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NCT Number: NCT03548779

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

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.

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Key information

Conditions

Epilepsy; Seizure Autism Spectrum Disorder Brain Diseases Brain Malformation Carbohydrate Metabolism, Inborn Errors Central Nervous System Diseases Child Development Disorders, Pervasive Chromosome Aberrations Chromosome Abnormality Communication Disorders Congenital Abnormalities Congenital Abnormality Congenital, Hereditary, and Neonatal Diseases and Abnormalities Connective Tissue Diseases Craniofacial Abnormalities Development Delay Dysmorphic Features Ear Diseases Epilepsy Genetic Disease Genetic Diseases, Inborn Hearing Disorders Hearing Loss Hypotonia Inborn Errors of Metabolism Intellectual Disability Learning Disabilities Lysosomal Storage Diseases Macrocephaly Malformations of Cortical Development Malformations of Cortical Development, Group I Megalencephaly Mental Disorders Metabolic Diseases Metabolism, Inborn Errors Microcephaly Movement Disorders Mucinoses Mucopolysaccharidoses Mucopolysaccharidosis IV Muscle Hypotonia Musculoskeletal Abnormalities Musculoskeletal Diseases Nervous System Diseases Nervous System Malformations Neurobehavioral Manifestations Neurodevelopmental Disorders Neurologic Manifestations Neuromuscular Diseases Neuromuscular Manifestations Nutritional and Metabolic Diseases Otorhinolaryngologic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Sensation Disorders Signs and Symptoms Skeletal Dysplasia Skin and Connective Tissue Diseases

Age range

0 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Mission Health, Asheville, North Carolina, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Both children and parents are participants:

Inclusion criteria

Parents meeting the following criteria:

  • Parent of a child who meets the criteria below
  • At least 18 years old.
  • Must be able to provide informed consent for child and self.
  • Must be fluent in English or Spanish.

Children meeting the following criteria:

  • Infants and children 15 years old or less.
  • Referred for initial evaluation of a possible monogenic disorder OR
  • Seen for evaluation of an undiagnosed disorder in a study-associated clinic.

Exclusion criteria

Parents:

  • Younger than 18 years old.
  • Unwilling to complete study surveys and other procedures.
  • Have cognitive or other impairments precluding ability to provide giving informed consent.
  • Not fluent in English or Spanish.
  • Unable to attend all clinic visits

Children:

  • Have a known genetic or non-genetic diagnosis (only referred for counseling or management).
  • Medically unstable.

Treatment and study plan

Pre-visit prep

Behavioral

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.

usual care + exome seq

Diagnostic Test

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.

Primary outcomes

  1. Initial Patient Pediatric Quality of Life (Peds QL) Score

    Time frame: 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.

  2. Final Patient Pediatric Quality of Life (Peds QL) Score

    Time frame: 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.

  3. Initial Caregiver QoL Score

    Time frame: 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.

  4. Intermediate Caregiver QoL Score

    Time frame: 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.

  5. Final Caregiver QoL Score

    Time frame: 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.

  6. Post-Clinic Visit 1 Mean Patient Centeredness Score

    Time frame: 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. Response values will be summed and divided by the total number of items (21) to obtain mean scores ranging from 0-7 where higher values indicate stronger perceptions of patient centeredness.

  7. Post-Return of Results Mean Patient Centeredness Score

    Time frame: 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). 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. Response values will be summed and divided by the total number of items (21) to obtain mean scores ranging from 0-7 where higher values indicate stronger perceptions of patient centeredness.

  8. Number of Questions Caregiver Asks in Clinic Visit 1

    Time frame: 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.

