Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 7,603
- 试验地点
- 2
- 主要终点
- Follow Through With Disclosure
研究概览
简要总结
The PopSeq Project is a prospective cohort study that will develop and implement a genomic return of results (gRoR) process in the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts and explore associated medical, behavioral, and economic outcomes. The study will interpret the genomic sequences of JHS/FHS participants previously sequenced by TOPMed who have consented to genomic return of results and/or genetic testing. We will develop and apply new methods for scalable screening/ classification of genomic variants and will explore genomic penetrance by phenotyping a subset of participants in the FHS and JHS.
详细描述
The objectives of this project are to: 1) Return clinically actionable genomic results to participants and track outcomes. Among living FHS/JHS participants who have consented to gRoR, we will contact those in whom a detrimental actionable variant is discovered in one of the genes noted on the ACMG recommended secondary findings list (estimate 2% of participants). 2) Improve high-throughput methods for identifying valid pathogenic variation. Refine and apply methods for high throughput screening of FHS/JHS genomes in a manner that retains high sensitivity for the detection of detrimental variants in ~3500 Mendelian disease-associated genes while reducing the false discovery rate of variants that are not pathogenic/likely pathogenic. 3) Explore aggregate penetrance for Mendelian diseases. Review phenotype data from a subset of FHS and JHS participants and compare this to genotypic data.
Data to be gathered include outcome and phenotypic data on the individuals who agree to gRoR and who learn that they have detrimental variant in one of the ACMG listed genes. These data will be self-reported through surveys and available medical records will be reviewed. Additional phenotypic data may be collected and reviewed for other non-actionable mendelian disease genes to explore genomic penetrance.
Research participants who are identified with a detrimental variant in an actionable gene may receive direct health benefits from learning this information; however, returning genomic results to healthy individuals not presenting for a medical indication may pose unexpected harms related to variant directed increases in screening and management. This study is focused on exploring the benefits and any potential harms related to returning genomic information in population-based cohorts. It will also allow us to better understand the penetrance of these variants in two populations not selected for disease status and will allow us to compare outcomes in a primarily African American population vs a Caucasian population. Developing methods to streamline variant analysis will help improve laboratory efficiency and will progress the field of variant curation and analysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Prevention
- 盲法
- None
盲法说明
There will be no masking all eligible individuals identified with an actionable genomic variant in an ACMG V2.0 gene will be notified.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Living individuals enrolled in the Framingham Heart Study and the Jackson Heart Study who have had their genomes sequenced as part of the TOPMed program.
- •Adults over the age of 18 years
- •Those who have consented to have their DNA samples used for research purposes (and those who participate in gRoR who have consented to receive genomic information).
排除标准
- •Participants of the Framingham Heart Study or Jackson Heart Study who have not had their genomes sequenced as part of TOPMed
- •Participants who did not opt for genomic/genetic research
- •Participants who did/do not consent to receiving a genomic result (for the gRoR portion of this study only)
研究组 & 干预措施
FHS & JHS participants with an actionable genomic finding
Framingham and Jackson Heart Study participants who have had their genomes sequenced as part of TOPMed will be notified if an actionable genetic result in an ACMG v2.0 gene is identified and will be offered the opportunity to have their research result clinically confirmed by the study.
干预措施: Genomic Sequencing (Genetic)
结局指标
主要结局
Follow Through With Disclosure
时间窗: From genetic result notification to 8 months post-disclosure
Living JHS/FHS participants sequenced as part of the TOPMed program who were notified about an actionable genetic result that warranted having the research result verified who followed through with having their result confirmed and disclosed to their health care provider.
Total Costs of Program Implementation
时间窗: From the initiation of bioinformatics analysis to disclosure of confirmed actionable genetic finding (approximately 6 months).
We will determine the costs and associated time demands of implementing gRoR using a microcosting approach in which study staff track the amount of time they spend and the resources they use for each step of the protocol. Ranges are based on 50% to 200% of point estimates given variability in wages and prices of services.
Costs of Follow-Up Care
时间窗: 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)
For follow-up medical care, we use a gross costing approach where we apply Centers for Medicare and Medicaid fee schedules to participant-reported referrals and tests.
次要结局
- Guideline Compliance(At the time of disclosure of confirmed findings (approximately 3 months after initial results notification))
- New and Modified Diagnoses(6 months Post-Disclosure Survey (6-9 months after disclosure of confirmed results);1 Year Post-Disclosure Survey (from 1 year to 15 months after disclosure of confirmed results))
- Self-Rated Health(Post Disclosure Survey (up to 1 month from disclosure of confirmed results); 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results))
- Number of Participants With Recommendations to Referrals or Services During Clinical Disclosure Sessions(From disclosure to 1 month post-disclosure)
- Health Care Utilization(1 year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results))
研究者
Robert C. Green, MD, MPH
Professor of Medicine
Brigham and Women's Hospital