Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts
2019 DEC 26 (NewsRx) -- By a
As a matter of record, on
Tracking Information
Trial Identifier | NCT04196374 |
First Submitted Date | |
First Posted Date | |
Results First Submitted Date | Not Provided |
Results First Posted Date | Not Provided |
Last Update Submitted Date | |
Last Update Posted Date | |
Primary Completion Date | |
Start Date | |
Current Primary Outcome Measures | •Follow Through with Disclosure [ Time Frame: 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 [ 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 |
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Current Secondary Outcome Measures | •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. |
•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. | |
•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. | |
•MD Recommendations [ Time Frame: Disclosure ] -- We will review chart notes from results disclosure sessions to determine services recommended in response to genetic findings. | |
•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 | •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. |
•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. | |
•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. | |
•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. | |
•Sharing with Relatives [ Time Frame: 1 year post-disclsoure ] -- The survey will assess with how many relatives participants shared their genetic information. | |
•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. | |
•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. | |
Change History | Complete list of historical revisions of study NCT04196374 |
Descriptive Information
Brief Title | Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts |
Official Title | Return of Genomic Results and Aggregate Penetrance in Population-Based Cohorts |
Brief Summary | |
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 |
Study Type | Observational |
Study Phase | Not Provided |
Study Design | Observational Model: Cohort |
Time Perspective: Prospective | |
Condition | Seemingly Healthy |
Genetic Predisposition to Disease | |
Intervention | •Genetic: Genomic Sequencing |
Whole Genome Sequencing and reporting of actionable genomic results for genes included on the ACMG secondary findings list. | |
Publications* | *Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline |
PubMed Link - Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014 Sep 18;371(12):1170. doi: 10.1056/NEJMc1408914. | |
PubMed Link - Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Herman GE, Hufnagel SB, Klein TE, Korf BR, |
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PubMed Link - Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, |
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PubMed Link - Wolf SM, Lawrenz FP, |
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PubMed Link - Wolf SM, Crock BN, Van Ness B, Lawrenz F, Kahn JP, Beskow LM, Cho MK, Christman MF, Green RC, Hall R, Illes J, Keane M, Knoppers BM, Koenig BA, Kohane IS, Leroy B, Maschke KJ, McGeveran W, Ossorio P, Parker LS, Petersen GM, |
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PubMed Link - Burke W, Evans BJ, Jarvik GP. Return of results: ethical and legal distinctions between research and clinical care. Am J Med Genet C Semin Med Genet. 2014 Mar;166C(1):105-11. doi: 10.1002/ajmg.c.31393. Epub 2014 Mar 10. | |
PubMed Link - National Heart, Lung, and |
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PubMed Link - Natarajan P, Gold NB, |
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PubMed Link - Christensen KD, Phillips KA, Green RC, Dukhovny D. Cost Analyses of Genomic Sequencing: Lessons Learned from the |
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PubMed Link - Christensen KD, Vassy JL, Phillips KA, Blout CL, Azzariti DR, Lu CY, Robinson JO, Lee K, Douglas MP, |
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PubMed Link - Roberts JS, Robinson JO, Diamond PM, Bharadwaj A, Christensen KD, Lee KB, Green RC, McGuire AL; |
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PubMed Link - Vassy JL, Christensen KD, Schonman EF, Blout CL, Robinson JO, Krier JB, Diamond PM, Lebo M, Machini K, Azzariti DR, Dukhovny D, Bates DW, MacRae CA, Murray MF, Rehm HL, McGuire AL, Green RC; |
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PubMed Link - Christensen KD, Dukhovny D, Siebert U, Green RC. Assessing the Costs and Cost-Effectiveness of Genomic Sequencing. J Pers Med. 2015 Dec 10;5(4):470-86. doi: 10.3390/jpm5040470. Review. | |
PubMed Link - Lupo PJ, Robinson JO, Diamond PM, Jamal L, Danysh HE, |
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PubMed Link - Wolf SM, Branum R, Koenig BA, Petersen GM, |
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PubMed Link - McLaughlin HM, Ceyhan-Birsoy O, Christensen KD, Kohane IS, Krier J, Lane WJ, Lautenbach D, Lebo MS, Machini K, MacRae CA, Azzariti DR, Murray MF, Seidman CE, Vassy JL, Green RC, Rehm HL; |
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PubMed Link - Machini K, Ceyhan-Birsoy O, Azzariti DR, Sharma H, Rossetti P, Mahanta L, Hutchinson L, McLaughlin H; |
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PubMed Link - Vassy JL, Lautenbach DM, McLaughlin HM, Kong SW, Christensen KD, Krier J, Kohane IS, Feuerman LZ, |
Recruitment Information
Recruitment Status | Not yet recruiting |
Estimated Enrollment | 200 |
Estimated Completion Date | |
Primary Completion Date | |
Eligibility | 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) | |
Sex/Gender | Sexes Eligible for Study: All |
Ages | 18 years to 100 years |
No | |
Contacts | Primary contact: Carrie L Blout, MS, 617-264-5837, [email protected] |
Listed Location Countries | |
Removed Location Countries |
Administrative Information
NCT Number | NCT04196374 |
Other Study ID Numbers | R01HL143295 |
Has Data Monitoring Committee | Not Provided |
Not Provided | |
Plan to Share Data | No |
Plan to Share Data (IPD) Description | Individual participant data will not be shared. Aggregate data will be shared through publication and will be considered upon request. |
Collaborators | ⚬Framingham Heart Study |
⚬Jackson Heart Study | |
⚬Broad Institute | |
⚬University of |
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⚬Boston University | |
⚬Partners HealthCare | |
Investigators | Not Provided |
Information Provided By | Brigham and Women’s Hospital |
Verification Date |
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