 Today I'm going to talk to you about some of the ethical issues that arise in the different types of genetic testing. Now many of you have probably heard of the Human Genome Project. It was a 13-year effort to map and sequence the entire human genome. It was funded by the National Institutes of Health and the Department of Energy. And if you're anything like me, when I heard this, I wondered what on earth was the Department of Energy doing, getting involved with the Human Genome Project? Well, it turns out the Department of Energy had a long-standing interest in genetics and genetic mutations since we dropped the atomic bomb on Japan. And they saw a way of putting some money into this effort as a way of keeping their scientists and their labs open. So this began formally in 1990 with funding of about $135 million and was increased to about $3 billion in public funding by the year 2000. In February 2001, a working draft of the Human Genome was published simultaneously in both Science and Nature magazine. The project goals were to identify all of the approximate 25,000 genes in human DNA. Now that number, I've given that version of this talk several times, and that number of the number of genes keeps going down. It was 30,000, then it was 25,000, maybe it's a little closer to 20,000 at about this point in time. So we're continuously refining our knowledge of the human genome. Another goal is to determine the sequences of the 3 billion chemical base pairs to make up human DNA, store this information in databases, and improve tools for data analysis. Now one of the things that was really interesting about the Human Genome Project and the area of the project with which I'm most familiar is ethical, legal, and social implications program, affectionately known as LC. It was funded on the concept that a new technology such as gene identification is likely to gender problems that could be minimized if anticipated and dealt with promptly. Now the interesting thing about this is it was the first time that the ethical issues of a large scientific enterprise were studied along with the enterprise itself. This program is also known as Full Employment for Philosophers. So what is a genetic test? A genetic test is the analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes. Now what are these clinical purposes? They can include predicting the risk of disease, identifying carriers, and establishing prenatal and clinical diagnoses or prognoses. Predicting the risk of disease. I'm also the director of the predictive testing program, so this is the area of genetic testing with which I'm most familiar. I deal primarily with late onset, autosomal dominant disorders like Huntington's disease and early onset Alzheimer's disease. So these predictive tests are tests that are performed on healthy or apparently healthy individuals with the goal of identifying their risk for developing disease in the future. And these tests are of two types. There's pre-symptomatic testing and susceptibility testing. Pre-symptomatic testing involves looking for genetic mutations that have high penetrance, usually autosomal dominant. A penetrance is a word we use in genetics, which basically is an estimate of if you carry genetic mutation that causes a particular disease, how likely are you to actually develop that disease. So in these kinds of tests, we're looking for disorders that for the most part, if you have the genetic mutation associated with the disorder, you will develop the disease in the future, so full penetrance. These tests need to be highly specific and sensitive, which means there are a few false negatives or false positives. Examples, as I mentioned, include genetic testing for Huntington's disease and early onset Alzheimer's disease. Now probably the most famous person that died of complications of Huntington's disease was the folk singer Woody Guthrie, who was the author of This Land is Your Land. So what we can do is basically identify healthy individuals who we now know are very likely, virtually 100%, to develop devastating and debilitating diseases at some point in the future, which at this time have no treatment or cure, which is one of the reasons why you want to make sure there are a few false negatives and a few false positives. We have developed testing protocols for this type of pre-symptomatic testing. These test protocols usually involve a neurological examination to establish a baseline, pretest counseling to construct an elaborate pedigree to get some sense of whether or not the person is making this decision to be tested freely of their own will, what kind of support system they have, what life changes might be riding on this decision to get some sense of who the person is and why they're making this decision. We usually get informed consent, written informed consent for this type of testing. Results are usually given in person and we make available several types of follow-up. They may include additional medical exams. They may include support groups. They may include individual or family therapy, depending on the needs of the individual. Some of the ethical issues we encounter in pre-symptomatic testing, the first would be, are we better off knowing our fate? Are we better off knowing that at some point in the future, we are going to die of a disease that at this time cannot be treated and cannot be cured, and especially disease that we've seen affect members of our family, usually one of our parents, one of our grandparents, aunts and uncles, perhaps, or cousins? And since there's no treatment or chore, it's very important that we respect personal autonomy, informed consent, as I mentioned, is an important part of the process. And we also have to respect people's right not to know. Part of the counseling process is to enable people, if they have second, if they're second guessing their decision, to opt out of testing at that time. They can come back later. They can refuse to get testing. They can change their mind. Also, because of our concerns about autonomy, we're very reluctant to test children. In the case of Huntington's disease, one of the things that we know over time is that the number of adults who are seeking testing at risk adults is usually about 10 to 13%, which is fairly low. So if fully autonomous adults are not rushing off to be tested, we believe it's very important to preserve the autonomy of children who are at risk to decide for him or herself when they reach the age of majority