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

摘要 RFA HL-23-001的本申请建议加州临床中心参与急性 呼吸窘迫综合征（ARDS）、肺炎和脓毒症（APS）联合研究。临床中心 由4个研究中心组成：加州大学弗朗西斯科分校（UCSF;牵头研究中心）; UCSF弗雷斯诺;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 开展APS联盟的前瞻性、纵向观察性队列研究，将招募5000名 成人ARDS、肺炎和/或脓毒症患者，随访约一半的存活者，时间为3、6和 12个月在计划进行期间，我们将招募1000名参与者加入这个联盟，并与我们的 APS联盟指导委员会的同事设计和实施该项目。我们的4个网站有 良好的合作记录，招募了不同人群的ARDS重症患者， 在干预性试验和观察性研究中， 数据和生物标本以及成功的门诊随访。此外，我们的团队率先识别了 ARDS的分子表型以及宏基因组测序在肺炎和脓毒症中的应用，作为证据 我们的相关内容专业知识。因此，我们已做好充分准备，作为一个临床 中心 本申请提出了一项联盟范围的研究（目标1），旨在确定以前是否 观察到的潜在的ARDS分子表型存在于危重患者中， ARDS、肺炎和脓毒症的标准，以及这些分子表型是否具有一致的预后 综合征诊断标准的价值。本申请还提出了一项临床中心特定研究（Aim 2)该研究旨在确定捕获宿主和微生物的宏基因组数据的整合是否能增强 ARDS、肺炎和脓毒症分子表型的机制理解和预后效用。 这些目标的完成将为危重病的新分类奠定基础， 走向精准医学范式，我们可以更好地将新疗法与独特的临床和 生物表型，最终目标是改善患者的预后。

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.