 The panel will be on Pediatric Ethics and it will be moderated by Dr. Laney Ross. Dr. Ross is the Carolyn and Matthew Bucksbaum Professor of Clinical Medical Ethics and a Professor of Pediatrics, Medicine and Surgery. Laney is also an Associate Director of the McClean Center and the Co-Director of the Institute for Translational Medicine. Laney Ross is the co-author of four books and many, many peer-reviewed papers on ethical issues in Peds Ethics and Transplant, Human Subject Protection, Genetic Testing. Dr. Ross has been the recipient of many honors including a John Simon Guggenheim Memorial Foundation fellowship and a William Bartholomew Award in Ethical Excellence from the American Academy of Pediatrics. Dr. Ross just completed a term on the board of the Directors of the American Society of Biorethics and Humanities and his Chair of the NIH Special Emphasis Panel on Societal and Ethical Issues in Research. Laney is on many editorial boards in addition to moderating today's panel on Pediatrics and Family. At the beginning of the panel, Dr. Ross will present a talk entitled Why We Are Still Not Ready to Incorporate Sequencing into Newborn Screening Programs. Please join me in warmly welcoming Dr. Laney Ross. Dr. G. E. M. Rysselmeyer-Squibb. I didn't even know that G. E. did medical equipment. I thought it was dishwashers. And I will not discuss off-label uses. Can you hear me? Sequencing is and what it does discuss the controversies regarding the identification of the ACMG-59 and discuss the risks and benefits of sequencing of healthy populations such as newborns. So let me begin with what I'm even talking about. So just a quick overview of genetics versus genomics. So in high school we all learned about Punnett squares and Mendelian genetics and we learned one gene, one disease. And we've come to realize that that's oversimplistic. It's also not accurate because we have modified genes and the fact is that our genes interact with the environment. So now though instead of talking about the genetics, we're going to talk about all of our genes and it turns out we have a little bit less than 20,000 genes and that they make up about 3 billion base pairs. So if I talk about the fact that we're all 0.1% difference, there's a lot of differences when you think of 0.1 times 3 billion. The thing is that most of our genes are actually small. They're about 3KB. And so it turns out that a lot of the genome has nothing to do with the genes there. Well, they have something to do with genes but they have to do with regulation and other things that we don't even fully understand. But our genes only make up about a quarter of our whole genome. And we don't actually still, we used to call it the junk DNA when I was in medical school, we still don't fully understand what all the rest of the genome does. So the bottom line is that just because we know your genes doesn't we know your phenotype which is who you actually are and what health issues you actually do experience. So sequencing in general when we're going to look at a large number of those 3 billion base pairs we're going to usually do it because you have a specific problem and we're trying to understand what the cause was. Now as I've been trying to say your whole genome has a lot more information and it turns out it's not like looking at an x-ray where you can see the heart and the lung zone on picture. You actually have to go interrogating and specifically looking at different parts of the gene code if you want to try to figure out could this part, this gene be related? Because again it's not one gene equals one diseases. So when you're doing that though you may pick up what we call incidental findings which are health issues that may or may not be relevant to you because again your genotype doesn't equal your phenotype and maybe about health problems that you're not worried about. So I may be doing this work up because you have seizures and I may find that you have a gene for cancer type of things. So that's what we call either an incidental or secondary finding and then we have things called the variants of unknown significance. So remember I said that every gene is about 3,000 base pairs but the fact is is we can find a variation and then we don't know is that a health problem or is that just a normal variation? So that's what we mean by variants of unknown significance. So this idea that you could take a genetic diary, I could read your genetic code and know what you're going to eat for breakfast tomorrow or who you're going to vote for in the election is just not true. Okay so given that as our understanding of genetics I want to look at three different areas of sequencing that have become popularized now. The first is looking for these diagnostic unknowns, trying to understand why you have a particular health problem and then we'll talk about the ACMG and then finally sequencing children. So this is really exciting and it's only eight years ago that this is the first case report in the literature where sequencing actually helped reach a clinical diagnosis and actually changed medical treatment for a particular patient, in this case a child. So the child was a 15 month old who had the symptoms of what looked like Crohn's disease but way too young to have Crohn's disease and so they thought it was an immunodeficiency but all the workups they did were negative. And so then they did sequencing and they actually found a missense mutation so they found something wrong in a gene that actually could be related to Crohn's but actually because of the type of gene that it was the treatment would actually be a bone