Data-driven Precision medicine in sepsis

描述（由申请人提供）：本K23提案的目的是为Vincent Liu，MD，MS提供受保护的时间和资源，以进行所需的额外培训，以实现其通过创新使用复杂临床数据来改善医院结局的长期目标。Liu博士是Kaiser Permanente研究部（KP-DOR）的委员会认证的重症监护医生和研究科学家。该建议建立在他的背景，在重症监护，传统的生物统计学，和应用高度详细的电子医疗 记录数据。它还利用KP-DOR提供的丰富培训环境，斯坦福大学的因果推理和信息学高级教学培训，以及一个有凝聚力的导师团队来提高我们对脓毒症的理解和治疗。脓毒症是对感染的炎症反应，每年影响全世界数百万患者，是美国住院费用最高的原因。在严重的情况下，超过三分之一的脓毒症患者死于医院，越来越多的脓毒症幸存者在出院后面临死亡率和残疾率的增加。最近的随机对照试验（RCT）未能确定脓毒症的有效治疗方法，并且在其最初描述十多年后，我们仍在等待三个多中心RCT，旨在明确证明有前途的治疗-早期目标导向治疗（EGDT）的益处。鉴于设计和开展脓毒症RCT的挑战，迫切需要利用来自真实世界实践的高度颗粒化观察数据的新方法：（1）提供对脓毒症疾病机制的新见解;（2）将脓毒症的病理生理学与新干预措施联系起来;（3）为临床医生和患者提供改进的疾病诊断。本项目概述了这样一种方法。其培训目标旨在通过以下方式扩展技能和知识：（1）优化我们在初步分诊和治疗后预测脓毒症患者不良结局的能力;（2）评估EGDT是否可以使严重程度较低的脓毒症患者受益;（3）量化急性器官功能障碍对脓毒症幸存者长期结局的具体影响。拟议的工作有很大的潜力，使一个显着的临床影响，因为这些目标不仅将促进我们对脓毒症的疾病机制的理解，而且还提供了在未来的干预性试验的目标推定的风险因素的初步数据。这项工作还将汇集在R 01提案中，旨在设计一种实时脓毒症风险预测工具。此外，该K23开发了脓毒症的具体实例，其逻辑扩展到其他重症监护综合征表明适用性超出了本提案的范围，因此具有高度的公共卫生意义。重要的是，拟议的工作在奖励期内是现实和可行的，将使刘博士能够继续培养研究技能，生成初步数据，建立额外的合作关系，并竞争R 01资金。总而言之，K23奖将支持和加速刘博士的职业发展活动，并使他能够成功地进入他作为独立研究者的职业生涯的下一阶段。

DESCRIPTION (provided by applicant): The purpose of this K23 proposal is to provide Vincent Liu, MD, MS with the protected time and resources to pursue the additional training needed to reach his long-term goal of improving hospital outcomes through the innovative use of complex clinical data. Dr. Liu is a board-certified intensivist and Research Scientist at the Kaiser Permanente Division of Research (KP-DOR). The proposal builds on his background in critical care, traditional biostatistics, and the applied use of highly-detailed electronic medical record data. It also leverages the rich training environment afforded by KP-DOR, advanced didactic training in casual inference and informatics at Stanford University, and a cohesive mentorship team to improve our understanding and treatment of sepsis. Sepsis, the inflammatory response to infection, affects millions of patients worldwide each year and is the most expensive cause of hospitalization in the United States. In severe cases, more than one- third of sepsis patients die in the hospital and a growing population of sepsis survivors face increased mortality and disability rates after discharge. Recent randomized controlled trials (RCTs) have failed to identify efficacious therapies for sepsis and, more than a decade after its original description, we still await three multi- center RCTs designed to definitively demonstrate the benefits of a promising therapy-early goal-directed therapy (EGDT). In light of the challenges of designing and conducting RCTs in sepsis, novel approaches that leverage highly granular observational data from real-world practice are urgently needed to: (1) provide novel insight into sepsis disease mechanisms; (2) link the pathophysiology of sepsis to new interventions; and (3) offer improved disease prognostication for clinicians and patients. This project outlines such an approach. Its training aims are designed to expand skills and knowledge by: (1) optimizing our ability to predict adverse outcomes in sepsis patients after initial triage and treatment; (2) assessing whether EGDT can benefit patients with less severe sepsis; and (3) quantifying the specific impacts of acute organ dysfunction on long-term outcomes among sepsis survivors. The proposed work has high potential to make a significant clinical impact, as these aims will not only advance our understanding of disease mechanisms in sepsis, but also provide preliminary data on putative risk factors to target in future interventional trials. This work will also converge in a R01 proposal aimed at designing a real-time sepsis risk prediction tool. Furthermore, this K23 develops specific examples in sepsis whose logical extension to other critical care syndromes indicates applicability beyond the scope of this proposal and, hence, high public health significance. Importantly, the proposed work is realistic and feasible within the award period and will allow Dr. Liu to continue to build research skills, generate preliminary data, create additional collaborative relationships, and compete for R01 funding. In summary, this K23 award will support and accelerate the career development activities of Dr. Liu and allow him to successfully launch into the next phase of his career as an independent investigator.