NCGENES2: North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2

Sponsor
University of North Carolina, Chapel Hill (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03548779
Collaborator
National Human Genome Research Institute (NHGRI) (NIH), East Carolina University (Other), Mission Health System, Asheville, NC (Other)
806
3
4
55.1
268.7
4.9

Study Details

Study Description

Brief Summary

The "North Carolina Clinical Genomic Evaluation by Next-gen Exome Sequencing, 2 (NCGENES 2)" study is part of a larger consortium project investigating the clinical utility, or net benefit of an intervention on patient and family well-being as well as diagnostic efficacy, management planning, and medical outcomes. A clinical trial will be implemented to compare (1) first-line exome sequencing to usual care and (2) participant pre-visit preparation to no pre-visit preparation. The study will use a randomized controlled design, with 2x2 factorial design, coupled with patient-reported outcomes and comprehensive clinical data collection addressing key outcomes, to determine the net impact of diagnostic results and secondary findings.

Detailed Description

The NCGENES 2 study is part of the "Clinical Sequencing Evidence-Generating Research (CSER2)"

  • Clinical Sites with Enhanced Diversity (U01), and brings together interdisciplinary experts from across North Carolina to address questions critical to the translation of genomic medicine to the care of patients with suspected genetic disorders.

In this renewal of the initial NCGENES study, NCGENES 2 will carry out a clinical trial of exome sequencing as a diagnostic test to answer the next set of questions vital to making genome-scale sequencing a routine clinical tool. The study population will be drawn from a state-wide network of Clinical Genetics and Pediatric Neurology clinics -- clinical domains in which patients are enriched for phenotypes caused by heterogeneous genetic conditions. Exome sequencing and genome sequencing (ES/GS) are efficient means of establishing a molecular diagnosis in these populations, with yields of positive or possible diagnostic results in at least 30% of patients examined based on findings from NCGENES and other work. Evidence will be generated regarding the clinical utility of ES/GS using a prospective randomized controlled trial that compares usual care plus exome sequencing to usual care. Patient-reported data, electronic health records data, and administrative claims data will be used to evaluate defined health outcomes, in collaboration with experts in health economics and health services research, to address pressing questions about the utility of exome sequencing. Furthermore, an examination of communication between patients and physicians, and between physicians and laboratories, and how these critical interactions affect the utility of genomic sequencing will be conducted. A second, nested randomized trial (crossed with exome sequencing in a full-factorial design) will be incorporated to test the hypothesis that a theory-based, multi-component pre-clinic preparation intervention for patients will improve patient-centered outcomes. An "embedded Ethical, Legal, and Social Implications (ELSI)" component will provide feedback to providers regarding communication discrepancies to iteratively improve care. Finally, the challenges of integrating clinical data and genomic information across a state-wide network of sites and examining different models of interaction between genomic clinicians and molecular diagnostic laboratorians will be explored.

Study Design

Study Type:
Interventional
Actual Enrollment :
806 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Care Provider, Outcomes Assessor)
Masking Description:
The study coordinator will assign the first randomization to pre-visit preparation arm and care providers will not be told of the patient's pre-visit preparatory randomization arm prior to the first usual care visit. Randomization to exome sequencing will be performed after the first usual care visit by the study coordinator. Investigators will receive de-identified coded data and thus will not be able to link a patient name to an intervention arm. Some analyses will require individual-level randomization arm status to allow for comparison of parent questionnaire responses or health outcomes by arm - a major focus of this study. All interviewers and medical records staff conducting telephone surveys and/or medical records abstraction for clinical data will be blinded to the participants randomization status. Access to this information will be blocked in the electronic patient tracking status by study role.
Primary Purpose:
Diagnostic
Official Title:
North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
Actual Study Start Date :
Sep 28, 2018
Anticipated Primary Completion Date :
May 1, 2023
Anticipated Study Completion Date :
May 1, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Pre-visit prep / usual care + exome seq

Participants randomized to pre-visit prep will receive a study packet with educational materials and a question prompt list. These participants will be instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to their clinic visit 1 appointment. Participants will receive usual care and will be offered research exome sequencing.

