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A Pilot Project Exploring the Impact of Whole Genome Sequencing in Healthcare

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ClinicalTrials.gov Identifier: NCT01736566
Recruitment Status : Active, not recruiting
First Posted : November 29, 2012
Results First Posted : November 7, 2018
Last Update Posted : December 4, 2018
Sponsor:
Collaborators:
National Human Genome Research Institute (NHGRI)
Baylor College of Medicine
Duke University
Information provided by (Responsible Party):
Robert C. Green, MD, MPH, Brigham and Women's Hospital

Brief Summary:
The MedSeq™ Project seeks to explore the impact of incorporating information from a patient's whole genome sequence into the practice of clinical medicine. In the extension phase of MedSeq we are attempting increase our participant diversity by increasing targeted enrollment of African/African American patient participants.

Condition or disease Intervention/treatment Phase
Healthy Adults (Full Study and Extension Phase) Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy Other: Family History + Whole Genome Sequencing Other: Family History Only Not Applicable

Detailed Description:

Whole genome sequencing (WGS) and whole exome sequencing (WES) services are currently available to and are being utilized by physicians and their patients in both research and clinical settings. The widespread availability and use of WGS and WES in the practice of clinical medicine is imminent. In the very near future, sequencing of individual genomes will be inexpensive and ubiquitous, and patients will be looking to the medical establishment for interpretations, insight and advice to improve their health. Developing standards and procedures for the use of WGS information in clinical medicine is an urgent need, but there are numerous obstacles related to integrity and storage of WGS data, interpretation and responsible clinical integration. MedSeq™ seeks to develop a process to integrate WGS into clinical medicine and explore the impact of doing so.

We believe that WGS will be used in many ways, including two distinct and complementary situations. In generally healthy patients, physicians will use the results of WGS to derive insight into future health risks and inform prevention and surveillance efforts, a category we refer to as General Genomic Medicine. In patients presenting with a family history or symptoms of a disease, physicians will use the results of WGS to interrogate particular sets of genes known to be associated with the disease in question, a category we refer to as Disease-Specific Genomic Medicine.

Beginning in fall 2012, we will enroll 10 primary care physicians and 100 of their healthy middle-aged patients to evaluate the use of General Genomic Medicine, and 10 cardiologists and 100 of their patients presenting with hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) to evaluate the use of Disease-Specific Genomic Medicine. We will randomize physicians and their patients within each of the above models to receive clinically meaningful information derived from WGS versus current standard of care without the use of WGS.

MedSeq™ is comprised of three distinct but highly collaborative projects. Project 1 will enroll physicians and patients into the protocol, educate the physicians on basic genomic principles and safely monitor the use of genomic information in clinical practice. Project 2 will use a WGS analysis/interpretation pipeline to generate a genome report on each patient randomized to receive WGS in this protocol. Project 3 will examine preferences and motivations of physicians and patients enrolled, evaluate the flow and utilization of genomic information within the clinical interactions, and assess understanding, behavior, medical consequences and healthcare costs associated with the use of WGS in these models of medical practice.

In an extension phase of the study, we will 1) recruit approximately 10-15 patient-participants who self-identify as African or African American, whose physicians deem to be healthy. All will be placed in the whole genome-sequencing arm of the study. They will undergo the same activities as traditional MedSeq participants except for randomization. 2) We will conduct a targeted phenotype assessment on MedSeq Project patient-participants who are identified to have a monogenic finding. We plan to perform additional analysis by reviewing their medical records and looking specifically with their variant in mind to see if features associated with the variants were known prior to the study or were identified by further testing or by their physical during the course of the study.

This initiative will significantly accelerate the use of genomics in clinical medicine by creating and safely testing novel methods for integrating information from WGS into physicians' care of patients.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 213 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Health Services Research
Official Title: The MedSeq Project Pilot Study: Integrating Whole Genome Sequencing Into the Practice of Clinical Medicine
Actual Study Start Date : December 2011
Actual Primary Completion Date : November 4, 2016
Estimated Study Completion Date : August 28, 2022


Arm Intervention/treatment
Experimental: Family History + Whole Genome Sequencing
Doctors and their patients receive a Genome Report and an Annotated Family History Report.
Other: Family History + Whole Genome Sequencing

Doctors and their patients receive a Genome Report and a Family History report.

There are two sections of the Genome Report:

  1. The General Genome Report, which include highly penetrant disease mutations, carrier status for recessive disease, and pharmacogenetic associations.
  2. The Cardiac Risk Supplement, which contain genetic information found in the genome regarding cardiac diseases or a risk of cardiovascular diseases that can help with the care of the patient.

Extension Phase: Experimental: Family History + Whole Genome Sequencing

*In the main study participants are randomized to either the Experimental or Other Arm, in the Extension phase of the study all participants are in the Experimental Arm.


Active Comparator: Family History Only
Doctors and their patients receive an Annotated Family History Report only.
Other: Family History Only
Doctors and their patients receive a Family History report.




