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Quest Evaluates NGS for Dx; First Entry is Sequencing-Based HIV Tropism Test

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Quest Diagnostics has launched an HIV tropism test using next-generation sequencing as part of a larger effort to develop NGS-based tests.

The company would not disclose what platform it offers its tropism test on, however, Andrew Grupe, the senior director of pharmacogenomics in Quest's Celera business, said that for future test offerings, the company is evaluating all the desktop sequencing instruments, including the Illumina MiSeq, Roche's 454 GS Junior, and Life Technologies' Ion Torrent PGM.

Aside from looking to develop diagnostics based on sequencing, Grupe said the company is also collaborating with pharmaceutical companies in research settings to use sequencing to identify biomarkers that predict response to drugs.

"We're trying to understand which platform provides good clinical information," he told Clinical Sequencing News. Accuracy and platform robustness are two critical factors, he said.

Data analysis tools are also critical, "because in addition to platform accuracy, you need to use those tools to determine the presence or absence of certain variants, so we're actively investigating tools on the bioinformatics side," he said.

"Something we feel strongly about is that it's probably not appropriate to have what I would call a black-box tool for a clinical test — a tool where you don't understand what's going on internally," he said. "We want to have a tool that we can also modify to dial in the best sensitivity and specificity of an assay, to give us the greatest flexibility and the ability to make accurate calls for the different clinical tests that we want to run."

Grupe declined to disclose specific tests the company is planning to develop on a next-gen platform, but said that in the short term, they would likely be targeted sequencing-based tests. The area of cancer is especially promising, he said, and Quest already offers Sanger sequencing-based testing for EGFR, KRAS, and ALK mutations in non-small cell lung cancer patients and a PCR-based test for the BRAF v600 mutation in melanoma patients.

Targeted sequencing tests will likely be the predominant way that next-gen is used in the clinic for the near and mid term, said Grupe, because a stronger "clinical justification" case can be made for this approach than for whole-genome sequencing. Additionally, "something that's critical for us is getting reimbursement for those tests," which he said would be a more difficult sell with something like whole-genome or exome sequencing.

In the case of the sequencing-based HIV tropism test, reimbursement depends on the type of health plan, region, and other factors.

In order to move sequencing into the clinic, one technical challenge that still remains is automation. "If you want to run this type of platform on a robust and reliable basis, I think the more you can automate any of the steps, the better off you will be in providing accurate, clinical information because you have less variability in the whole workflow," he said.

Additionally, improving the robustness and accuracy of the platforms will also be important.

From a regulatory standpoint, one current hurdle is that there are not set standards for using next-gen sequencing in a clinical setting, just drafts of guidelines that are still in flux.

For instance, The American College of Medical Genetics and Genomics has developed draft guidelines for clinical sequencing. And, earlier this year, the College of American Pathologists has formed a workgroup to develop a checklist for certifying labs running clinical tests based on NGS technology (CSN 9/14/2011).

Additionally, Quest is a part of the Centers for Disease Control's Evaluating Genomic Applications for Practice and Prevention workgroup to develop guidelines for clinical sequencing.

"It's difficult right now because we're dealing with draft guidelines, because everybody is trying to understand the platforms," he said.

Some of these guidelines include requirements to revalidate every finding with a secondary method, which becomes "unfeasible if you have to do that for all the variants you identify," he said. "So there has to be some other way of validating the platform and showing the accuracy of the results."

One suggestion, he said, is to use statistical methods to determine the read depth required to have confidence that the platform is detecting different types of variants, such as germline mutations.

Finally, he said, figuring out how to deliver a report to the physician is another major hurdle of implementing sequencing in the clinic. The report has to be short and easy to understand, he said, because the physician has limited time, but it also has to be comprehensive enough so that it is the physician that is making the medical decisions, not the laboratory scientists.

Grupe also thinks RNA-seq could have clinical applications in the future. "It allows you to look at variants that are not accessible by DNA sequencing," he said, including gene fusions and rearrangements.

Currently, targeted sequencing will be the main way in which sequencing is used in the clinic, with exome and whole-genome sequencing being used in "cases of last resort," until there is a significant improvement in turnaround time, data analysis, and interpretation, such that the costs are feasible, he said.

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