Wisconsin Public Television University Place  50 Years of Newborn Screening  Charles Brokopp  4/3/13 UP855  cc [APPLAUSE]  >> Thank you, Tom. I think this is my third time to present before this group, and every time we keep coming up with something exciting. Newborn screening is really exciting. Fifty years of doing newborn screening in this country. 1963 to 2013 a lot has been accomplished. We've led not only the state, the country, and in many cases the world in newborn screening. But the other thing that's exciting about today is, and Tom mentioned a little bit about public health. This is a special week for public health. It's National Public Health Week. And if I can get this to run, I have a little video I'd like to share with you. 

Don't fall asleep. It's less than two minutes long.  If I... >> Slide show, at the top.  The very, very top. All the way to the top. There you go.  >> Done. Okay, newborn screening is public health at its best. You just saw what public health does that many people really do not realize how many different areas of public health is involved in. 

The newborn screening has been a spectacular public health success because it saves lives, it prevents disability, and it saves money. Tonight, I'd like to talk to you a little bit about how newborn screening does this and why it is so important. But first, this has been a long winter. [LAUGHTER] A very long winter. [LAUGHTER] However, I think spring is coming. The necks are a little bit shorter, so that must mean the animals are a little closer to the ground. [LAUGHTER] In 1903, the Wisconsin legislature did something that was really quite remarkable. They passed a law to establish a public health laboratory at the University of Wisconsin here in Madison. Not only did they pass a law, they appropriated $1500 to set up this laboratory in the basement of what is known as CALS. If you walk out of the building tonight and look to the right, you can see this building up on the hills. 

That was the home of the first laboratory of hygiene housed at the University of Wisconsin. The State Lab of Hygiene is really a partner in public health research, education, and service, and it was placed here at the university specifically to benefit from the university's scientific capabilities, the research that goes on here, and the teaching to promote public health. All states have a public health laboratory, but there's only three states where the laboratory is placed at a teaching university and not part of a executive agency like the State Health Department. That slide before showed our two buildings. We have a building on campus, and we have a building off-campus over on Ag Drive. And this particular part of this slide is our existing building on Ag Drive. And we're looking forward to moving into the other part of that slide, which is a new addition that will be opening up in July of this year. Just to give you a little idea about the State Lab of Hygiene before I get into talking specifically about newborn screening, we're organized with six major divisions: a lab improvement division, and occupational health division, a communicable disease division, environmental health division, and a disease prevention division. I think each one of these I could spend an hour telling you about what we do to promote public health in those major divisions, but tonight I'm only going to talk about newborn screening, which is part of this disease prevention division over here. We have a staff of about 340 scientists, 10 fellows, and at any point in time we have 25 or so faculty and academic staff that are part of our laboratory. 

We have annual budget of about $43 million. Three-quarters of that comes from grants, contracts, and fee for service work that we do. About one-quarter, or about $10 million, is money that the legislature appropriates to the university to support our laboratory on an ongoing basis. What do we do? We do reference testing in both the clinical area and in environmental testing and occupational health testing. Our staff are involved in teaching. They have faculty appointments in at least seven departments across campus. We also have a research mission and an outreach mission where we take what we do in the lab and use the Wisconsin Idea to push it out throughout the state. But back to newborn screening. This is an area that is really something I'm very proud of. The staff in our lab has really been on the cutting edge of developing newborn screening programs here in Wisconsin and throughout the nation. 

A couple people on this slide I'd like to point out. The center picture right here is the same as over here. And that is Robert, I'm drawing a blank on his name, Robert Guthrie. Dr. Robert Guthrie is sort of the father of newborn screening in this country. And I'll talk a little bit more about some of his accomplishments later. But he was the first person to really recognize that we could do something about children who were born with inborn errors of metabolism, that we could identify them, and if we could identify them, there's a way to treat them with a special diet that would allow them to develop normally. A few facts I'd like to make about newborn screening. One of them is that newborn screening touches every baby born in the United States. There may be an exception or two, a child that may not be born in a hospital or a child that, for one reason or another, may not be in a place where they can take advantage of newborn screening. But our programists work very hard here in Wisconsin to assure that 98% to 99% of all infants born in the state will go through this process toward newborn screening. 

