The MUltidimenSional phenotyping In Critical care (MUSIC) Consortium: A pathway to precision medicine at the bedside

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PROJECT SUMMARY Current approaches to classifying critical illness focus on broad clinical syndromes including sepsis and the acute respiratory distress syndrome (ARDS). However, application of consensus definitions of these syndromes has not translated to syndrome-specific, targeted therapies. Recent transformative studies of ARDS have revealed underlying (latent) biological phenotypes, termed hyper- and hypo-inflammatory, that are remarkably consistent across multiple ARDS cohorts. Further, in post hoc analysis, these phenotypes respond differentially to both process of care (fluids, PEEP) and pharmacologic (simvastatin) treatments. These findings suggest that biological phenotyping in ARDS, pneumonia and sepsis may pave the way towards a deeper understanding of the biology of critical illness that will translate, for the first time, into targeted, personalized therapies. Our multidisciplinary team of investigators and clinical enrollment sites brings together deep scientific expertise in pathophysiologic mechanisms and phenotyping of ARDS, sepsis and pneumonia, world- class infrastructure for collecting long-term outcomes after critical illness, strong experience in designing and implementing observational clinical cohort studies that include long-term follow-up, and proven ability to enroll large numbers of critically ill patients in observational and clinical studies. Our team proposes two studies: (1) a Consortium-wide 5,000 patient observational cohort study, the MUltidimenSional phenotyping In Critical care (MUSIC) Study. The primary Aim of this study is to test the hypothesis that latent phenotypes are generalizable across critical illness syndromes and associate with both short- and long-term outcomes. Determining whether inflammatory phenotypes are identifiable across common critical illness syndromes can fundamentally alter our approach to classifying critical illness in a way that captures a more uniform biological phenotype agnostic to syndromic diagnosis. (2) a Clinical Center Study that addresses the critical need to better understand airspace biology in patients with ARDS and other etiologies of acute respiratory failure (ARF). It has long been recognized that airspace biology differs significantly from that of the circulation, but the field has lacked a non- invasive, inexpensive, simple, and safe method of sampling the distal airspace in ARF. Our group has pioneered a new method for sampling the airspace in intubated, mechanically ventilated patients with ARF using fluid extracted from heat moisture exchanger (HME) filter. The HARMONY study (HME for Acute Respiratory failure MultidimensiONal phenotYping) has a primary goal of identifying lung-specific phenotypes in ARF that will be tested for associations with long term functional and structural respiratory outcomes. Our Center will leverage our expertise in critical illness phenotyping, robust ED/ICU patient enrollment (37,756 patients in 5 years), pioneering work in long term outcomes in ICU survivors, decades of experience studying biomarkers of critical illness and novel approaches to study airspace biology, to play a key role in the APS Consortium and have a major and sustained impact in the field of ARDS, pneumonia, and sepsis.