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Issue link: https://clinicalomics.epubxp.com/i/853204
14 Clinical OMICs July/August 2017 www.clinicalomics.com In the Clinic There is a lot of chatter about moving from exome sequencing to whole genome sequencing. What do you think about that? HR: My general answer is that if run appropriately, whole– genome sequencing can increase the yield of diagnoses compared to exome sequences. But you have to run enough depth of coverage so that the overall average lower coverage doesn't cause you to miss things on a genome that you would have caught on an exome because of its higher average coverage. In general, for clinical diagnosis, I think the whole genome is the way to go. But it is more expensive right now and the cost of testing is a huge fac- tor in the clinical market. It is also a large factor in the research mar- ket more because of the volume factor. If it was one case you were sequencing, you would probably do a genome. But if you were sequencing 10,000 cases for a research study, the added costs of a genome over an exome across 10,000 samples is enormous,;whereas with one patient for a diagnosis you might be willing to pay that price. Today, if you look across the market, I don't think the market has reached a point of going to genome broadly, but I think the cost drops that are happening right now will make it such that in the next year there will be a fairly significant transition to [whole] genome sequenc- ing. You mentioned cost being a significant factor in the clin- ical setting. Do you think payers may balk at reimburs- ing for whole—genome sequencing? HR: I don't think they are going to treat whole genome over exome differently. The whole issue is a big difference in how they treat any genomic approach—exome or genome—compared to panel-based testing. What the payers are freaked out about are the downstream cas- cade of things from incidental findings of sequencing lots of genes that aren't relative to the patient's phenotype. From their standpoint, if you are just sequencing a panel, you are just looking at things relevant to a patient's indi- cation. You are not at risk for a bunch of other things you weren't intending to look for that gets back to the patient and lead to a series of medical interventions for an at-risk patient that are unclear in their utility. We just published a paper from our MedSeq study in the Annals of Internal Medicine that showed only a very modest increase in cost when you give an enormous range of results back to healthy patients. I think that will help allay the fears of the incidental findings issue. Can you give an update on ClinVar? HR: ClinVar has been enormously successful. More so than I thought it would be when we started if five years ago. Why do you think that is? HR: I think there were a core set of laboratories that recog- nized about five years ago that we were headed for an untenable situation in our ability to interpret variation in our genomes, and that no single laboratory could manage the interpretations of millions of variants, all very rare in patients. We started with the intent to crowdsource this prob- lem. However, we recognized it is not just a question of crowdsourcing. As we began sharing, we recognized that we each had interpreted variants differently and so it became instead of a just a voluntary, crowdsourc- ing mission, it became a quality assurance issue in that we recognized that laboratories that were sharing their data—subjecting it to comparison and peer review of the community—would develop higher quality stan- dards and provide more accurate results to patients. I just wrote a commentary for Genetics in Medicine that is a list of clinical laboratories that meet what we con- sider a minimum standard for data sharing for quality assurance. The reason we are doing this is it will allow payers and providers to decide where to order tests from and decide which tests to reimburse because of the belief that labs that share data are higher quality and you should only reimburse or order from labs that are taking those quality-assurance steps. Some of the major laboratories have engaged in data sharing and have come to these conclusions themselves, without us mandating it. I have been delightfully amazed how many laboratories were willing to do this on a voluntary basis. But now we are at a stage where we need all of them to do it, because there are a small number who aren't. We sent a letter to all of the labo- ratories that had at least some submissions to ClinVar and said we would be launching the list in part to allow insurer and provider decisions on reimbursement and "In general, for clinical diagnosis, I think the whole genome is the way to go. But it is more expensive right now and the cost of testing is a huge factor in the clinical market." (continued from previous page)