV; Acute; Acute Renal Failure with Renal Papillary Necrosis; Acute Respiratory Distress Syndrome; Address; Age; Autoantibodies; Biological; Blood Vessels; COVID-19 patient; Cells; Cessation of life; Characteristics; Clinical; Clinical Data; Cognitive; Cohort Studies; Collaborations; Critical Illness; Critical Pathways; Data; Data Collection; Dimensions; Emergency Situation; Emotional; Enrollment; Etiology; Event; Failure; Fibrinolysis; Flow Cytometry; Gene Expression; Genetic Transcription; Genomics; Glycocalyx; Health; Heterogeneity; Hospitalization; Human; Human Resources; Immune; Immune response; Immunologic Markers; Individual; Informatics; Infrastructure; Injury; Intensive Care Units; Intervention; Investigation; Joints; Leukocytes; Longitudinal cohort study; Lymphoid; Machine Learning; Malignant Neoplasms; Mediating; Mediation; Mendelian randomization; Methods; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Myelogenous; Myelopoiesis; Organ Survival; Organ failure; Outcome; Pathway interactions; Patients; Pattern; Pharmacotherapy; Phenotype; Physiological; Plasma; Pneumonia; Population; Positioning Attribute; Precision therapeutics; Prevention; Productivity; Proteins; Proteome; Proteomics; Quality of life; Recording of previous events; Recovery; Reporting; Reproducibility; Risk Assessment; Risk Factors; Role; Sepsis; Severities; Site; Source; Stratification; Stream; Survivors; Syndrome; Testing; Time; Vascular Diseases; Vascular Permeabilities; Work; candidate marker; clinical center; clinical phenotype; cohort; comorbidity; disability; functional status; high dimensionality; high risk; immune health; improved; individual response; inflammatory marker; molecular marker; molecular phenotype; molecular subtypes; mortality; mortality risk; multiple omics; nerve injury; neuromuscular; novel; pathogen; performance tests; peripheral blood; personalized medicine; pharmacologic; prognostic; response; sarcopenia; septic patients; skills; success; tool; trait; transcriptomics; treatment response; vascular contributions; vascular factor; vascular injury

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.

该建议是支持急性呼吸窘迫综合征的强大人类人群 （ARDS），肺炎或败血症（统称为APS）作为APS财团的一部分，并确定临床 以及更好地预测，分层和解释器官失败，死亡率和残疾之后的分子特征 APS。我们假设不同的和可重现的分子亚型是常见的，并且可以检测到所有人 3种AP综合征，我们将确定最大程度地促进器官衰竭和 通过这种驱动的分子队列的恢复轨迹。作为整个财团纵向的一部分 队列研究，我们建议开发新的工具，以评估APS的风险评估，分层和恢复。在 AIM 1A，我们将使用关节建模来整合炎症，血管失调的多个等离子体标记， 肌肉减少症和神经损伤以识别与器官衰竭最相关的组合，推断哪个 等离子体中间体可能会导致器官失败有因果关系，并确定死亡率风险的比例 由特定器官故障介导。在AIM 1B中，我们专注于更好地预测长期残疾后的助攻， 测试Katz-和Lawson信息的功能状态特征的能力，以预测持续的残疾和 询问炎症，血管损伤的血浆标记是否会增强残疾的预测 或神经肌肉损伤。我们的中心特异性目标采用新型分子表型来更好地解释器官 失败，死亡和残疾后。在AIM 2A中，我们测试了特定假设驱动的候选标记 免疫失调作为潜在器官衰竭标记。 AIM 2B标识宿主免疫健康的模式 在使用高维流式细胞术中恢复过程中，以了解外周血宿主免疫 反应，并询问免疫细胞轨迹是否与残疾或恢复相关。 AIM 2C专注于 血管损伤标志物，并询问哪些血管损伤的组成部分与特定器官失败有关 并与后的残疾。在AIM 3中，我们整合了多个生物学数据流，并确定 在AP敏锐且恢复过程中，使用机器学习选择最有用的信息 联合建模的功能，并测试不同的急性或长期残疾模型的性能 APS国家。我们的网站将为APS财团做出持久的贡献，我们完成的目标将 提高对ARD，肺炎和败血症的预防和个性化处理，以改善整体 健康。