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

Insurance Daily News

2019 DEC 26 (NewsRx) -- By a News Reporter-Staff News Editor at Insurance Daily News -- Staff editors report on the newly launched clinical trial, NCT04196374, which has the following summary description: “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.”

As a matter of record, on December 13, 2019, NewsRx staff editors report that the available information provided by Brigham and Women’s Hospital on this trial include:

Tracking Information

Trial Identifier	NCT04196374
First Submitted Date	December 10, 2019
First Posted Date	December 12, 2019
Results First Submitted Date	Not Provided
Results First Posted Date	Not Provided
Last Update Submitted Date	December 10, 2019
Last Update Posted Date	December 12, 2019
Primary Completion Date	June 30, 2023
Start Date	December 1, 2019
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 Centers for Medicare and Medicaid fee schedules to completed referrals and tests, hospitalizations and medication changes identified as described above.
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	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.
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, McKelvey KD, Ormond KE, Richards CS, Vlangos CN, Watson M, Martin CL, Miller DT. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017 Feb;19(2):249-255. doi: 10.1038/gim.2016.190. Epub 2016 Nov 17. Erratum in: Genet Med. 2017 Apr;19(4):484.
	PubMed Link - Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG; American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013 Jul;15(7):565-74. doi: 10.1038/gim.2013.73. Epub 2013 Jun 20. Erratum in: Genet Med. 2017 May;19(5):606.
	PubMed Link - Wolf SM, Lawrenz FP, Nelson CA, Kahn JP, Cho MK, Clayton EW, Fletcher JG, Georgieff MK, Hammerschmidt D, Hudson K, Illes J, Kapur V, Keane MA, Koenig BA, Leroy BS, McFarland EG, Paradise J, Parker LS, Terry SF, Van Ness B, Wilfond BS. Managing incidental findings in human subjects research: analysis and recommendations. J Law Med Ethics. 2008 Summer;36(2):219-48, 211. doi: 10.1111/j.1748-720X.2008.00266.x. Review.
	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, Richardson HS, Scott JA, Terry SF, Wilfond BS, Wolf WA. Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med. 2012 Apr;14(4):361-84. doi: 10.1038/gim.2012.23.
	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 Blood Institute working group, Fabsitz RR, McGuire A, Sharp RR, Puggal M, Beskow LM, Biesecker LG, Bookman E, Burke W, Burchard EG, Church G, Clayton EW, Eckfeldt JH, Fernandez CV, Fisher R, Fullerton SM, Gabriel S, Gachupin F, James C, Jarvik GP, Kittles R, Leib JR, O’Donnell C, O’Rourke PP, Rodriguez LL, Schully SD, Shuldiner AR, Sze RK, Thakuria JV, Wolf SM, Burke GL. Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ Cardiovasc Genet. 2010 Dec;3(6):574-80. doi: 10.1161/CIRCGENETICS.110.958827.
	PubMed Link - Natarajan P, Gold NB, Bick AG, McLaughlin H, Kraft P, Rehm HL, Peloso GM, Wilson JG, Correa A, Seidman JG, Seidman CE, Kathiresan S, Green RC. Aggregate penetrance of genomic variants for actionable disorders in European and African Americans. Sci Transl Med. 2016 Nov 9;8(364):364ra151.
	PubMed Link - Christensen KD, Phillips KA, Green RC, Dukhovny D. Cost Analyses of Genomic Sequencing: Lessons Learned from the MedSeq Project. Value Health. 2018 Sep;21(9):1054-1061. doi: 10.1016/j.jval.2018.06.013. Epub 2018 Aug 14.
	PubMed Link - Christensen KD, Vassy JL, Phillips KA, Blout CL, Azzariti DR, Lu CY, Robinson JO, Lee K, Douglas MP, Yeh JM, Machini K, Stout NK, Rehm HL, McGuire AL, Green RC, Dukhovny D; MedSeq Project. Short-term costs of integrating whole-genome sequencing into primary care and cardiology settings: a pilot randomized trial. Genet Med. 2018 Dec;20(12):1544-1553. doi: 10.1038/gim.2018.35. Epub 2018 Mar 22.
	PubMed Link - Roberts JS, Robinson JO, Diamond PM, Bharadwaj A, Christensen KD, Lee KB, Green RC, McGuire AL; MedSeq Project team. Patient understanding of, satisfaction with, and perceived utility of whole-genome sequencing: findings from the MedSeq Project. Genet Med. 2018 Sep;20(9):1069-1076. doi: 10.1038/gim.2017.223. Epub 2018 Jan 4.
	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; MedSeq Project. The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients: A Pilot Randomized Trial. Ann Intern Med. 2017 Jun 27;167(3):159-169. doi: 10.7326/M17-0188. Print 2017 Aug 1.
	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, Blumenthal-Barby J, Lehmann LS, Vassy JL, Christensen KD, Green RC, McGuire AL; MedSeq Project team. Patients’ perceived utility of whole-genome sequencing for their healthcare: findings from the MedSeq project. Per Med. 2016 Jan 1;13(1):13-20. Epub 2016 Jan 8.
	PubMed Link - Wolf SM, Branum R, Koenig BA, Petersen GM, Berry SA, Beskow LM, Daly MB, Fernandez CV, Green RC, LeRoy BS, Lindor NM, O’Rourke PP, Breitkopf CR, Rothstein MA, Van Ness B, Wilfond BS. Returning a Research Participant’s Genomic Results to Relatives: Analysis and Recommendations. J Law Med Ethics. 2015 Fall;43(3):440-63. doi: 10.1111/jlme.12288.
	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; MedSeq Project. A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet. 2014 Dec 14;15:134. doi: 10.1186/s12881-014-0134-1.
	PubMed Link - Machini K, Ceyhan-Birsoy O, Azzariti DR, Sharma H, Rossetti P, Mahanta L, Hutchinson L, McLaughlin H; MedSeq Project, Green RC, Lebo M, Rehm HL. Analyzing and Reanalyzing the Genome: Findings from the MedSeq Project. Am J Hum Genet. 2019 Jul 3;105(1):177-188. doi: 10.1016/j.ajhg.2019.05.017. Epub 2019 Jun 27.
	PubMed Link - Vassy JL, Lautenbach DM, McLaughlin HM, Kong SW, Christensen KD, Krier J, Kohane IS, Feuerman LZ, Blumenthal-Barby J, Roberts JS, Lehmann LS, Ho CY, Ubel PA, MacRae CA, Seidman CE, Murray MF, McGuire AL, Rehm HL, Green RC; MedSeq Project. The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials. 2014 Mar 20;15:85. doi: 10.1186/1745-6215-15-85.

Recruitment Information

Recruitment Status	Not yet recruiting
Estimated Enrollment	200
Estimated Completion Date	June 30, 2023
Primary Completion Date	June 30, 2023 (Final data collection date for primary outcome measure)
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
Accepts Healthy Volunteers	No
Contacts	Primary contact: Carrie L Blout, MS, 617-264-5837, [email protected]
Listed Location Countries	United States
Removed Location Countries

Administrative Information

NCT Number	NCT04196374
Other Study ID Numbers	R01HL143295
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	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.
Responsible Party	Robert C. Green, MD, MPH, Brigham and Women’s Hospital
Collaborators	⚬Framingham Heart Study
	⚬Jackson Heart Study
	⚬Broad Institute
	⚬University of Mississippi Medical Center
	⚬Boston University
	⚬Partners HealthCare
Investigators	Not Provided
Information Provided By	Brigham and Women’s Hospital
Verification Date	November 2019

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