I mentioned earlier about newborn screening being a public health success story. It's probably one of the most cost-effective public health programs ever. For the dollars we spend identifying infants with conditions that can be very debilitating or could result in their early death, we can prevent so much suffering by doing newborn screening and treat these individuals so that they can develop and have a normal life. Newborn screening is really more than just a laboratory test. In our lab, we test 200-300 plus infants per day. I'll go into a little bit more of that. But there's a lot more than just doing a test to identify the infant. Newborn screening also involves  a follow-up assuring that a diagnostic confirmation test is performed and that those infants are connected with providers who understand the condition and can treat them properly. Newborn screening is also a very dynamic program. We think we're kind of at the point where things slow down for a while, and then somebody comes up with a great idea: could you screen for another condition? And so we scratch our head, go into the lab and say, sure, we can do that. 

And when we do that, we can bring a new test on. When we bring new tests on, there's always something new on the horizon that we can be working on. Robert Guthrie once said, no child should die or suffer disabilities if a single blood spot can prevent it. And that's sort of the kind of a statement that's at the heart of newborn screening the way it's practiced today. A little history of newborn screening. In 1908, an Englishman by the name of Archibald Garrod hypothesized that there was something called inborn errors of metabolism. People just didn't metabolize proteins or fats the way they should, and there was some error, probably due to a chemical that may have been missing in their metabolic pathway. 1934, a Swedish physician by the name of Folling discovered PKU, and it took about 10, 12, 13 years later before Dr. Guthrie sort of got interested in this, and he became interested because he had a son that was born with an intellectual disability. Now, prior to newborn screening here in Wisconsin, we had state hospitals that were full of infants who were diagnosed or who had PKU, they were not diagnosed. They were put in these state institutions, and, in most cases, they could maybe live to be 30 or 40, but they would have very, very severe intellectual disability. 

We don't have that anymore as a result of newborn screening. In 1951, Horace Bickle discovered a treatment, a special diet for PKU. Once they understood that phenylketonuria was a disease where the person could not break down phenylalanine to tyrosine. There's an enzymatic defect there. And so what happens, phenylpyruvic acid builds up and that's very, very toxic to the brain. Once they discovered the cause of PKU, they realized that if they could provide a diet that was very low in phenylalanine or had no phenylalanine, this whole condition could be pretty much prevented. In 1958, Dr. Guthrie really decided he needed to do something about this because he had a niece that was diagnosed with classical PKU. Dr. Guthrie was a cancer researcher in New York, and he used some of those technologies that he had applied to cancer research to actually look at how one could go about detecting a metabolic condition like PKU. In 1960, he developed what's known as a bacterial inhibition assay that actually measured phenylalanine levels in dried blood spots. The dried blood spot was another one of his ideas that basically allowed us to screen infants without having to draw a blood sample. 

It's rather difficult to get a significant blood sample out of a newborn. But by using this dried blood spot technique, all we had to do was prick the infant's heel, collect a couple drops of blood on a piece of filter paper, let it dry, send it into the lab where we could extract the blood from the filter paper, and run our test on that tiny little bit of blood that we get out of the dried blood spot. A couple years later, Massachusetts, Oregon, and Delaware were the first states to implement universal newborn screening for PKU. This followed several studies that Dr. Guthrie performed where he was able to identify infants with PKU shortly after they were born and long before they started to develop serious consequences. During the 1960s, many states began screening for PKU, and during that time, they realized similar tests could be used to screen for another metabolic condition, maple syrup urine disease, homocystinuria, and then later, congenital hypothyroidism. All of these conditions can have serious implications for infants. In the '70s and '80s, newborn screening technology really revolutionized with new technology. The tandem mass spectrometry came in where we were no longer indirectly measuring for those chemicals involved, but we're actually doing an analytical chemistry test on a sophisticated piece of equipment. This greatly expanded our ability to identify infants with a whole host of metabolic conditions. In 1987, HRSA funded a Council of Regional Genetic Networks, often referred to as CORN. 

