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

Primary Purpose

Seemingly Healthy, Genetic Predisposition to Disease

Status
Enrolling by invitation
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Genomic Sequencing
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Seemingly Healthy

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Framingham Heart Study
  • Jackson Heart Study

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

FHS & JHS participants with an actionable genomic finding

Arm Description

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.

Outcomes

Primary Outcome Measures

Follow Through with 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.
Costs of 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

Guideline Compliance
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.
New and Modified Diagnoses
We will examine cases to determine the percentage of individuals with a new or modified diagnosis attributed to results disclosure.
Self-Rated Health
We will administer a single item of self rated health derived from the SF-12v2.
MD Recommendations
We will review chart notes from results disclosure sessions to determine services recommended in response to genetic findings.
Health Care Utilization
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

Full Information

First Posted
December 10, 2019
Last Updated
June 15, 2022
Sponsor
Brigham and Women's Hospital
Collaborators
Framingham Heart Study, Jackson Heart Study, Broad Institute, University of Mississippi Medical Center, Boston University, Partners HealthCare
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1. Study Identification

Unique Protocol Identification Number
NCT04196374
Brief Title
Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts
Acronym
PopSeq
Official Title
Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Enrolling by invitation
Study Start Date
June 9, 2021 (Actual)
Primary Completion Date
June 30, 2023 (Anticipated)
Study Completion Date
June 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital
Collaborators
Framingham Heart Study, Jackson Heart Study, Broad Institute, University of Mississippi Medical Center, Boston University, Partners HealthCare

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Seemingly Healthy, Genetic Predisposition to Disease

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Individuals who have had their DNA sequenced as part of TOPMed and are living will be notified if they have an actionable genomic result in an ACMG gene. There is no comparison group for this study.
Masking
None (Open Label)
Masking Description
There will be no masking all eligible individuals identified with an actionable genomic variant in an ACMG V2.0 gene will be notified.
Allocation
N/A
Enrollment
110 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
FHS & JHS participants with an actionable genomic finding
Arm Type
Experimental
Arm Description
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.
Intervention Type
Genetic
Intervention Name(s)
Genomic Sequencing
Intervention Description
Whole Genome Sequencing and reporting of actionable genomic results for genes included on the ACMG secondary findings list.
Primary Outcome Measure Information:
Title
Follow Through with Disclosure
Description
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.
Time Frame
From genetic result notification to 8 months post-disclosure
Title
Costs of Disclosure
Description
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.
Time Frame
1 year post-disclosure
Secondary Outcome Measure Information:
Title
Guideline Compliance
Description
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.
Time Frame
History before disclosure
Title
New and Modified Diagnoses
Description
We will examine cases to determine the percentage of individuals with a new or modified diagnosis attributed to results disclosure.
Time Frame
1 year post-disclosure
Title
Self-Rated Health
Description
We will administer a single item of self rated health derived from the SF-12v2.
Time Frame
Post disclosure and 1 year post-disclosure
Title
MD Recommendations
Description
We will review chart notes from results disclosure sessions to determine services recommended in response to genetic findings.
Time Frame
From disclosure to 1 month post-disclosure
Title
Health Care Utilization
Description
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
Time Frame
1 year post-disclosure
Other Pre-specified Outcome Measures:
Title
Health Behaviors
Description
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.
Time Frame
1 year post-disclsoure
Title
Disclosure-specific Impact
Description
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.
Time Frame
6 months post-disclosure
Title
Satisfaction with Disclsoure
Description
Surveys will assess how helpful participants felt the results disclosure session was using a novel single question.
Time Frame
6 months post-disclosure and 1 year post-disclosure
Title
Decisional Regret
Description
Surveys will assess if participants regretted their decisions to receive their genetic findings using a novel single question.
Time Frame
6 months post-disclosure and 1 year post-disclosure
Title
Sharing with Relatives
Description
The survey will assess with how many relatives participants shared their genetic information.
Time Frame
1 year post-disclsoure
Title
Family Testing
Description
The survey will assess whether participants had relatives that received genetic testing based on disclosure to the participant.
Time Frame
1 year post-disclsoure
Title
General Anxiety
Description
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.
Time Frame
Post-disclosure and 6 months post-disclosure

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Facility Information:
Facility Name
Framingham Heart Study
City
Framingham
State/Province
Massachusetts
ZIP/Postal Code
01702
Country
United States
Facility Name
Jackson Heart Study
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39213
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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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Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts

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