The 1200 Patients Project: Studying Clinical Implementation of Pharmacogenomics

描述（由申请人提供）：我以前的培训和我的直接和长期的愿望，使这个翻译学者奖在药物基因组学和个性化医学（K23）的理想机会，进一步塑造我的职业生涯。在过去的三年里，我获得了芝加哥大学临床药理学和药物基因组学的奖学金。我的奖学金研究集中在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深入的了解，并为我提供了设计和分析药物基因组学中全基因组关联研究的重要经验。我开发并启动了两项不同的药物基因组学主要终点的前瞻性临床观察性研究。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的翻译领域。药物基因组学的研究已经允许发现影响数百种药物的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-基因关系的知识贫乏，测试途径有限，以及药物基因组学结果的接收延迟，实施受到阻碍。我变得特别感兴趣的追求临床研究项目，以评估是否越来越多的新兴药物基因组学的发现可以在临床实践中使用，如果共同的障碍，实施可以确定和克服。基因组发现的有效临床转化可能由系统/技术变化和行为变化介导。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对医生-患者来确定是否以及如何将抢先药物基因组学检测信息纳入常规临床治疗决策。该假设是，先发制人的“医疗系统模式”的个性化护理，使相关的药物基因组学信息即时访问的处方时，将改变知识和态度的方式，将改善处方行为的药物基因组学。通过提供一个个性化的医疗保健模式的先发制人的药物基因组学检测，我将研究如何药物基因组学信息是访问和利用的医生时，及时，相关的结果是可用的;其对医生的处方习惯和患者和医生的满意度护理的影响;和医生的知识和态度/看法的药物基因组学作为调解人的处方行为的变化。拟定的项目是前瞻性招募和抢先基因分型（使用一组根据其药物基因组学作用选择的变体）1200名接受门诊治疗的成人。研究医生可通过创建的研究门户网站或基因组处方系统（GPS）获得患者特定结果，该系统提供即时药物基因组学指导。将收集数千次访问的遭遇层面数据，以评估目标。据推测，不适当或高 如果预先知道药物基因组学结果，则不太可能将风险药物处方给遗传风险患者。在研究计划中，我描述了在药物基因组学结果立即可用的情况下，将用于测量处方行为的介导者和调节者的具体方法。我已经开发了，从我的导师的投入，一个概念框架，结合传播和实施模式的元素，以及健康行为的自我调节理论。我们的目标是围绕这个模型来写的。成功的可行性示范，并通过这项研究的模型的完善，然后证明应用更广泛的不同的实践环境，在未来的传播和实施项目。有效性、未来疗效和对公共卫生的影响不仅来自我们用于提供药物基因组学信息的创新技术，而且来自我们对促进和采用风险降低行为的提供者-患者对决策过程的理解。为了在临床药物基因组学的这类转化工作中取得成功，我需要获得特定的 在知识转化/采用和行为改变方面的培训和经验。我已经确定了在这些领域具有专业知识的新导师来指导我的培训计划。在他们的指导下，我提出了一个全面和定制的课程和研讨会计划，用于社会科学和实施研究的高级培训。芝加哥大学提供了丰富的资源和指导氛围，以追求这种培训和职业发展。通过这次K奖的培训，我将为药物基因组学临床实施的独立研究生涯做好准备。该项目的结果与我的伴随培训相结合，将为我的第一个R 01提案奠定基础，在该提案中，来自不同环境的许多患者-提供者对可以被随机分配到先发制人的基因分型/GPS可用性，而不是在没有药物基因组学的情况下开处方，以开发关于药物基因组学检测对药物不良事件/反应结局及其可持续传播的疗效和有效性的更明确证据。

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.