@article{c5573a2bb48f48d3b8a28a4eb66f4516,
title = "Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders",
abstract = "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.",
author = "Adeline Vanderver and Genevi{\`e}ve Bernard and Guy Helman and Omar Sherbini and Ryan Boeck and Jeffrey Cohn and Abigail Collins and Scott Demarest and Katherine Dobbins and Lisa Emrick and Fraser, {Jamie L.} and Diane Masser-Frye and Jean Hayward and Swati Karmarkar and Stephanie Keller and Samuel Mirrop and Wendy Mitchell and Sheel Pathak and Elliott Sherr and {van Haren}, Keith and Erica Waters and Wilson, {Jenny L.} and Leah Zhorne and Raphael Schiffmann and {van der Knaap}, {Marjo S.} and Amy Pizzino and Holly Dubbs and Justine Shults and Cas Simons and Taft, {Ryan J.}",
note = "Funding Information: Clinical genome sequencing, analysis, and interpretation were provided by Illumina and the Illumina Clinical Services Laboratory. The study is in part supported by the Pennsylvania Department of Health's Commonwealth Universal Research Enhancement Program Tobacco Formula award SAP# 4100077047. Creation of a diagnostic algorithm was supported by the Leukodystrophy Care Network of the Hunter's Hope Foundation. The Children's Hospital of Philadelphia and the Jacob A. Kamens endowed chair supported all other study‐related activities. No non‐Illumina staff received any direct financial work or compensation for this effort. The participation of G.H. and C.S. is in part financed by the Australian National Health and Medical Research Council (1068278). G.B. has received the New Investigator Salary Award from the Canadian Institutes of Health Research (2017–2022). Funding Information: Clinical genome sequencing, analysis, and interpretation were provided by Illumina and the Illumina Clinical Services Laboratory. The study is in part supported by the Pennsylvania Department of Health's Commonwealth Universal Research Enhancement Program Tobacco Formula award SAP# 4100077047. Creation of a diagnostic algorithm was supported by the Leukodystrophy Care Network of the Hunter's Hope Foundation. The Children's Hospital of Philadelphia and the Jacob A. Kamens endowed chair supported all other study-related activities. No non-Illumina staff received any direct financial work or compensation for this effort. The participation of G.H. and C.S. is in part financed by the Australian National Health and Medical Research Council (1068278). G.B. has received the New Investigator Salary Award from the Canadian Institutes of Health Research (2017?2022). We thank the patients and their families. The LeukoSEQ group dedicates this article to their coauthor and collaborator, James Weisfeld-Adams, MD (1979?2018). Publisher Copyright: {\textcopyright} 2020 American Neurological Association",
year = "2020",
month = aug,
day = "1",
doi = "10.1002/ana.25757",
language = "English",
volume = "88",
pages = "264--273",
journal = "Annals of neurology",
issn = "0364-5134",
number = "2",
}