Genomic Diagnosis and Individualized Therapy of Highly Penetrant Genetic Diabetes (Administrative Supplment)

高渗透性遗传性糖尿病的基因组诊断与个体化治疗（行政增补）

基本信息

批准号：
9116573
负责人：
TONI I. POLLIN
金额：
$ 4.19万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-18 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116573
关键词：
Accounting Adult Advertisements Affect Age Algorithms American Architecture Awareness Baltimore Blindness Blood Glucose Cardiovascular Diseases Cessation of life Clinic Clinical Clinical Research Communities Community Healthcare Complex Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diagnosis Diet Disease Early Diagnosis Early treatment Electronic Health Record End stage renal failure Endocrinology Etiology Family Family Practice Family member Gene Mutation Genes Genetic Genetic Counseling Genetic screening method Genomics Genotype Glucose tolerance test Goals Health Health Personnel Health system Healthcare Hereditary Disease Housing Hyperglycemia Impact evaluation Individual Inherited Insulin Insulin-Dependent Diabetes Mellitus Insurance Coverage Laboratories Lead Life Maryland Measures Medical Medical center Medicine Modeling Molecular Diagnosis Morbidity - disease rate Mutation Non-Insulin-Dependent Diabetes Mellitus Oral Outcome Patient Outcomes Assessments Patients Phenotype Prevention Primary Health Care Private Practice Process Publishing Quality of life Questionnaires Recommendation Recording of previous events Registries Resources Risk Assessment Single-Gene Defect Site Visit System Techniques Testing Translating United States United States Department of Veterans Affairs Universities Variant base blood glucose regulation clinical practice clinically significant cost diabetes educator diabetes mellitus genetics diabetes risk diabetic effective therapy evidence base gene panel genetic counselor genetic variant glycemic control health care delivery improved individualized medicine medical specialties meetings mortality novel outcome forecast patient population personalized medicine population based programs research clinical testing screening tool treatment strategy variant of unknown significance

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus affects over 25 million individuals in the United States and is a leading cause of morbidity and mortality. At least 1% of diabetes (>250,000 individuals) results from high penetrant single gene defects, in HNF1A, GCK and HNF4A and several other genes. Unfortunately, as a result of phenotypic overlap with more common forms of diabetes, lack of awareness and/or techniques for identifying them among health care providers, and the cost and labor historically involved in sequencing several genes as required to make a diagnosis, the vast majority of cases of highly penetrant and genetic diabetes are misdiagnosed as type 1 (T1DM) or type 2 diabetes (T2DM). Published evidence shows that diagnosing highly penetrant genetic forms of diabetes enables personalized treatment resulting in improved glucose control, better prediction of prognosis, and an enhanced familial risk assessment. To meet this need, we propose to implement and evaluate in four diverse health care settings our Personalized Diabetes Medicine Program (PDMP). The PDMP is currently based at the University of Maryland Center for Diabetes and Endocrinology and will be disseminated to UM Family Medicine and three partner centers: the Baltimore Veterans Administration Medical Center (BVAMC, with opportunities to disseminate nationally), Geisinger Medical Center (an integrated health system) and Bay West Endocrinology Associates (a community-based private practice group). We will also engage the community through advertisements and site visits to local primary care practices by our genetic counselor/diabetes educator team. The PDMP consists of: a simple patient screening questionnaire, chart/electronic health record (EHR) review, an algorithm that includes utilizes questionnaire data, routine lab testing, and family history review to identify patients most likely to have highl penetrant genetic diabetes; customized multiplex gene panel sequencing of eligible patients followed by confirmation of diabetes-causal mutations in our CLIA-approved Translational Genomics Laboratory; incorporation of mutations and decision support in the EHR; genetic counseling; implementing a mutation-based treatment strategy; and family screening. Deliverables include EHR-based implementation tools, the sequencing panel and contribution of genotype/phenotype data regarding diabetes-causal variants and variants of unknown clinical significance to ClinVar and other similar public resources. We will track implementation metrics of the PDMP and conduct an impact evaluation, including evaluation of clinical outcomes as measured by changes in glycemic control in patients diagnosed with a genetic form of diabetes. Finally, we will engage a Payer Advisory Panel in the development of the impact evaluation process to enhance our ability to collect meaningful evidence to inform clinical practice recommendations and guide insurance coverage decisions as a first step to enabling diagnosis of inherited forms of diabetes across the United States and more broadly, genomic diagnosis and treatment of highly penetrant genetic forms of other common diseases.

描述（由申请人提供）：糖尿病影响美国超过 2500 万人，是发病和死亡的主要原因。至少 1% 的糖尿病（>250,000 人）是由 HNF1A、GCK 和 HNF4A 以及其他几个基因的高渗透性单基因缺陷引起的。不幸的是，由于表型与更常见的糖尿病形式重叠、医疗保健提供者缺乏识别它们的意识和/或技术，以及历史上根据诊断所需对多个基因进行测序所涉及的成本和劳动力，大多数高渗透性遗传性糖尿病病例被误诊为 1 型 (T1DM) 或 2 型糖尿病 (T2DM)。已发表的证据表明，诊断高渗透性遗传形式的糖尿病可以实现个性化治疗，从而改善血糖控制、更好地预测预后并增强家族风险评估。为了满足这一需求，我们建议在四个不同的医疗保健环境中实施和评估我们的个性化糖尿病医学计划（PDMP）。 PDMP 目前位于马里兰大学糖尿病和内分泌中心，并将分发给 UM 家庭医学中心和三个合作中心：巴尔的摩退伍军人管理局医疗中心 (BVAMC，有机会在全国范围内分发)、Geisinger 医疗中心 (综合性医疗中心)卫生系统）和 Bay West Endocrinology Associates（一个以社区为基础的私人执业团体）。我们还将通过广告和遗传咨询师/糖尿病教育团队对当地初级保健实践的现场访问来吸引社区的参与。 PDMP 包括：简单的患者筛查问卷、图表/电子健康记录 (EHR) 审核、算法，其中包括利用问卷数据、常规实验室测试和家族史审核来识别最有可能患有高渗透性遗传性糖尿病的患者；对符合条件的患者进行定制的多重基因组测序，然后在我们 CLIA 批准的转化基因组学实验室中确认糖尿病致病突变；将突变和决策支持纳入 EHR；遗传咨询；实施基于突变的治疗策略；和家庭筛查。可交付成果包括基于 EHR 的实施工具、测序面板以及有关糖尿病致病变异和临床意义未知的变异的基因型/表型数据对 ClinVar 和其他类似公共资源的贡献。我们将跟踪 PDMP 的实施指标并进行影响评估，包括通过诊断为遗传性糖尿病的患者的血糖控制变化来评估临床结果。最后，我们将聘请付款人咨询小组参与影响评估流程的制定，以增强我们收集有意义的证据的能力，为临床实践建议提供信息并指导保险承保决策，作为在整个美国诊断遗传性糖尿病的第一步更广泛地说，是其他常见疾病的高渗透性遗传形式的基因组诊断和治疗。