marrow transplant and they did the bone marrow transplant and the child can now eat and drink. So this was a child who was actually being G tube fed and IV fluids for the first 15 months of life and gets cured. So that's the incredible power of sequencing. Here's another study four years later which looked at again many different types of complicated diseases to try to see these are kids who had lots and lots of workups could we figure out what their health problem was if we did sequencing and what was important of the first 40 cases they were actually able to find explanations in 12 or in 30% of them the highest yield being in those who had complicated disabilities and anomalies as well as immunodeficiencies and what's important to know is that before they had done the sequencing many of these children had actually undergone lots of genetic tests and so one question is do you do five or six different genetic tests or do you just do sequencing as the first line which is going to be cheaper, which is going to be more efficient and the authors of this paper were trying to argue we should just be sequencing everybody because it'll be cheaper in the long run. But there's an important article that came out by Dr. Martis which points out that even if we can do your genome sequencing cheaply it's the interpretation that's really expensive so her article was entitled the $1,000 genome, the $100,000 analysis because what she pointed out were all the different healthcare providers and informaticians and all the other providers who had to be involved in order to try to interpret your genome so again it's not like just looking at an x-ray it's going to take a lot more work and so pointing out that it took molecular and computational biologists geneticists, pathologists and physicians with exquisite knowledge of the diseases and treatment modalities research nurses, genetic counselors, information technology and system support specialists among others and so her argument is that even if we make sequencing really cheap and we have, we're now under $1,000 a sequence it's not going to lead to availability and ability to do it in all different parts of the country and so her argument was sequencing is not ready to be a first line test the second ethical issue then is this concept of the ACMG-59 so the ACMG stands for the American College of Medical Genetics and Genomics and what's important is they gave some guidance on how we should deal with sequencing and in March of 2013 their first statement came out and they said that they recommend reporting of incidental findings so those findings and even if I'm looking to try to understand why you have seizures if I find cancer genes I should be reporting those but they went beyond that they actually didn't just say I should be reporting them they actually said I should be specifically looking for it so I need to interrogate all those aspects of the genome for these 56 at that time now 59 variants that could be related to cancer and they said we should do it regardless of whether the physician orders it and we should do it regardless of whether the patient wants to know this information and remember this information may be being obtained on some competent adult like you or me but it also may be being done on a child or even on a newborn and they called this what they called was opportunistic screening since we already have your sequence we can just do this and the critics called it a mandatory hunt it was mandatory to hunt for incidental findings or an oxymoron in terms so what were these 56 genes most of them are cancer or cardiac genes and virtually all of them only present in adulthood and in fact as I mentioned that in 2017 they added some genes and they actually removed one because they realized that it was less dominant than they thought so these are genes that they state are high-risk alleles and they are in high-risk populations so if you have a family history and you have one of these genes you're at high likelihood the fact is we have no idea how impactful they are in populations in the low-risk general population and so again the fight that ensued after this was it doesn't require consent of the ordering physician or of the patient and they kept saying well it's just like radiology since it's already there the American College of Medical Pathology said no it's going to take a lot of work and what you haven't even told us is who's going to pay for it and what do we do when we call up the ordering physician who said I didn't order that information I really don't want it and things of that sort and so and more concerning was there have been several studies now that have come out to show that those genes that are highly penetrant in high-risk populations tend to be much less penetrant in minority populations just because of genetic variants and so we may be doing a lot of harm without getting all the benefit as was hoped meanwhile so the geneticists, the ethicists, everyone was fighting there was a lot of pushback from many stakeholders and they actually the biggest fight actually came in pediatrics because the question is why are we testing children for adult onset disorders the ACMG had actually written a policy statement one month before they came out with this new statement working with the American Academy of Pediatrics saying we shouldn't be doing predictive genetic testing on children for conditions that are going to present in adulthood and the argument was that it was against the best interest of the child the ACMG said no no no we still affirm that you shouldn't do predictive genetic testing in families that