Genomic Sequencing for Genetic Predisposition

(PopSeq Trial)

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Brigham and Women's Hospital

Disqualifiers: Unsequenced genomes, No genomic consent, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

110 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment Genomic Sequencing for Genetic Predisposition?

Genomic sequencing, including whole-genome and whole-exome sequencing, has shown promise in accurately diagnosing diseases that are hard to identify with traditional methods and in improving cancer diagnosis and management. However, its effectiveness in routine patient care without specific genetic indications is still being evaluated, and it is currently recommended for limited clinical situations. ^{1 2 3 4 5}

Is genomic sequencing safe for humans?

Genomic sequencing, which includes methods like whole genome sequencing and next-generation sequencing, is generally considered safe for humans. It helps identify genetic variations that can predict adverse drug reactions, potentially improving drug safety by tailoring treatments to individual genetic profiles. ^{6 7 8 9 10}

How does genomic sequencing differ from other treatments for genetic predisposition?

Genomic sequencing is unique because it analyzes an individual's entire genetic code to identify variations that may predispose them to certain conditions, unlike traditional treatments that focus on managing symptoms or specific genes. This comprehensive approach can provide a more personalized understanding of genetic risks. ^{11 12 13 14 15}

What is the purpose of this trial?

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.

Eligibility Criteria

This trial is for adults over 18 who are part of the Framingham Heart Study or Jackson Heart Study, have had their genomes sequenced by TOPMed, and consented to use their DNA for research. It's not open to those who haven't opted in for genomic research or haven't had genome sequencing through TOPMed.

Inclusion Criteria

I am over 18 years old.

I have agreed to use my DNA for research and to receive genetic information.

I am part of the Framingham or Jackson Heart Study and my genome has been sequenced in the TOPMed program.

Exclusion Criteria

I chose not to participate in genetic research.

Participants who did/do not consent to receiving a genomic result (for the gRoR portion of this study only)

I am part of the Framingham or Jackson Heart Study and my genome hasn't been sequenced by TOPMed.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Genomic Results Disclosure

Participants are notified of actionable genetic results and offered clinical confirmation

Up to 8 months

1 visit (in-person or virtual) for results disclosure

Follow-up

Participants are monitored for outcomes related to the disclosure of genomic results, including health care utilization and psychological impact

1 year

Surveys at 6 months and 1 year post-disclosure

Data Collection and Analysis

Collection and analysis of outcome and phenotypic data to explore genomic penetrance and other study objectives

Ongoing throughout the study

Treatment Details

Interventions

• Genomic Sequencing

Trial Overview The PopSeq Project will give some participants their genomic results (gRoR) and study the medical, behavioral, and economic impacts. It involves interpreting previously sequenced genomes from two heart studies and assessing how genes manifest into physical traits in a group.

Participant Groups

Group I: FHS & JHS participants with an actionable genomic finding Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Framingham Heart Study

Collaborator

Trials

1

Recruited

110+

Jackson Heart Study

Collaborator

Trials

1

Recruited

110+

Broad Institute

Collaborator

Trials

21

Recruited

16,300+

University of Mississippi Medical Center

Collaborator

Trials

185

Recruited

200,000+

Broad Institute of MIT and Harvard

Collaborator

Trials

21

Recruited

16,300+

Partners HealthCare

Collaborator

Trials

15

Recruited

55,000+

Boston University

Collaborator

Trials

494

Recruited

9,998,000+

Findings from Research

Human genomic sequencing can provide valuable insights for diagnosis, prognosis, and treatment across various medical fields, but its widespread use is limited by a lack of evidence showing improved patient outcomes in those without specific testing indications.

The paper reviews clinical outcome studies in genomic medicine, highlighting the challenges of generating robust evidence to support the integration of next-generation sequencing into standard patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building evidence and measuring clinical outcomes for genomic medicine. Peterson, JF., Roden, DM., Orlando, LA., et al.[2020]

Next-generation gene sequencing can sequence an individual's entire genome in under a week for $5000 to $10,000, making it a promising tool for diagnosing complex diseases that are hard to identify through traditional methods.

While there have been successful applications in diagnosing diseases and improving tumor management, significant challenges remain, including data interpretation, physician training, and the need for rigorous studies to validate its effectiveness in larger patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise and challenges of next-generation genome sequencing for clinical care. Johansen Taber, KA., Dickinson, BD., Wilson, M.[2022]

Serious adverse drug reactions are a leading cause of death in the USA and contribute significantly to healthcare costs, highlighting the need for better risk management in drug prescriptions.

