LDTs, Incidental Findings, and the Need for More Geneticists

Marshall L. Summar, MD; Michael S. Watson, PhD


November 16, 2015

Editorial Collaboration

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Marshall L. Summar, MD: Hi. I'm Dr Marshall Summar, chief of genetics at Children's National Medical Center. I'm here today at the NORD Summit doing some interviews for Medscape on rare diseases. I have the distinct privilege of having Dr Mike Watson here with me today. He is the executive director of the American College of Medical Genetics and Genomics. We have some really good, trendy topics to talk about. Mike, thank you so much for taking the time to be here.

Michael S. Watson, PhD: Glad to do it, Marshall.

Laboratory Diagnostic Testing

Dr Summar: Let's dive right in. One of the hot topics right now is laboratory diagnostic testing in genetics. Obviously, there has been an explosion in both the technology and the use of genetic testing. When you look at the US Food and Drug Administration (FDA), the Clinical Laboratory Improvement Amendments (CLIA), the clinicians, and the geneticists, how do you see this all shaping up?

Dr Watson: I think the bottom line is that among the laboratory developed tests (LDTs), genetics and genomics are very different. These tests don't give you an answer that every physician understands or can independently interpret the test results. Virtually all test results have to be put into the context of a person's medical history and family history to give them the specificity they need for that individual and family.

That is a very important aspect of the practice of medicine and the part of these tests that I think is often lost in discussions about LDTs. They are complex tests. I think we're going to have to find a mix of a CLIA enhancement model that ensures that high-complexity testing is really done well and that personnel standards are at the levels that they need to be, as well as all of the quality aspects of the test. But it's not going to have the same clinical validity and utility associated with it. That's a much more complex area.

The bottom line is that among the laboratory developed tests (LDTs), genetics and genomics are very different.

Dr Summar: One model that I've heard being used to describe genetic testing in particular is that it's almost like a pathologist evaluating a sample. The DNA sequence is like the tissue sample that they have to look at, and then they have to use their skill, knowledge, and experience in interpreting the results. Do you think that's a good analogy for how we're handling DNA results now?

Dr Watson: I think it has a strong independent professional training and experience aspect to it that makes it somewhat like pathology. There are independent board certification programs in medical genetics in each of its four or five specialties that are similar to what goes on in the pathology world with their subspecialties, including molecular pathology.

Dr Summar: Some of your background is in that type of testing. How do you see it evolving going forward? Right now, the field is focused on conducting the tests, obviously, and doing the interpretation. What do you see as the evolutionary process in this field?

Dr Watson: I think it's variable. Within genetics, we have at least three kinds of testing that we do. Biochemical genetics is really about the product of the gene. It tells you an awful lot, and that's why we use it in screening. It's preferable to looking in the genome. When you get into cytogenetics and molecular diagnostics, you're either at the low-resolution level of the genome or a high-resolution level.

Within that, we're partly being driven by the healthcare system itself. It favors targeted tests where somebody can look at the tests and say, "You've done that well. You understand it, and you're interpreting it correctly." That's not going to fit into the model that's coming, which is something that I think you've experienced with tandem mass spectrometry. You can either look at one peak that you think is associated with the disease, or you could look at the whole profile and learn lots more about an individual than you might by looking at just the target.

Genomes are a lot like that in that you may go in looking for something very specific. You may not actually even know what you're going to go looking for. Probably the most common clinical use right now of entire genomes is undiagnosed kids in the neonatal intensive care unit or other pediatric patients who we haven't been able to diagnose. We can look at the entire exome and see if we can find it. Then it's a question of applying your professional skills to interpret that result and saying that this gene could cause this phenotype or this kind of biochemical imbalance, whatever it might be.

Incidental Findings and Unintended Consequences

Dr Summar: That, of course, brings up another topic that is very hot right now, which is unintended consequences. As we're using more and more next-generation sequencing, we might find that our primary question may not be able to be answered. But now there are whole panels of results that actually have lifetime implications for the patient.

The American College of Medical Genetics and Genomics has obviously been very active in making recommendations. How is that going?

Dr Watson: Certainly, there are two unknowns that can happen—incidental findings where you find something within the group of things that you were really looking for based on your patient's presentation or things that you go looking for in addition to those things that your patient presented with. Those are secondary findings. We made recommendations for a group of 56 genes or conditions for which we have the clear ability to intervene, such as cancer risks and cardiovascular disease risks. It's very clear that we can make a significant intervention in individuals who are identified presymptomatically. We just need to collect data for the long term and look at how many people are developing the diseases. We think that penetrance is going to be high for many of these conditions, certainly high enough to be concerned about them. As you know from newborn screening, penetrance is not always as well understood as we wish.

