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The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants

Josh E. Petrikin, Julie A. Cakici, Michelle M. Clark, Laurel K. Willig, Nathaly M. Sweeney, Emily G. Farrow, Carol J. Saunders, Isabelle Thiffault, Neil A. Miller, Lee Zellmer, Suzanne M. Herd, Anne M. Holmes, Serge Batalov, Narayanana Veeraraghavan, Laurie D. Smith, David P. Dimmock, Steven J. Leeder, Stephen F. Kingsmore
doi: https://doi.org/10.1101/218255
Josh E. Petrikin
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
2Department of Pediatrics, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
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Julie A. Cakici
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
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Michelle M. Clark
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
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Laurel K. Willig
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
2Department of Pediatrics, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
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Nathaly M. Sweeney
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
6Department of Pediatrics, University of California – San Diego, Rady Children’s Hospital, CA 92123, USA.
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Emily G. Farrow
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
2Department of Pediatrics, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
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Carol J. Saunders
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
5Department of Pathology, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA
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Isabelle Thiffault
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
5Department of Pathology, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA
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Neil A. Miller
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
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Lee Zellmer
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
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Suzanne M. Herd
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
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Anne M. Holmes
2Department of Pediatrics, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
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Serge Batalov
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
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Narayanana Veeraraghavan
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
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Laurie D. Smith
1Center for Pediatric Genomic Medicine, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
7Department of Pediatrics, University of North Carolina – Chapel Hill, NC 27599.
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David P. Dimmock
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
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Steven J. Leeder
2Department of Pediatrics, Children’s Mercy - Kansas City, Kansas City, Missouri 64108, USA.
3School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
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Stephen F. Kingsmore
4Rady Children’s Institute for Genomic Medicine, San Diego, CA 92123.
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Abstract

Importance Genetic disorders, including congenital anomalies, are a leading cause of morbidity and mortality in infants, especially in neonatal and pediatric intensive care units (NICU and PICU). While genomic sequencing is useful for diagnosis of genetic diseases, results are usually reported too late to guide inpatient management.

Objective To test the hypothesis that rapid whole genome sequencing (rWGS) increases the proportion of infants in NICUs and PICUs receiving a genetic diagnosis within 28 days.

Design An investigator-initiated, partially blinded, pragmatic, randomized controlled study with enrollment from October 2014 - June 2016, and follow up until December 2016.

Setting A regional neonatal and pediatric intensive care unit in a tertiary referral childrens hospital.

Participants Sixty five of 129 screened families with infants aged less than four months, in neonatal and pediatric intensive care units, and with illnesses of unknown etiology, completed the study.

Intervention Parent and infant trio rWGS.

Main Outcome and Measure The hypothesis and end-points were formulated a priori. The primary end-point was rate of genetic diagnosis within 28 days of enrollment or first standard test order.

Results Twenty six female proband infants, 37 male infants, and two infants of undetermined sex were randomized to receive rWGS plus standard tests (n=32, cases) or standard tests alone (n=33, controls). The study was terminated early due to loss of equipoise: 63% (21) controls received genomic sequencing as standard tests. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days to be higher in cases (31%, ten of 32) than controls (3%, one of 33; difference, 28% [95% CI, 10% to 46%]; p=0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, seven of 22) than controls (0%, zero of 23; difference, 32% [95% CI, 11% to 53%]; p=0.004). Age at diagnosis (median in cases 25 days, range 14-90 days vs median in controls 130 days, range 37-451) and time to diagnosis (median in cases thirteen days, range 1-84 days vs median in controls 107 days, range 21-429 days) were significantly less in cases than controls (p=0.04).

CONCLUSIONS rWGS increased the proportion of infants in a regional NICU and PICU who received a timely diagnosis of a genetic disease. Additional, adequately powered studies are needed to determine whether accelerated diagnosis is associated with improved outcomes in this setting. ClinicalTrials.gov Identifier: NCT02225522.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 13, 2017.
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The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants
Josh E. Petrikin, Julie A. Cakici, Michelle M. Clark, Laurel K. Willig, Nathaly M. Sweeney, Emily G. Farrow, Carol J. Saunders, Isabelle Thiffault, Neil A. Miller, Lee Zellmer, Suzanne M. Herd, Anne M. Holmes, Serge Batalov, Narayanana Veeraraghavan, Laurie D. Smith, David P. Dimmock, Steven J. Leeder, Stephen F. Kingsmore
bioRxiv 218255; doi: https://doi.org/10.1101/218255
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The NSIGHT1 Randomized Controlled Trial: Rapid Whole Genome Sequencing for Accelerated Etiologic Diagnosis in Critically Ill Infants
Josh E. Petrikin, Julie A. Cakici, Michelle M. Clark, Laurel K. Willig, Nathaly M. Sweeney, Emily G. Farrow, Carol J. Saunders, Isabelle Thiffault, Neil A. Miller, Lee Zellmer, Suzanne M. Herd, Anne M. Holmes, Serge Batalov, Narayanana Veeraraghavan, Laurie D. Smith, David P. Dimmock, Steven J. Leeder, Stephen F. Kingsmore
bioRxiv 218255; doi: https://doi.org/10.1101/218255

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