NCGENES: North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing (NCGENES)

This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. This sub-project is investigating benefits and harms of providing WES diagnostic and different types of incidental findings to adult patients and parents of pediatric patients who undergo WES because they have symptoms suggesting genetic disease.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Congenital Abnormalities; Cancer; Hearing Loss; Neurologic Dysfunction
• Intervention / Treatment: Behavioral: Experimental

Detailed Description

This study is part of a larger consortium project investigating the validity and best use of next-generation sequencing (in particular, whole exome sequencing, or WES) in clinical care. Participants are patients who were either seen in the University of North Carolina Cancer and Adult Genetics Clinic or referred to the study by their physician. They will be approached by their physician or a genetic counselor for recruitment. Once enrolled, a clinical geneticist or genetic counselor will obtain consent and collect blood samples to be analyzed using WES. Results may include information related to a diagnosis and incidental information. Medically actionable incidental findings will be CLIA (Clinical Laboratory Improvement Amendments)-certified and returned to participants in a routine genetic counseling session, along with diagnostic findings. Eligible adult participants will be randomized to have the opportunity to choose to get certain types of non-medically actionable incidental findings, as well. Their decisions will be investigated, as will psychosocial and behavioral responses to sequencing and receiving sequencing information. This is a longitudinal, mixed methods study (i.e., multiple assessments pre- and post-return of results, with both quantitative and qualitative methods used to gather data). Because only the quantitative component of the study uses randomization, only measures and procedures associated with that component are described here.

• Study Type: Interventional
• Enrollment (Actual): 645
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

- To receive whole exome sequencing in the study, adult or child patients must have a significant chance of having a genetic disorder, as determined by experts on the study team using criteria that depend on the genetic disorder in question. Representative criteria are listed below and will be considered together to determine whether patterns indicate a likely genetic etiology.

Cancer

• Age of diagnosis
• Presence of bilateral (or multiple) cancers
• Diagnosis of a rare type of cancer
• Details of the family history

Cardiovascular Conditions

• Certain clinical findings, such as prolonged QT interval on electrocardiogram.
• Presence of hypertrophic cardiomyopathy or aortic aneurysm
• Age of diagnosis
• Presence of family history

Pediatric neurodevelopmental disorders

• Specific brain structural brain abnormalities
• Presence of certain seizure types
• Dysmorphic features

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Option to request non-medically actionable incidental information (after receiving education about them)	Behavioral: Experimental; Option to request non-medically actionable incidental information (after receiving education about them)
No Intervention: Control; No option to request non-medically actionable incidental information

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extent of test-specific distress 2 weeks after return of results	Measured with an adapted version of the multidimensional impact of testing scale (MICRA)	2 weeks after return of diagnostic results; for adult patient participants who are eligible and who request them, 2 weeks after return of non-medically actionable incidental results