It was realized if newborn screening was going to expand, one of the things we really needed to do was to bring some standardization to the testing and the follow-up of these infants who could be diagnosed. In '92, the CORN, the Council of Regional Genetic Networks issued a series of reports, not only on standardizing the testing, but also adding appropriate follow-up management and evaluation of infants that had been identified. In 2001, HRSA again funded the American College of Medical Genetics to come up with a uniform panel of conditions that should be screened for in all newborn screening programs. They came up with a panel that had 29 conditions on it, and, at the time, only a very few states were screening for all 29 of these. Some states were only screening for three conditions or eight conditions, maybe 10 conditions. I'm happy to say today that all states are now screening for that panel of 29 and, in many cases, many more conditions that involve these infants. In 2003, the Secretary of Health and Human Services established an advisory committee on inheritable disease in newborn children. This committee has played a key role in looking at newborn screening and reviewing the scientific evidence that needs to be there before we can go about adding something to our panel. A couple years later, the ACMG again reviewed the panel and came up with this, not only the core panel but also a list of 25 secondary conditions that should be part of newborn screening. 2008, I left a word out there. 

That was President Bush, believe it or not, signed a bill, the Newborn Screening Saves Lives Act, and that basically provided some significant funding to enhance newborn screening and the efforts of several federal agencies. In 2010, the Secretary's advisory committee, and ultimately the Secretary, decided to add something called severe combined immunodeficiency to the panel. Much of the early work on that was done by Dr. Baker in our lab just a couple doors from here. That is a condition that occurs when infants are born without the ability to produce a protective immunity. They have improper development of T cells. And because of that, these infants are susceptible to a whole host of bacterial and viral infections, and if they're not detected and properly handled, they will generally die within 12 months to 24 months of age. But because we developed this test, we can now identify those infants, they can go in for a transplant, and actually be given cells that develop after the transplant so that they can have a normal functioning immune system. This is the first time when we've actually been able to cure an infant with a genetic defect. And that's something that was basically something that happened here at the University of Wisconsin. There's now 20 some states that either brought in online in the last couple years, and about 17 countries that I'm aware of that have come to us and asked for help implementing this type of test. 

In 2011, the Secretary's committee added another component to newborn screening, and that was adding a screening for critical congenital heart disease to the panel. And unlike the laboratory test, this and newborn hearing screening are things that are actually performed in the hospital. Screening for critical congenital heart disease is done by pulse oximetry where they check the baby's blood for the amount of oxygen in the blood, and if it's low, there may be a critical heart defect that needs further investigation. And now, 2013, there's 31 core conditions and then 26 secondary conditions that are part of our panel. Back then we were using something called a Guthrie test. It was a bacterial inhibition test that he published in 1962. Basically, it detected an elevation in phenylalanine from the infant's blood. Literally, that test saved babies. It saved them from a life of severe mental retardation. Today, we still use these Guthrie cards, so that's what they're referred to, to collect a small volume of blood. 

Overall, the incidents of infants that we identify with one or more of these conditions is about one in every 4,000 infants that we screen today. And it's an extremely cost-effective public health program. I'll share with you some of the actual dollars on some of these programs a little later. Now we don't use those true tests. We use things like tandem mass spectroscopy, molecular assays, gel electrophoresis, and sophisticated chemical instruments to identify these infants. We screen in Wisconsin for 47, some people will say 46, different diseases and conditions, but we still do it with that tiny drop of blood from the infant's heel. The tests are very sensitive, they're highly specific, and they give us a very good opportunity to identify infants with a whole host of these conditions. We still use the Guthrie card, and, again, the procedures we use today are extremely cost efficient. We screen infants in the state of Wisconsin for $109, but only $59 of that goes for the testing. The rest of it goes for the follow-up activities and some of the special formulas that these infants get. 

So, for $59 you get a battery of tests that if you were to go into a clinical laboratory and pay for each one of those tests, that would run somewhere probably around $2,000 per sample.  Newborn screening is probably the most commonly practice genetic testing that there is. We screen about 68,000 Wisconsin newborns a year. And because we're good at that, other people come to us and want us to screen babies from their jurisdiction too. So we are now screening babies from Kuwait, from Turkey, and from other countries either on a routine basis or as part of a research project that we entered into. We can detect 46 metabolic conditions, and in addition to the laboratory component, there's sort of this non-laboratory piece that involves screening for hearing loss and screening for critical coronary heart disease that are simple tests that are performed while the infant is still in the newborn nursery. So, 50 years of newborn screening. This is an opportunity to really celebrate accomplishments in this particular area. Fifty years of newborn screening, these are just some of the things that will be happening this year, primarily on the national stage. There's a national/international newborn screening symposium coming up in a couple weeks in Atlanta. 

