Characterization of response to lipid-modifying regimens for atherosclerotic cardiovascular disease using electronic health records

项目摘要/摘要 最近的药理进展减轻了动脉粥样硬化性心血管疾病的负担 (ASCVD)是美国死亡的主要原因，但需要做更多的工作来进一步改善 病人的结果。特别是，我们还不能完全了解个别患者对脂质的反应。 随着时间的推移降低治疗方法，包括改变反应的人口统计学、临床和遗传变量。 来自随机对照试验(RCT)的数据在很大程度上形成了临床研究的证据基础 管理调脂治疗方案，但回答参与者的狭隘问题 代表更广泛的ASCVD风险人群。因此，我们不能依靠区域技术合作来全面 引导药学服务。电子健康记录(EHR)是一种宝贵而有效的评估资源 调脂疗法。EHR的结果可以补充RCT的结果，以提供更全面的信息 治疗建议。这项建议的总体目标是促进我们对如何 患者对预防ASCVD的血脂调节剂有反应。我们预计新的记号笔可以 确定不同调脂方案的应答者、无应答者和不良反应应答者。我们 将使用来自Kaiser Permanente North California(KPNC)的EHR来表征治疗反应。成员 的KPNC(约350万成员)代表了ASCVD患者或有风险的患者的广泛和多样化的背景 用于ASCVD。此外，KPNC EHR代表来自集成医疗保健提供系统的健康记录 经过特别长时间的后续行动(1996年至今)，允许应用创新的 评估治疗反应的方法学。在目标1中，Akinyemi Oni-Orisan博士(首席调查员)将 建立纵向非高密度脂蛋白-C水平模型，用于开发使用非高密度脂蛋白-C水平的调脂药物剂量算法 线性混合效果建模。在目标2中，Oni-Orisan博士将描述脂类的有效性和安全性- 使用COX回归对ASCVD的治疗方案进行修改。在目标3中，Oni-Orisan博士将确定基因预测因素 使用全基因组关联研究他汀类药物的反应。这项提案的发现将(1)确定预测因素 对调脂药物方案的反应，(2)发现对调脂重要的关键生物学途径 药物反应；及(3)协助临床医生提供个别化护理，以减轻公众健康负担 ASCVD的发病率。ONI-Orisan博士将由一个具有数学专业知识的经验丰富的研究人员团队进行指导 建模、生物统计学、流行病学、基因组学和血脂学。加州大学旧金山分校 世界领先的生物医学研究中心之一。奥尼-奥里桑博士将占富人的便宜 在这一研究环境内的资源，以完成建议。总体而言，研究、培训和 本提案中描述的机构环境将有助于Oni-Orisan博士实现他的长期职业目标：(1) 进行高影响力的转化性研究，促进药学保健并直接使 (2)成为一名成功的独立研究人员。

PROJECT SUMMARY/ABSTRACT Recent pharmacological advancements have reduced the burden of atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality in the United States, but more work is necessary to further improve patient outcomes. In particular, we do not thoroughly understand how individual patients respond to lipid lowering therapies over time including the demographic, clinical and genetic variables which modify response. Data from randomized controlled trials (RCTs) have largely shaped the evidence base for the clinical management of lipid-modifying therapeutic regimens, but answer narrow questions in participants who may not be representative of the broader population at risk for ASCVD. Thus, we cannot rely on RCTs to comprehensively guide pharmaceutical care. Electronic health records (EHRs) are a valuable and efficient resource for evaluating lipid-modifying therapies. Results from EHRs can complement RCT findings to provide more comprehensive treatment recommendations. The overall objective of this proposal is to advance our understanding of how patients respond to lipid-modifying agents for the prevention of ASCVD. We anticipate that novel markers can identify responders, non-responders, and adverse-effect responders to different lipid-modifying regimens. We will use EHRs from Kaiser Permanente Northern California (KPNC) to characterize therapy response. Members of KPNC (~3.5 million members) represent a broad and diverse background of patients with ASCVD or at risk for ASCVD. In addition, KPNC EHRs represent health records from an integrated healthcare delivery system with an exceptionally long period of follow-up (1996-present), allowing for the application of innovative methodologies to evaluate therapy response. In Aim 1, Dr. Akinyemi Oni-Orisan (Principal Investigator) will model longitudinal non-HDL-C levels for the development of a lipid-modifying drug dosing algorithm using non- linear mixed effects modeling. In Aim 2, Dr. Oni-Orisan will characterize the efficacy and safety of lipid- modifying regimens for ASCVD using Cox regression. In Aim 3, Dr. Oni-Orisan will identify genetic predictors of statin response using genome wide association studies. Findings from this proposal will (1) identify predictors of response to lipid-modifying drug regimens, (2) uncover key biological pathways important to lipid-modifying drug response, and (3) aid clinicians in providing individualized care that will reduce the public health burden of ASCVD. Dr. Oni-Orisan will be mentored by a team of experienced researchers with expertise in mathematical modeling, biostatistics, epidemiology, genomics, and lipidology. The University of California, San Francisco is one of the leading biomedical research centers in the world. Dr. Oni-Orisan will take advantage of the rich resources within this research environment to complete the proposal. Overall, the research, training, and institutional environment described in this proposal will aid Dr. Oni-Orisan in his long-term career goals of (1) conducting high-impact translational research that advances pharmaceutical care and directly benefits the cardiovascular health of the nation and (2) becoming a successful independent investigator.