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Investigators Weigh Nitty Gritty of Sequencing Costs, Question $1,000 Genome

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NEW YORK (GenomeWeb) – What exactly does a $1,000 genome mean? 

Investigators from the Netherlands recently took a stab at this question, providing what they argue is much-needed transparency about the true costs of next-gen sequencing, and offering a roadmap for other groups to calculate how the variables particular to their own lab affect these cost calculations.

The group published its analysis in the journal Clinical Chemistry last week, concluding that despite recent moves by commercial companies that have crossed the $1,000 genome threshold in terms of consumer prices, a detailed cost analysis suggests that it looks unlikely that most labs can achieve clinical whole genomes at such a low cost based on factors like platform and consumables costs, technological and practical limitations, and operational or personnel costs.

More precisely, the paper pulls out per-sample cost numbers for three sequencing strategies — whole-genome, whole-exome, and targeted gene panels — based on list prices for technology and consumables from the market leader, Illumina, as well as current clinical practice procedures at Radboud University Medical Center. The study also included a spreadsheet to allow other diagnostic laboratories to adjust for variables to their specific institution.

Overall, the team calculated a per-sample cost of €1,669 ($1,874) for whole-genome sequencing, €792 ($889) for whole-exome sequencing, and €333 ($374) for a targeted panel based on static list prices and clinical practices from their own center.

In an email to GenomeWeb, Kirsen van Nimwegen, first author of the study and a Radboud researcher, said that she and her coauthors hoped that their analysis could provide insight and transparency into the real, total costs of genome sequencing, in a way that may aid future health economic evaluations and comparisons.

Because of the swift evolution of new medical technologies like next-gen sequencing, and their impact on increases in healthcare costs, it's important to make sure that scarce spending power is directed toward interventions that provide the most bang for one's buck, she wrote. To figure that out will require more health economic studies and to do those, the field will need good ways to assess the true costs of these procedures.

Van Nimwegen said that she and her coauthors hope their analysis will create "awareness that, although commercial parties claim that a genome can be sequenced for $1,000, there are more costs to consider than only the consumable costs, for example personnel and data storage costs."

Although she and her colleagues used the clinical practice of their own lab to inform parts of their calculation — for example, personnel costs — other aspects, such as the list prices of equipment and consumables suppliers, are directly transferrable from one lab to another, van Nimwegen wrote in her email.

Moreover, those aspects that are not static from one lab to the next "can be adapted [in an Excel sheet that accompanies the paper] so laboratories can quickly calculate their own total costs for the entire sequencing process, from DNA extraction until data report and storage," she explained.

To come up with its own end numbers, the Radboud team calculated per-sample capital, maintenance, and operational costs using a set of assumptions, including things like specific coverage requirements for each of the three categories of sequencing test, estimates of capacity and throughput, blood sampling, personnel costs, interpretation, and data storage, based on Radboud's own operations and on public list prices for sequencing instruments, consumables, and things like cloud computing.

This doesn't mean that the exact costs of whole-genome, exome, or targeted sequencing can't and don't vary significantly from lab to lab.

For example, Mark Cowley from the Garvan Institute in Australia told GenomeWeb at the Biology of Genomes meeting earlier this year that because of increased buying power as one of the first three Illumina HiSeq X Ten sites, a clinical genome only costs his lab 1.1 times as much as an exome.

"Of course, laboratories that buy large amounts of equipment, for instance three HiSeq X Ten sites, will receive large discounts from Illumina," van Nimwegen wrote in her email.

"We choose not to include discounts in our calculation, as these are very laboratory-specific. The larger the sequencing center, the better discount they probably receive. Also, the larger the throughput, the lower the per-sample costs. So I can imagine that the Garvan Institute indeed can reach lower cost prices for a genome than a smaller center like Radboud. However, I think most sequencing centers are smaller. This is why it is so important to have a realistic cost estimate for each individual center, which our analysis and Excel sheet provides," she said.

The University of Washington's Michael Bamshad told GenomeWeb in an email that UW, like many other institutions, would have different input parameter values for many of the factors in the Radboud group's calculation scheme.

According to Bamshad, costs at UW are different — lower for exome sequencing and WGS — which would be expected due to capital, maintenance, and operational costs that diverge from those of the Radboud center.

