NEW YORK (GenomeWeb) – Members of a large research consortium are reaching genetic diagnoses for a significant proportion of individuals with rare, undiagnosed diseases who were previously denied insurance coverage or reimbursement for such tests.
At the annual meeting of the American College of Medical Genetics and Genomics, held in Phoenix last month, Stanford University researcher Matthew Wheeler presented preliminary findings from a retrospective analysis of research exomes generated for the Undiagnosed Diseases Network (UDN). The group included dozens of individuals who had been recommended for clinical exome sequencing, but had been unable to get the tests. So far, the UDN team has uncovered pathogenic or likely pathogenic mutations in almost 28 percent of those individuals.
"We noticed from relatively early on in opening our center for undiagnosed diseases — as part of the Undiagnosed Diseases Network — that we had gotten a fair number of referrals from our medical genetics colleagues who had attempted to get whole-exome sequencing covered by insurance," Wheeler said in an interview. "At Stanford and across the UDN … a substantial number of patients were not getting exome sequencing when their clinicians thought that was appropriate."
The diagnostic yield associated with WES is known to fluctuate depending on the cohort considered, the availability of parent samples for trio testing, and the type of condition involved, Wheeler noted during his ACMG conference presentation. Even so, investigators and clinicians are increasingly considering WES as a first-line test for individuals with rare and/or syndromic conditions suspected of having a genetic basis.
Through a series of discussions spearheaded by one of the UDN working groups, members of the team decided it would be valuable to consider not only the diagnostic yield of exome sequencing, but also its utility in a health economics and test utilization context, he explained.
And from a practical perspective, the project presented a research-based avenue for clinicians to obtain exome sequencing for patients who had struggled with reimbursement, while getting a look at the clinical features and diagnostic outcomes in such individuals.
"Usually if a procedure or intervention or diagnostic test is denied by insurance, and people don't have a mechanism to afford it, you have no idea what the outcome would be," Wheeler said. "This is a case where you can actually assess the clinical outcome after having a test being denied and a patient not having a way to pay for it."
With sequencing and analysis being done at no cost to the patient in the UDN research setting, National Human Genome Research Institute genomic medicine researcher and UDN member John Mulvihill said in an interview, "this is a natural experiment that [Wheeler and colleagues] took advantage of to address the question."
Though the UDN was not specifically designed to ask that question, he added, Wheeler and others "recognized that the question could be asked on this infrastructure," which was designed for diagnosing rare, undiagnosed genetic conditions and establishing a community and scientific resources for patients with these conditions.
The UDN encompasses seven clinical sites across the US. It also includes a coordinating center at Harvard Medical School, a Battelle Pacific Northwest Laboratories-based metabolomics core, biorepository and model organism screening sites, and two core DNA sequencing sites — one at the Baylor College of Medicine and another at the HudsonAlpha Institute for Biotechnology.
"As the service at Stanford was growing, one of the things we decided to track was whether or not individuals coming into the [UDN] program had previous genetic testing attempts and whether or not those had been covered by insurance," co-author Chloe Reuter, a genetic counselor at the Stanford Center for Undiagnosed Diseases, said in an interview.
For their current analysis, Wheeler, Reuter, and colleagues focused on 123 exome-sequenced individuals enrolled at half a dozen UDN clinical sites. That group included 27 children and 16 adults for whom WES had previously been proposed but deemed non-reimbursable. Exome sequencing testing and/or reimbursement had not been requested in the remaining 80 cases.
Nearly three-quarters of the 43 non-reimbursable cases had experienced direct insurance denial for exome sequencing. Others had insurance providers known for denying WES test coverage or had been denied coverage for other genetic tests, dampening their doctors' optimism about securing coverage for a clinical exome.
"Many of the cases had had targeted genetic testing," Wheeler said, but he noted that a few "had had essentially all genetic testing [requests] denied."
More than half of cases previously refused exome test coverage relied on public insurance, while around one-quarter of the individuals had private insurance. The researchers also identified smaller groups of individuals who were uninsured or had unknown insurance coverage.
Somewhat surprisingly, the diagnostic yield for exome sequences from individuals who'd already dealt with anticipated or documented insurance denial far surpassed the diagnostic rate in the group for whom clinical exome sequencing was not pursued in the past.
The UDN team managed to make diagnoses in nearly 28 percent of the coverage-denied cases, but just 7.5 percent of the remaining cases. Another 7.5 percent of individuals in the latter group have potential diagnoses pending verification, though, and the diagnostic yields in each group may even out somewhat as the researchers weed through variants of unknown significance, Wheeler noted.
Beyond that, investigators suspect that including individuals already considered for exome sequences may bias the analysis to cases with genuine genetic problems. Generally speaking, the UDN preferentially accepts patients with apparent congenital or genetic conditions, for example. But cases where doctors pushed most fervently for exome sequencing may be even more enriched for patients with positive exome tests, Mulvihill said.
"A lot of the patients who are being accepted into the network had an increased a priori chance to be finding a unifying diagnosis, because we do go through a very extensive review process of past medical history and past workups, both genetic and other types of diagnostics," Reuter added. "We can be somewhat biased in who we think are the patients most likely to benefit from the workup that would be done as part of participation in the [UDN]."
The higher diagnostic rate in the non-reimbursed individuals might also be chalked up in part to the number of pediatric and cases involving neurological features in that group, she noted, which are more prone to diagnosis by exome sequences than some other rare undiagnosed conditions.
The UDN investigators cautioned that it's not yet clear how common it actually is for payors to refuse clinical WES test coverage, even through the public insurance system.
"In most states, Medicaid plans do not cover exome sequencing. Oklahoma is an exception, but we're not aware of other states where Medicaid covers exome sequencing," Wheeler said. "In terms of other insurance plans, again, it's quite variable — some of that is payor dependent and some is plan dependent."
Reuter said the team is interested in starting to tackle the question of reimbursement rates for clinical exome sequencing, if they can get their hands on relevant national data and data from other investigators working with similar patient groups.
"We're interested in collaborating with other departments at Stanford and also trying to tap into some of the national databases for insurance coverage and denial to get a sense of what the rates are overall," she said. "We've opened the call to other providers at other institutions who have had similar experiences to get a sense of whether they have run into this problem as well, in terms of insurance reimbursement."
In the meantime, by beginning to generate data that addresses clinical utility of testing in individuals already refused reimbursement, the team hopes to convince more payers to open their pocketbooks to cover clinical exomes in appropriate cases.
"We're hoping to add to the evidence that whole-exome sequencing is actually a pretty effective test when done in appropriate patients," Wheeler said. "We're also trying to find data sources that support this concept."
Such analysis may even help to refine the clinical features associated with positive results on a clinical exome test, according to Mulvihill. "If we can define the subset of patients that really must have it, that's a place where we can continue the discussion to justify coverage."