expect it but these are unsuspecting patient participants this is the general population and maybe if you diagnose it you can then if you diagnose in the child you can then sort of go back figure out which parent has it and maybe you can save one of the parent's lives again assuming that this family is going to have a high-risk gene which we again know is not the case in the general population so they kept fighting and then they finally conceded that okay maybe people should be allowed to say no so they now said that patients and physicians can both refuse this type of testing but they still felt that if parents wanted it they should be allowed to test their children for adult onset conditions leaving them in a sense with two disjoint policy statements one saying you can test children for adult onset conditions and the other saying you can't just a few months ago they actually came out with another revision because this is still creating a lot of pushback and basically they've now come to acknowledge that how highly penetrant they are is really unknown in the general population and so that they're now only talking that you need to return these results in the clinical setting not necessarily in the research setting where there are many other objectives at stake and so they acknowledge in the absence of penetrance data that can only be obtained through robust genotype-phenotype correlation the medical ethical principle of non-maleficence should dominate of importance is in this correction update in 2019 nothing specifically written about the sequencing of children so why are the identification and reporting of the secondary findings so controversial in pediatrics as I've mentioned to the extent that we don't want to be testing children predictive testing for adult onset conditions so if you really want to know about the parents test the parents children do not need to be the canaries in the coal mine and it's sort of denying that the children has some right we could argue whether there is this notion of a right to an open future we could talk even about the child's right as an adult not to know disinformation many of us don't want to undergo sequencing ourselves and there's also the issue whether a child has a right to privacy even against his or her own parents about conditions that will not present until the child is an adult and so most of the ethicists have been writing against offering this mandatory hunt at least in the pediatric setting which gets to an interesting issue then so I'm now arguing against all the sequencing and yet we're now talking about sequencing newborns so the history of newborn screening is basically that in the beginning we added one disease and we had one test and then in the 1990s we developed something called tandem spectrometry which is a platform technology which means you can test for many different disorders at one time and sequencing in a sense is another platform technology you can look for a lot of different genes all at one time and because of all these new technologies we've come up with actually in 2005 they came up with something called the RUST the recommended uniform screening panel because before 2005 some states were testing for only four or five conditions of childhood in the newborn screening panel and other states were testing for as many as 40 so to create some equity we decided we would all screen at least for the same ones although some states including Illinois test for even more than on the recommended uniform screening panel meanwhile at the same time the National Institute of Childhood Health and Human Development decided to actually give money $25 million over five years to look at the question of what are the benefits of doing sequencing of newborns I've already been pretty critical of it but meanwhile as I said they funded different type of studies some looking at healthy kids, some looking at sick kids some trying to see could we actually pick up the same diseases that we're doing by picking it up with other platforms and the answer was no and things of that sort but here's the problem with doing whole genome sequencing and a healthy person so I'm going to give you one that comes from the literature of a healthy person and the first two things you're going to see are circled are really irrelevant in telling us about an antigen that they have and another aspect which you'll also notice if you follow the asterisk it says that the coverage was very low so probably inaccurate and what it means by coverage we actually don't read the 3 billion base pairs like from left to right and keep reading it's not like a book you actually take out pieces and then you combine them together and you want to get overlap to make sure that you have accuracy and that you're putting the base pairs in the right order in the second one they now had enough coverage they thought these were accurate and they were able to find in this healthy person two homozygous meaning that they had two abnormal genes which would mean in an autosomal recessive condition that they most likely have this disorder and the two that they found were cocaine syndrome which is failure to thrive, microcephaly and cognitive disability and the other one they found was Usher syndrome which was type 1b which is associated with deafness progressive vision loss so as you're reading this think about whether we did this as a newborn think about whether we did it prenatally or think about whether we did it on a healthy adult like James Watson the Nobel Laureate this is his genome that was published in the journal Nature so to be fair Watson's genome was sequenced