Many of our staff will be participating in that, presenting papers, and attending that meeting. There will be a national celebration on the mall in Washington, DC, on September 18th where families who have children that have been saved by newborn screening are being invited, and a number of awards are being made to organizations that have led to the wonderful newborn screening program we have today. There are public service announcements running in Times Square. I don't know how many of you have been to New York's Times Square, but even at midnight it looks like Las Vegas with all of the lights. Some of those huge screens up on the buildings are now running, periodically, these messages about newborn screening and the value that newborn screening plays. There's some traveling exhibits that will be going around the country, and that will be coming here in July. I'll mention a little bit more about that. We've also have been working with Dr. Richard Besser, who's the ABC Chief Medical Correspondent. And he's going to be doing a series on newborn screening that coincides with the celebration in Washington, DC. In addition to that, state and local organizations are planning a number of different celebrations. 

This little picture right there, get the facts, was just a shot of the promotion that's running in Times Square. Here in Wisconsin, we're going to be doing similar things in July. We'll have the national exhibit coming through July 1st through the 18th. That will be set up in several places around Wisconsin. One of those will be on July 12th right next door in our lab where we hope to have the celebration with families here on Henry Mall. We'll be offering laboratory tours and a program briefing from the follow-up people to highlight the success of this program. Well, I didn't know that bird flew. I guess it does. [LAUGHTER] That's what happens when you borrow someone else's slides. A little bit about the Wisconsin newborn screening program. 

There are two people who played a key role in the development of this program. One is my predecessor Dr. Ron Laessig and the other is Gary Hoffman. Ron Laessig was the director of the Wisconsin State Lab of Hygiene for 25 years. During his tenure, one of his priorities was to build the best newborn screening lab in the country. I think he succeeded in doing that. He had an opportunity to hire a chemist by the name of Gary Hoffman who just recently retired as director of the Wisconsin Newborn Screening Laboratory. These gentlemen really represent the past of newborn screening here in Wisconsin. Today, we have two fine individuals who are serving as co-director of the Wisconsin Newborn Screening Lab. One is Dr. Mei Baker, and the other is Dr. Patrice Held. Mei Baker did a fellowship here with our laboratory, and we're fortunate enough to have her stay on with us. 

Dr. Held also did a fellowship, but she was honored to do the fellowship that was actually named after Ron Laessig, the National Newborn Screening Fellowship that was sponsored by the Centers for Disease Control, Modell Foundation, and our laboratory. So we're really honored to have the two of them be part of our laboratory today. Oh, boy. I'm going to just click through this. The next few slides are a little history of newborn screening here in the state of Wisconsin. In '78, we added galactosemia,  and we've screened over 2.3 million. In '78, we also added maple syrup urine disease and screened  about 1.6 million. And that has a very low prevalence to about one in 250,000 births here in Wisconsin. '82, we added screening for homocystinuria.  And I really wish I would have turned that thing off. 

And in 1988, we added screening for sickle cell disease. In some cases, and this is an example, sickle cell disease, where not only do we screen for the disease but, in the process, we can identify individuals who have other abnormal hemoglobins, and we can identify individuals who may be a carrier for that condition, which opens up another issue that I will address. >> Can I ask how you do 1.3 million in that first year? >> That wasn't the first year. That's total. Since we've been screening, it's been at least that number. Biotinidase deficiency was added in '91. Congenital adrenal hyperplasia was added in '93.  And in '94, we added cystic fibrosis. And there's a little history on cystic fibrosis. Wisconsin was probably the state the did much of the initial research on screening children for cystic fibrosis in cooperation with Dr. Phil Farrell and others in the Department of Pediatrics. 

And we're still doing research to look for additional markers for cystic fibrosis today. In 2000, we added fatty acid oxidation and organic acidemias because we had new equipment. The tandem mass spec was available to us.  In 2003, aminoacidopathies, again, using that same equipment, we were able to identify additional conditions. And in 2008, we added severe combined immunodeficiency, and we've screened a little over 300,000 infants here in the state to date. And the prevalence of that is somewhere around, and it varies depending on the population, I've seen it as low as about one in 20,000, one in 40,000, one in 60,000 is sort of where we're at here in Wisconsin. I'm going to just give you a little idea about a cost model. One of the things that Ron Laessig shared with me shortly after I came back to Wisconsin was he was a great storyteller, and these data here are part of the story that he liked to tell. And, basically, we sat down one day and we ran the numbers. If we just looked at two conditions, PKU and hypothyroidism, and we made some assumptions. 

