1. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants
- Author
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David Dimmock, Dorjee Tamang, Sarah White, Peter Schols, Michelle M. Clark, Zaira Bezares, Richard S. Song, Sandra Leibel, Denise Suttner, Jennie Le, Charlotte A. Hobbs, Casey Cohenmeyer, Katarzyna A. Ellsworth, Brian Lane, Amber Hildreth, Lauge Farnaes, Kelly Watkins, Kiely N. James, Terence C. Wong, Cinnamon S. Bloss, Nicole G. Coufal, Laura Puckett, Mari Tokita, Lance Prince, Amy S. Kimball, Narayanan Veeraraghavan, Shareef Nahas, Cyrielle Kint, Yan Ding, Paulina Ordonez, Jaime Barea, Erica Sanford, Kristen Wigby, Daniken Orendain, Maria Ortiz-Arechiga, Meredith S. Wright, Dana Mashburn, Sara A. Caylor, Nathaly M. Sweeney, Joshua J.A. Braun, Christina Clarke, Audra Wise, Lisa Salz, Charles Sauer, Jenni Friedman, George Chiang, Jerica Lenberg, Mark Speziale, Laurel Moyer, Michele Feddock, Jeanne Carroll, Patrick Mulrooney, Raymond Hovey, Stephen F. Kingsmore, Marva Evans, Sergey Batalov, Albert Oriol, Joe Gleeson, Jose Honold, Carlos Diaz, Mary Gaughran, Julie A. Cakici, Crystal Le, Catherine Yamada, Shimul Chowdhury, Gail Knight, Matthew N. Bainbridge, Lucitia Van Der Kraan, Daeheon Oh, and Iris Reyes
- Subjects
0301 basic medicine ,ultra-rapid whole-genome sequencing ,Pediatrics ,medicine.medical_specialty ,diagnosis ,precision medicine ,RCIGM Investigators ,Clinical Trials and Supportive Activities ,030105 genetics & heredity ,Genome ,intensive care unit ,Medical and Health Sciences ,Article ,law.invention ,03 medical and health sciences ,Randomized controlled trial ,law ,genetic disease ,Clinical Research ,Exome Sequencing ,medicine ,Genetics ,Humans ,Genetic Testing ,whole-exome sequencing ,Genetics (clinical) ,Exome sequencing ,Whole genome sequencing ,Pediatric ,Genetics & Heredity ,Whole Genome Sequencing ,business.industry ,Singleton ,Human Genome ,Infant, Newborn ,Infant ,Biological Sciences ,Precision medicine ,Newborn ,Intensive care unit ,030104 developmental biology ,genomic medicine ,Good Health and Well Being ,whole-genome sequencing ,Etiology ,business - Abstract
The second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology. Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96h of admission. 24 infants (11%) were very ill and received ultra-rapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p < 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p = 0.004) and time to result was less (median 4.6days, p < 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly.
- Published
- 2019