The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.

Petrikin, Josh E.; Cakici, Julie A.; Clark, Michelle M.; Willig, Laurel K.; Sweeney, Nathaly M.; Farrow, Emily G.; Saunders, Carol J.; Thiffault, Isabelle; Miller, Neil A.; Zellmer, Lee; Herd, Suzanne M.; Holmes, Anne M.; Batalov, Serge; Veeraraghavan, Narayanan; Smith, Laurie D.; Dimmock, David P.; Leeder, J. Steven; Kingsmore, Stephen F.

doi:10.1038/s41525-018-0045-8

Cited by 229Genomics and Rare DiseasesMetabolism and Genetic DisordersConnective tissue disorders research

The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants.

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Petrikin, Josh E., Cakici, Julie A., Clark, Michelle M., Willig, Laurel K., Sweeney, Nathaly M., Farrow, Emily G., Saunders, Carol J., Thiffault, Isabelle +10 more·2018·npj Genomic Medicine

DOI 10.1038/s41525-018-0045-8PMC PMC5807510

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Abstract

Genetic disorders are a leading cause of morbidity and mortality in infants in neonatal and pediatric intensive care units (NICU/PICU). While genomic sequencing is useful for genetic disease diagnosis, results are usually reported too late to guide inpatient management. We performed an investigator-initiated, partially blinded, pragmatic, randomized, controlled trial to test the hypothesis that rapid whole-genome sequencing (rWGS) increased the proportion of NICU/PICU infants receiving a genetic diagnosis within 28 days. The participants were families with infants aged <4 months in a regional NICU and PICU, with illnesses of unknown etiology. The intervention was trio rWGS. Enrollment from October 2014 to June 2016, and follow-up until November 2016. Of all, 26 female infants, 37 male infants, and 2 infants of undetermined sex were randomized to receive rWGS plus standard genetic tests ( n = 32, cases) or standard genetic tests alone ( n = 33, controls). The study was terminated early due to loss of equipoise: 73% (24) controls received genomic sequencing as standard tests, and 15% (five) controls underwent compassionate cross-over to receive rWGS. Nevertheless, intention to treat analysis showed the rate of genetic diagnosis within 28 days of enrollment (the primary end-point) to be higher in cases (31%, 10 of 32) than controls (3%, 1 of 33; difference, 28% [95% CI, 10–46%]; p = 0.003). Among infants enrolled in the first 25 days of life, the rate of neonatal diagnosis was higher in cases (32%, 7 of 22) than controls (0%, 0 of 23; difference, 32% [95% CI, 11–53%]; p = 0.004). Median age at diagnosis (25 days [range 14–90] in cases vs. 130 days [range 37–451] in controls) and median time to diagnosis (13 days [range 1–84] in cases, vs. 107 days [range 21–429] in controls) were significantly less in cases than controls ( p = 0.04). In conclusion, rWGS increased the proportion of NICU/PICU infants who received timely diagnoses of genetic diseases.

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A blinded randomized trial comparing rapid genome sequencing with standard care ended early due to loss of equipoise.
“a blinded randomized clinical trial 9 of rapid genome sequencing vs standard care was terminated prematurely due to loss of equipoise.”
From Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System (2020) · cites this paper as [9]

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Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings
Willig, L., Petrikin, J., Smith, L. D., Saunders, C., Thiffault, I., Miller, N. A., Soden, S., Cakici, J. A., Herd, S. M., Twist, G. P., et al. (2015) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(15)00139-3 · Cited by 340 · see citing works
Self-citation

Authors: Petrikin, J. E., Cakici, J. A., Clark, M. M., Willig, L. K., Sweeney, N. M., Farrow, E. G., Saunders, C. J., Thiffault, I., Miller, N. A., Zellmer, L., Herd, S. M., Holmes, A. M., Batalov, S., Veeraraghavan, N., Smith, L. D., Dimmock, D. P., Leeder, J. S., & Kingsmore, S. F.
Affiliations: Children's Mercy Hospital (US)
Rady Children's Institute for Genomic Medicine (US)
University of California San Diego (US)
University of North Carolina at Chapel Hill (US)
Corresponding author: Kingsmore, Stephen F.
ORCID: Cakici, Julie A.
Clark, Michelle M.
Willig, Laurel K.
Sweeney, Nathaly M.
Farrow, Emily G.
Saunders, Carol J.
Thiffault, Isabelle
Miller, Neil A.
Batalov, Serge
Veeraraghavan, Narayanan
Dimmock, David P.
Leeder, J. Steven
Kingsmore, Stephen F.
Venue: npj Genomic Medicine
Publisher: Springer Science and Business Media LLC
Published: 2018-02-09
Volume: 3
Issue: 1
Pages: 6-6
ISSN: 2056-7944 (ISSN-L)
DOI: 10.1038/s41525-018-0045-8
PMC: PMC5807510
OpenAlex: W2949506289
Cited by: 229
References: 67
Citations by year: 2026: 16 · 2025: 26 · 2024: 26 · 2023: 26 · 2022: 37 · 2021: 21 · 2020: 34 · 2019: 30 · 2018: 12 · 2012: 1
FWCI: 14.87
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: npj Genomic Medicine (publishedVersion, cc-by)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders: National Human Genome Research Institute
Eunice Kennedy Shriver National Institute of Child Health and Human Development (U19HD077693)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Keywords: rapid whole genome sequencing, trio sequencing, genetic diagnosis, critically ill infants, neonatal intensive care, pediatric intensive care, etiological diagnosis, time to diagnosis, genetic disorders

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