Evidence Needed for Cost-Effectiveness of Sequencing

The price of whole genome sequencing (WGS) and whole exome sequencing (WES) is approaching the point where the cost-effectiveness for the technology may trump conventional testing strategies for the evaluation of children with neurodevelopmental disorders (NDDs), according to a study published in Science Translational Medicine Dec. 3, 2014. While this is not the first study to show that WGS and WES can improve the diagnostic yield over traditional molecular methods, this is one of the first studies to pinpoint a price linked to the cost-effectiveness of sequencing. The cost-effectiveness estimates and the time savings to diagnosis associated with WGS/WES lead the authors to conclude initial diagnostic evaluation of children with NDDs should include trio WGS or WES testing. "WGS and WES provided prompt diagnoses in a substantial minority of children with NDD who were undiagnosed despite extensive diagnostic evaluations," the authors summarize. "Preliminary analyses suggested that WES was less costly than continued conventional diagnostic testing of children with NDD in whom initial testing failed to yield a diagnosis."
So called diagnostic odysseys for an underlying cause of NDD are notoriously lengthy and costly, and frequently fail to yield a definitive diagnosis in more than half of patients. Primary tests currently used for etiologic evaluation of NDD include neuroimaging, karyotype, array comparative genome hybridization and/or single-nucleotide polymorphism arrays, and phenotype-driven metabolic, molecular, and serial gene sequencing studies. Follow-up invasive tests, including biopsies and cerebrospinal fluid assessment, can lead to a small number of additional diagnoses.
The Economics of WGS/WES For NDD The current study, undertaken at Children's Mercy (Kansas City, Missouri), involved 100 families with 119 children affected by NDDs (intellectual disability, global developmental delay, and autism) who received diagnostic WGS and/or WES of parent-child trios over a 33-month period. Rapid WGS was reserved for families with symptomatic infants and children in intensive care units (50-hour protocol turnaround with the research-use-only STAT-Seq test, versus 16 days for WES in ambulatory patients). The researchers found a definitive molecular diagnosis of an established genetic disorder in 53 of 119 affected children (44.5 percent) overall. However, rapid WGS yielded diagnoses in 73 percent of families with acutely ill children (11 of 15), while testing of children in ambulatory care yielded diagnosis of 40 percent of the 85 children for whom traditional methods failed to yield a diagnosis (33 by WES and one by staged WES followed by WGS). The researchers noted that while they intended to test parent-child trios, they found that in practice, an average of 2.55 individuals per family were tested.
The researchers found that the cost of prior negative tests in the ambulatory patients was $19,100 per family (range of $3,248 to $55,321). The nonacute, ambulatory clinic patients were older and had received a much longer period of subspecialty care and considerable prior diagnostic testing (an average of 13.3 prior tests/panels), compared to acute patients which had on average, seven prior diagnostic tests with a mean total cost of $9,550. The researchers calculated that at a cost of up to $7,640 per family, sequencing would be cost-effective, assuming a rate of diagnosis of 40 percent and an average charge for prior testing of $19,100 per family. If the average uptake of testing was assumed to be 2.55 per family (instead of the intended 3.0), sequencing would be cost-effective up to $2,996 per individual tested. "Although $2,996 is at the lower end of the cost of clinical WES today, next-generation sequencing continues to decline in cost," write the authors led by Sarah Soden, M.D., from Children’s Mercy. "Furthermore, the cost-effectiveness estimates reported herein excluded potential changes in health care cost associated with earlier diagnosis."
Additionally, the authors note there is a benefit to increased speed to diagnosis. A diagnosis could have been made 77 months earlier if WGS or WES had been performed at initial symptom onset. Among the 11 families receiving 50-hour WGS, the fastest times to final report of a confirmed diagnosis were 6 days to 10 days, although cases of recently described or previously undescribed genetic diseases and in patients whose phenotypes were atypical for the causal gene, time to diagnosis took longer.
More Evidence Needed Experts say that up to now the focus has been on the challenges and opportunities of implementing NGS in clinical practice. Given mounting evidence of the feasibility of using the technology, the focus is shifting towards the economics of sequencing—including the cost-effectiveness of clinical sequencing.
David L. Veenstra, a member of the Institute of Medicine's Roundtable on Translating Genomic-Based Research for Health, argues in a Feb. 12 discussion paper on the cost-effectiveness of clinical sequencing, that future research on cost-effectiveness must look beyond just cost savings and must incorporate the value derived from "improving patients’ lives as efficiently as or more so than current clinical practice."
The Canadian Agency for Drugs and Technologies in Health (CADTH) recently released a rapid response report reviewing existing evidence of the cost effectiveness of next-generation sequencing (NGS). The agency could find one published systematic review analyzing the cost-effectiveness of NGS in the literature and one health technology assessment and one systematic review in the grey literature.
While the report cited evidence that the costs associated with Sanger sequencing were reported to be approximately $500/Mb versus $0.50/Mb using NGS, the agency concluded that given "the distinct lack of robust published data" there is not "sufficient information to make an informed analysis" regarding the cost-effectiveness of NGS.
"The question of the cost-effectiveness of NGS remains unclear," the CADTH writes. "All studies identified in this report have concluded that there is a lack of powerful economic investigations published to date. This is a result of the complexity of analyzing the costs associated with all processes subsequent to the sequencing run itself. In addition health-care costs related to the high proportion of ambiguous variants detected using NGS techniques remain unknown."
To fill the evidence void, Veenstra recommends both large observational studies of the direct and indirect costs of clinical sequencing implementation in the near and intermediate term and modeling studies of the long-term clinical and economic impacts of clinical sequencing for both intended and incidental findings.
Takeaway: As comprehensive NGS-based tests, including WGS and WES, make their way into clinical practice, there are increasing calls for demonstration of the cost-effectiveness of the approach. Emerging evidence indicates that in the case of NDD, which is typically associated with long diagnostic odysseys, the price of WGS/WES is reaching the point where it may be cost-effective for the initial evaluation of cases.