Primary Outcome Measures :
  1. Change in Attitudes and Trust [ Time Frame: Change at 6-weeks post-results disclosure relative to baseline, administered approx.12.5 months after baseline ]
    Adapted measures (Hall, MA, et al. 2006) assessed participants' attitudes toward genetic information, trust of their physicians and the medical system regarding interpretation and use of genetic information. Higher scores on a 12-60 scale represent more positive attitudes and greater trust.

  2. Change in Self Efficacy [ Time Frame: Baseline and 6-months post-results disclosure (6 mos. follow-up administered approx. 17 months after baseline) ]
    Assessed through a scale developed for the Multiplex Initiative (Kaphingst, K.A., et al. 2012). Higher scores on a 0-24 scale indicate greater confidence in participants' abilities to understand genetic information.

  3. Change in Preferences for WGS Information [ Time Frame: Baseline and 6-weeks post-disclosure (6 wks follow-up administered approx. 12.5 mos. after baseline) ]
    Through nine novel survey items, participants were asked about their preferences for the types of genetic testing results they would like to receive from their whole genome sequence. Scores on an 0-9 scale represent the change in the number of categories of types of genetic testing results out of 9 that participants wanted to learn about from Baseline to 6-weeks follow-up.

  4. Change in Perceived Health [ Time Frame: Baseline, at the disclosure visit (about 1 hour after results disclosure, avg. 11 mos. after baseline) and 6-months post-disclosure (6 mos. follow-up follow-up administered approx. 17 months after baseline) ]
    A single-item measure assessed how participants perceived their own health on a 1-5 scale. Adapted from the SF-12 (DeSalvo KB, Qual Life Res, 2006). Higher scores indicate more positive perceptions of health at follow-up

  5. Change in Shared Decision Making [ Time Frame: Baseline and 6-weeks post-disclosure (6 wks follow-up administered approx. 12.5 mos. after baseline) ]
    Changes in shared decision making were assessed through a single item adapted from the Control Preferences Scale, a measure designed to ascertain the degree of control an individual wants to assume when decisions are being made about medical treatment. Higher scores on a scale of 1-3 indicate preferences towards more equally shared decision making (Heisler et al 2003). Higher mean changes over time indicate a change in preference towards more equally shared decision making at follow-up.

  6. Change in Intolerance of Uncertainty [ Time Frame: Baseline and 6-months post-disclosure (6 mos. follow-up administered approx. 17 mos. after baseline) ]
    Changes in participants' tolerance for uncertainty were assessed through a short 12-item version of the Intolerance of Uncertainty Scale (Carleton, 2007). Total summed scale range is 12-60, with higher scores indicating increased negative feelings about uncertainty from baseline to follow-up.

  7. Change in General Anxiety and Depression [ Time Frame: Baseline, at the disclosure visit (about 1 hour after results disclosure, avg. 11 mos. after baseline), 6-weeks post-disclosure and 6-months post-disclosure (6 wks. follow-up administered approx. 12.5 mos and 6 mos follow-up approx 17 mos. after baseline) ]
    The Hospital Anxiety and Depression Scale (HADS) scale was administered through a survey. This is a validated scale designed to assess the participants' level of depression and anxiety through Likert-type questions. Total ranges for each summed subscale, anxiety and depression, is 0-21. Any participant scoring >14 on the anxiety subscale or >16 on the depression subscale were contacted by study staff for evaluation. Higher scores indicate increased anxiety or depression from baseline to follow-up.

  8. Change in Health Behaviors [ Time Frame: 6-weeks post-disclosure and 6-months post-disclosure (6 wks. follow-up administered approx. 12.5 mos. and 6 mos. follow-up approx. 17 mos. after baseline) ]
    Novel items that asked whether participants changed vitamin use, supplement use, medication use, diet, exercise, or "other" health behaviors. Counts and percentages represent participants who reported any health behavior changes.

  9. Information Sharing [ Time Frame: At the disclosure visit (about 1 hour after results disclosure, avg. 11 mos. after baseline) and 6-months post-disclosure (approx. 17 mos. after baseline) ]
    Sharing of information was assessed by asking patients if they intended to share results with others (at the end of the disclosure visit) and if they had shared their results with others (6 months after disclosure) adapted from the Health Information National Trends Survey (HINTS).

  10. Changes in Genomic Literacy [ Time Frame: Assessing Genomic Literacy at baseline and 6-months post-disclosure (approx. 17 mos. after baseline) ]
    Changes in participants' genomic literacy were measured with an 11-item measure adapted from the ClinSeq Study (Kaphingst K.A. et al. 2012) administered at baseline and 6 months post-disclosure. Items are marked as correct (1) or incorrect (0) and summed for a total scale range of 0 to 11, with higher scores indicating higher genomic literacy.

  11. Changes in Health Care Utilization [ Time Frame: 6 months prior to disclosure and 6-months post-disclosure (approx. 17 mos. after baseline) and 5-years post-disclosure ]
    Participants' health care utilization was assessed through a combination of medical record reviews and novel and adapted measures from the Behavioral Risk Factor Surveillance System (BRFSS). Changes are assessed by comparing the number of services and procedures received in 6 months following disclosure against the number of services and procedures received in the 6 months prior to disclosure.

