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; Jamie L. Fraser; Diane Masser-Frye; Jean Hayward; Swati Karmarkar; Stephanie Keller; Samuel Mirrop; Wendy Mitchell; Sheel Pathak; Elliott Sherr; Keith van Haren; Erica Waters; Jenny L. Wilson; Leah Zhorne; Raphael Schiffmann; Marjo S. van der Knaap; Amy Pizzino; Holly Dubbs; Justine Shults; Cas Simons; Ryan J. Taft

doi:10.1002/ana.25757

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, Jamie L. Fraser, Diane Masser-Frye, Jean Hayward, Swati Karmarkar, Stephanie Keller, Samuel Mirrop, Wendy Mitchell, Sheel Pathak, Elliott Sherr, Keith van HarenErica Waters, Jenny L. Wilson, Leah Zhorne, Raphael Schiffmann, Marjo S. van der Knaap, Amy Pizzino, Holly Dubbs, Justine Shults, Cas Simons, Ryan J. Taft

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	264-273
Number of pages	10
Journal	Annals of Neurology
Volume	88
Issue number	2
DOIs	https://doi.org/10.1002/ana.25757
Publication status	Published - 1 Aug 2020

Funding

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).

Funders	Funder number
Illumina Clinical Services Laboratory
National Institute of Neurological Disorders and Stroke	K23NS087151
Pennsylvania Department of Health	4100077047
Hope Foundation
Canadian Institutes of Health Research
National Health and Medical Research Council	1068278

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Vanderver, A., Bernard, G., Helman, G., Sherbini, O., Boeck, R., Cohn, J., Collins, A., Demarest, S., Dobbins, K., Emrick, L., Fraser, J. L., Masser-Frye, D., Hayward, J., Karmarkar, S., Keller, S., Mirrop, S., Mitchell, W., Pathak, S., Sherr, E., ... Taft, R. J. (2020). Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders. Annals of Neurology, 88(2), 264-273. https://doi.org/10.1002/ana.25757

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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.}",

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doi = "10.1002/ana.25757",

language = "English",

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Vanderver, A, Bernard, G, Helman, G, Sherbini, O, Boeck, R, Cohn, J, Collins, A, Demarest, S, Dobbins, K, Emrick, L, Fraser, JL, Masser-Frye, D, Hayward, J, Karmarkar, S, Keller, S, Mirrop, S, Mitchell, W, Pathak, S, Sherr, E, van Haren, K, Waters, E, Wilson, JL, Zhorne, L, Schiffmann, R, van der Knaap, MS, Pizzino, A, Dubbs, H, Shults, J, Simons, C & Taft, RJ 2020, 'Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders', Annals of Neurology, vol. 88, no. 2, pp. 264-273. https://doi.org/10.1002/ana.25757

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T1 - Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders

AU - Vanderver, Adeline

AU - Bernard, Geneviève

AU - Helman, Guy

AU - Sherbini, Omar

AU - Boeck, Ryan

AU - Cohn, Jeffrey

AU - Collins, Abigail

AU - Demarest, Scott

AU - Dobbins, Katherine

AU - Emrick, Lisa

AU - Fraser, Jamie L.

AU - Masser-Frye, Diane

AU - Hayward, Jean

AU - Karmarkar, Swati

AU - Keller, Stephanie

AU - Mirrop, Samuel

AU - Mitchell, Wendy

AU - Pathak, Sheel

AU - Sherr, Elliott

AU - van Haren, Keith

AU - Waters, Erica

AU - Wilson, Jenny L.

AU - Zhorne, Leah

AU - Schiffmann, Raphael

AU - van der Knaap, Marjo S.

AU - Pizzino, Amy

AU - Dubbs, Holly

AU - Shults, Justine

AU - Simons, Cas

AU - Taft, Ryan J.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

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

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