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Completed

NCT Number: NCT04196374

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

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.

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Key information

Conditions

Seemingly Healthy Disease Attributes Disease Susceptibility Genetic Predisposition to Disease Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year–100 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Framingham Heart Study, Framingham, Massachusetts, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Genomic sequencing

Genetic

Whole Genome Sequencing and reporting of actionable genomic results for genes included on the ACMG secondary findings list.

Primary outcomes

  1. Follow Through With Disclosure

    Time frame: 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.

  2. Total Costs of Program Implementation

    Time frame: 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.

  3. Costs of Follow-Up Care

    Time frame: 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.

Secondary outcomes

  1. Guideline Compliance

    Time frame: At the time of disclosure of confirmed findings (approximately 3 months after initial results notification)

    Number of participants with actionable genetic results who, per the judgement of a genetic specialist, had already met clinical criteria for genetic testing based on their personal and family histories of disease.

  2. New and Modified Diagnoses

    Time frame: 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)

    We will examine cases to determine the percentage of individuals who report a new or modified diagnosis attributed to results disclosure.

  3. Self-Rated Health

    Time frame: 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)

    A single item of self rated health derived from the SF-12v2.

  4. Number of Participants With Recommendations to Referrals or Services During Clinical Disclosure Sessions

    Time frame: From disclosure to 1 month post-disclosure

    We reviewed chart notes from results disclosure sessions to determine whether referrals or services were recommended in response to genetic findings.

  5. Health Care Utilization

    Time frame: 1 year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)

    Health care utilization in response to results disclosure reported by participants in the one year follow-up survey, including referrals, tests and/or procedures, and changes to medications.

Other outcomes

  1. Self-Reported Changes to Health Behaviors

    Time frame: 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)

    A series of standardized yes/no questions that assess whether disclosed genetic information motivated participants to make changes to health behaviors, including diet, exercise, dietary supplements use, alcohol use, stress management, and smoking.

  2. Disclosure-specific Impact

    Time frame: 6 months Post-Disclosure Survey (6-9 months after disclosure of confirmed results)

    The survey assessed the disclosure-specific impact of information on distress and positive emotions using an adapted 12-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. Subscales assess negative emotions (range: 3 to 15), positive feelings (reverse-scored, range: 4 to 20), uncertainty (range: 3 to 15), and privacy concerns (range: 2 to 10), with higher scores on each subscale indicating more negative experiences.

  3. Satisfaction With Disclosure

    Time frame: 6 months Post-Disclosure Survey (6-9 months after disclosure of confirmed results); 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)

    Surveys assessed how helpful participants felt the results disclosure session was using a novel single question.

  4. Decisional Regret

    Time frame: 6 months Post-Disclosure Survey (6-9 months after disclosure of confirmed results); 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)

    Surveys assessed if participants regretted their decisions to receive their genetic findings using a novel single question.

  5. Sharing With Relatives

    Time frame: 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)

    The survey assessed with whether participants shared their genetic information with relatives .

  6. Family Testing

    Time frame: 1 Year Post-Disclosure Survey (from 12 months to 15 months after disclosure of confirmed results)

    The survey assessed whether participants had relatives that received genetic testing based on disclosure to the participant.

  7. General Anxiety

    Time frame: Post Disclosure Survey (up to 1 month from disclosure of confirmed results); 6 months Post-Disclosure Survey (6-9 months after disclosure of confirmed results)

    We measure general anxiety using a 4-item version of the General Anxiety Disorder Scale, a validated scale that allows investigators to identify individuals with a potential mood disorder. Scores range from 4 to 16, with higher scores indicating greater anxiety.

Sponsors and collaborators

Lead sponsor

Brigham and Women's Hospital

Other

Collaborators

  • Boston University
  • Broad Institute of MIT and Harvard
  • Framingham Heart Study
  • Jackson Heart Study
  • Partners HealthCare
  • University of Mississippi Medical Center

Registry information

Acronym: PopSeq

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Dec 12, 2019
Registry last updated
Aug 3, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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