Case Study 2: Unexpected Consequences PHILIP REILLY I think today as we enter the world of predictive testing, genetic information does carry the possibility of creating anxiety in people's lives. I think that this is partly why I'm so convinced of the importance of public and professional education in this area. The problem is that diagnosis is going to outrun therapy in this area for probably many years, decades, and therefore, we aren't going to have neat, nice interventions to help people right away. It's natural that they'd feel anxiety. Hopefully, we'll only use the tests that provide a net benefit good for people. DR. DANIEL RADER I see a lot of people who have family histories of early heart disease, whose parents, one parent, for example, had a heart attack at an early age. DANIEL RADER How are you? Are these the charts for our patients for this morning? KAREN OBERMAN Yes, doctor. DANIEL RADER Great. Are you the medical student who's working with me? KAREN OBERMAN Yes, Karen Oberman. DANIEL RADER Hi, Karen, nice to meet you. Dan Rader. Let's go back and start going through some of these charts. This is one of the patients we'll be seeing today, a 45-year-old gentleman whose father had died of a heart attack at 53. And he came because he was concerned about genetic risk and wanted to learn more about it. So we do a variety of tests, genetic tests, and also an x-ray... DANIEL RADER Many people think that people who develop heart disease are people who basically don't take care of themselves. In point of fact, we can only explain about half of early heart disease based on these traditional risk factors. DANIEL RADER Swallow, please. DANIEL RADER A lot of people don't know that about 45% of men and 60% of women who die of heart disease die suddenly, without having had any proper symptoms of heart disease. It's absolutely critical, if we're ever going to make a substantial dent in death from heart disease, to identify people in advance, without waiting for the first symptom, because the first symptom of heart disease is often sudden death. DANIEL RADER Everything checks out on your exam, but you do have somewhat of a family history for early heart disease and we know that family history of heart disease can be a predictor of risk and we know that some people inherit genetic factors that put them at risk even though they lead fairly healthy lifestyles like you do. DANIEL RADER The beauty is that even if it's genetically determined, as it is in most cases, we can actually do something. Diet, and in many cases, drugs, to lower the cholesterol, to decrease their risk. So I talk to patients a lot about well, it's in your genes but you can overcome your genes by doing this and this and this. DANIEL RADER The other test we do that's a true genetic test is called APOE. Do you know about APOE, have you heard about that? KAREN OBERMAN No, I don't know anything about that. DANIEL RADER APOE's a gene that is responsible for impacting upon cholesterol metabolism, but it also is independently associated with heart disease, so there's a form of APOE called APOE-4, which is present in 25% of people, so a quarter of the people have this, a form of this gene. And if they have that, they're statistically at greater risk for developing heart disease. One of the... Two years ago, we wanted to set up a program that used other tests, including genetic tests, to predict risk of heart disease, and we realized that APOE testing could be one way to help better predict risk of heart disease, and we began fairly routinely testing for APOE as another way to assess their risk. With this patient we're in a somewhat difficult situation. There's one other patient that we're going to go in to see today who I saw a couple months ago, but I need to review her results. She's a patient with a very high cholesterol, a cholesterol of about 350, and very high triglycerides. KAREN OBERMAN What are you currently using to treat the cholesterol? DANIEL RADER Well, we, in patients like this we really do need to use medications. And we can discuss that after we've seen her. NURSE Hi, how are you? KATHLEEN CLAYTON Oh, hanging in there. DANIEL RADER Kathleen Clayton was a patient who came to me with a very severe lipid problem. And in that context, I performed APOE testing as a way to try to diagnose a particular type of hypolipidemia, a genetic with the disorder. NURSE OK, great. Sit down... Want me to tell you the number or do you want to be surprised? KATHLEEN CLAYTON Oh, I know what it is. NURSE OK, have a seat up here. KATHLEEN CLAYTON I have heart disease which almost killed me. I was in intensive care and ended up on the critical list, and my husband was told at that point that I was going to die. I was at the end of the line. I mean, I was ready to just say, oh, chuck it all. I'm just going to go to sleep. I'm not even going to wake up, because I had no answers, and I was getting so frustrated with having people tell me it was my fault, I'm doing this, doctors saying I don't know what to do, we don't know where to go, we don't know how to help you. And I've even had doctors say to me, I can't help you. DANIEL RADER We also did some other tests to help predict her risk and to try to understand why her cholesterol is so high. And one of the tests we did was the APOE test. And I see here that her APOE is the E4-E4. She has a double dose of the APOE 4 gene. This is actually quite unusual, although 25% of people have one dose of that, having two doses is quite unusual. Less than 1% of people. And this is important and going to be difficult for us, because this not only means her risk of heart disease is quite high, but APOE 4, do you know what other association APOE 4 has? KAREN OBERMAN No, I don't. DANIEL RADER It has an association with Alzheimer's disease. It's been really clearly proven now over the last several years. So it's a very interesting genetic test in that it actually predicts risk of two different, totally different diseases, heart disease and Alzheimer's disease. KAREN OBERMAN How do you go about handling a situation like this? DANIEL RADER I don't know. I don't know. I must say, I haven't been faced with this particular situation before. I think we're going to have to go in and talk to her about the testing in general, and the implications of heart disease. And then I'm just going to need to play it by ear and see how interested she seems to be in knowing the other implications of the test. DANIEL RADER Hi, Miss Clayton. Good to see you. This is Karen, a medical student working with me. KATHLEEN CLAYTON Hi, Karen. DANIEL RADER Do you mind if she sits in with us? KATHLEEN CLAYTON Of course not. DANIEL RADER Great. Thanks. DANIEL RADER I go into the office with her, unprovoked, she starts talking about some memory problems she's had over the last several months. KATHLEEN CLAYTON I had a couple experiences that really kind of scared me, and I wondered, does this hyperlipidemia