Journal article
Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders
Annals of neurology, Vol.88(2), pp.264-273
08/2020
DOI: 10.1002/ana.25757
PMCID: PMC8061316
PMID: 32342562
Abstract
Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied.
A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS.
Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study.
In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273.
Details
- Title: Subtitle
- Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders
- Creators
- Adeline Vanderver - University of PennsylvaniaGeneviève Bernard - Montreal Children's HospitalGuy Helman - Royal Children's HospitalOmar Sherbini - University of PennsylvaniaRyan Boeck - The University of Texas at AustinJeffrey Cohn - Broadlands Family Practice at AshburnAbigail Collins - University of DenverScott Demarest - University of DenverKatherine Dobbins - Walter Reed Army Institute of ResearchLisa Emrick - Baylor College of MedicineJamie L Fraser - Children’s National Health SystemDiane Masser-Frye - Boston Children's HospitalJean Hayward - Kaiser Permanente Oakland Medical CenterSwati Karmarkar - University of Tennessee Health Science CenterStephanie Keller - Emory UniversitySamuel Mirrop - Hospice AustinWendy Mitchell - University of Southern CaliforniaSheel Pathak - Clinical Research AssociatesElliott Sherr - University of California, San FranciscoKeith van Haren - Stanford UniversityErica Waters - Pediatric Associates of StocktonJenny L Wilson - Oregon Health & Science UniversityLeah Zhorne - University of IowaRaphael Schiffmann - Scott & White Memorial HospitalMarjo S van der Knaap - VU AmsterdamAmy Pizzino - University of PennsylvaniaHolly Dubbs - University of PennsylvaniaJustine Shults - University of PennsylvaniaCas Simons - The University of QueenslandRyan J Taft - IlluminaLeukoSEQ Workgroup
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.88(2), pp.264-273
- DOI
- 10.1002/ana.25757
- PMID
- 32342562
- PMCID
- PMC8061316
- NLM abbreviation
- Ann Neurol
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Grant note
- K23 NS087151 / NINDS NIH HHS CIHR U54 NS115052 / NINDS NIH HHS
- Language
- English
- Date published
- 08/2020
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Neurology (Pediatrics)
- Record Identifier
- 9984303021502771
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