Genetic Predisposition to Disease, Seemingly Healthy
Conditions
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.
Interventions
GENETICGenomic Sequencing
Whole Genome Sequencing and reporting of actionable genomic results for genes included on the ACMG secondary findings list.
Sponsors
Brigham and Women's Hospital
Framingham Heart Study
Jackson Heart Study
Broad Institute of MIT and Harvard
University of Mississippi Medical Center
Boston University
Partners HealthCare
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
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.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Follow Through With Disclosure | 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 | 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 | 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
| Measure | Time frame | Description |
|---|---|---|
| Guideline Compliance | 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. |
| 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) | We will examine cases to determine the percentage of individuals who report a new or modified diagnosis attributed to results disclosure. |
| 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) | A single item of self rated health derived from the SF-12v2. |
| Number of Participants With Recommendations to Referrals or Services During Clinical Disclosure Sessions | 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. |
| Health Care Utilization | 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. |
Countries
United States
Participant flow
Pre-assignment details
FHS and JHS participants who had a disclosure session to discuss actionable genetic findings that were clinically confirmed.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized Age of FHS participants | 67.73 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7581 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3408 Participants |
| Race (NIH/OMB) More than one race | 21 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants |
| Race (NIH/OMB) White | 4162 Participants |
| Sex: Female, Male Female | 4419 Participants |
| Sex: Female, Male Male | 3184 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 71 |
| other Total, other adverse events | 2 / 71 |
| serious Total, serious adverse events | 0 / 71 |
Outcome results
None listed