The 1200 Patients Project: Studying Clinical Implementation of Pharmacogenomics

描述（由申请人提供）：我之前的培训以及我近期和长期的愿望使这个药物基因组学和个性化医学转化学者奖（K23）成为进一步塑造我职业生涯的理想机会。在过去的三年里，我在芝加哥大学完成了临床药理学和药物基因组学的研究。我的奖学金研究重点是研究抗癌药物的药物基因组学。这次培训使我对药物基因组学方法有了更深入的了解，并为我提供了设计和分析药物基因组学全基因组关联研究的重要经验。我开发并发起了两项不同的前瞻性临床观察研究，以药物基因组学为主要终点。这些项目巩固了我对以患者为导向的研究的兴趣，特别是在药物基因组学翻译领域。药物基因组学的研究已经允许发现影响数百种药物反应或毒性的遗传变异，但这些信息很少用于处方决策。由于对关联的临床效用持怀疑态度，医生对药物-基因关系的认识不足，检测途径有限，以及收到药物基因组学结果的延迟，实施受到阻碍。我对从事一个临床研究项目特别感兴趣，该项目旨在评估如果能够识别和克服常见的实施障碍，越来越多的新兴药物基因组学发现是否可以用于临床实践。很可能基因组发现的有效临床转化将受到系统/技术变化和行为变化的双重调节。这是我对设计“1200名患者项目”的兴趣的起源——临床研究是本申请的主题。该研究旨在通过检查1200对医患对，确定是否以及如何将先发制人的药物基因组学检测信息纳入常规临床治疗决策。假设是，先发制人的个性化护理“医疗系统模型”，使相关的药物基因组学信息在处方时立即可获得，将以改善处方行为的方式改变对药物基因组学的认识和态度。通过提供一种先发制人的药物基因组学检测的个性化医疗模式，我将研究医生如何在及时获得相关结果时访问和利用药物基因组学信息；它对医生的处方习惯以及患者和医生对护理的满意度的影响；以及医生对药物基因组学的知识和态度/看法作为处方行为改变的中介的影响。拟建的项目是前瞻性地招募1200名接受门诊治疗的成年人并进行预先基因分型（使用一组根据药物基因组学作用选择的变异）。通过创建的研究门户或基因组处方系统（GPS），研究医生可以获得患者特定的结果，该系统可以提供即时的药物基因组学指导。将收集数千次访问的接触级数据，以评估目标。假设是不合适的或高的

DESCRIPTION (provided by applicant): My prior training and my immediate and long-term aspirations make this Translational Scholar Award in Pharmacogenomics and Personalized Medicine (K23) an ideal opportunity to further shape my career. Within the past three years I completed a fellowship in Clinical Pharmacology and Pharmacogenomics at the University of Chicago. My fellowship research focused on studying the pharmacogenomics of anticancer drugs. This training allowed me to develop an advanced understanding of pharmacogenomic approaches, and provided me with significant experience in designing and analyzing genome-wide association studies in pharmacogenomics. I developed and initiated two different prospective clinical observational studies with pharmacogenomic primary endpoints. These projects solidified my interest in patient-oriented research, particularly in the field of translaton of pharmacogenomics. The study of pharmacogenomics has allowed the discovery of genetic variants impacting response or toxicity for hundreds of drugs, but the information has infrequently been utilized in prescribing decisions. Implementation has been hampered by skepticism regarding the clinical utility of associations, poor physician knowledge about drug-gene relationships, limited avenues for testing, and delays in the receipt of pharmacogenomic results. I became especially interested in pursuing a clinical research project to assess whether the growing number of emerging pharmacogenomic discoveries could be used in clinical practice if common barriers to implementation could be identified and overcome. It is likely that the efficacious clinical translation of genomic discovery will be mediated by both systems/technology changes and changes in behaviors. This was the genesis for my interest in designing "The 1200 Patients Project"-the clinical research study which is the subject of this application. The study aims to determine whether and how preemptive pharmacogenomic test information might be incorporated into routine clinical treatment decisions by examining 1200 physician-patient pairs. The hypothesis is that a preemptive 'medical system model' for personalized care that makes relevant pharmacogenomic information instantaneously accessible at the time of prescribing will alter knowledge and attitudes about pharmacogenomics in ways that will improve prescribing behaviors. By providing an individualized health care model of preemptive pharmacogenomic testing, I will study how pharmacogenomic information is accessed and utilized by physicians when timely, relevant results are available; its impact on physician prescribing habits and patient and physician satisfaction with care; and the effect of physician knowledge and attitudes/perceptions about pharmacogenomics as mediators of prescribing behavior change. The proposed project is prospectively enrolling and preemptively genotyping (using a panel of variants selected for their pharmacogenomic role) 1200 adults receiving outpatient care. Patient-specific results are available to study physicians through a created research portal, or genomic prescribing system (GPS), which provides instantaneous pharmacogenomic guidance. Encounter-level data will be collected for thousands of visits to assess the aims. It is hypothesized that inappropriate or high risk medications will be less likely to be prescribed to genetically at-risk patients if pharmacogenomic results are preemptively known. In the research plan, I describe the specific methods which will be used to measure the mediators and moderators of prescribing behavior in the context of immediate availability of pharmacogenomic results. I have developed, with input from my mentors, a conceptual framework that combines elements of a dissemination and implementation model, and the self-regulation theory of health behavior. The aims are written around this model. Successful demonstration of feasibility, and refinement of the model through this study, would then justify application more widely-in diverse practice settings-in future dissemination and implementation projects. The effectiveness, future efficacy, and impact on public health will result not just from the innovative technology we employ to make pharmacogenomic information available, but from our understanding of provider-patient pair decision-making processes involved in promoting and adopting risk-reductive behavior. To be successful in this type of translational work in clinical pharmacogenomics, I need to gain specific training and experience in the areas of knowledge translation/adoption, and behavior change. I have identified new mentors with expertise in these areas to guide my Training Plan. With their direction, I have proposed a comprehensive and customized program of courses and workshops for advanced training in the social sciences and in implementation research. The University of Chicago offers a rich atmosphere of resources and mentorship in which to pursue this training and career development. With such training through this K award, I will be prepared for an independent research career in clinical implementation of pharmacogenomics. Results from the project, combined with my concomitant training, would form the foundation for my first R01 proposal in which many patient-provider pairs from diverse settings could be randomized to preemptive genotyping/GPS availability versus prescribing without pharmacogenomics, to develop more definitive evidence concerning the efficacy and effectiveness of pharmacogenomic testing on adverse drug event/response outcomes and its sustainable dissemination.