NEW YORK (GenomeWeb) – Physician scientists at Boston Children's Hospital are gathering data to demonstrate the utility of rapid exome sequencing for babies in the neonatal intensive care unit suffering from conditions where the diagnoses or treatments are unclear.
Although Boston Children's has been using exome sequencing for some time, a year-and-a-half ago the hospital employed GeneDx's XomeDxXpress testing service within a study involving NICU babies. Specifically, babies with complex metabolic disorders, with low muscle strength (hypotonia), unexplained seizures, and multiple abnormalities that don't fit with known characteristics of a condition, are offered rapid exome sequencing, according to Cynthia Gubbels, a research fellow involved in the study.
"In the cohort that we have, we find we're diagnosing babies a lot earlier than the average patient that you read about in the literature," said Gubbels, who is often the first person doctors call when there's a baby in the NICU who might be helped by testing. "This is a special group of patients where it matters how fast you have the diagnosis."
GeneDx launched its XomeDxXpress test a few years ago. The service provides verbal communication of pathogenic and likely pathogenic results in known disease-causing genes in seven working days and a report with all clinically relevant, confirmed results in two weeks. Comparatively, turnaround time for GeneDx's standard exome sequencing reports is eight weeks or less.
At the American College of Medical Genetics and Genomics annual meeting this year, GeneDx presented data from the first 500 cases tested on XomeDxXpress, which showed the lab was able to deliver verbal results in five days on average, 41 percent of patients received a definite molecular diagnosis, and out of 70 physicians who completed surveys, 57 percent said they made medical management decisions based on tests results.
Benjamin Solomon, GeneDx's managing director, estimated that the company has sequenced the exomes of 100,000 individuals in total and employed the rapid service in 700 cases, which can involve testing not just patients but also family members. Based on the data from these 700 cases, around 45 percent of tested individuals received a definitive molecular diagnosis.
Despite this and other data showing the clinical utility of exome sequencing, particularly in specific scenarios in the NICU, many insurers don't have coverage policies for exome sequencing, and the few that do enforce stringent criteria. Payor reluctance in this regard has to do with cost. Although GeneDx didn't reveal the list price for XomeDxXpress, standard exome sequencing for trios is between $4,000 and $6,000.
Rapid exome sequencing can be twice the cost of standard exomes and can amount to around $10,000 for trio testing. The higher price tag is largely due to the fact that samples are prioritized for testing as soon as they're received and aren't batched.
This has made clinical adoption of exome sequencing frustratingly slow, according to Tim Yu, neurologist and geneticist at Boston Children's, who is co-principal investigator of the NICU study with Pankaj Agrawal, director of the neonatal genomics program at the hospital.
Before launching the study, Yu and his colleagues met with insurers to gauge their attitudes toward exome sequencing. "One of the things they kept saying was, 'Show us the data,'" he recalled. "The insurance policies around this is something we were quite conscious of as we elected to start this project."
Within Boston Children's NICU so far, 20 babies have had their exomes sequenced. While researchers are still analyzing the data, Gubbels estimated that for approximately 17 babies, rapid exome analysis has led to a likely diagnosis. She and her colleagues are gathering data they hope will sway payors to change their coverage policies and drive greater adoption of rapid exome sequencing in settings where it has shown to benefit sick children and their families.
"In every case, we're learning that rapid exome sequencing is helping the families in unique ways," said Agrawal. But this also makes it challenging to demonstrate the value of this testing to insurers, because for the families of these critically ill NICU babies there is a psychological component that is not easily quantified in financial terms or measured in improved patient outcomes.
"Sometimes [exome sequencing] can point to an exotic new therapy, but sometimes it doesn't," Yu said. "Sometimes you can help a family that is exhaustively leaving no stone unturned and looking for a magic bullet, and you can clarify for them that there unfortunately isn't something that can be easily addressed and that other measures are appropriate."
At Boston Children's, sometimes rapid sequencing results have pointed to the need for other specialists to get involved with a baby's care. In the case of severely hypotonic babies who need breathing support, exome sequencing has helped them get to rehabilitation sooner. In one case, this analysis uncovered a previously unseen candidate gene for a condition, while for other babies, exome sequencing helped identify the most appropriate therapy.
Agrawal recounted the case of a baby suffering from multiple, unexplained seizures every day and a brain development condition called polymicrogyria. Initial seizure and brain malformation gene panel testing had identified three different genetic mutations in this baby. "But which gene mutation was responsible for the seizures was unclear," he said. Exome sequencing on the baby and parents helped doctors zero in on a sodium-channel gene, SCN2A, associated with seizure disorders.