Behavioral: Pre-visit prep
Patient and provider surveys will be used to measure the impact of pre-visit preparation on the primary outcomes of engagement of participants in the clinical interaction and their view of the interaction as patient-centered, in addition to secondary outcomes that may be affected by this intervention (described above). The study investigators will test the hypothesis that patients will benefit from pre-visit preparation by: (1) rating their clinical encounters as more patient-centered and (2) asking more questions during their clinical encounters.

Diagnostic Test: usual care + exome seq
Provider surveys will be used to assess impact of exome sequencing on diagnostic thinking and management planning. Health utilization and condition-specific general clinical outcomes will be assessed from health records data.

Experimental: Pre-visit prep / usual care

Participants randomized to pre-visit prep will receive a study packet with educational materials and a question prompt list. These participants will be instructed to review the materials, discuss them with family members if desired, use the question prompt list to select questions they would like to ask at clinic visit 1, and bring the list to their clinic visit 1 appointment. Participants will receive usual care.

Behavioral: Pre-visit prep
Patient and provider surveys will be used to measure the impact of pre-visit preparation on the primary outcomes of engagement of participants in the clinical interaction and their view of the interaction as patient-centered, in addition to secondary outcomes that may be affected by this intervention (described above). The study investigators will test the hypothesis that patients will benefit from pre-visit preparation by: (1) rating their clinical encounters as more patient-centered and (2) asking more questions during their clinical encounters.

Experimental: No prep / usual care + exome seq

Participants in the no pre-visit preparation arm will receive a mailed card reminding them about their upcoming clinic visit. Participants will receive usual care and will be offered research exome sequencing.

Diagnostic Test: usual care + exome seq
Provider surveys will be used to assess impact of exome sequencing on diagnostic thinking and management planning. Health utilization and condition-specific general clinical outcomes will be assessed from health records data.

No Intervention: No prep / usual care

Participants in the no pre-visit preparation arm will receive a mailed card reminding them about their upcoming clinic visit. Participants will receive usual care.

Outcome Measures

Primary Outcome Measures

  1. Number of in-patient hospital admissions 1 year prior to return of results [1 year prior to return of results]

    Count of number of in-patient hospital admissions during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  2. Number of in-patient hospital admissions 1 year after return of results [1 year after return of results]

    Count of number of in-patient hospital admissions during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  3. Number of in-patient hospital days 1 year prior to return of results [1 year prior to return of results]

    Count of number of in-patient hospital days during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  4. Number of in-patient hospital days 1 year after return of results [1 year after return of results]

    Count of number of in-patient hospital days during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  5. Number of long-term care admissions 1 year prior to return of results [1 year prior to return of results]

    Count of number of long-term care admissions during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  6. Number of long-term care admissions 1 year after return of results [1 year after return of results]

    Count of number of long-term care admissions during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  7. Number of long-term care days 1 year prior to return of results [1 year prior to return of results]

    Count of number of long-term care days during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  8. Number of long-term care days 1 year after return of results [1 year after return of results]

    Count of number of long-term care days during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  9. Number of ER visits 1 year prior to return of results [1 year prior to return of results]

    Count of number of ER visits during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  10. Number of ER visits 1 year after return of results [1 year after return of results]

    Count of number of ER visits during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  11. Number of specialists visits 1 year prior to return of results [1 year prior to return of results]

    Count of number of specialists visits during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  12. Number of specialists visits 1 year after return of results [1 year after return of results]

    Count of number of specialists visits during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff.

  13. Initial Patient Pediatric Quality of Life (Peds QL) score [4-6 weeks prior to clinic visit 1]

    The Peds QL Measurement Model for the Pediatric Quality of Inventory measures the core dimensions of health as delineated by the World Health Organization as well as role (school) functioning. The 23-item PedsQL Core Scales (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are developmentally appropriate surveys (Ages 2-4, 5-7, 8-12, 13-18) designed for parent proxy report. The 23 items are grouped together on the questionnaire, and are answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better Health-Related Quality of Life (HRQOL). This questionnaire will be self-administered at home.