The assumptions that we would identify about five babies with PKU and 25 with congenital hypothyroid a year, roughly 30 babies a year, before newborn screening, most of these babies were institutionalized. And they were institutionalized either at the expense of the family, insurance paid a little bit of this, but the state ended up paying for much of the ongoing care for these infants. Roughly $70,000 a year. That would be in today's cost. If we assumed they lived 40 years, the annual cost today would be about $84 million if we were not screening these infants and getting them treated and this condition prevented. And I mentioned earlier that the newborn screening is $109 per card per baby. $58 of that goes to the lab, $51 goes to the follow-up, and the screening diagnosis and treatment cost are estimated at about $7 million. Run the numbers. It's pretty easy. $77 million a year saved by newborn screening. 

And Ron Laessig liked to tell the story about meeting, I don't remember who the governor was, but he liked to talk about the good things public health does. And I remember him talking about having a chat with the governor here in Wisconsin and telling him, you know what this lab does? We save babies' lives and we save money. We saved $77 million last year. And the governor, whoa, that's really good. But then Ron would say, and guess what, governor? I'm going to save you $77 million next year. There are not very many public health programs that can make a statement like that and back it up with numbers like this. The newborn screening process in Wisconsin is sort of outlined here. Basically, hospitals purchase these kits, these cards are basically a piece of paper with some filter paper on one end that they collect the blood spots on. They purchase those from us. They do education of the mother, along with others. 

Sometimes the expectant mother receives some education during the prenatal period, other times it happens in the hospital right after the baby is born. The hospitals then do this heel stick. They collect the blood. They fill out the form. They submit the form, the dried blood spot to us. It comes into the lab. We punch just a tiny little piece of that saturated filter paper out. We do the lab analysis. We report it back to the hospital and the healthcare provider and then make sure that those infants who are positive are connected with their healthcare provider and we provide consultants for each of the various disorders. So, if the local physician who maybe heard of PKU but has never seen one in 25 years of practice, we can say, well, we have a consultant who's very familiar with this, and we link the consultant with the local physician so that they can promptly and adequately treat the individual. 

It's probably not fun for the infant to get stuck in the heel. It's a rather noisy process, but in the long run, it's really good for the infant. This is an example of the card. We collect information. Right here are the actual blood spots that are collected from the infant. They're dried, and then those are sent into the lab. We provide a specimen transport system that picks these up around the state and overnight brings them in. In some conditions, it's very important that we test as soon as possible. In other conditions, if we test it later in the week, it would not result in any adverse effect. But for some of the conditions, like galactosemia, it's very important we do the test and we report it, especially if it's abnormal. 

And in many cases, some of the infants that have this particular condition, by the time we report it, the infant's already crashing and is probably in an intensive care unit is where they locate the unit. But once physicians understand that some of these conditions are involved, then their whole treatment modality changes, and we can save these infants in almost all cases. Oh, no. I apologize for not turning these off. But I'll just talk briefly about characteristics of the good screening tests. In order for a test to be used in newborn screening, it really needs to be simple, it needs to be something we can do rapidly, fairly inexpensively, safe to use, and something that's going to be acceptable. And those are the key criteria that we look for when we're trying to select a test. There's a number of issues right now around newborn screening, and what I'd like to do is wrap up and just kind of talk about some of those or just ask the question and then maybe we can discuss some of those after I finish when we have some of our experts up here who really understand this a whole lot better than I do. There's a number books that have been written. Rachel Grob, who's actually an attorney here at the University of Wisconsin, did a real nice review of newborn screening, the screening process, and the policies behind that and has written a book called Testing Baby. 

