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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Seemingly Healthy, Genetic Predisposition to Disease

Intervention / Treatment
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* Genetic: Genomic Sequencing


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FHS & JHS participants with an actionable genomic finding<br>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. | Genetic: Genomic Sequencing<br>* Whole Genome Sequencing and reporting of actionable genomic results for genes included on the ACMG secondary findings list.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From genetic result notification to 8 months post-disclosure | 
| 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. | 1 year post-disclosure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | History before disclosure | 
| New and Modified Diagnoses | We will examine cases to determine the percentage of individuals with a new or modified diagnosis attributed to results disclosure. | 1 year post-disclosure | 
| Self-Rated Health | We will administer a single item of self rated health derived from the SF-12v2. | Post disclosure and 1 year post-disclosure | 
| MD Recommendations | We will review chart notes from results disclosure sessions to determine services recommended in response to genetic findings. | From disclosure to 1 month post-disclosure | 
| 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 | 1 year post-disclosure |