affect your brain in any way? DANIEL RADER And it was kind of a spooky feeling. Here I had done this genetic test that I know is predictive of Alzheimer's disease, and a patient starts telling me about memory loss that could be the first harbinger of that disease. I of course ended up going into an explanation of the test, I felt she had to know that this test also had some implications for Alzheimer's... DANIEL RADER As you know, there's not a whole lot you can do right now to prevent Alzheimer's, but we have an Alzheimer's program here, and they have agreed to counsel people who have this test in terms of what it means for Alzheimer's. Of course, that's not my specialty, and you'd be welcome to chat with them if you'd like. DANIEL RADER When it comes to testing for heart disease, I really believe in it, because people can make changes and do something about it. But here was a situation where I had done a test for one purpose, I had not told the patient about its implications for anything else, and in reality, the test suggests a very high risk of some other disease that she hadn't been told about, and that I can't do anything about in terms of having her try to prevent it. So the dilemma for me was sort of one of information. Here was a situation where I felt obligated to provide a patient information that they had never requested from me, that they had no idea that they were going to be getting, and that in reality, that they may not want. And that provided some tension that really was difficult to work through and decide exactly how to handle. KATHLEEN CLAYTON When I got the results from the blood test back and I was questioning him about whether this could affect...and when he told me what I was predisposed to the heart disease and the Alzheimer's, I was scared and I was shocked and I was like, oh, boy, here's another one. Just add it to the pile, you know. But he said, don't give up. You know, he said, they're doing research and they're coming up with medications, and so...I had no intention of giving up, but I got scared, because when somebody starts talking about you losing your facility of your brain and functioning as a normal human being, that's scary as hell. DANIEL RADER She turned out to be very appreciative, and didn't mind that we had done the test, didn't mind that we hadn't told her about it in advance, and was happy to know the information. But I can easily imagine patients who would have a very difficult, different response to that situation, and that some patients might be very upset that we hadn't told them in advance that this test might predict some other disease. DANIEL RADER But can I just do a real brief exam first, just to check on a few things. Do you mind having a seat up here? KATHLEEN CLAYTON No, no problem. DANIEL RADER Karen, I always like to look in people's eyes to look for evidence of lipemia retinalis, the buildup of the cholesterol and lipid within the retina, and I just want to take a look at that... DANIEL RADER So I'm a specialist in the genetics of heart disease, but even I wasn't prepared for a lot of the ethical issues that come up in the clinic when we test for these genetic factors in people and then find that gosh, now we have to explain to people what this really means. I don't know very much about Alzheimer's disease, I'm not an expert in that, and most importantly, the patient hasn't come to me expecting information about Alzheimer's disease. DANIEL RADER I'd like to listen for... but I don't hear any evidence of blockage, so that's good. DANIEL RADER And I think we'll see more and more of this, tests that don't just predict one disease, but might predict several. So I think about the physician in practice, who's not a specialist in any one area, who's faced now with this bewildering array of lots of new tests that are going to come out, genetic tests where he or she doesn't know that much specifically about the genes, doesn't know as much about the specific diseases that they might predict for, and yet is faced with this issue of how does the physician guide the patient through this maze of tests and what they all mean for the long-term health of that particular individual. DESK CLERK And your insurance coverage is still with... KATHLEEN CLAYTON Medicare. DESK CLERK Medicaid, Medicare, A&B, correct... just want to double check the numbers. KATHLEEN CLAYTON Dr. Rader invited me to have my siblings come in for testing, and I asked all of them, and three sisters agreed to come in. I have one sister who came in to have the genetic testing done to help me, and to find out results, and we have the same primary care physician and Dr. Rader forwarded all of our information to him, and he didn't realize that everybody didn't want to know, and went in, my sister went in for her check-up, the first thing the doctor said to her was, oh, I see you have the E4-E4 gene, and she liked to faint. I had already had the results, asked her if she wanted to know them and she said no. And I said fine. She said, you just keep the paper. I said, that's fine, but when the doctor told her...see, she was one of the ones that didn't want to know. DANIEL RADER I recently found out that the results on one of the sisters got communicated to her doctor, who communicated them to her, despite the fact that she wasn't particularly eager to know those results. This raises the whole issue of the fact that information, not just genetic information, but it carries more weight than a lot of other information, once out there, may be learned by patients even though they don't necessarily want to know the result. DESK CLERK I just want to confirm your information while we have you here, you need to be updated.... DANIEL RADER I'll be perfectly honest with you. Even though I think it's an indicative test that does help us treat patients, I'm actually considering for a while, stopping to do the test until we've resolved these issues. That's how important and difficult this has become. And what I'm afraid of is that that's going to happen with other genetic tests, that physicians will conclude that even if the test is valuable, they'll decide not to do the test for fear of the other ethical and social and financial issues that have to do with insurability. And that's a tremendous, important issue that I think as a society we really have to start to deal with. TEXT SCROLL With two copies of the APOE4 gene, Kathleen faces about a 40-99% chance of getting Alzheimer's disease. As scientists learn more about the relationship between APOE and factors like gender, family history and ethnicity, they expect to be able to predict risk more precisely. APOE genetic testing has been available commercially and in cardiac clinics for three years. Tens of thousands of people have been tested, most of whom have not been told their Alzheimer's risk. Their results are now part of their medical records and legally cannot be removed. Continue to A Daughter's Tale.