The 1200 Patients Project: Studying Clinical Implementation of Pharmacogenomics

简介(由申请人提供)：我之前的培训和我近期和长期的抱负使这个药物基因组学和个性化医学翻译学者奖(K23)成为进一步塑造我的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。我的研究员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。我开发并启动了两项关于药物基因组学主要终点的不同的前瞻性临床观察研究。这些项目巩固了我对以患者为中心的研究的兴趣，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发现了影响数百种药物反应或毒性的遗传变异，但这些信息很少被用于处方决策。由于对关联的临床效用的怀疑、医生对药物-基因关系的缺乏了解、测试途径有限以及药物基因组结果的延迟接收，这些因素阻碍了实施。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实施的共同障碍，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翻译将受到系统/技术变化和行为变化的影响。这就是我对设计“1200名患者项目”感兴趣的缘起--这项临床研究研究是本申请的主题。这项研究旨在通过检查1200对医生-患者来确定是否以及如何将先发制人的药物基因组测试信息纳入常规临床治疗决策。这一假设是，一种用于个性化护理的先发制人的“医疗系统模型”，使相关的药物基因组学信息在处方时即时可用，将以改善处方行为的方式改变对药物基因组学的知识和态度。通过提供先发制人的药物基因组测试的个性化医疗保健模型，我将研究当及时、相关的结果可用时，医生如何获取和利用药物基因组信息；它对医生开药习惯以及患者和医生对护理的满意度的影响；以及医生关于药物基因组学的知识和态度/认知作为处方行为改变的中介的影响。拟议的项目是前瞻性地招募1200名接受门诊护理的成年人并先发制人地进行基因分型(使用一组因其药物基因组学作用而选择的变种)。研究医生可以通过创建的研究门户或基因组处方系统(GPS)获得针对患者的结果，该系统提供即时的药物基因组学指导。将收集数千次访问的遭遇级别数据，以评估目标。假设是不适当的或高的 如果先发制人知道药物基因组学结果，风险药物将不太可能被开给遗传高危患者。在研究计划中，我描述了在药物基因组学结果立即可用的背景下，将用于测量处方行为的中介和调节因素的具体方法。在我导师的指导下，我开发了一个概念框架，它结合了传播和实施模式的元素，以及健康行为的自我调节理论。目标是围绕这一模式写成的。通过这项研究成功地证明了该模式的可行性，并对该模式进行了改进，从而证明有理由在今后的传播和实施项目中在不同的实践环境中更广泛地应用该模式。其有效性、未来的有效性和对公共健康的影响不仅来自我们用来提供药物基因组信息的创新技术，还来自我们对促进和采用降低风险行为所涉及的提供者-患者对决策过程的理解。为了在临床药物基因组学中成功地进行这种类型的翻译工作，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讲习班计划，用于社会科学和实施研究方面的高级培训。芝加哥大学提供了丰富的资源和指导氛围，在其中进行培训和职业发展。通过这次K奖的培训，我将为在药物基因组学临床实施方面的独立研究生涯做好准备。该项目的结果，结合我的伴随培训，将形成我的第一个R01提案的基础，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为先发制人的基因分型/GPS可用性和不使用药物基因组学的处方，以开发关于药物基因组测试对不良药物事件/反应结果的有效性和有效性及其可持续传播的更明确的证据。

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.