at a time that we didn't have as powerful technologies that we do now so if we redid James Watson's sequencing I don't think we'd necessarily find Usher syndrome and cocaine syndrome but the fact is is that it still gets to the point that even if we did it doesn't matter he is neither deaf nor blind nor does he have microcephaly which is associated with cognitive disabilities as a Nobel Laureate so we know that genotype doesn't equal phenotype and yet decisions will need to be made if we do it in a newborn based on genotype without really knowing what the child's future health really will pretend so there's a real serious potential for over treatment for creating patients and waiting where parents know that their child's at risk for this disease and waiting for this in the sense the second shoe to drop there's the potential for stigma and labeling would James Watson if he didn't speak in nine months his first word would be worrying about cognitive disabilities and things of that and there's also actually believe it or not the possibility for misdiagnosis because the way we read sequencing there's certain types of genetic information that we actually are unlikely to pick up so my concluding remarks are we're not ready for genomic sequencing of children let alone of newborns we should only do sequencing in children for cause and we should not be offering parents the option of receiving these adult onset information unless the condition is known to present in childhood thank you very much since I get to supervise myself I'll take questions the final findings that are coming up the 23 and me have lots of implications for young parents and I've got to have a tall child, a short child that's actually just retarded what is the society thinking through on that recovery well I mean 23 and me claims that you're supposed to be an adult to give your samples now parents can give their child samples we also really aren't at all close to doing a lot of the phenotypic descriptions you just said it turns out that there isn't a tall gene it's going to be many many different genes and with our genetic information at this point we're probably still able to explain less than 10% of our height variation so we're far away from it but the question is will we ever get there and I'm not sure because I'm not sure we're ever going to be able to separate out genotype from the environment but these are the questions we need to be asking today in order to be prepared for the future John Thanks, great talk you mentioned the society level and you argued compellingly against those three you gave those three examples of why we shouldn't be doing this genome sequencing give us a sense of the market forces I mean 23 and me got mentioned who's pushing and saying we should just be doing this technologists and you know and the fact is is that the first whole genome sequence that we did which we started in 1991 with the whole genome project took 10 years and cost $3 billion and we can now do it in 72 hours and it cost less than $1000 so the cost has come down and so now the question is let's just get all this information and it's tantalizing I mean people love to use 23 and me they like to know their ancestry I love that they learn whether they can curl their tongue to which I say look in the mirror and you'll know whether you can curl your tongue so I mean so a lot of it has become entertainment John Hey John Lantos from Kansas City thanks a lot I agree with almost everything you said and also know that our place has been pushing the envelope on trying to sequence more and more babies and as you know the Vermont Oxford Network the largest network of neonatal intensive care units has just started a collaboration with Radies Genomic Center and they want to start sequencing thousands of babies do you think there's any chance that all these arguments for why this is a bad idea will convince anybody not to do it? Well so you know it's interesting that you're saying that because the Boston Children's when they tried to do their sequencing project in a very I would say in a very appropriate way with good consent we're only able to enroll 6% of all the babies over a two-year period so part of the answer is how robust a consent process and how much follow-up and how much genetic counseling is the network going to have because the fact is is that over 90% of parents refuse to participate when they truly understood what the risks and benefits were Harold and that'll be the last question there are a bunch of you raised a number of points about who we should screen for what and why I just wonder independent of that if we thought about infrastructure one of the big challenges here is that we don't have anywhere near the infrastructure required to support people for the genetic testing that probably would be evidence based if I were to make you the czar of the American healthcare system and said you have several billion dollars to spend to improve our capacity to do genetic testing and we thought it was appropriate where would you spend the money to improve that infrastructure so that we could really support people when it's a good idea to do genetic testing do we really want to put the 7 billion in genetics I would start with the first premise I think there's a lot of other places a lot of more low hanging fruit like controlling hypertension, diabetes and obesity both in childhood as well as in adulthood because many of our health problems as adults start in childhood to childhood education because education has more of a health impact in childhood than healthcare itself is that what I suppose to answer