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

Autism Spectrum Disorder Clinical Trial

— NCGENES2  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03548779
• Other study ID #: 17-0816
• Secondary ID: U01HG006487
• Status: Active, not recruiting
• Phase: N/A
• Start date: September 28, 2018
• Est. completion date: September 8, 2024

Study information

• Verified date: February 2024
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 806
• Est. completion date: September 8, 2024
• Est. primary completion date: September 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Autism Spectrum Disorder
• Brain Malformation
• Chromosome Aberrations
• Chromosome Abnormality
• Chromosome Disorders
• Congenital Abnormalities
• Congenital Abnormality
• Development Delay
• Dysmorphic Features
• Epilepsy; Seizure
• Genetic Disease
• Genetic Diseases, Inborn
• Hearing Loss
• Hypotonia
• Inborn Errors of Metabolism
• Intellectual Disability
• Macrocephaly
• Metabolism, Inborn Errors
• Microcephaly
• Movement Disorders
• Neuromuscular Diseases
• Seizures
• Skeletal Dysplasia

Intervention

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.

Locations

Country	Name	City	State
United States	Mission Health	Asheville	North Carolina
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	East Carolina University	Greenville	North Carolina

Sponsors (4)

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

Country where clinical trial is conducted

United States, 

References & Publications (60)

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* Note: There are 60 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of in-patient hospital admissions 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.	1 year prior to return of results
Primary	Number of in-patient hospital admissions 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.	1 year after return of results
Primary	Number of in-patient hospital days 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.	1 year prior to return of results
Primary	Number of in-patient hospital days 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.	1 year after return of results
Primary	Number of long-term care admissions 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.	1 year prior to return of results
Primary	Number of long-term care admissions 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.	1 year after return of results
Primary	Number of long-term care days 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.	1 year prior to return of results
Primary	Number of long-term care days 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.	1 year after return of results
Primary	Number of ER visits 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.	1 year prior to return of results
Primary	Number of ER visits 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.	1 year after return of results
Primary	Number of specialists visits 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.	1 year prior to return of results
Primary	Number of specialists visits 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.	1 year after return of results
Primary	Initial Patient Pediatric Quality of Life (Peds QL) score	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.	4-6 weeks prior to clinic visit 1
Primary	Final Patient Pediatric Quality of Life (Peds QL) score	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.	6 months after return of results
Primary	Initial Caregiver QoL score	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.	4-6 weeks prior to clinic visit 1
Primary	Intermediate Caregiver QoL score	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.	2 weeks after return of results
Primary	Final Caregiver QoL score	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 months after return of results
Primary	Post-Clinic Visit 1 Mean Patient Centeredness Score	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.	Immediately after clinic 1 day of visit 1
Primary	Post-Return of Results Mean Patient Centeredness Score	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.	2 weeks after return of results
Primary	Number of questions caregiver asks in Clinic Visit 1	Count of number of questions caregiver asks provider in the audio recording of clinic visit 1. Coded by trained study staff.	During clinic 1 day of visit 1
Secondary	Initial Average Peds QL score for "missing school for not feeling well"	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.	4-6 weeks prior to clinic visit 1
Secondary	Final Average Peds QL score for "missing school for not feeling well"	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.	6 months after return of results
Secondary	Initial Average Peds QL score for "missing school for doctors visit"	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.	4-6 weeks prior to clinic visit 1
Secondary	Final Average Peds QL score for "missing school for doctors visit"	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.	6 months after return of results
Secondary	Initial Amount of work missed because of child's condition or treatments score	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.	4-6 weeks prior to clinic visit 1
Secondary	Final Amount of work missed because of child's condition or treatments score	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.	6 months after return of results
Secondary	Initial Difficulty with finishing normal work (including both work outside of the home and housework) because of child's condition or treatments score	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.	4-6 weeks prior to clinic visit 1
Secondary	Intermediate Difficulty with finishing normal work (including both work outside of the home and housework) because of child's condition or treatments score	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.	2 weeks after return of results
Secondary	Final Difficulty with finishing normal work (including both work outside of the home and housework) because of child's condition or treatments score	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.	6 months after return of results
Secondary	Vital status at final f/u	Based on NC Vital Statistics, the child's vital status will be reported as living or deceased.	final follow-up, up to approximately three years after clinic visit 1
Secondary	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.	final follow-up up to approximately three years after clinic visit 1
Secondary	Percent concordance of caregiver and provider reports of genetic or genomic test 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.	2 weeks after return of results
Secondary	Mean Baseline Self Efficacy Score	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.	4-6 weeks prior to clinic visit 1
Secondary	Mean Pre-Clinic Visit 1 Self Efficacy Score	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.	Immediately before Clinic Visit 1
Secondary	Post-Return of Results Mean FACToR Uncertainty Subscale Score	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.	2 weeks after return of results

External Links

•   Agency for Healthcare Research and Quality. Ambulatory care sensitive conditions: age-standardized acute care hospitalization rate for conditions where appropriate ambulatory care prevents or reduces the need for admission to the hospital
•   Ales M, Luca L, Marija V, Gorazd R, Karin W, Ana B, Alenka H, Peterlin B. Phenotype-driven gene target definition in clinical genome-wide sequencing data interpretation. Genet Med [Internet]. 2016 Mar 31 [cited 2016 Aug 3]