Pharmacogenomic testing, which identifies genetic factors that affect drug response, is becoming increasingly important, with regulatory agencies pushing for mandatory testing for certain medications to prevent adverse reactions and improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of adverse drug reactions: practical applications and perspectives. Becquemont, L.[2013]

Pharmacogenomics can help predict adverse drug reactions (ADRs) by identifying genetic variations that affect how individuals respond to medications, addressing a significant issue in drug safety.

The review highlights successful examples of pharmacogenomics influencing clinical practice and discusses future areas where it could improve drug safety, while also acknowledging the challenges in implementing these tests in healthcare.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging era of pharmacogenomics: current successes, future potential, and challenges. Lee, JW., Aminkeng, F., Bhavsar, AP., et al.[2021]

Genetic research is uncovering specific genes that influence how safely and effectively patients respond to medications, which can help prevent adverse drug reactions.

Primary care physicians are being targeted with advertisements for genetic tests that identify these variations, highlighting the need for a careful evaluation of these tests to ensure they are used optimally in patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating pharmacogenetic tests: a case example. Freund, CL., Gregory, DF., Clayton, EW.[2019]

In a study of 52,942 patients over five years, 64.8% were prescribed at least one medication that could be influenced by genetic variants, highlighting the commonality of pharmacogenetic prescribing opportunities.

Implementing a preemptive genotyping program could potentially prevent 383 adverse events linked to specific medications, suggesting that this approach may enhance patient safety compared to traditional reactive methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing drug outcomes through pharmacogenetics: a case for preemptive genotyping. Schildcrout, JS., Denny, JC., Bowton, E., et al.[2022]

The definition of an adverse drug event (ADE) should be tailored to the specific purpose of the evaluation, with stricter definitions needed for scientific studies and more flexible ones for clinical use.

Postmarketing safety data for drugs is limited at launch, but can be supplemented through systems like the FDA's Spontaneous Reporting System and targeted research projects, emphasizing the importance of robust epidemiological evidence for regulatory actions like drug recalls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events: identification and attribution. Rogers, AS.[2022]

Whole exome sequencing can yield a substantial number of high-quality SNPs (single nucleotide polymorphisms) outside the targeted coding regions, with increases of 129% to 461% compared to SNPs within target regions across different sequencing platforms.

The study analyzed data from 22 subjects using Agilent SureSelect and 6 subjects using Illumina TrueSeq, revealing that these high-quality SNPs outside target regions are valuable and should be included in genetic epidemiology studies for a more comprehensive understanding of genetic variants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exome sequencing generates high quality data in non-target regions. Guo, Y., Long, J., He, J., et al.[2021]

Whole genome sequencing (WGS) is becoming the preferred method for identifying genetic variations due to its comprehensive nature and decreasing costs, moving away from traditional microarray-based genotyping.

There are two main approaches to assembling genomic sequences from short reads: de novo assembly, which builds sequences by overlapping reads, and reference-based assembly, which maps reads to a known genome, each with its own advantages and challenges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole genome sequencing. Ng, PC., Kirkness, EF.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Building evidence and measuring clinical outcomes for genomic medicine. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

The promise and challenges of next-generation genome sequencing for clinical care. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Controversy and debate on clinical genomics sequencing-paper 1: genomics is not exceptional: rigorous evaluations are necessary for clinical applications of genomic sequencing. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Impact of Next Generation Sequencing on Clinical Practice in Oncology in France: Better Genetic Profiles for Patients Improve Access to Experimental Treatments. [2020]

5. Italy pubmed.ncbi.nlm.nih.gov

Genomic profiling in oncology clinical practice. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Pharmacogenomics of adverse drug reactions: practical applications and perspectives. [2013]

7. Denmark pubmed.ncbi.nlm.nih.gov

The emerging era of pharmacogenomics: current successes, future potential, and challenges. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Evaluating pharmacogenetic tests: a case example. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Optimizing drug outcomes through pharmacogenetics: a case for preemptive genotyping. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Adverse drug events: identification and attribution. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Exome sequencing generates high quality data in non-target regions. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Whole genome sequencing. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Future perspectives of genome-scale sequencing. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

The impact of next-generation sequencing in immunogenetics: current status and future directions. [2018]

15. United States pubmed.ncbi.nlm.nih.gov

Advancements in Next-Generation Sequencing. [2022]