Evaluating the clinical utility of early exome sequencing in diverse pediatric outpatient populations in the North Carolina Clinical Genomic Evaluation of Next-generation Exome Sequencing (NCGENES) 2 study: a randomized controlled trial

Brooke S Staley, Laura V Milko, Margaret Waltz, Ida Griesemer, Lonna Mollison, Tracey L Grant, Laura Farnan, Myra Roche, Angelo Navas, Alexandra Lightfoot, Ann Katherine M Foreman, Julianne M O'Daniel, Suzanne C O'Neill, Feng-Chang Lin, Tamara S Roman, Alicia Brandt, Bradford C Powell, Christine Rini, Jonathan S Berg, Jeannette T Bensen, Brooke S Staley, Laura V Milko, Margaret Waltz, Ida Griesemer, Lonna Mollison, Tracey L Grant, Laura Farnan, Myra Roche, Angelo Navas, Alexandra Lightfoot, Ann Katherine M Foreman, Julianne M O'Daniel, Suzanne C O'Neill, Feng-Chang Lin, Tamara S Roman, Alicia Brandt, Bradford C Powell, Christine Rini, Jonathan S Berg, Jeannette T Bensen

Abstract

Background: Exome sequencing (ES) has probable utility for shortening the diagnostic odyssey of children with suspected genetic disorders. This report describes the design and methods of a study evaluating the potential of ES as a routine clinical tool for pediatric patients who have suspected genetic conditions and who are in the early stages of the diagnostic odyssey.

Methods: The North Carolina Clinical Genomic Evaluation by Next-generation Exome Sequencing (NCGENES) 2 study is an interdisciplinary, multi-site Phase III randomized controlled trial of two interventions: educational pre-visit preparation (PVP) and offer of first-line ES. In this full-factorial design, parent-child dyads are randomly assigned to one of four study arms (PVP + usual care, ES + usual care, PVP + ES + usual care, or usual care alone) in equal proportions. Participants are recruited from Pediatric Genetics or Neurology outpatient clinics in three North Carolina healthcare facilities. Eligible pediatric participants are < 16 years old and have a first visit to a participating clinic, a suspected genetic condition, and an eligible parent/guardian to attend the clinic visit and complete study measures. The study oversamples participants from underserved and under-represented populations. Participants assigned to the PVP arms receive an educational booklet and question prompt list before clinical interactions. Randomization to offer of first-line ES is revealed after a child's clinic visit. Parents complete measures at baseline, pre-clinic, post-clinic, and two follow-up timepoints. Study clinicians provide phenotypic data and complete measures after the clinic visit and after returning results. Reportable study-related research ES results are confirmed in a CLIA-certified clinical laboratory. Results are disclosed to the parent by the clinical team. A community consultation team contributed to the development of study materials and study implementation methods and remains engaged in the project.

Discussion: NCGENES 2 will contribute valuable knowledge concerning technical, clinical, psychosocial, and health economic issues associated with using early diagnostic ES to shorten the diagnostic odyssey of pediatric patients with likely genetic conditions. Results will inform efforts to engage diverse populations in genomic medicine research and generate evidence that can inform policy, practice, and future research related to the utility of first-line diagnostic ES in health care.

Trial registration: ClinicalTrials.gov NCT03548779 . Registered on June 07, 2018.

Keywords: Clinical trial; Community engagement; Diagnostic odyssey; ELSI; Genetic disease; Patient education; Precision medicine; Question prompt list; Sequencing; Under-represented populations.

Conflict of interest statement

The authors have no competing financial interests to disclose

Figures

Fig. 1
Fig. 1
NCGENES 2 study recruitment, enrollment, and clinical trajectory with trial arms and anticipated sample size. aAll eligible participants are new patients presenting for evaluation to pediatric genetics or pediatric neurology clinics. bEnrollment is completed by phone before the scheduled new patient visit. cPlanned enrollment is 850 parent-child dyads, for ease of distribution across groups, 800 was used here. dIntervention 1 (PVP) is a behavioral intervention that involves randomizing parents/guardians to receive or not receive a pre-visit educational booklet and a question prompt list for their child’s first clinic visit. Intervention 2 (ES) is a diagnostic intervention where parent-child dyads are randomized to be offered first-line exome sequencing for the child. The trial applies a full-factorial design, resulting in four arms, as illustrated in the figure: 1a PVP, exome sequencing, and usual care; 1b PVP and usual care; 2a exome sequencing and usual care; and 2b usual care (control arm). Estimates of positive, uncertain, and negative findings in the groups receiving ES are based on prior experience. eParents complete two post-return of result (ROR) surveys: (1) 2-week post-ROR (approximately 6 months after the clinic visit) and (2) 6-month post-ROR (approximately 12 months after the clinic visit). fClinicians complete survey measures at two timepoints: (1) post-visit survey after the clinical interaction with the child and parent and (2) approximately 6 months after the clinical visits when clinical diagnostic and ES results (if relevant) have been returned
Fig. 2:
Fig. 2:
SPIRIT figure. Schedule of enrollment, interventions, and assessments for the North Carolina Clinical Genomic Evaluation of Next-generation Exome Sequencing (NCGENES) 2 randomized controlled trial

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