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Randomized Clinical Trial of First‐Line Genome Sequencing in Pediatric White Matter Disorders
Author(s) -
Vanderver Adeline,
Bernard Geneviève,
Helman Guy,
Sherbini Omar,
Boeck Ryan,
Cohn Jeffrey,
Collins Abigail,
Demarest Scott,
Dobbins Katherine,
Emrick Lisa,
Fraser Jamie L.,
MasserFrye Diane,
Hayward Jean,
Karmarkar Swati,
Keller Stephanie,
Mirrop Samuel,
Mitchell Wendy,
Pathak Sheel,
Sherr Elliott,
Haren Keith,
Waters Erica,
Wilson Jenny L.,
Zhorne Leah,
Schiffmann Raphael,
Knaap Marjo S.,
Pizzino Amy,
Dubbs Holly,
Shults Justine,
Simons Cas,
Taft Ryan J.
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25757
Subject(s) - medicine , randomization , randomized controlled trial , confidence interval , clinical trial , crossover study , white matter , pediatrics , magnetic resonance imaging , pathology , alternative medicine , radiology , placebo
Objective Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. Methods 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. Results 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. Interpretation 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.