whether or not they want to be tested. It also means that we're very reluctant to test anyone at the request of a third party, be that a lawyer, a judge, the police, a spouse in the middle of a divorce, that issue has certainly come up. Our concern also is the psychological costs for those tested. We certainly, in the essence of do no harm, would not want to create difficulties in the time that people have left while they're healthy. So we're very concerned about depression and psychological difficulties that people test positive. We also have somebody reluctant to pursue prenatal testing for late onset disorders. Prenatal testing is possible, but most of the onset and these disorders that I primarily deal with are perhaps in the late 40s, early 50s. So that's many years of healthy life before people do become affected. Now, acceptability testing involves looking for genetic mutations that confer a high risk for developing disease, but not necessarily a yes or no 100% answer. These disorders are usually multifactorial, being a mix of genetic and environmental effects. They have variable sensitivity and specificity. Examples would include testing for apolipoprotein E4 allele for Alzheimer's disease and the BRCA1 or BRCA2 for breast cancer. Test results of this type do not mean that disease will inevitably occur or remain absent. They replace an individual's prior risk based on population data or family history with risks based on genotype. One of the ethical issues is acceptability testing, education and counseling for those at risk. These results, since they're not black and white, you get a level of risk and as a species, we are not very good at dealing with risk. Test interpretation can be very complex. Many of these diseases, primarily cancers, there is a potential for increased monitoring and possible treatment. So there is something that may, that can be done. But a question that comes up is what counts as useful information. If I look at my family history and know that my mother had breast cancer at an early age, my grandmother had breast cancer at an early age, my maternal aunt had breast cancer at an early age, I could probably figure out that my risk for getting breast cancer at some point is pretty high. Does it help me that much to put an exact number on it? Maybe yes, maybe no, that's an individual decision. One of the things that we do see is what we call the Angelina Jolie effect. When Angelina Jolie went public with her genetic test results about BRCA1 and BRCA2 and subsequent double mastectomy, interesting genetic testing for breast cancer spiked considerably. And I think many physicians see that if there's a television show, for example, that features a specific genetic disorder, there's often a spike in requests for testing across the country at that point. Now carrier identification identifies individuals who do not themselves have a particular disease, but who are at risk for having a child with a particular disease. These are usually disorders. Carrier testing involves individuals known to be at high risk because of the family history. For example, testing a woman whose sister had a son with cystic fibrosis, which means she has a possibility of being a carrier. Carrier screening involves testing all individuals with no family history. For example, testing all Caucasian women of childbearing age for cystic fibrosis. A major sun example of carrier screening, the prevalence of casex disease in the Ashkenazi Jewish population is approximately 1 in 27. For sickle cell anemia in the African American population it's approximately 1 in 13. And cystic fibrosis in the Caucasian population is approximately 1 in 25. Some of the ethical issues in carrier screening and testing since this involves reproduction primarily is respect for individuals and couples' beliefs and values concerning tests taken for assisting productive decisions. Mutations for certain diseases may have a higher prevalence in certain ethnic populations, raising the issue of stigmatization in that particular population. And we've seen this historically certainly with sickle cell screening back in the 60s. There are few choices available to those identified as carriers. You can refrain from childbearing, you can pursue donor eggs or donor sperm, or you can pursue, and this is an option that's becoming more popular, pre-implantation genetic diagnosis. And what that would be is that we would hyper-stimulate a woman's ovaries and harvest a number of eggs as opposed to the one that she usually drops a month. We would fertilize those in a petri dish. We would wait until the embryo grew to about the eight-cell stage. And then we would actually be able to take one of those cells and test it for the presence or absence of the genetic mutations that we're looking for, such as 50 fibrosis or sickle cell or whatever. Then we would only implant back in the woman those embryos that did not carry those particular mutations. There's an obligation to offer education and counseling because these are complicated situations that just through being a carrier and being effective when you have two copies of the mutation can be a little bit more challenging in terms of education and counseling. Prenatal genetic testing is testing of the fetus prior to birth in order to identify genetic mutations that may cause disease. The aim is to enable parents to have children they otherwise would not have been willing to have because of the fear of birth defects or genetic disease. For example, a common prenatal test, approximately 2.5 million pregnant women are screened each year to see if their fetuses are high risk for Down syndrome or mental tube defects. Some of the ethical issues in prenatal testing is respect for individuals and couples' beliefs and values is crucial. The ideology of non-directiveness is compromised by the fact that you are offering a test for a specific disorder. And what I mean by this is in genetic counseling we have an ethos of non-directiveness which is we, our job is to give you the genetic information. What youths you make about information is going to be up to you and your partner based on what your religious values are, your social values, what your family structure is like, your financial situation, and a host of other things that are personal to you. But the fact that you're actually offering a particular test means that at some point in time a value judgment has already been made that you might not want to have a child