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

项目摘要 目前对危重病进行分类的方法集中于广泛的临床综合征，包括脓毒症和 急性呼吸窘迫综合征（ARDS）。然而，这些共识定义的应用 综合征尚未转化为综合征特异性靶向治疗。最近的变革性研究 ARDS已经揭示了潜在的（潜在的）生物学表型，称为高炎症和低炎症， 在多个ARDS队列中具有显著一致性。此外，在事后分析中，这些表型响应 不同的护理过程（液体，PEEP）和药物（辛伐他汀）治疗。这些发现 提示ARDS、肺炎和败血症的生物学表型可能为更深入的研究铺平道路。 对危重病生物学的理解，将首次转化为有针对性的，个性化的， 治疗我们的多学科研究者团队和临床招募中心汇集了深入的 在ARDS、脓毒症和肺炎的病理生理机制和表型方面的科学专业知识， 一流的基础设施，用于收集重大疾病后的长期结果，在设计和 实施观察性临床队列研究，包括长期随访，并证明有能力招募 在观察性和临床研究中大量危重患者。我们的团队提出了两项研究：（1）a 联合会范围内5，000例患者观察性队列研究：危重病护理中的多维表型 学习。本研究的主要目的是检验潜在表型具有普遍性的假设 跨危重病综合征，并与短期和长期结果相关。确定是否 炎症表型在常见的危重病中是可识别的， 一种对危重疾病进行分类的方法，以捕获更统一的生物表型， 综合征诊断(2)一项临床中心研究，解决了更好地了解空域的关键需求 生物学在患有ARDS和急性呼吸衰竭（ARF）的其他病因的患者中。人们早就 认识到空域生物学与环流生物学有很大不同，但该领域缺乏非 有创、廉价、简单、安全的ARF远端空气腔采样方法。我们集团 开创了一种新的方法，用于对ARF插管、机械通气患者的空域进行采样 使用从热湿交换器（HME）过滤器提取的流体。HARMONY研究（HME用于急性 呼吸衰竭多维表型）的主要目标是鉴定肺特异性表型 在ARF中，将测试与长期功能和结构性呼吸结果的相关性。我们 中心将利用我们在危重病表型分析、稳健的艾德/ICU患者入组（37，756例）方面的专业知识 5年内的患者），在ICU幸存者的长期结局方面的开创性工作，数十年的研究经验 关键疾病的生物标志物和研究空域生物学的新方法，在APS中发挥关键作用 在ARDS、肺炎和脓毒症领域具有重大和持续的影响。

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.