  14. Intermediate Patient Pediatric Quality of Life (Peds QL) score [2 weeks after return of results]

    The Peds QL Measurement Model for the Pediatric Quality of Inventory measures the core dimensions of health as delineated by the World Health Organization as well as role (school) functioning. The 23-item PedsQL Core Scales (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are developmentally appropriate surveys (Ages 2-4, 5-7, 8-12, 13-18) designed for parent proxy report. The 23 items are grouped together on the questionnaire, and are answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL. This questionnaire will be interviewer-administered by telephone.

  15. Final Patient Pediatric Quality of Life (Peds QL) score [6 months after return of results]

    The Peds QL Measurement Model for the Pediatric Quality of Inventory measures the core dimensions of health as delineated by the World Health Organization as well as role (school) functioning. The 23-item PedsQL Core Scales (Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning) are developmentally appropriate surveys (Ages 2-4, 5-7, 8-12, 13-18) designed for parent proxy report. The 23 items are grouped together on the questionnaire, and are answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL. This questionnaire will be interviewer administered by telephone.

  16. Initial Caregiver QoL score [4-6 weeks prior to clinic visit 1]

    The Short-Form Health Survey (SF-12) questionnaire is a reliable measure of perceived health that describes the degree of general physical health status and mental health distress. It consists of 12 items, derived from the physical and mental domains. Scores have a range of 0 to 100 and were designed to have a mean score of 50 and a standard deviation of 10 in a representative sample of the US population, with higher scores indicating greater functioning. This questionnaire will be self-administered at home.

  17. Intermediate Caregiver QoL score [2 weeks after return of results]

    The SF-12 questionnaire is a reliable measure of perceived health that describes the degree of general physical health status and mental health distress. It consists of 12 items, derived from the physical and mental domains. Scores have a range of 0 to 100 and were designed to have a mean score of 50 and a standard deviation of 10 in a representative sample of the US population, with higher scores indicating greater functioning. This questionnaire will be interviewer administered by telephone.

  18. Final Caregiver QoL score [6 months after return of results]

    The SF-12 questionnaire is a reliable measure of perceived health that describes the degree of general physical health status and mental health distress. It consists of 12 items, derived from the physical and mental domains. Scores have a range of 0 to 100 and were designed to have a mean score of 50 and a standard deviation of 10 in a representative sample of the US population, with higher scores indicating greater functioning. This questionnaire will be interviewer administered by telephone.

  19. Post-Clinic Visit 1 Mean Patient Centeredness Score [Immediately after clinic 1 day of visit 1]

    Patient centeredness scale, which measures the caregiver's perception of the level of patient centeredness of their visit with their child's provider (developed by Little et al., 2001). Self-administered in the clinic, immediately after clinic visit 1. Item responses will be coded as: 1=Very strongly disagree; 2=Strongly disagree; 3=Moderately disagree; 4=Neither agree nor disagree; 5=Moderately agree; 6=Strongly agree; 7=Very strongly agree. Mean scores will be calculated by summing the response values and dividing by the total number of items (21). Higher scores indicate stronger perceptions of patient centeredness.

  20. Post-Return of Results Mean Patient Centeredness Score [2 weeks after return of results]

    Patient centeredness scale, which measures the caregiver's perception of the level of patient centeredness of their visit with their child's provider (developed by Little et al., 2001). Interviewer administered by telephone. Item responses will be coded as: 1=Very strongly disagree; 2=Strongly disagree; 3=Moderately disagree; 4=Neither agree nor disagree; 5=Moderately agree; 6=Strongly agree; 7=Very strongly agree. Mean scores will be calculated by summing the response values and dividing by the total number of items (21). Higher scores indicate stronger perceptions of patient centeredness.

  21. Number of questions caregiver asks in Clinic Visit 1 [During clinic 1 day of visit 1]

    Count of number of questions caregiver asks provider in the audio recording of clinic visit 1. Coded by trained study staff.

Secondary Outcome Measures

  1. Initial Average Peds QL score for "missing school for not feeling well" [4-6 weeks prior to clinic visit 1]

    This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This questionnaire will be self-administered at home.

