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Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts (PopSeq)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04196374
Recruitment Status : Enrolling by invitation
First Posted : December 12, 2019
Last Update Posted : February 3, 2021
Framingham Heart Study
Jackson Heart Study
Broad Institute
University of Mississippi Medical Center
Boston University
Partners HealthCare
Information provided by (Responsible Party):
Robert C. Green, MD, MPH, Brigham and Women's Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment
Seemingly Healthy Genetic Predisposition to Disease Genetic: Genomic Sequencing

Detailed Description:

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.

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Study Type : Observational
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts
Estimated Study Start Date : February 17, 2021
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2023

Intervention Details:
  • Genetic: Genomic Sequencing
    Whole Genome Sequencing and reporting of actionable genomic results for genes included on the ACMG secondary findings list.

Primary Outcome Measures :
  1. Follow Through with Disclosure [ Time Frame: From genetic result notification to 8 months post-disclosure ]
    JHS/FHS participants who have been sequenced through TOPMed, are alive and have consented for result return will be notified if an actionable genetic result is discovered. We will contact them and offer them the opportunity to have their research result clinically confirmed. We will evaluate the proportion of individuals who elect to have their result confirmed and disclosed to their health care provider.

  2. Costs of Disclosure [ Time Frame: 1 year post-disclosure ]
    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. For follow-up medical care, we will use a gross costing approach where we apply Centers for Medicare and Medicaid fee schedules to completed referrals and tests, hospitalizations and medication changes identified as described above.

Secondary Outcome Measures :
  1. Guideline Compliance [ Time Frame: History before disclosure ]
    Comparison of participants' personal and family histories of disease and their relevant available medical data against existing guidelines to identify instances where genetic testing and/or referral had been warranted but was never ordered.

  2. New and Modified Diagnoses [ Time Frame: 1 year post-disclosure ]
    We will examine cases to determine the percentage of individuals with a new or modified diagnosis attributed to results disclosure.

  3. Self-Rated Health [ Time Frame: Post disclosure and 1 year post-disclosure ]
    We will administer a single item of self rated health derived from the SF-12v2.

  4. MD Recommendations [ Time Frame: From disclosure to 1 month post-disclosure ]
    We will review chart notes from results disclosure sessions to determine services recommended in response to genetic findings.

  5. Health Care Utilization [ Time Frame: 1 year post-disclosure ]
    We will track health care utilization in response to results disclosure in the one year follow-up survey, including a) referrals and tests, b) hospitalizations, and c) medication changes

Other Outcome Measures:
  1. Health Behaviors [ Time Frame: 1 year post-disclsoure ]
    The survey includes a series of standardized yes/no questions to assess whether disclosed genetic information motivated participants to make changes to health behaviors. A summary score will be created based on the number of behaviors that participants report.

  2. Disclosure-specific Impact [ Time Frame: 6 months post-disclosure ]
    The survey assess the disclosure-specific impact of information on distress and positive emotions using an adapted 8-item version of the FaCTOR, a validated instrument developed for genomic sequencing that is sensitive to responses to high- and low-risk genetic risk results.

  3. Satisfaction with Disclsoure [ Time Frame: 6 months post-disclosure and 1 year post-disclosure ]
    Surveys will assess how helpful participants felt the results disclosure session was using a novel single question.

  4. Decisional Regret [ Time Frame: 6 months post-disclosure and 1 year post-disclosure ]
    Surveys will assess if participants regretted their decisions to receive their genetic findings using a novel single question.

  5. Sharing with Relatives [ Time Frame: 1 year post-disclsoure ]
    The survey will assess with how many relatives participants shared their genetic information.

  6. Family Testing [ Time Frame: 1 year post-disclsoure ]
    The survey will assess whether participants had relatives that received genetic testing based on disclosure to the participant.

  7. General Anxiety [ Time Frame: Post-disclosure and 6 months post-disclosure ]
    We will measure general anxiety using the General Anxiety Disorder Scale 2 (GAD-2), a validated 2-item instrument that will allow investigators to identify individuals with a potential mood disorder.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
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.

Inclusion Criteria:

  • 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).

Exclusion Criteria:

  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04196374

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United States, Massachusetts
Framingham Heart Study
Framingham, Massachusetts, United States, 01702
United States, Mississippi
Jackson Heart Study
Jackson, Mississippi, United States, 39213
Sponsors and Collaborators
Brigham and Women's Hospital
Framingham Heart Study
Jackson Heart Study
Broad Institute
University of Mississippi Medical Center
Boston University
Partners HealthCare

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Responsible Party: Robert C. Green, MD, MPH, Professor of Medicine, Brigham and Women's Hospital Identifier: NCT04196374    
Other Study ID Numbers: R01HL143295 ( U.S. NIH Grant/Contract )
First Posted: December 12, 2019    Key Record Dates
Last Update Posted: February 3, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data will not be shared. Aggregate data will be shared through publication and will be considered upon request.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Disease Susceptibility
Genetic Predisposition to Disease
Disease Attributes
Pathologic Processes