NEW YORK (GenomeWeb) – Researchers at the Rady Children's Institute for Genomic Medicine have demonstrated that their rapid whole-genome sequencing diagnostic test for infants with unknown but suspected genetic disorders who are in the neonatal intensive care can save babies' lives and be cost effective.
In a study published this week in the journal NPJ Genomic Medicine, the team reported that of 42 babies who were sequenced, 43 percent received a diagnosis, resulting in net healthcare savings of $128,544. Importantly, the sequencing-based test avoided morbidity in 11 infants, major morbidity in four infants, and in one patient, the test reduced the likelihood of death by 43 percent, the authors reported.
While rapid whole-genome sequencing "merits consideration as a first-tier test in a subset of acutely ill inpatient infants, further studies are needed to delineate clinical presentations for which outcomes are consistently improved and optimal timing of rWGS orders and time-to-result," the authors wrote.
In the study, the researchers used the rWGS protocol on 42 infants. They also analyzed the genomes of both parents in 30 cases, the mother in nine cases, and an additional affected sibling in one case. For three cases, the team only analyzed the affected infant.
In all cases, the infants also received standard-of-care diagnostic workup for genetic disease. The Rady team's rWGS test diagnosed 18 infants, or 43 percent, including one who received two diagnoses, compared to just four patients, or 10 percent, who were diagnosed via standard of care. The rWGS test identified all diagnoses made by standard-of-care testing with no false positives.
Diagnosis via rWGS led to a change in management for 13 patients versus just one with standard of care, and rWGS led to a change in outcome for 11 patients, versus none for standard of care. In addition, standard-of-care testing led to 33 infants receiving 144 genetic tests.
The team at Rady, led by Stephen Kingsmore, has been steadily building its case for performing diagnostic whole-genome sequencing on infants with suspected genetic disease. In 2015, Kingsmore led a team at Children's Mercy Hospital and published a retrospective study in The Lancet Respiratory Medicine of 35 infants showing that around half were diagnosed via whole-genome sequencing and that two-thirds of those saw a change in their treatment management.
Last year, Kingsmore presented case examples at a conference, including a three-day-old infant who had been suffering from seizures since birth. Sequencing was able to diagnose the infant and pointed to a treatment that stopped the infant's seizures and enabled the baby to be discharged.
And, at last year's American Society of Human Genetics and Genomics conference, Rady's Shimul Chowdhury presented preliminary results from the 42 infants described in this study.
In the study, aside from evaluating the clinical utility of the method, the researchers also analyzed healthcare utilization and hospital costs. The researchers used Delphi, which surveys outside physicians, in order to do an in-depth analysis of costs. There were six cases diagnosed by sequencing for whom there were similar previous cases diagnosed either at Rady or for which there were historical published accounts of costs and treatments, and for these cases the researchers did a side-by-side comparison to evaluate outcomes and costs.
In total, the team found that sequencing-based diagnoses reduced healthcare costs by $803,200 and reduced hospital stay by 124 days. In one case, a diagnosis enabled parents to decide to end treatment and provide palliative care for the baby, since the condition was fatal with no known treatments. The researchers noted that if the diagnosis had been made even sooner, palliative care could have started sooner, saving an additional $1.2 million.
Cost savings were seen in cases where sequencing led to an earlier diagnosis and treatment compared to standard of care. For instance, in the case of an infant who started having seizures immediately after birth, sequencing was able to diagnose and lead to a treatment that could control the seizures when she was four days old. By contrast, for an infant with nearly identical symptoms who had been admitted to the NICU six months earlier, standard-of-care testing took an additional six weeks. He continued to have uncontrollable seizures, which caused developmental delay, and had to stay in the hospital for 59 days, costing $211,484.
The researchers estimated that the earlier diagnosis for the infant who had the sequencing test led to a savings of $181,481. That cost savings only included the avoided hospitalization, however. "Cost savings of preventing neurological devastation were not calculated," the authors wrote.
The researchers reported that since preparing this study, they have analyzed around 250 additional infants and that a full analysis of those cases may provide a more accurate cost analysis. Among those cases, they have identified several similar cases, including a baby with the same seizure disorder as in this study, as well as a second infant who received a diagnosis of nemaline myopathy, which enabled the baby to avoid a muscle biopsy.
They also noted that their cost analysis was conservative and did not take other important factors into account. For instance, "infant genetic diseases exert profound emotional, financial, social, and physical stress within families," the authors wrote, including "parental divorce, depression and anxiety, and sibling behavioral, developmental, and persistent health complications. The costs of these complications were omitted."
The Rady team is now also in the process of expanding the rapid sequencing protocol and plans to implement the test at six pediatric hospitals that are part of the Sanford Children's Genomic Medicine Consortium.