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Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders
Journal article   Open access   Peer reviewed

Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders

Adeline Vanderver, Geneviève Bernard, Guy Helman, Omar Sherbini, Ryan Boeck, Jeffrey Cohn, Abigail Collins, Scott Demarest, Katherine Dobbins, Lisa Emrick, …
Annals of neurology, v 88(2), pp 264-273
Aug 2020
DOI: https://doi.org/10.1002/ana.25757
PMID: 32342562
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061316View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Child Child, Preschool Cross-Over Studies Female Humans Infant Leukoencephalopathies - diagnosis Leukoencephalopathies - genetics Male Prospective Studies Sequence Analysis, DNA - methods White Matter - pathology
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.

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Industry collaboration
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Web of Science research areas
Clinical Neurology
Neurosciences
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