Data-driven Precision medicine in sepsis

描述(由申请人提供)：本K23计划的目的是为医学博士、医学硕士文森特·刘博士提供必要的时间和资源，以继续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果的长期目标。刘博士是Kaiser Permanente研究部(KP-DOR)董事会认证的集约主义者和研究科学家。该提案的基础是他在重症监护、传统生物统计学和高度详细的电子医疗应用方面的背景 记录数据。它还利用了KP-DOR提供的丰富的培训环境，斯坦福大学在随意推理和信息学方面的高级教学培训，以及一个有凝聚力的指导团队，以提高我们对脓毒症的理解和治疗。败血症是对感染的炎症反应，每年影响全球数百万患者，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在医院死亡，越来越多的败血症幸存者在出院后面临更高的死亡率和伤残率。最近的随机对照试验(RCT)未能确定有效的脓毒症治疗方法，在最初描述十多年后，我们仍在等待三项多中心随机对照试验，旨在明确证明一种有前景的治疗方法-早期目标定向治疗(EGDT)的好处。鉴于在脓毒症中设计和实施随机对照试验的挑战，迫切需要利用来自真实世界实践的高粒度观察数据的新方法来：(1)为脓毒症的疾病机制提供新的见解；(2)将脓毒症的病理生理学与新的干预措施联系起来；以及(3)为临床医生和患者提供更好的疾病预测。这个项目概述了这样一种方法。它的培训目标旨在通过以下方式扩展技能和知识：(1)优化我们在最初分诊和治疗后预测脓毒症患者不良结局的能力；(2)评估EGDT是否可以使不太严重的脓毒症患者受益；以及(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。这项拟议的工作有很高的潜力产生重大的临床影响，因为这些目标不仅将促进我们对脓毒症发病机制的了解，而且还将为未来的干预试验提供可能的危险因素的初步数据。这项工作还将汇聚在旨在设计实时脓毒症风险预测工具的R01提案中。此外，这本K23开发了脓毒症的具体例子，其逻辑延伸到其他重症监护综合征表明其适用性超出了本提案的范围，因此具有很高的公共卫生意义。重要的是，拟议的工作在获奖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，建立更多的合作关系，并竞争R01资金。综上所述，这一K23奖项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职业生涯的下一阶段，成为一名独立调查人员。

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.