"As an academic sequencing center we also focus mainly on research … rather than CLIA-certified [exome and genome sequencing], both of which are more expensive," Bamshad said in his email.

However, he added, "We can't do genomes for 1.1X the cost of exomes and I don't know of any center that can."

In an email to GenomeWeb, the Garvan Institute's Cowley argued that there are more factors involved in delivering clinical genome or exome sequencing than the Radboud group included in its breakdown — such as genetic counseling, bioinformaticians and genomic analysts, clinical geneticists, variant curators, and genetic pathologists, not to mention additional variant validation tests.

"The authors acknowledge that they did not model many of the costs that in our experience far exceed the sequencing reagents [and] capital," he wrote.

Moreover, Cowley said, a straight comparison of exome versus whole-genome sequencing ignores the clinical reality that exomes often accompany, or are accompanied by, other tests like array CGH or additional mitochondrial studies.

"WGS can replace all three from a single assay, bringing the cost margin closer," he explained.

In the Radboud group's analyses, capital costs account for only a small percentage of per-sample costs and even if they could be halved, it would have only a modest impact on per-sample sequencing costs, van Nimwegen and her coauthors wrote.

In contrast, reducing consumable costs by half would decrease per-sample costs between about 32 percent and 37 percent, depending on the comprehensiveness of sequencing.

Varying sequencing depth between 30x and 100x coverage would moderately affect per-sample costs for targeted panels, but could influence WGS considerably, the group wrote, with cost increases up to more than $5,000 by their calculations, the authors wrote.

The team also calculated best- and worst-case scenarios representing the greatest possible impact of cost reductions compared to what might be seen with especially poor variable conditions like inefficient platform use or a need for higher-depth sequencing.

With "very efficient and long-term application of sequencing equipment, cost reductions of 50 percent in both capital and consumables, and technological advances allowing for 30x coverage," the group wrote, per-sample costs could go down to €1,006, €401, and €206 for WGS, WES, and targeted sequencing respectively.

In a worst-case scenario, WGS could reasonably cost up to 260 percent higher than under the team's baseline assumptions, the authors added.

According to van Nimwegen and her colleagues, the calculations indicate that overall the best way to bring costs down is by making consumables cheaper.

This reflects again the potential for sharp differences between a center with a very high volume of sequencing — or special discounts like Garvan or the other Illumina X Ten sites enjoy — and another with lower volume and without access to discounts.

"It is certainly true that operational costs including consumables have a substantial impact on the cost of sequencing and a greater impact when the outcome measured [for example, WGS versus exome sequencing] requires more sequencing [coverage or depth,]" Bamshad wrote in his email.

"Deeply discounted consumables do therefore drive the cost for WGS down proportionately greater than for exome sequencing," he added.

One challenge, the Radboud authors wrote, is that the sequencing market is currently dominated by a few large players which could prevent consumable costs from falling. Hopefully, though, growing use of clinical sequencing may result in new competition and economies of scale that drive cost reductions in both equipment and consumables, they added.

In the meantime, van Nimwegen and her colleagues stressed that their findings don't imply that exome sequencing or targeted sequencing are necessarily preferable just because they are cheaper and more solidly over the $1,000 genome border.

"The choice of NGS approach depends not only on the per-sample costs but also on its diagnostic yield, which defines its effectiveness," the authors wrote. "For each patient population, the decision as to which NGS approach and what sequencing depth to use should be based on a careful tradeoff between the per-sample costs, sequencing quality, and consequences for the patient."

"[The Radboud authors] discuss at length that the most appropriate test must take into account clinical utility and cost. In our experience the clinical utility has been higher with whole-genome sequencing than targeted panels or exomes," the Garvan Institute's Cowley said in his email.

For his part, Bamshad said that as both PI of one of the National Human Genome Research Institute-funded Centers for Mendelian Genomics and as a clinical geneticist, he sees immediate room for cost improvements in both whole-genome sequencing and exome sequencing.

The ability to use all of Illumina's platforms for exome sequencing without a price bump for consumables for example, would be a boon, he wrote.

Exome sequencing, rather than WGS, "is still driving gene discovery and clinical genetic diagnosis for rare conditions, and while I understand there is an approaching crossover to genomes, I think there is a lot remaining to be discovered by [exome sequencing] and many families would benefit … if it was more affordable," he added.

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