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

doi:10.1186/s13063-021-05341-2

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

^*Corresponding author for this work

Medical Social Sciences

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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.govNCT03548779. Registered on June 07, 2018.

Original language	English (US)
Article number	395
Journal	Trials
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13063-021-05341-2
State	Published - Dec 2021

Funding

The NCGENES 2 study is funded by Grant Number #U01HG006487 from the National Human Genome Research Institute (NHGRI). The National Research Service Award from the Agency for Healthcare Research and Quality (T32 HS000032) supported I. Griesemer and the Genetic Epidemiology of Heart, Lung, and Blood (HLB) Traits Training Grant (GenHLB, T32HL129982) supported B.S. Staley for the writing of this manuscript. Trial funders had no role in the study design, collection, analysis, and interpretation of data nor in writing this manuscript. NCGENES 2 is carried out as a collaborative study supported by the National Hufman Genome Research Institute, National Cancer Institute, and National Institute of Minority Health and Health Disparities of the National Institutes of Health for RFA-HG-12-009 under Award Number U01HG006487. The authors thank the Clinical Sequencing Evidence-Generating Research consortium, and staff, advisory committees, and families participating in the NCGENES 2 study for their significant contributions. The authors would also like to acknowledge important contributions to this study made by the entire NCGENES 2 team, the High-Throughput Sequencing Facility at UNC, the Renaissance Computing Institute, the Mission Fullerton Genetics Lab, the Carolina Data Warehouse for Health, and the North Carolina Translational and Clinical Sciences Institute. We want to acknowledge the UNC BioSpecimen Processing Facility (https://genome.unc.edu/bsp) and the UNC Health Molecular Genetics Laboratory for our DNA extractions, blood processing, storage, and sample disbursement. NCGENES 2 is carried out as a collaborative study supported by the National Hufman Genome Research Institute, National Cancer Institute, and National Institute of Minority Health and Health Disparities of the National Institutes of Health for RFA-HG-12-009 under Award Number U01HG006487. The authors thank the Clinical Sequencing Evidence-Generating Research consortium, and staff, advisory committees, and families participating in the NCGENES 2 study for their significant contributions. The authors would also like to acknowledge important contributions to this study made by the entire NCGENES 2 team, the High-Throughput Sequencing Facility at UNC, the Renaissance Computing Institute, the Mission Fullerton Genetics Lab, the Carolina Data Warehouse for Health, and the North Carolina Translational and Clinical Sciences Institute. We want to acknowledge the UNC BioSpecimen Processing Facility ( https://genome.unc.edu/bsp ) and the UNC Health Molecular Genetics Laboratory for our DNA extractions, blood processing, storage, and sample disbursement. The NCGENES 2 study is led by researchers at the University of North Carolina at Chapel Hill, one of six sites participating in the CSER 2 consortium, which is a national multi-site research program jointly funded by the National Human Genome Research Institute (NHGRI), the National Cancer Institute (NCI), and the National Institute on Minority Health and Health Disparities (NIMHD). The CSER 2 consortium sites and a coordinating center use interdisciplinary, translational research to evaluate the integration of GS into the clinical care of diverse and medically underserved individuals with suspected genetic disorders by developing and sharing best practices in areas such as informed consent, informed and shared decision making, patient-reported outcomes, and return of results.

Keywords

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

ASJC Scopus subject areas

Medicine (miscellaneous)
Pharmacology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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
Staley, B. S. (Creator), Milko, L. V. (Creator), Waltz, M. (Creator), Griesemer, I. (Creator), Mollison, L. (Creator), Grant, T. L. (Creator), Farnan, L. (Creator), Roche, M. (Creator), Navas, A. (Creator), Lightfoot, A. (Creator), Foreman, A. K. M. (Creator), O’Daniel, J. M. (Creator), O’Neill, S. C. (Creator), Lin, F.-C. (Creator), Roman, T. S. (Creator), Brandt, A. (Creator), Powell, B. C. (Creator), Rini, C. (Creator), Berg, J. S. (Creator) & Bensen, J. T. (Creator), figshare, 2021
DOI: 10.6084/m9.figshare.c.5467378, https://springernature.figshare.com/collections/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/5467378
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Staley, B. S., Milko, L. V., Waltz, M., Griesemer, I., Mollison, L., Grant, T. L., Farnan, L., Roche, M., Navas, A., Lightfoot, A., Foreman, A. K. M., O’Daniel, J. M., O’Neill, S. C., Lin, F. C., Roman, T. S., Brandt, A., Powell, B. C., Rini, C., Berg, J. S., & Bensen, J. T. (2021). 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. Trials, 22(1), Article 395. https://doi.org/10.1186/s13063-021-05341-2

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title = "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",

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{\textquoteright}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.govNCT03548779. 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",

author = "Staley, {Brooke S.} and Milko, {Laura V.} and Margaret Waltz and Ida Griesemer and Lonna Mollison and Grant, {Tracey L.} and Laura Farnan and Myra Roche and Angelo Navas and Alexandra Lightfoot and Foreman, {Ann Katherine M.} and O{\textquoteright}Daniel, {Julianne M.} and O{\textquoteright}Neill, {Suzanne C.} and Lin, {Feng Chang} and Roman, {Tamara S.} and Alicia Brandt and Powell, {Bradford C.} and Christine Rini and Berg, {Jonathan S.} and Bensen, {Jeannette T.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s13063-021-05341-2",

language = "English (US)",

volume = "22",

journal = "Trials",

issn = "1745-6215",

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Staley, BS, Milko, LV, Waltz, M, Griesemer, I, Mollison, L, Grant, TL, Farnan, L, Roche, M, Navas, A, Lightfoot, A, Foreman, AKM, O’Daniel, JM, O’Neill, SC, Lin, FC, Roman, TS, Brandt, A, Powell, BC, Rini, C, Berg, JS & Bensen, JT 2021, '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', Trials, vol. 22, no. 1, 395. https://doi.org/10.1186/s13063-021-05341-2

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. / Staley, Brooke S.; Milko, Laura V.; Waltz, Margaret et al.
In: Trials, Vol. 22, No. 1, 395, 12.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

T2 - a randomized controlled trial

AU - Staley, Brooke S.

AU - Milko, Laura V.

AU - Waltz, Margaret

AU - Griesemer, Ida

AU - Mollison, Lonna

AU - Grant, Tracey L.

AU - Farnan, Laura

AU - Roche, Myra

AU - Navas, Angelo

AU - Lightfoot, Alexandra

AU - Foreman, Ann Katherine M.

AU - O’Daniel, Julianne M.

AU - O’Neill, Suzanne C.

AU - Lin, Feng Chang

AU - Roman, Tamara S.

AU - Brandt, Alicia

AU - Powell, Bradford C.

AU - Rini, Christine

AU - Berg, Jonathan S.

AU - Bensen, Jeannette T.

PY - 2021/12

Y1 - 2021/12

N2 - 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.govNCT03548779. Registered on June 07, 2018.

AB - 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.govNCT03548779. Registered on June 07, 2018.

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KW - Community engagement

KW - Diagnostic odyssey

KW - ELSI

KW - Genetic disease

KW - Patient education

KW - Precision medicine

KW - Question prompt list

KW - Sequencing

KW - Under-represented populations

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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

Abstract

Funding

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ASJC Scopus subject areas

UN SDGs

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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

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