  2. Intermediate Average Peds QL score for "missing school for not feeling well" [2 weeks after return of results]

    This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This questionnaire will be interviewer-administered by telephone. Edit on 3/18/21: this outcome will not be measured because of a protocol amendment to not include the PedsQL survey at 2-weeks post-RoR parent survey.

  3. Final Average Peds QL score for "missing school for not feeling well" [6 months after return of results]

    This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This questionnaire will be interviewer-administered by telephone.

  4. Initial Average Peds QL score for "missing school for doctors visit" [4-6 weeks prior to clinic visit 1]

    This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This measure will be included in the questionnaire that will be self-administered at home.

  5. Intermediate Average Peds QL score for "missing school for doctors visit" [2 weeks after return of results]

    This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This measure will be interviewer administered by telephone. Edit on 3/18/21: this outcome will not be measured because of a protocol amendment to not include the PedsQL survey at 2-weeks post-RoR parent survey.

  6. Final Average Peds QL score for "missing school for doctors visit" [6 months after return of results]

    This is a single item measure from the Peds QL that will be answered on a scale of 0-4. Items are reversed scored and linearly transformed to a 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0), so that higher scores indicate better HRQOL for this single measure. This measure will be interviewer administered by telephone.

  7. Initial Amount of work missed because of child's condition or treatments score [4-6 weeks prior to clinic visit 1]

    This is a single item measure that will be answered on a scale of 1-6 where 1=None, 2=Less than a week, 3=Between 1 and 4 weeks, 4= Between 4 and 8 weeks, 5=Between 8 and 12 weeks, 6=I stopped working altogether. Higher scores indicate greater amounts of work missed because of the child's condition or treatments. This measure will be included in the questionnaire that will be self-administered at home.

  8. Intermediate Amount of work missed because of child's condition or treatments score [2 weeks after return of results]

    This is a single item measure that will be answered on a scale of 1-6 where 1=None, 2=Less than a week, 3=Between 1 and 4 weeks, 4= Between 4 and 8 weeks, 5=Between 8 and 12 weeks, 6=I stopped working altogether. Higher scores indicate greater amounts of work missed because of the child's condition or treatments. This measure will be interviewer-administered by telephone.

  9. Final Amount of work missed because of child's condition or treatments score [6 months after return of results]

    This is a single item measure that will be answered on a scale of 1-6 where 1=None, 2=Less than a week, 3=Between 1 and 4 weeks, 4= Between 4 and 8 weeks, 5=Between 8 and 12 weeks, 6=I stopped working altogether. Higher scores indicate greater amounts of work missed because of the child's condition or treatments. This measure will be interviewer-administered by telephone.

  10. Initial Difficulty with finishing normal work (including both work outside of the home and housework) because of child's condition or treatments score [4-6 weeks prior to clinic visit 1]

    This is a single item measure that will be answered on a scale of 1-5, where 1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much. Higher scores indicate greater difficulty finishing normal work (including both work outside of the home and housework) because of child's condition or treatments. This measure will be included in the questionnaire that will be self-administered at home.

  11. Intermediate Difficulty with finishing normal work (including both work outside of the home and housework) because of child's condition or treatments score [2 weeks after return of results]

    This is a single item measure that will be answered on a scale of 1-5, where 1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much. Higher scores indicate greater difficulty finishing normal work (including both work outside of the home and housework) because of child's condition or treatments. This measure will be interviewer-administered by telephone.

  12. Final Difficulty with finishing normal work (including both work outside of the home and housework) because of child's condition or treatments score [6 months after return of results]

    This is a single item measure that will be answered on a scale of 1-5, where 1=Not at all, 2=A little bit, 3=Somewhat, 4=Quite a bit, 5=Very much. Higher scores indicate greater difficulty finishing normal work (including both work outside of the home and housework) because of child's condition or treatments. This measure will be interviewer-administered by telephone.

  13. Vital status at final f/u [final follow-up, up to approximately three years after clinic visit 1]

    Based on NC Vital Statistics, the child's vital status will be reported as living or deceased.

  14. Child causes of death related to the primary condition [final follow-up up to approximately three years after clinic visit 1]

    Based on NC Vital Statistics, child causes of death will be reported as related to the disorder of the child or not related to the disorder of the child.