with that particular condition. So the ideology that we carry for non-directiveness is compromised by the fact that you're actually offering this test. There can be potential for increased pressure on couples not to have children who so-called deviate from normal. There's the possibility of decreased tolerance and fewer resources for those with disabilities because you can say in essence these parents have a choice. There's also the possible termination of a fetus based on ambiguous information. And I, for example, got a call from a friend yesterday whose niece had had a particular mutation identified. And her report actually said a microarray result of uncertain likely pathogenetic clinical significance. And when it talked about what the prognosis might be, it says generally mild but can include intellectual and or learning disabilities, delayed psychomotor development, growth, retardation, and hypotonia. So it could be nothing. It could be fairly serious. And you have to make a decision. So that's, I think, the ambiguous information. And you can't go without New Yorker cartoons. The good news is that you will have a healthy baby girl. The bad news is that she's a congenital liar. So there's your ambiguous information. As the mother of two teenage girls, I'd have to think twice about that. So newborn screening is screening newborns shortly after birth to identify genetic conditions. The aim is to identify conditions that are treatable in order to begin treatment as soon as possible to prevent serious mental or physical handicaps. Materials have been set up for effective newborn screening programs. That there is a treatment available, that early treatment can reduce or eliminate permanent damage. That the disorder would not be revealed in a newborn without a test. That there is rapid and economical laboratory test is available and that is highly sensitive and reasonably specific. That the conditions frequent and furious enough to justify the expense of screening. And that there is a societal infrastructure in place to inform the newborn's parents and their physicians of the results, confirm the results, begin treatment and offer counseling. So there's a lot of pieces that need to be in place for effective newborn screening. There is some indications that those criteria may be changing somewhat. So traditionally the major justification for all newborn screening programs was for the benefit of the child. In 2005 guidelines from the American College of Medical Genetics expanded that justification to include a benefit to the family as well as a benefit to the public such as contributions to the advancement of science. This expanded justification could be used to include virtually any test. Not as somewhat concerning because in most states newborn screening is mandatory and parental permission is rarely sought. 2008 there was some pushback from this in 2008 the president's council on bioethics reiterates that screening should follow the classic criteria and that would be for the benefit of the child. In 2013 the American Academy of Pediatrics policy statement reaffirms that screening decisions should be based on the child's best interest. Using newborn screening voluntary versus mandatory testing. The value decision was made a long time ago that because the purpose of screening was to identify disorders that could be treated to prevent permanent damage that on balance we would do mandatory testing for the most part. But since you're doing mandatory testing there's a lack of informed parental consent. You're not asking permission you're just getting the heel stick. Therefore there's a lack of education and counseling of parents prior to coming up with a result. Also what's happening as the tech the genetic technology expands and gets cheaper there is what we call technology creep. Tests are often added to a panel without assessing the benefit to the child because it's only a couple pennies and it can be serious and why not add it. There is necessity for treatment and follow-up to prevent damage and there's increasing pressure to use residual samples for population based research raising issues of informed consent for research. So we're not even getting consent for the actual clinical use but now the question of whether we should be getting consent for research use of the samples. At least two states Texas and Wisconsin have been sued for using newborn blood spots and research for which they did not have permission. Also be parental anxiety about false positive results and usually if you get a positive result from a newborn screening test you would do a confirmatory testing. But for many parents if you've been told that there's something wrong with your child even if confirmatory testing finds out that your child is fine there may be residual anxiety about whether your child actually is healthy or not. There may be harm to parent-child relationships by a parent misunderstanding the meaning of the child's carrier status. With something like testing for cystic fibrosis the child may be a carrier but may never be affected and parents may not understand that difference between being a carrier and being affected with a disorder. There's also the possibility that children will be subjected to needless monitoring and potentially risky medical interventions or monitoring based on this misunderstanding. There are two types of people in the world. They're genetic libertarians who feel that patients have a right to a full and complete accounting of all possible risks conveyed by both established and novel variants found through genetic testing or even variants of unknown significance in disease genes. And then there are genetic empiricists who believe that there is insufficient evidence about the penetrance of most pathogenic variants in the general population to warrant the sharing of these incidental findings and that it is irresponsible to create the psychological burdens of being a patient waiting or to expose patients to unnecessary surveillance or diagnostic testing. So certainly in genetics there is a tension between the empiricists and libertarians about how much information as we're finding we're doing more and more screening for more and more things and finding variants that aren't normal but we don't really know what they mean there's a tension between how much to give patients and even research participants for that matter and how much how much to hold on to that information and wait until we actually