Neil Osterweil

October 20, 2017

ORLANDO — For patients in the neonatal intensive care unit (NICU), suspected genetic disorders can be diagnosed using whole-genome sequencing in a fraction of the time it takes to arrive at a diagnosis with standard testing methods, and at a lower cost, new research shows.

In fact, savings related to care that was eliminated because of sequencing were substantially greater than the cost of the sequencing itself, said Shimul Chowdhury, PhD, from the Rady Children's Institute for Genomic Medicine in San Diego.

Sequencing also prevented potential harm for at least one patient, he reported here at the American Society of Human Genetics 2017 Annual Meeting.

The NICU setting is ideal for demonstrating both the clinical utility and cost-effectiveness of on-site, rapid whole-genome sequencing, Dr Chowdhury told Medscape Medical News.

We project that there are around 50,000 kids in the United States who need this testing but aren't getting it right now.

"The intensive care unit population is, I think, a great sweet spot, because you have these scenarios where genetic diagnoses can really affect management, and it's a very undersequenced population," he said. "We project that there are around 50,000 kids in the United States who need this testing but aren't getting it right now."

For their study, Dr Chowdhury and his colleagues sequenced infants who presented with signs and symptoms indicating a single-gene disorder or who had a clinical course that did not follow a typical pattern. None of the patients had a known genetic diagnosis at baseline.

Of the first 42 infants who underwent whole-genome sequencing, a genetic disorder was diagnosed in 18 (43%), management was changed in 13 (31%), and outcomes changed in 11 (26%).

Twelve of the infants had multiple congenital abnormalities. Others had neurologic, hepatic, cardiac, hematologic, gastrointestinal, endocrine, musculoskeletal, or pulmonary abnormalities or symptoms.

One infant experiencing infantile spasms was found to have epilepsy related to the GABRA1 gene, which is involved in the development of the neurotransmitter gamma-aminobutyric acid, so a change in antiepileptic agents was implemented.

And an infant with preterm pulmonary atresia, poor weight gain, feeding intolerance, and recurrent pneumonia was found to have a mutation in the ACTG2 gene, which encodes for gamma-2 actin, a protein involved in intestinal smooth-muscle contraction. After the child was started on cisapride, a gastric motility agent, gut motility improved and the child was spared from undergoing a gut transplant.

Cost Modeling

To estimate cost savings, Dr Chowdhury's team looked at data on six of the infants whose management and outcomes changed after the diagnosis of a genetic disorder.

They compared the actual use of health resources by five of the infants with use by historic controls and/or values from the medical literature for diagnoses made after a "standard diagnostic odyssey." For the sixth infant, who received a sequencing diagnosis during a second hospital admission for recurring symptoms, the researchers estimated the money that would have been saved had no second admission been required.

When whole-genome sequencing was used instead of standard testing, the reduction in hospital stays ranged from 2 to 42 days (6% to 69%).

In the most extreme example, a child with cholestasis and congenital heart disease was diagnosed with Alagille syndrome 3 days after sequencing. The syndrome is caused by a JAG1 mutation that impairs Notch signaling, resulting in bile duct abnormalities and cardiopulmonary dysfunction. The child had been scheduled for a cholangiogram and Kasai portoenterostomy to reconstruct the extrahepatic bile ducts.

With a diagnosis of Alagille syndrome, the Kasai procedure is not indicated, so we were able to stop this intervention from occurring.

"With a diagnosis of Alagille syndrome, the Kasai procedure is not indicated, so we were able to stop this intervention from occurring," Dr Chowdhury said. He noted that reports in the literature suggest that the risk for morbidity and mortality related to the Kasai procedure is markedly higher for children with Alagille syndrome than for those without, and that rates of liver transplantation are higher.

In this case alone, an estimated $860,903 was saved.

In another case, a 1-week-old child experiencing seizures was diagnosed with abnormalities in the KCNQ2 gene, which encodes for potassium channels. Mutations in KCNQ2 are known to cause Ohtahara syndrome, an intractable form of childhood epilepsy. The NICU team added carbamazepine — not a standard first-line therapy — to the child's treatment regimen and reduced doses of other antiepileptics. The child was discharged in 18 days.

One year earlier, the same NICU team had cared for a child with suspected Ohtahara syndrome but did not have the benefit of whole-genome sequencing. It took 6 weeks for molecular testing to confirm Ohtahara syndrome, during which the child — who spent 59 days in the hospital — experienced persistent seizures.

The child treated first "is seriously developmentally compromised," whereas the child who underwent sequencing, "at this point, is developmentally normal," said Dr Chowdhury.

Rapid whole-genome sequencing was estimated to reduce length of stay by 31%, and the inpatient cost by $1.8 million.

In these six infants, "rapid whole-genome sequencing was estimated to reduce length of stay by 31%, and the inpatient cost by $1.8 million," he reported. That more than offsets the $700,000 it cost to sequence all 42 children.

The researchers are planning to expand their study so that they can evaluate the approach in a variety of populations and health systems, and have recently launched partnerships with children's hospitals in California and Minnesota.

Convincing the Insurance Companies

"We, as geneticists, are confident that sequencing is absolutely fabulous, and even the physicians who are sending their patients to us are convinced that it's a great thing and a cost-saving intervention," said Christian Gilissen, PhD, associate professor of genome bioinformatics at Radboud University in Nijmegen, the Netherlands.

However, "we have a lot of difficulty explaining this to health insurance companies for reimbursement," he told Medscape Medical News. This study could change that.

The researchers "tried to be really rigorous in how they calculated their costs, taking cases and showing two trajectories, and really showing that it's actually cheaper," he explained.

"I think this is one of the best-use cases for the genome right now in newborns who are critically ill," said Gail Jarvik, MD, head of the division of medical genetics at the University of Washington in Seattle.

"The faster you can come to a diagnosis, the better you can effectively treat," she told Medscape Medical News. And "you can reduce a lot of testing costs."

"Unfortunately, some of these children have disorders that are not treatable. But in that case, you can make the decision to stop treating them," she added.

This study was funded with grants from the Rady Family Foundation and other philanthropies, and the National Institutes of Health. Dr Chowdhury, Dr Gilissen, and Dr Jarvik have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2017 Annual Meeting: Abstract 215. Presented October 19, 2017.

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