  15. Percent concordance of caregiver and provider reports of genetic or genomic test results [2 weeks after return of results]

    Concordance between caregiver and provider reports of whether patients' diagnostic results were positive, negative, or uncertain. Coded as a dichotomous variable: 0=discordant diagnostic reports; 1=concordant diagnostic reports.

  16. Mean Baseline Self Efficacy Score [4-6 weeks prior to clinic visit 1]

    Self-efficacy scale, which measures caregivers' confidence in communicating with their child's provider. Self-administered as part of the intake questionnaire. Measured with adapted Decision Self Efficacy Scale (developed by O'Connor, 1995). Adapted wording from the original scale so items refer to general communication, as opposed to a specific decision. Shorted scale to 7 items from 11 since not all items were applicable to this study. Item responses will be coded as: 1=Not at all confident; 5=Very confident. Mean scores will be calculated by summing the response values and dividing by the total number of items (7). Higher scores indicate higher confidence in communicating with their child's provider.

  17. Mean Pre-Clinic Visit 1 Self Efficacy Score [Immediately before Clinic Visit 1]

    Self-efficacy scale, which measures caregivers' confidence in communicating with their child's provider. Self-administered as part of the intake questionnaire. Measured with adapted Decision Self Efficacy Scale (developed by O'Connor, 1995). Adapted wording from the original scale so items refer to general communication, as opposed to a specific decision. Shorted scale to 7 items from 11 since not all items were applicable to this study. Item responses will be coded as: 1=Not at all confident; 5=Very confident. Mean scores will be calculated by summing the response values and dividing by the total number of items (7). Higher scores indicate higher confidence in communicating with their child's provider.

  18. Post-Return of Results Mean FACToR Uncertainty Subscale Score [2 weeks after return of results]

    Subscale of the Feeling About genomiC Testing Results measure assesses caregivers' level of uncertainty about their child's genetic test results (developed by Gallego et al., 2014). Interviewer administered by telephone. Item responses will be coded as: 1=Not at all; 2=A little; 3=Somewhat; 4=A good deal; 5=A great deal. Mean scores will be calculated by summing the response values and dividing by the total number of items (3). Higher scores indicate greater uncertainty about their child's genetic test results.

Eligibility Criteria

Criteria

Ages Eligible for Study:
0 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Both children and parents are participants:
Inclusion Criteria:
Parents meeting the following criteria:
  1. Parent of a child who meets the criteria below

  2. At least 18 years old.

  3. Must be able to provide informed consent for child and self.

  4. Must be fluent in English or Spanish.

Children meeting the following criteria:
  1. Infants and children 15 years old or less.

  2. Referred for initial evaluation of a possible monogenic disorder OR

  3. Seen for evaluation of an undiagnosed disorder in a study-associated clinic.

Exclusion Criteria:
Parents:
  1. Younger than 18 years old.

  2. Unwilling to complete study surveys and other procedures.

  3. Have cognitive or other impairments precluding ability to provide giving informed consent.

  4. Not fluent in English or Spanish.

  5. Unable to attend all clinic visits

Children:
  1. Have a known genetic or non-genetic diagnosis (only referred for counseling or management).

  2. Medically unstable.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Mission Health Asheville North Carolina United States 28801
2 University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27599
3 East Carolina University Greenville North Carolina United States 27858

Sponsors and Collaborators

  • University of North Carolina, Chapel Hill
  • National Human Genome Research Institute (NHGRI)
  • East Carolina University
  • Mission Health System, Asheville, NC

Investigators

  • Study Director: Jeannette T Bensen, Ph.D, University of North Carolina, Chapel Hill
  • Principal Investigator: Jonathan S Berg, MD, PhD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Responsible Party:
University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT03548779
Other Study ID Numbers:
  • 17-0816
  • U01HG006487
First Posted:
Jun 7, 2018
Last Update Posted:
Dec 16, 2021
Last Verified:
Dec 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
Yes
Additional relevant MeSH terms:

Study Results

No Results Posted as of Dec 16, 2021