By Monica Heger
New York's Mount Sinai Hospital is planning to launch next year a series of targeted sequencing-based diagnostic tests on the Pacific Biosciences RS.
Eric Schadt, PacBio's chief scientific officer and director of the Institute for Genomics and Multiscale Biology at Mt. Sinai, told Clinical Sequencing News that the hospital would first launch an autism panel, followed by a carrier screening test, a newborn test for metabolic disorders, and eventually a cancer panel and other panels for common disorders.
Schadt said that he expects to receive New York state approval for the first tests, which the hospital will offer through its CLIA-certified lab, within the next six months. New York's requirements for clinical lab validation are more stringent than CLIA, so labs offering diagnostic tests in the state must have clearance from the New York State Department of Health.
The hospital is initially focused on developing gene panels for diseases for which it already has state-approved Sanger-based tests, said Schadt. Those tests target specific mutations within disease genes, he said, so the idea is that by sequencing the entire gene, "we're getting not only the variation that the current state-approved tests get, but everything else that's occurring in that gene."
Additionally, the lab plans to combine several single-disease tests into comprehensive sequencing panels. For example, the carrier screen will target around 100 genes encompassing 20 different diseases, he said, while the newborn screening test for metabolic disorders will target 40 to 50 genes for about 10 to 15 diseases.
The autism panel, meantime, will focus on "rare, hard-hitting Mendelian mutations," he said.
The goal is that once the state is "comfortable with that data, we'll begin moving into more common diseases," Schadt said. In addition to a cancer panel, the hospital plans to develop a pharmacogenomics panel to determine what drugs would be effective for specific patients. It also envisions sequencing panels for more common conditions like cardiovascular disease or diabetes.
Schadt said he expects reimbursement for some, but not all, of the tests. For example, the hospital currently runs a series of tests on newborns when a metabolic disorder is suspected. Those tests are all currently reimbursed, but in about half the cases a diagnosis is not confirmed, he said.
In those cases, a more comprehensive sequencing test that screens for 10 to 15 diseases at once could be more cost-effective, and thus likely reimbursable. Additionally, said Schadt, if the Mt. Sinai team finds that the panel is more accurate than the current testing regimen and can help reduce false positives, it would further increase the likelihood for reimbursement.
On the other hand, the carrier screening tests offered by Mt. Sinai are not currently reimbursed, so it is unlikely that the PacBio test would be reimbursed, he said.
All of the tests must be ordered by a physician, and patients will also meet with a genetic counselor or board-certified medical geneticist before getting sequenced.
A genetic counselor will also go through the results with the patient in order to explain not only actionable results, but also results of unknown significance that are still deemed worth returning to the patient, Schadt said. Having a genetic counselor to help interpret results is an "important piece to the puzzle," he added.
Securing NY State Approval
If Mt. Sinai secures New York state approval within the next six months as planned, it would be the first lab to garner clearance from the state for a next-gen sequencing test.
Lisa Edelmann, associate professor of genetics and genomics at Mt. Sinai and head of the clinical genetics lab, said that the process of gaining state approval has been tricky because while New York has looked at single-gene tests before, it does not have experience with multi-gene panels.
First, the state wants to see that "every gene on the panel has been substantiated with the disease you are interrogating," she told CSN. Typically that requires at least two publications showing that the gene has been mutated and also showing its inheritance pattern.
Additionally, there are many diseases in which one gene is commonly mutated, but other genes may be mutated in only a small proportion of affected patients. The state will want to know how the lab will prioritize analysis of those genes in a multi-gene test. For example, said Edelmann, the hospital currently offers multiple single-gene tests for Noonan syndrome, but the tests are performed in a tiered manner, with sequencing done on the most commonly mutated gene first.
"When you do next-gen, the tiered approach goes away," she said. So in the case of Noonan syndrome, for example, the team would have to decide whether to prioritize its analysis so that it scrutinizes the most commonly mutated gene first and then, if a causative mutation is found, whether to analyze the remaining genes.
"When you set these panels up, you have to think about that and what makes the most sense for the patient," she said, adding that the lab needs to detail all of these steps for the New York State Department of Health.
Next-gen based tests pose an additional hurdle because they require a second testing method for validation. Anything that will be returned to the patient must be confirmed by Sanger sequencing.
The state "won't peruse your sequencing data, but they'll want to see what is your final result, how many positives did you get … and they expect you to follow them up with Sanger sequencing," Edelmann said.
Labs must report metrics such as sensitivity and specificity and must validate their tests on known samples as well as on the same sample in different runs.
The state must approve the entire testing protocol, including the exact concentrations of each reagent, the software used to analyze the data, and quality control steps.
For quality control, Edelmann said that the team is planning to have a certain read depth as a cut-off, probably between 20 and 30 reads. Anything below that would either require follow-up via Sanger sequencing or a disclaimer saying that certain regions did not have adequate coverage and may not adequately reflect the sequence.
The Mt. Sinai team is hoping that once the first test is approved, the remaining tests will be much easier. Edelmann said that the team does not have plans to pursue clearance from the US Food and Drug Administration.
"I think the fact that there's some level of regulation is a good thing," Edelmann added. "It's a very complicated technology and I could see where if you're not careful about setting it up the quality might not be as high as it should be for patients."
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