Inside the Diagnostics Industry: Ambry Genetics Leading the Way With Clinical Next-Generation Sequencing

In early March, Ambry Genetics (Aliso Viejo, Calif.) reached the milestone of having sequenced 10,000 clinical diagnostic samples with next-generation sequencing (NGS) and processed 100,000 total NGS samples. Ambry has a proud history of being on the forefront of genetic testing, having been among the first purchasers of commercially available sequencing instruments back in 2007. The company says it was the first to offer an NGS-based diagnostic test in April 2010, with the introduction of its 81-gene panel for X-linked intellectual disability. Ambry continued with its list of firsts by launching the first clinically available whole-exome sequencing test at a CLIA-certified laboratory in 2011. Evolving from its roots in cystic fibrosis (CF) testing, Ambry continues to develop and enhance its comprehensive testing menu with significant investments in automation. This has allowed the company to focus on reducing test turnaround time while retaining its focus on quality client service and steadfast attention to their guiding ethical principles. Recently, Ambry CEO Charles Dunlop and Ardy Arianpour, Ambry’s vice president of business development, spoke to DTTR about the evolution of NGS in clinical care and Ambry’s commitment to rapid, yet responsible, growth in the future. Ambry Genetics has been a leader in clinically utilizing NGS technology. Tell us about how Ambry is using NGS and how it makes the decision of which tests to transition over to an NGS-platform? Arianpour: We started NGS back in 2007 with one of the first Illumina Gene Analyzers. We took the technology and applied it in the clinical market to yield actionable data. We now have 12 dedicated clinical sequencers running 24 hours a day. Double shifts here are important because they allow our throughputs to be super high. Dunlop: We are using NGS technology with a lot of things, but I still like to use Sanger technology with single genes because it is quick and reliable. But next-gen technologies are very good for a larger amount of genes to analyze—things like cancer, XLMR [X-linked mental retardation], exomes. We have 10 next-gen tests on our menu. Arianpour: You really need to have volume to have it at a certain cost point, as well. Not every lab can launch NGS unless they have the volumes for those tests. Dunlop: When you look at the data—enough good-quality data for making real clinical calls—you need to have a lot of samples on one run to take advantage of the economics and you also need to do a lot of replications per run to make it accurate enough. It’s not the cost savings that people think it is and that is why not all of our tests get transferred over. For a lot of our neonatal tests it is better to keep them on Sanger. It is more cost-efficient and more cost-effective. . . . Whether things go to next-gen or not is basically economics. It is not as medical of a decision as you would think. Our cancer panel or XLMR are good examples of tests that you couldn’t do without next-gen because there are just so many genes. But CF is perfectly good on Sanger. If we were to move it over it would be an economic decision. It wouldn’t be a technological decision at all. Ambry has a wide test menu covering everything from carrier screening and prenatal testing to cancer and cardiology panels. Which segments are seeing the most growth at Ambry? Dunlop: We are seeing growth all over the menu, which is at over 300-plus tests including a couple clinical versions of exome testing. There is no test that is not growing—even our CF business keeps growing. There is no really hot segment inside Ambry, which is a safer type of growth for us. I would say the market likes the clinical exome tests. Clinical exome testing has so much application potential. We are really just scratching at the surface of that test, in terms of where that test will eventually wind up. But we are doing it in a responsible way and not pushing it into the market or trying to do it on autism kids, where we are not really ready for that kind of data analysis. We are sensitive in how we treat those markets. But for really sick infants we are doing really well with that test. With our biomarkers pipeline, we are seeing about a 15 percent higher detection rate in our exome than other people who are using commercially available bioinformatics software. Bioinformatics is spoken of as one of the current rate-limiting steps to wider NGS adoption. How does Ambry address the bioinformatics needs associated with sequencing? Dunlop: I look at bioinformatics not as a solution. Bioinformatics, for us, just gives geneticists tools, not necessarily creating these automatic reporting engines that you hear about, which I think are a little irresponsible and a little risky. We have developed our own bioinformatics in house and it is awesome. Arianpour: We call it the Ambry Variant Analyzer (AVA). The great thing about AVA is that it has been developed around patient samples and around our systems. We started developing it four years ago and it custom fits our system well. It is quite elegant. Using existing databases and our own curated databases it filters and comes up with data points. The pipelines we have developed are so good at detecting mutations—again we are having 10 percent to 15 percent higher detection rates than anyone else with the exome right now. You mentioned that Ambry has genetic counselors on staff. How are they utilized and as an industry, how will their role evolve with the clinical adoption of more widespread molecular testing? Dunlop: Everyone is all excited about NGS and they think that we might sequence everybody’s genome. But that is very complicated and can be very touchy. We don’t really know how it will work. Let’s look at both extremes. If nothing changes then genetic counselors will basically be doing what they are doing and you can use bioinformatics tools like AVA to help as more genetic material and analysis is going through each sample. If genome sequencing becomes a fad of our civilization and 5 million to 10 million are done a year, which are really absurd numbers, I don’t know what their role could be. . . . Would counselors be doing data analysis? Counseling patients? If it comes to that point there aren’t enough geneticists and counselors in the world to do all of that counseling. Ambry has 30 or so genetic counselors and some have migrated to operations, some to R&D, a lot do reporting and double check results. We have a few counselors full-time, which is kind of unique, in accessioning. When it seems like there is a doctor that has ordered too much, or something that doesn’t seem right for the indication, or maybe there is a paperwork error and they checked the wrong box, they’ll go ahead and give them a call. We try to do it responsibly, not to call back and order 50 more tests. We do the opposite. We want to make sure we are doing what is appropriate for patient care. At Ambry the geneticists and counselors define what good patient care means—not the CEO, not the people in research. They live and breathe quality patient care, quality results, and quality ethics. They define in large part how and what we launch as well as what we report out and how we report it out. Labs have been anxious about reimbursement with the recent transition to the new molecular pathology codes. How is Ambry handling this transition? Dunlop: I’m cautiously optimistic. We live in a civilization that places a high premium on the value of human life, generally speaking, and I don’t think we, as a culture, are going to block out the coolest technology that can frankly save lives just to save health care dollars. Exome comes with a price tag. At the same time, think about how much money the health care system is wasting on diagnostic odysseys to figure out a condition. If payments are an issue in the lab, you are playing with products that don’t have utility in the health care system. Tests have to make sense for insurance companies when they do their cost-benefit analysis. When I find out some of the things that are done out there in the somatic cell world and they are taking more money out of the overall health care system than chemotherapy is and the prognosis of the cancer patients with these new technologies isn’t really any better, then why should we pay for that? . . . If a lab launches quality products that make sense for the system and they focus on the ethics of what they are launching—not what they can get away with—like we have and some of our competitors that I respect for have, then I don’t think you need to be too worried about the reimbursements.