  12. Change in Perceived Utility [ Time Frame: At baseline and 6-months post-disclosure (approx. 17 mos. after baseline) ]
    A novel survey item asked participants to rate the usefulness of whole genome sequencing results for managing health on a 1-10 scale. Scores at 6 months were compared to scores at baseline.


Secondary Outcome Measures :
  1. Psychological Impact [ Time Frame: 6-weeks post-disclosure and 6-months post-disclosure (6wks. follow-up administered approx. 12.5 mos. and 6 mos. follow-up approx. 17 mos. after baseline) ]
    Psychological impact was assessed by a modified version of the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire. Higher scores indicated more distress related to study results.

  2. Decisional Regret [ Time Frame: At post-disclosure visit (about 1 hour after results disclosure, avg. 11 mos. after baseline), at 6-weeks post-disclosure, and at 6-months post-disclosure (6 wks follow-up approx. 12.5 mos. and 6 mos. follow-up approx. 17 mos. after baseline) ]
    Participants' satisfaction with their decision to participate in the MedSeq Project through a 5-item validated scale (Brehaut 2003). Average score computed after reversing scores of 2 negatively phrased items and converting score to range from 0-100 by subtracting 1 and multiplying by 25. Higher scores indicate greater regret.

  3. Understanding [ Time Frame: At post-disclosure visit (about 1 hour after results disclosure, avg. 11 mos. after baseline), at 6-weeks post-disclosure, and at 6-months post-disclosure (6 wks follow-up approx. 12.5 mos. and 6 mos. follow-up approx. 17 mos. after baseline) ]
    A novel item assessed participants' subjective understanding of their study results on a 1-5 scale, where higher scores indicate greater subjective understanding.

  4. Expectations [ Time Frame: Baseline ]
    Novel survey items asked participants about whether or not their genetic test results would be useful for specific reasons. Response options were "no," "probably not", "probably yes," and "yes." Responses of "probably yes" and "yes" were combined to simplify presentation of data.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Note for Age Eligibility:

  • Cardiology patients 18 Years to 90 Years OR
  • Primary Care Patients 40 Years to 65 Years (Adult, Senior)

Inclusion Criteria:

Primary Care

  • Generally healthy (as defined by the primary care provider) adult patients at Brigham and Women's Hospital ages 40-65. All patients must be fluent in English.

Cardiology

  • Patients in the Partners Healthcare System who are 18 years or older with a diagnosis of hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) and a family history of HCM or DCM who previously had or who are candidates for targeted HCM or DCM genetic testing through routine clinical practice within Partners. All patients must be fluent in English.

Exclusion Criteria:

Primary Care

  • Patients who do not meet the above criteria. Patients with cardiac disease or a progressive debilitating illness. Patients who are pregnant or patients whose spouses/significant others are pregnant. Patients with untreated clinical anxiety or depression (as measured by a Hospital Anxiety and Depression Scale (HADS) score > 11 administered at the baseline study visit.)

Cardiology

  • Patients who do not meet the above criteria. Patients with a progressive debilitating illness. Patients who are pregnant or patients whose spouses/significant others are pregnant. Patients with untreated clinical anxiety or depression (as measured by a Hospital Anxiety and Depression Scale (HADS) score > 11 administered at the baseline study visit.)

Extension Phase - Additional Inclusion Criteria

Part 1:

  • Above inclusion and exclusion criteria PLUS:
  • Inclusion: Self-identify as African or African American.

Part 2:

Inclusion Criteria

  • MedSeq participants determined to have a monogenic finding

Exclusion Criteria

  • Participants not previously enrolled in MedSeq Project
  • Participants not identified to have a monogenic finding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01736566


Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Brigham and Women's Hospital
National Human Genome Research Institute (NHGRI)
Baylor College of Medicine
Duke University
Investigators
Principal Investigator: Robert C Green, MD, MPH Brigham and Women's Hospital
  Study Documents (Full-Text)

Documents provided by Robert C. Green, MD, MPH, Brigham and Women's Hospital:

Additional Information:
NHGRI  This link exits the ClinicalTrials.gov site

Publications of Results:
Other Publications:
Green RC, Rehm H, Kohane I. Clinical Genome Sequencing. Genomic and Personalized Medicine 2nd Edition: 102- 122, 2012.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Robert C. Green, MD, MPH, Principal Investigator, The MedSeq Project, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT01736566     History of Changes
Other Study ID Numbers: MedSeq™
U01HG006500 ( U.S. NIH Grant/Contract )
First Posted: November 29, 2012    Key Record Dates
Results First Posted: November 7, 2018
Last Update Posted: December 4, 2018
Last Verified: November 2018

Keywords provided by Robert C. Green, MD, MPH, Brigham and Women's Hospital:
Primary Care
Cardiology
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Whole Genome Sequencing

Additional relevant MeSH terms:
Cardiomyopathies
Hypertrophy
Cardiomyopathy, Hypertrophic
Cardiomyopathy, Dilated
Heart Diseases
Cardiovascular Diseases
Pathological Conditions, Anatomical
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Cardiomegaly