EMERGE PHASE III CLINICAL CENTER AT PARTNERS HEALTHCARE

 描述（由申请人提供）：Partners HealthCare的eMERGE III临床中心提案利用了大型生物库、来自新英格兰最大的综合医疗保健提供商的超过400万参与者的电子病历（EMR）中的临床数据、先进的生物信息学专业知识和最先进的遗传分析。我们提出三个目标。(1)目标1.的发现我们将测试一个假设，即来自定制芯片的常见和罕见变异，包括50，000个功能丧失（LoF）等位基因，将与来自EMR的心血管、神经精神和免疫介导的表型相关。我们目前正在用定制芯片对25，000名Partners HealthCare Biobank受试者进行基因分型，该芯片包括来自我们分析的63，000个外显子组的LoF等位基因。(2)目标二。外显性和多效性。我们将测试的假设，测序一组已建立的基因或基因座将允许我们发现额外的变化，并使用EMR表型定义多态性和多效性。将通过PheWAS和图表审查研究eMERGE网络选择的基因中的罕见变体的多态性和多效性结局。此外，我们准备进行基因型召回研究，因为所有生物库参与者都同意进行这种召回。(3)目标3：实施.我们将检验这样一个假设，即医生将根据自愿返回的可操作变体改变对患者的监测和治疗，为患者提供安全和具有成本效益的益处。我们会筛选整个生物样本库 在25，000人的人群中检测LDLR基因的致病性变异，LDLR基因是早发性冠状动脉疾病的主要遗传原因，并进行探索性试验以披露这一信息。具有LDLR致病性变异的生物样本库参与者将被纳入一项随机试验，在该试验中，他们的发现将得到CLIA证实，在一个组中，该结果 将通过EMR传达给他们的医生。在一年多的时间里，我们将通过参与者调查和EMR查询收集以下结果：医生访问，实验室检测，药物处方的变化，LDL水平，医疗费用以及因干预而筛选和治疗的家庭成员数量。我们将与整个eMERGE III网络合作，将我们从这项试点试验中学到的知识纳入网络选择的基因测序的大规模实施方案中。最后，我们将参加所有网络活动，以加强遗传学的运动到临床实践。

 DESCRIPTION (provided by applicant): The eMERGE III Clinical Center proposal from Partners HealthCare leverages a large biobank, clinical data in the electronic medical records (EMR) for >4 million participants from the largest integrated health care provider in New England, advanced bioinformatics expertise and state-of-the-art genetic analysis. We propose three aims. (1) Aim 1. Discovery. We will test the hypothesis that common and rare variants from a custom chip including 50,000 loss of function (LoF) alleles will be associated with cardiovascular, neuropsychiatric and immune-mediated phenotypes derived from the EMR. We are currently genotyping 25,000 Partners HealthCare Biobank subjects with a custom chip that includes LoF alleles from 63,000 exomes that we have analyzed. (2) Aim 2. Penetrance and Pleiotropy. We will test the hypothesis that sequencing a set of established genes or loci will allow us to discover additional variation, and define penetrance and pleiotropy using EMR phenotypes. Rare variants in genes selected by the eMERGE network will be studied for penetrance and pleiotropic outcomes by PheWAS and chart review. In addition, we are poised to perform recall-by-genotype studies because all Biobank participants have provided consent for such callback. (3) Aim 3. Implementation. We will test the hypothesis that physicians will alter their surveillance and treatment of patients based upon voluntary return of actionable variants to provide safe and cost-effective benefits to patients. We will screen our entire Biobank population of 25,000 individuals for pathogenic variants in the LDLR gene, the leading genetic cause of premature coronary artery disease, and conduct an exploratory trial in disclosing this information. Biobank participants with pathogenic variants in LDLR will be offered enrollment into a randomized trial, in which their finding will be CLIA-confirmed, and in one arm, this result will be communicated to their physicians through the EMR. Over one year, we will collect the following outcomes through participant surveys and EMR queries: physician visits, laboratory testing, changes in medication prescriptions, LDL levels, medical costs and the number of family members screened and treated as a result of the intervention. We will collaborate with the entire eMERGE III Network to incorporate what we learn from this pilot trial into large-scale implementation protocols for the genes selected by the Network for sequencing. Finally, we will participate in all Network activities to enhance the movement of genetics into clinical practice.