Dr Summar: I think it's like a lot of things. Once you start looking, you find a lot more than you ever expected to.

Dr Watson: No doubt. I can't think of a condition that turned out to be what we thought it would be when it went into newborn screening, but everything we do is based on the sick people who present to us. Once you get into the asymptomatic population, it's always a much broader range of severity and being affected or not.

Policy Development

Dr Summar: One of the hats that you wear as executive director for the American College is dealing with policy. With genetic testing, I know that the different federal agencies—whether it's the US Department of Health and Human Services, the FDA, or others—are trying to look at their level of involvement. What is the College's view and role in this?

Dr Watson: We are very active in policy development. We work with legislators. We work with regulatory agencies. More importantly, because we are on the front lines of delivering these services, we look often at the impediments to good regulation and good legislation.

My sense is that one of the biggest impediments is the rarity of the disorders at a gene level, and even rarer within a gene as to what might cause the disease. That really begins to change the way you think about the problem. I think it's why device companies have not been able to put out test kits. The magnitude of the study required for that clinical trial is enormous and incredibly expensive. I think it's why we have LDTs now—because that step was something that the industry couldn't address.

They addressed it well in the Orphan Drug Act but not so well on the devices side of the FDA. I think that finding ways through those impediments means professionals taking on the responsibility of saying, "This is the clinically valid target." We did that for cystic fibrosis carrier screening and Ashkenazi Jewish carrier screening. We basically reviewed the literature carefully and said, "If you're going to do this test, here are the valid targets to go for." You take that problem away from industry, and they will go crazy with developing analytical tools that could find those targets because that is something that is tractable for them. The clinical validity part is very difficult.

Dr Summar: That's obviously a new model, and the FDA will react to that, as will other regulatory agencies. I'm assuming that the College will be involved in that, too.

Dr Watson: We are. The ClinGen project is an international data-sharing project where we get people to bring their different cases together from all over the world. We now have over 200,000 cases. It really is a matter of bringing those rare things together to a centralized place so that the power of what we can learn about the disease is much, much improved.

The Workforce in Clinical Genetics

Dr Summar: Let's pivot for a second. One of the other issues that you have to deal with is the workforce in medical genetics. Speaking as a clinical geneticist, it's something that concerns me. I'm seeing shortages in a couple of the different areas in genetics, particularly in the clinical field. How do you see that landscape evolving?

Dr Watson: There certainly is a workforce shortage across all of genetics. When I was training, we used to muse that the average age of a biochemical geneticist went up by 1 year every year because we didn't have new people coming in at the base. I think that we're starting to get more. Newborn screening has attracted more people into the field because of the excitement of disorders. The ability to intervene and make a huge difference in outcome is very attractive to medical students.

If you look across all of genetics, the United Kingdom has probably done the best job of looking at what kind of workforce is needed for a population. They basically suggest that it's about one for 250,000 people in a population, one clinical geneticist and a team of counselors.

In the United States, we are at about one in 650,000, so we're at one third of the actual workforce needs based on analyses done 10 years ago, before newborn screening and before genomics. I think the need is probably higher than it used to be. Certainly, there is a lot of demand for people to take patients who screen positively from newborn screening programs.

Dr Summar: All right. As a leader in the field—and you've got a chance here to talk to some of the young physicians who are making their career decisions right now—why should they want to become a geneticist?

Dr Watson: Well, it's certainly exciting. There is nothing more exciting, moving more rapidly, or likely to have a transformative impact on medicine. When I talk to medical students about why they don't go into genetics, it's usually one of two reasons. It's daunting because it is spread across all of medicine. It looks like a very daunting field. And it's fast-moving, vast with information.

The world is changing. We don't know everything about genetics. We know where to find it when we need it, systems that support people in service, such as clinical decision support tools that we can share across medicine. We bring our expertise to them because there are not enough of us for them to bring their patients to. We are going to be bridging across specialties, trying to develop cadres of people in every specialty of medicine who have at least expertise up to the level of the most common genetic causes of the diseases in their specialty.

My experience has always been that if you can get somebody up to that level, they begin to know their own limitations. When they hit their limitations, they're much more likely to go find a person who can actually take it to the next step instead of just leaving it to the diagnostic odyssey and stopping the workup.

Dr Summar: We'll see who that pulls into the field going forward. Mike, thank you so much for taking the time to talk to us today. I really do appreciate it.

Dr Watson: I enjoyed it. Thanks.

Dr Summar: I'm Marshall Summar. We're here today finishing up for Medscape at the NORD Summit. We've just talked with Dr Mike Watson from the American College of Medical Genetics and Genomics.


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