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.

该提案旨在支持一个强有力的人类队列招募急性呼吸窘迫综合征受试者 （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 和分子特征，更好地预测，分层，并解释器官衰竭，死亡率和残疾， APS。我们假设，不同的和可重复的分子亚型是常见的，并在所有 3 APS综合征，我们将确定最大限度地促进器官衰竭的途径， 恢复轨迹通过这个强大的分子队列。作为联盟范围纵向的一部分， 队列研究，我们建议开发新的工具进行风险评估，分层，并从APS中恢复。在 目标1a，我们将使用联合建模来整合炎症、血管失调， 肌肉减少症和神经损伤，以确定与器官衰竭最相关的组合， 血浆中间体可能导致器官衰竭，并确定死亡风险的比例 由特定器官衰竭介导。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知情功能状态特征预测持续性残疾的能力， 询问是否通过增加炎症，血管损伤， 或神经肌肉损伤。我们的中心特定目标采用新的分子表型，以更好地解释器官 APS后的失败、死亡和残疾。在目标2a中，我们测试了特定的假设驱动的候选标记， 免疫失调作为潜在的器官衰竭标志物。目标2b确定宿主免疫健康的模式 在恢复期间使用高维流式细胞术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的重点是 血管损伤标志物，并询问血管损伤的哪些成分与特定器官衰竭相关 以及APS后残疾患者。在aim3中，我们整合了多个生物数据流，并识别了 在APS急性和恢复期间的反应，使用机器学习来选择最具信息性的 特征的关节建模，并测试不同的急性或长期残疾的模型的性能 APS表示。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、肺炎和脓毒症的预防和个性化治疗， 健康