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in test-specific distress at 3 and 6 months after return of results	Measure is an adapted version of the multidimensional impact of testing scale MICRA)	Adult patient participants: change from 2 weeks after return of diagnostic results to 3 months and 6 months after return of diagnostic results
Extent of communication of test results with other people	Motivations of communications will also be assessed and examined for descriptive analyses.	2 weeks after return of diagnostic results
Extent of information seeking	Participants will answer questions about the extent to which they sought information about whole exome sequencing and results it produces. Questions also ask about sources of that information (e.g., the Internet, doctors) to provide descriptive data about how participants get information.	2 weeks after consent (T1) and change from T1 to 2 weeks after return of diagnostic results
Extent of Decision Regret 2 weeks after consent		All participants: 2 wks after consent (T1)
Extent of Decision Regret 2 weeks after return of results	Also administered 2 wks after return of non-medically actionable incidental results for eligible adult patient participants who request them.	All participants: 2 wks after return of diagnostic (dx) results and, for eligible adults who request them, return of incidental results
Change in decision regret		For all participants: Change from post-consent to post-return of results; Additional for adults: change at 3 and 6 months after return of dx results
Extent of Healthcare Utilization 2 weeks after consent		All participants: 2 wks after consent (T1)
Extent of Healthcare Utilization 2 weeks after return of results		All participants: 22 wks after return of diagnostic (dx) results
Change in Healthcare Utilization		All participants: Change in utilization from post-consent to post-return of results; Additional for adult patients: Change at 3 and 6 months after return of dx results
Enactment of health-related lifestyle behaviors 2 weeks after consent	Behaviors include those related to diet, physical activity, smoking, drinking, and substance use.	Adult participants: 2 wks after consent (T1)
Enactment of health-related lifestyle behaviors 2 weeks after return of results	Behaviors include those related to diet, physical activity, smoking, drinking, and substance use.	Adult participants: 2 wks after return of diagnostic (dx) results
Change in enactment of health-related lifestyle behaviors	Behaviors include those related to diet, physical activity, smoking, drinking, and substance use.	Adult participants: Change in behaviors from 2 wks after consent (T1) to 2 wks, 3 months, and 6 months after return of dx results
Extent of psychological distress 2 weeks after consent	Symptoms of depression and anxiety measured with the Hospital Anxiety and Depression Scale	All participants: 2 wks after consent
Extent of psychological distress 2 weeks after return of results	Symptoms of depression and anxiety measured with the Hospital Anxiety and Depression Scale	All participants: 2 wks after return of diagnostic (dx) results
Change in extent of psychological distress	Symptoms of depression and anxiety measured with the Hospital Anxiety and Depression Scale	All participants: Change from 2 wks after consent (T1) to 2 wks after return of diagnostic (dx) results; Additional for adult patients: Change at 3 and 6 months after return of dx results
Extent of health-related Quality of Life 2 weeks after consent	Measured with the Medical Outcomes Study Short Form-12	All participants: 2 wks after consent (T1)
Extent of health-related Quality of Life 2 weeks after return of results	Measured with the Medical Outcomes Study Short Form-12	All participants: 2 wks after return of diagnostic results
Change in extent of health-related Quality of Life	Measured with the Medical Outcomes Study Short Form-12	All participants: Change from 2 wks after consent to 2 weeks after return of diagnostic results

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Human Genome Research Institute (NHGRI); UNC Lineberger Comprehensive Cancer Center
• Investigators: Principal Investigator: James P Evans, MD, Ph.D, University of North Carolina, Chapel Hill; Principal Investigator: Gail Henderson, Ph.D, University of North Carolina; Principal Investigator: Jonathan S Berg, MD, Ph.D, University of North Carolina; Study Director: Christine Rini, Ph.D, University of North Carolina

Publications and helpful links

General Publications

• Rini C, Roche MI, Lin FC, Foreman AKM, Khan CM, Griesemer I, Waltz M, Lee K, O'Daniel JM, Evans JP, Berg JS, Henderson GE. Burden or benefit? Effects of providing education about and the option to request additional genomic findings from diagnostic exome sequencing: A randomized controlled trial. Patient Educ Couns. 2021 Dec;104(12):2989-2998. doi: 10.1016/j.pec.2021.04.026. Epub 2021 Apr 29.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: October 16, 2013
• First Submitted That Met QC Criteria: October 21, 2013
• First Posted (Estimate): October 25, 2013

Study Record Updates

• Last Update Posted (Actual): May 3, 2017
• Last Update Submitted That Met QC Criteria: May 2, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Cardiovascular disease; Cancer; Hearing loss; Neurodegenerative disease; Neurodevelopmental disease; Dysmorphology; Other conditions, including ophthalmic conditions
• Additional Relevant MeSH Terms: Nervous System Diseases; Otorhinolaryngologic Diseases; Ear Diseases; Sensation Disorders; Hearing Disorders; Cardiovascular Diseases; Congenital Abnormalities; Hearing Loss; Deafness; Neurologic Manifestations
• Other Study ID Numbers: 11-1865; U01HG006487 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Raw genotype calls from whole exome sequencing are shared with the database of Genotypes and Phenotypes (dbGaP). Other participant demographic variables include: age of onset, birthplace, sex, race, education level, age.

Data is uploaded in batches to the dbGaP website. Currently, the data for 403 participants who have consented for release of their data is available on the dbGaP website.

To access data, users must request authorized access by submitting a Data Use Agreement certified by their institution. This is reviewed by the DbGaP Data Access Committee for approval prior to accessing study data.

All data that is submitted to dbGaP, including individual participant data, is anonymous.