Molecular Phenotyping of ARDS, Pneumonia, and Sepsis using Latent Class Analysis and Metagenomic Sequencing
NIH
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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. NARRATIVE The acute respiratory distress syndrome (ARDS), pneumonia, and sepsis are some of the most common clinical problems encountered in critically ill patients, and each of these syndromes is frequently fatal. This Consortium project is seeking to understand variability within and overlap between these syndromes, so that we can determine how best to design new studies and new therapies for patients with these problems and thereby hopefully improve patient outcomes. In addition, this Consortium will create a database of clinical data and biological samples that can be used by future researchers to study related problems.
Non-SBIR/STTR