This baby was already on several drugs to try to control the seizures, but based on rapid exome sequencing results, doctors decided to prescribe the sodium-channel blocker fosphenytoin, known to work best against SCN2A-related seizures. "That really changed the course of the child's seizures," Agrawal said.
In another case, after exome sequencing identified a gene of interest, researchers performed additional functional analysis to characterize the role of the genetic abnormality in the baby's condition. "That family was really waiting to get an answer, so they can use this information for pre-implantation genetic diagnosis," Agrawal said.
He noted that there is a protocol in place within this program that allows researchers to explore newly identified genetic variants via functional analysis and other methods. In the case of this child, Agrawal's group was able to confirm the disease causality in three months, a much shorter time frame he said than how long it would have taken without the aid of rapid exome sequencing.
Gubbels estimated that for about half the NICU babies who have received exome sequencing to date, the tests results have impacted their management, while for the other half this information has helped the families make decisions about palliative care. "Management change doesn't always mean that there is something we can do to fix the underlying problem of the baby," she said. "In some cases, this means more supportive therapy, or the ability to anticipate what might happen in the future."
She described one case where the baby had a severe form of myotubular myopathy, characterized by muscle weakness and life-threatening breathing difficulties. Soon after researchers arrived at a diagnosis following exome sequencing, the parents decided to opt for palliative care due to the grim prognosis of the disease.
"Sometimes cases [like this] can go on for months before a diagnosis is reached, and all this time the baby is on a respirator in the ICU," Gubbels said. "That's definitely one of the cases that the outcome was the same, but the path to it is very different for the families and for the physicians."
These examples highlight the different ways in which rapid exome sequencing is informing patient management for these difficult cases, but also helping families navigate diagnostic odysseys and make informed decisions about palliative care, noted Yu. In an effort to articulate this value to payors, Gubbels is formally analyzing the clinical utility of this approach in the NICU by comparing the exome-sequenced cohort against a control group. She plans to publish the findings after a few more NICU babies are tested.
GeneDx's Solomon noted that although the reimbursement climate has remained challenging for the entire genetic testing space, particularly as commercial payors institute broad prior-authorization policies, some insurers are starting to advance policies around exome sequencing based on data from programs like the one at Boston Children's.
For example, a cooperative group formed by Seattle Children's Hospital, called Patient-centered Laboratory Utilization Guidance Services (PLUGS), drafted a coverage policy for children who could benefit most from whole-exome sequencing and took it to EviCore Healthcare, a lab benefit manager that contracts with insurers to guide coverage decisions. EviCore previously didn't have a policy related to whole-exome sequencing, which meant insurers were likely denying a lot of these test claims. But based on the coverage criteria drafted by PLUGS, EviCore crafted a policy that defined which types of children qualified for covered testing.
Clinical utility data is also beginning to show the value of exome sequencing. For example, a follow-up study on a cohort of 80 infants who had undergone whole-exome sequencing to try to diagnose what appeared to be Mendelian disorders demonstrated that changes in clinical management based on test results resulted in savings of $1,186 per quality-adjusted life year gained. Although, after infants were diagnosed, siblings and parents got further testing, which added costs.
Perhaps based on these types of emerging data, physicians and hospital administrators are starting to warm to exome sequencing. According to Solomon, physicians are turning to exome sequencing in a variety of settings and ordering it much earlier in the care continuum than they did previously. GeneDx's testing volumes in the rapid exome sequencing segment are also steadily increasing, Solomon noted.
Agrawal recalled that at the start of the NICU rapid exome sequencing program at Boston Children's, neonatologists and physicians were skeptical because these tests are expensive, and they weren't sure of the value it would add. Based on the experience in the NICU to date, however, "people are changing their perception and are a lot more open to reaching out to us if they have a child with these types of conditions to get a quick answer," he noted.
Hospital administrators also seem more willing to use rapid exome sequencing for NICU babies at Boston Children's. "We have a committee that decides when to do whole-exome sequencing," said Gubbels. "They went from being very skeptical and only approving exome sequencing when the genetics division put in a lot of effort to make the case for it, to recently approving rapid exome sequencing for a few babies who didn't fit our criteria but would also benefit from it."
However, in order to get payors on board, researchers realize the importance of demonstrating clinical utility on a tightly defined subset of patients. "We're not saying we should do rapid exome sequencing on every single baby in the NICU. That's not our goal," Agrawal said. "It's important for us to publish this data to show that if we use certain criteria to choose [to test] patients with certain phenotypes, we can really make a difference."