know what it means which is a moving target. In general ethical issues related to genetic testing and these include lack of knowledge direct marketing of tests to consumers and fear of discrimination indicated that only 26 percent of a population based sample knew what DNA was. As far as physicians go a 2012 study in the cancer journal reviewed dozens of cases in which doctors ordered wrong or unnecessary genetic tests misinterpreted the results of correct tests or failed to refer a patient to a genetic counselor despite a strong family history of a genetic condition. In a study funded by the National Human Genome Research Institute 74% of more than 200 internists said their knowledge of genetics was very to somewhat poor yet 44% admitted to going ahead and ordering genetic tests anyway. So this lack of knowledge on the part of both consumers and healthcare professionals is somewhat worrisome in the face of the sheer volume of genetic tests that are coming down the pike ever faster. In terms of direct marketing in July 2001 myriad genetics based in Salt Lake City, Utah announced that it was preparing to market genetic tests directly to consumers. These are primarily genetic tests to identify risks for certain familial cancers breast and ovarian primarily which are really only appropriate for a relatively small number of individuals but for which myriad held the patent. This decision was made primarily because the sales of these tests were not up to the original sales projections and many of you may remember that there was a period of time on on television where there were commercials for BRCA1 and BRCA2 testing. Go ask your doctor and these were really tests that were not appropriate for the vast majority of women. This is a screenshot of 23 in May a company that was offering direct genetic testing to consumers. In 2013 the FDA issued a directive to 23 in May to stop offering their health related genetic tests. One of my concerns is given the fact that many consumers don't understand genetic information a lot of these direct marketing tests for example for cystic fibrosis they are only testing for the most common cystic fibrosis mutation Delta 508 but there are over 900 cystic fibrosis mutations so someone might get a test back that no you do not have the mutation for cystic fibrosis and yet they may still be at risk and not pursue further genetic testing because they don't understand the context and that's true there the breast cancer they're only looking at three mutations that are common in the Ashkenazi Jewish population but there are many many many more discrimination in insurance employment and law enforcement. In this slide unfortunately you have what we call no insurance which was a big big concern of many people that I dealt with primarily in the autosomal dominant late onset kind of testing situation. The genetic information non-discrimination act or GINA was signed into law on May 21st 2008 and protects consumers from discrimination by health insurers and employers on the basis of genetic information. The health insurance regulation took effect in May 2009 and the employment regulation in November 2009 does not apply to those in military interestingly enough and affordable care act prohibits insurers from discriminating against persons with pre-existing conditions. So there are where there weren't before at least some legal protections for people with genetic conditions. I think it remains to be seen how much protection is actually afforded people. Concerns people have got discrimination and employment. Very nice resume. Leave a sample of your DNA with my secretary. Between 2014 the cost to employers of providing medical and dental insurance increased 10 to 15% per year. By 2013 health insurance benefits comprised approximately 11.7% of employee wages and benefits. The employers have major incentives to have a healthy workforce and as we find out more and more about how a person's genetics relate to the possibility or risk of them developing serious diseases in the future it's easy to see that employers would have an interest in knowing the genetics of their workforce. And then there's law enforcement. The greatest advance in forensic science in the past decade has been the application of DNA analysis. The ability of DNA analysis to exclude suspects with virtually 100% certainty may be the single largest cause for a major shift in attitudes towards the death penalty in this country. In cases where they were in projects like the innocence project were able to go back and actually analyze DNA samples that were evidence in cases of rape or murder. They often exonerated people that had been on death row for many, many years. Function creep. In 1930 the social security number was invented to be used only as an aid to access the new retirement program and it is now pretty much a universal identifier. DNA banks that were established by the military in the early 90s in order to identify the remains of soldiers with the idea that there would never again be a tomb of an unknown soldier have been accessed in criminal cases that have occurred on or around military basis. So if you have a data bank people are going to want to use that bank. In less than a decade sample collection for forensic databases has gone from convicted sex offenders to all violent offenders to all persons convicted to juvenile offenders in 28 states to all persons arrested. In this case the judge says please accept the apologies at this court you're free to go now and by the way here's your DNA back except they don't give it back. It enters a database where it all likelihood will remain. So in summary the completion of the human genome project in 2003 will provide a wealth of genetic information and an ever increasing rate of genetic tests. I'm sure many of which were covered in your previous webinars. The results of testing can help individuals make important decisions about their own health and about reproductive decisions in the space of genetic risk. There's a lack of education about genetics in general and the proper use of genetic testing on the part of consumers as well as health care providers. The use of genetic test results by third parties ensures employers law enforcement may be caused for concern and it remains to be seen whether recent laws path to prevent discrimination in employment and health care actually do so. So this is my contact information I would be happy to take any questions that you may have.