Molecular Phenotyping of ARDS, Pneumonia, and Sepsis using Latent Class Analysis and Metagenomic Sequencing

摘要 这份对RFA HL-23-001的申请建议加州临床中心参与急性 呼吸窘迫综合征(ARDS)、肺炎和败血症(APS)联合研究。我们的临床中心 由4个站点组成：加州大学旧金山分校(加州大学旧金山分校；领先站点)；加州大学弗雷斯诺分校；扎克伯格旧金山 弗朗西斯科总医院和斯坦福大学。我们的临床中心将为设计和 进行APS联盟的前瞻性纵向观察队列研究，该研究将纳入5000人 总体上患有ARDS、肺炎和/或脓毒症的成年人，对大约一半的幸存者在3、6和 12个月。我们将在项目期间招募1000名参与者加入该联盟，并与我们的 APS联盟指导委员会的同事们共同设计和实施该项目。我们的4个站点有 有很好的合作记录，招募了不同人群的ARDS危重患者， 介入性试验和观察性研究中的肺炎和败血症，包括广泛的临床收集 数据和生物制品以及成功的门诊随访。此外，我们的团队率先确定了 ARDS的分子表型和元基因组测序在肺炎和败血症中的应用作为证据 我们的相关内容专业知识。因此，我们已经做好了充分的准备，为APS协会做出临床贡献 中心。 本申请提出了一项联盟范围的研究(目标1)，旨在确定之前 观察到的ARDS的潜在分子表型存在于危重患者的症状诊断中 ARDS、肺炎和败血症的标准，以及这些分子表型是否具有一致的预后 跨症状诊断标准的价值。此应用程序还建议临床中心特定研究(AIM 2)寻求确定同时捕获宿主和微生物的元基因组数据的整合是否增强 ARDS、肺炎和败血症分子表型的机制理解和预后作用。 这些目标的完成将为危重疾病的新分类奠定基础，移动危重护理 走向精准医学范式，在这种范式中，我们可以更好地将新疗法与不同的临床和 生物学表型，最终目标是改善我们患者的预后。

ABSTRACT This application to RFA HL-23-001 proposes a California Clinical Center for participation in the Acute Respiratory Distress Syndrome (ARDS), Pneumonia, and Sepsis (APS) Consortium study. Our Clinical Center consists of 4 sites: University of California, San Francisco (UCSF; lead site); UCSF Fresno; Zuckerberg San Francisco General Hospital; and Stanford University. Our Clinical Center will contribute to the design and conduct of the APS Consortium’s prospective, longitudinal observational cohort study which will enroll 5000 adults with ARDS, pneumonia, and/or sepsis overall, with follow up of approximately half of survivors at 3, 6 and 12 months. We will enroll 1000 participants in this Consortium during the project period and work with our colleagues on the APS Consortium Steering Committee to design and implement the project. Our 4 sites have a strong track record of working well together to enroll a diverse population of critically ill patients with ARDS, pneumonia, and sepsis in interventional trials and observational studies, including collection of extensive clinical data and biospecimens and successful outpatient follow-up. Moreover, our group pioneered the identification of molecular phenotypes in ARDS and the use of metagenomic sequencing in pneumonia and sepsis, as evidence of our relevant content expertise. Thus, we are well-prepared to contribute to the APS Consortium as a Clinical Center. This application proposes a Consortium-wide study (Aim 1) that seeks to determine whether previously observed latent molecular phenotypes of ARDS are present in critically ill patients across syndromic diagnostic criteria for ARDS, pneumonia and sepsis, and whether these molecular phenotypes have consistent prognostic value across syndromic diagnostic criteria. This application also proposes a Clinical Center-specific study (Aim 2) that seeks to determine whether integration of metagenomic data capturing both host and microbe enhances mechanistic understanding and prognostic utility of ARDS, pneumonia, and sepsis molecular phenotypes. Completion of these aims will lay the groundwork for a new taxonomy of critical illness, moving critical care towards a precision medicine paradigm in which we can better match novel therapies with distinct clinical and biological phenotypes, with the ultimate goal of improving outcomes for our patients.