Randomized trial demonstrates whole-genome sequencing leads to precision care for critically ill infants

A randomized trial in which CHOC teamed up with four other children’s hospitals across the U.S. shows that clinical whole-genome sequencing (cWGS) outperforms usual care by two-fold both in terms of diagnostic efficacy and change of clinical management of acutely ill newborns suspected of having a genetic condition.

The study, published Sept. 27, 2021 in the online journal JAMA Pediatrics, demonstrates that cWGS should be considered a first-line test for patients with suspected genetic disease.

CHOC, in conjunction with Rady Children’s Institute for Genomic Medicine (RCIGM) in San Diego and its senior medical director, Dr. David Dimmock, took part in the study with Children’s Hospital of Philadelphia; University of Nebraska Medical Center (including the Munroe-Meyer Institute) and in partnership with Children’s Hospital & Medical Center in Omaha; Washington University/St. Louis Children’s Hospital; and Le Bonheur Children’s Hospital, the University of Tennessee Health Science Center.

Scientists from Illumina Inc. in San Diego also were involved in the NICUSeq study, which enrolled a racially and ethnically diverse, and geographically distributed, population of acutely ill infants.

The patient population of 354 infants was randomized to either receive cWGS within 15 days or 60 days of admission, with a total observation period of 90 days. In both populations, access to cWGS doubled the proportion of patients receiving a precision diagnosis of their condition and a change of clinical management.

CHOC has been involved in rapid whole genome sequencing (rWGS) since 2017 and has had great success in determining a precise diagnosis for patients. Many of these case have resulted in life-changing care.

The NICUSeq study included five authors from CHOC: pediatric intensive care unit (PICU) medical director Dr. Jason Knight, medical geneticist Dr. Neda Zadeh, neonatologist Dr. John Cleary, PICU Dr. Adam Schwarz, and Ofelia Vargas-Shiraishi, a senior clinical research coordinator in critical care/neonatology research at CHOC. 

“The NICUSeq study result illustrates that this advanced molecular genetic testing technology has and will continue to have a significant role in our ability to provide accurate and timely medical care and treatment for our critically ill pediatric patients,” Dr. Zadeh said.

The NICUSeq study mirrored the real-world variability of infant care, and as such shows that whole-genome sequencing implementation is practical and superior to current diverse usual care practices, according to the study investigators.

“This study demonstrates that whole genome sequencing for infants with a suspected genetic disease is possible in diverse clinical sites and patient populations,” said Ryan Taft, PhD, vice president of scientific research at Illumina. “This brings us one important step closer to a precision diagnosis for every child that needs one.”

CHOC’s rWGS research program was championed by the late Dr. Nick Anas, CHOC’s former pediatrician-in-chief who was director of pediatric intensive care and a beloved figure at the hospital. Dr. Anas, who started at CHOC in 1984, died on April 3, 2018.

At CHOC, rWGS testing became prominent with the launch of Project Baby Bear in fall 2018. CHOC was among five hospitals to participate in that program, led by Rady, which has a lab that runs sequencing.

“We at CHOC are slowly building a case for early introduction of rWGS into the clinical management of these difficult cases in high-acuity settings to improve lifelong clinical outcomes and quality of life,” says Brent Dethlefs, executive director of the CHOC Research Institute.

“There’s growing evidence that early introduction of this technology results in overall cost savings,” Brent adds. “It’s important to get more insurance carriers to cover the cost of this testing over time, which will make rapid whole genome sequencing more available to vulnerable and underserved populations. CHOC always has been an advocate for social justice in health care, which includes greater access to genomic testing.”