An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm

David P Dimmock; Michelle M Clark; Mary Gaughran; Julie A Cakici; Sara A Caylor; Christina Clarke; Michele Feddock; Shimul Chowdhury; Lisa Salz; Cynthia Cheung; Lynne M Bird; Charlotte Hobbs; Kristen Wigby; Lauge Farnaes; Cinnamon S Bloss; Stephen F Kingsmore; RCIGM Investigators

doi:10.1016/j.ajhg.2020.10.003

An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm

Am J Hum Genet. 2020 Nov 5;107(5):942-952. doi: 10.1016/j.ajhg.2020.10.003.

Authors

David P Dimmock¹, Michelle M Clark², Mary Gaughran², Julie A Cakici³, Sara A Caylor², Christina Clarke², Michele Feddock², Shimul Chowdhury², Lisa Salz², Cynthia Cheung⁴, Lynne M Bird⁵, Charlotte Hobbs², Kristen Wigby⁶, Lauge Farnaes², Cinnamon S Bloss⁴, Stephen F Kingsmore²; RCIGM Investigators

Collaborators

RCIGM Investigators:
Matthew N Bainbridge, Jaime Barea, Sergey Batalov, Zaira Bezares, Lynne M Bird, Cinnamon S Bloss, Joshua J A Braun, Julie A Cakici, Miguel Del Campo, Jeanne Carroll, Cynthia Cheung, Casey Cohenmeyer, Nicole G Coufal, Carlos Diaz, Yan Ding, Katarzyna Ellsworth, Marva Evans, Annette Feigenbaum, Jennifer Friedman, Joe Gleeson, Christian Hansen, Jose Honold, Kiely James, Marilyn C Jones, Amy Kimball, Gail Knight, Lucitia Van Der Kraan, Brian Lane, Jennie Le, Sandra Leibel, Jerica Lenberg, Dana Mashburn, Laurel Moyer, Patrick Mulrooney, Shareef Nahas, Daeheon Oh, Daniken Orendain, Albert Oriol, Maria Ortiz-Arechiga, Lance Prince, Seema Rego, Iris Reyes, Erica Sanford, Charles Sauer, Leila Schwanemann, Mark Speziale, Denise Suttner, Nathaly Sweeney, Richard Song, Mari Tokita, Narayanan Veeraraghavan, Kelly Watkins, Terence Wong, Meredith S Wright, Catherine Yamada

Affiliations

¹ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: ddimmock@rchsd.org.
² Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
³ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA; Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA 92093, USA.
⁴ Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA 92093, USA; Department of Psychiatry, University of California San Diego, San Diego, CA 92093, USA.
⁵ Rady Children's Hospital, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA.
⁶ Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA; Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA.

Abstract

The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of clinician surveys of the clinical utility of rapid genomic sequencing (RGS). The primary end-point-clinician perception that RGS was useful- was met for 154 (77%) of 201 infants. Both positive and negative tests were rated as having clinical utility (42 of 45 [93%] and 112 of 156 [72%], respectively). Physicians reported that RGS changed clinical management in 57 (28%) infants, particularly in those receiving urWGS (p = 0.0001) and positive tests (p < 0.00001). Outcomes of 32 (15%) infants were perceived to be changed by RGS. Positive tests changed outcomes more frequently than negative tests (p < 0.00001). In logistic regression models, the likelihood that RGS was perceived as useful increased 6.7-fold when associated with changes in management (95% CI 1.8-43.3). Changes in management were 10.1-fold more likely when results were positive (95% CI 4.7-22.4) and turnaround time was shorter (odds ratio 0.92, 95% CI 0.85-0.99). RGS seldom led to clinician-perceived confusion or distress among families (6 of 207 [3%]). In summary, clinicians perceived high clinical utility and low likelihood of harm with first-tier RGS of infants in ICUs with diseases of unknown etiology. RGS was perceived as beneficial irrespective of whether results were positive or negative.

Keywords: NSIGHT2; clinical utility; diagnostic testing outcomes; healthcare cost-benefit analysis; neonatal intensive care unit; pediatric intensive care unit; rapid whole-exome sequencing; rapid whole-genome sequencing; ultra-rapid whole-genome sequencing.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural

MeSH terms

Chromosome Mapping
Clinical Decision-Making / methods*
Critical Illness
Disease Management*
Female
Genetic Diseases, Inborn / diagnosis*
Genetic Diseases, Inborn / genetics
Genetic Testing*
Genome, Human*
Humans
Infant
Infant, Newborn
Intensive Care Units, Neonatal
Logistic Models
Male
Prospective Studies
Time Factors
Whole Genome Sequencing / methods*

Abstract

Publication types

MeSH terms

Grants and funding