Identification of the Components of Frailty Using Administrative Data and Metabolite Profiling

项目总结 候选人：斯特罗姆博士获得哈佛医学院医学博士学位，并已完成临床 内科(MGH)、心脏病学(BIDMC)和无创心脏成像(BIDMC)方面的培训。 此外，他还在哈佛大学公共卫生学院完成了流行病学硕士课程， 2018年5月。他现在是BIDMC的初级教员，有75%的保护时间来指导临床 研究。通过这一拟议的5年计划，斯特罗姆博士将继续进行高级 预测建模、机器学习、以患者为中心的研究和代谢组学。候选人的长久以来- 学期目标是成为R01资助的应用成果研究领域的研究员。 环境：候选人将由罗伯特·W·叶(小学导师)指导，副教授 HMS医学和史密斯心脏病学结果研究中心主任罗伯特·E·格斯滕 HMS医学教授、BIDMC心血管内科主任(共同导师)和张宇 沈(共同导师)，HMS即将上任的医学副教授，史密斯大学的首席生物统计学家 中心。叶博士拥有领先的实践改变研究和临床医生成功指导的记录 调查人员。Gerszten博士是国际公认的心血管分子表型专家 使用代谢组学和蛋白质组学的疾病，并指导了几个K-奖和R01资助的临床 调查人员。沈博士在NIH的资助方面有着长期的记录，在评估异质性方面的专业知识 在心血管疾病方面的治疗效果，并曾指导过多名先前的学员。 研究：对于特定的主动脉狭窄患者，最佳治疗方案仍不确定。这项建议 旨在确定可改变主动脉瓣置换术后风险的脆弱的临床和生物成分 (AVR)和改变治疗福利。对于AIMS 1-2，我们将利用Medicare数据与 美国CoreValve Pivotal试验，一组临床试验，随机选择患有严重主动脉狭窄的患者 比较经导管AVR(TAVR)与外科AVR(SAVR)的异同。在目标1中，我们将 我们将确定与脆弱性和候选脆弱性代码的面对面评估相关的哪些变量最好 预测AVR术后的不良结果。在目标2中，我们将确定目标1中是否发现了新的变量，确定了 接受动静脉动静脉再造术的个体的异质性治疗反应。在AIM 3中，我们将前瞻性地招收 在BIDMC接受TAVR的患者同时进行脆弱表型分析以确定代谢物 与长寿相关与虚弱相关，并预测不良后果，独立于年龄和 合并症。这项研究将确定脆弱带来不利风险和差异化的机制。 AVR的治疗受益，提供了可能个性化治疗选择和改善患者护理的见解。

PROJECT SUMMARY Candidate: Dr. Strom received an MD from Harvard Medical School (HMS), and has completed clinical training in internal medicine (MGH), cardiology (BIDMC), and non-invasive cardiac imaging (BIDMC). Additionally, he completed an MSc in Epidemiology program at the Harvard T.H. Chan School of Public Health, in May, 2018. He is now a junior faculty member at BIDMC with 75% protected time to conduct clinical research. Through this proposed 5-year program, Dr. Strom will pursue additional training in advanced prediction modeling, machine learning, patient-oriented research, and metabolomics. The candidate’s long- term goal is to become an R01-funded investigator in the area of applied outcomes research. Environment: The candidate will be mentored by Robert W. Yeh (Primary Mentor), Associate Professor of Medicine at HMS and Director of the Smith Center for Outcomes Research in Cardiology, Robert E. Gerszten (Co-Mentor), Professor of Medicine at HMS and Chief of Cardiovascular Medicine at BIDMC, and Changyu Shen (Co-Mentor), upcoming Associate Professor of Medicine at HMS and Lead Biostatistician for the Smith Center. Dr. Yeh has a track record of leading practice-changing studies and successful mentorship of clinician investigators. Dr. Gerszten is an internationally recognized expert in molecular phenotyping of cardiovascular diseases using metabolomics and proteomics and has mentored several K-award and R01 funded clinical investigators. Dr. Shen has a long track record of NIH funding, expertise in evaluating heterogeneity of treatment effect in cardiovascular diseases, and has mentored multiple prior trainees. Research: The optimal therapy for a given individual with aortic stenosis remains uncertain. This proposal seeks to define the clinical and biologic components of frailty that modify risk after aortic valve replacement (AVR) and alter treatment benefit. For Aims 1-2, we will leverage the unique linkage of Medicare data to the US CoreValve Pivotal trials, a collection of clinical trials that randomized individuals with severe aortic stenosis to transcatheter AVR (TAVR) with a self-expanding bioprosthesis vs. surgical AVR (SAVR). In Aim 1, we will we will identify which variables, related to in-person assessments of frailty and candidate frailty codes, best predict adverse outcomes after AVR. In Aim 2, we will identify if novel variables identified in Aim 1, identify a heterogeneous treatment response in individuals undergoing AVR. In Aim 3, we will prospectively enroll patients undergoing TAVR at BIDMC with concurrent frailty phenotyping to identify whether metabolites associated with longevity correlate with frailty and predict adverse outcomes, independent of age and comorbidities. The research will identify the mechanisms by which frailty confers adverse risk and differential treatment benefit in AVR, providing insights that may personalize treatment selection and improve patient care.