  9. Number of In-patient Hospital Admissions Among Child Participants 1 Year Prior to Return of Results

    Time frame: 1 year prior to return of results

    Count of number of in-patient hospital admissions among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

  10. Number of In-patient Hospital Admissions Among Child Participants 1 Year After Return of Results

    Time frame: 1 year after return of results

    Count of number of in-patient hospital admissions among child participants during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

  11. Number of In-patient Hospital Days Among Child Participants 1 Year Prior to Return of Results

    Time frame: 1 year prior to return of results

    Count of number of in-patient hospital days among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

  12. Number of In-patient Hospital Days Among Child Participants 1 Year After Return of Results

    Time frame: 1 year after return of results

    Count of number of in-patient hospital days among child participants during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

  13. Number of Long-term Care Admissions Among Child Participants 1 Year Prior to Return of Results

    Time frame: 1 year prior to return of results

    Count of number of long-term care admissions among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

  14. Number of Long-term Care Admissions Among Child Participants 1 Year After Return of Results

    Time frame: 1 year after return of results

    Count of number of long-term care admissions among child participants during 1 year after return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Admissions were summed across all participants.

  15. Number of Long-term Care Days Among Child Participants 1 Year Prior to Return of Results

    Time frame: 1 year prior to return of results

    Count of number of long-term care days among child participants during 1 year prior to return of results using data obtained from the Electronic Medical Record. Coded by trained study staff. Days were summed across all participants.

  16. Number of Long-term Care Days Among Child Participants 1 Year After Return of Results

    Time frame: 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. Days were summed across all participants.

  17. Number of ER Visits Among Child Participants 1 Year Prior to Return of Results

    Time frame: 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. Visits were summed across all participants.

  18. Number of ER Visits Among Child Participants 1 Year After Return of Results

    Time frame: 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. Visits were summed across all participants.

  19. Number of Specialists Visits Among Child Participants 1 Year Prior to Return of Results

    Time frame: 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. Visits were summed across all participants.

  20. Number of Specialists Visits Among Child Participants 1 Year After Return of Results

    Time frame: 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. Visits were summed across all participants.

Secondary outcomes

  1. Initial Average Peds QL Score for "Missing School for Not Feeling Well"

    Time frame: 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. Final Average Peds QL Score for "Missing School for Not Feeling Well"

    Time frame: 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.

  3. Initial Average Peds QL Score for "Missing School for Doctors Visit"

    Time frame: 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.

  4. Final Average Peds QL Score for "Missing School for Doctors Visit"

    Time frame: 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.

  5. Initial Amount of Work Missed Because of Child's Condition or Treatments Score

    Time frame: 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.

  6. Final Amount of Work Missed Because of Child's Condition or Treatments Score

    Time frame: 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.

  7. Initial Difficulty With Finishing Normal Work (Including Both Work Outside of the Home and Housework) Because of Child's Condition or Treatments Score

    Time frame: 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.

  8. Intermediate Difficulty With Finishing Normal Work (Including Both Work Outside of the Home and Housework) Because of Child's Condition or Treatments Score

    Time frame: 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.

  9. Final Difficulty With Finishing Normal Work (Including Both Work Outside of the Home and Housework) Because of Child's Condition or Treatments Score

    Time frame: 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.

  10. Percent Concordance of Caregiver and Provider Reports of Genetic or Genomic Test Results

    Time frame: 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. Results are given as the number of parent/caregiver participant responses for each group that were concordant with the provider's diagnostic interpretation of the exome results.

  11. Mean Baseline Self Efficacy Score

    Time frame: 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.

  12. Mean Pre-Clinic Visit 1 Self Efficacy Score

    Time frame: 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.

  13. Post-Return of Results Mean FACToR Uncertainty Subscale Score

    Time frame: 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.

  14. Vital Status at Final f/u

    Time frame: 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.

  15. Number of Child Participants With Causes of Death Unrelated to the Study

    Time frame: Final follow-up, up to approximately three years after clinic visit 1

    Child causes of death related to the primary condition 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.

Sponsors and collaborators

Lead sponsor

University of North Carolina, Chapel Hill

Other

Collaborators

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

Registry information

Acronym: NCGENES2

Important dates

Study start
2018
Primary completion
2023
Study completion
2024
First posted
Jun 7, 2018
Registry last updated
May 13, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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