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

University of North Carolina (UNC)

Status: Completed

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

Treatments: Diagnostic Test: usual care + exome seq; Behavioral: Pre-visit prep

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03548779

U01HG006487 (U.S. NIH Grant/Contract)

17-0816

Details and patient eligibility

About

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.

Full 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.

Enrollment: 548 patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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548 participants in 4 patient groups

Pre-visit prep / usual care + exome seq

Experimental group

Description:

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.

Treatment:

Behavioral: Pre-visit prep

Diagnostic Test: usual care + exome seq

Pre-visit prep / usual care

Experimental group

Description:

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.

Treatment:

Behavioral: Pre-visit prep

No prep / usual care + exome seq

Experimental group

Description:

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.

Treatment:

Diagnostic Test: usual care + exome seq

No prep / usual care

No Intervention group

Description:

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.