There's also another book called Ethics in Newborn Genetic Screening that is the first book that started to highlight some of the concerns that we need to take into place or take into consideration when we are putting programs like this in place. A couple of weeks ago, the cover of the Time magazine said would you want to know your future? Would you want to know if your baby has a condition that might not present itself until a child is 20 years old? Would you want to know if your child is a carrier of a serious disease? Would you want to know if your child is susceptible to maybe having high blood pressure as a young person? Or maybe would you want to know if your child has genes that's going to predispose them to diabetes? These are all things that we either do now or we're going to be able to do in the near future, but we're going to have to deal with the ethical issues around questions like that. These are some of the issues that we have to deal with. What are the criteria for population-based screening? Not only what criteria should we use but who's going to decide whether we add the test or we don't add the test? It's been pretty simple for us here in Wisconsin. We have a very supportive Department of Health. Very understanding and they've been very good to work with when it comes to adding new things to newborn screening. Informed consent comes up.  There have been a number of studies where they've tried to apply traditional, kind of the informed consent to newborn screening. So, say, the mother would have to give informed consent before the blood sample is taken. If it's truly informed and you can really inform the mother of the risk and the benefit, I believe most parents would say, let's do this. 

If the information isn't correct, isn't complete, it sometimes scares people to think that somebody is going to take some blood from their child and take it off to the lab and do a whole bunch of tests for it. So, in some states there's been quite a problem with the lack of informed consent for this. Most newborn screening programs do not follow a true informed consent because they've realized the by the time you get the informed consent, some people will really opt out. Now, people can opt out for maybe religious reasons or for other reasons, but obtaining informed consent has the negative impact of maybe reducing the infants who are screened by 5% to 10%. And then the issue comes up, what happens if that's the individual who has one of these conditions and they opted out from screening? And if we'd only tested them, we could have prevented it. And hardly a month goes by when we don't have a situation similar to that come up here in Wisconsin. There are a number of issues around the retention and use of the dried blood spot. We only take, what is it, five or six little punches out of the dried blood spot, and we have a couple dried blood spots we don't use. Should we be allowed to retain that and then to use that for maybe other things? Like for research or for method development? For quality assurance of our process? In some places they are finding it more difficult today to do that. Here in Wisconsin, we still think it's useful to take that, de-identify, it's simply a blood spot, or it's a piece of filter paper with a blood spot on it, no identifying information with it, and if we can strip the identifiers off, then to use that in other ways to further research and further develop methods, I think is a valuable use for that material. 

The alternative is simply to destroy it. Do infants need to be screened twice? In some cases, newborn screening programs will screen an infant as soon as they can after birth, and then they'll wait 48 hours or as long as two weeks and re screen them. There is some evidence that you might be able to pick up additional infants doing that, but the timing of the specimen that we recommend is after 48 hours. We're one of the states that still only screens the infant just once, but some states, I think it's probably a third or more, are screening infants with two samples. Then the impact of new technologies is going to impact us quite a bit. Today, with new molecular technologies, we can look for not only chemicals in this dried blood spot, but we can actually extract the DNA and look for various genes that may be associated with a whole host of conditions. Some of the criteria for population screening, there's several of these that have been proposed, but one of them is you have to ask the question, is an appropriate test available? You have to look at cost. Is this a common condition or something that's very rare? Is there a confirmatory test available if they screen positive? Can you make a definitive diagnosis on those who screen positive? Does early detection make a difference? And are there negative consequences to screening? Can the information that you get from screening have a negative impact on the child, the family, or relatives? And, in some cases, if it's not handled properly, that certainly could occur. These are the types of questions that would be asked of a parent. Should you or your child be tested? If we identify a child with cystic fibrosis, should you test other children? Should you be tested? Are you carrier? Is your spouse a carrier? These are all questions that can come up. 

Should newborn screening be mandatory? Can screening specimens or DNA taken for specimens be saved for later use? We can do that, but should we? I think there's some real benefit in doing it as long as we do it in a way that protects the confidentiality and the privacy of the person from whom that specimen was obtained. Who should pay for this? It's so cost-effective. Now the hospitals pay it and they bill insurance companies or they bill Medicaid for it. 30% of the babies born in Wisconsin are Medicaid eligible. So the Medicaid program reimburses the hospital for that. In some cases, private insurance and private individuals will pay. And then there's questions around the use and possibly misuse of new genetic methodologies. Some of the other elements include if we're going to screen, we really want to screen all babies. It doesn't work if you really only screen some, and then those who might benefit by it don't get screened. You really, if we're setting up to do that, it's best to screen all babies. 

There's questions around education of parents and the care providers. What do they know about the condition? We want to make sure there are plenty of providers there who can see these infants and care for them once we identify them. We have to understand how reliable our tests are and make sure that there's timely notification and follow-up on the tests. What must we report? More and more we're starting to have tests that not only do we get a positive test result on one analyte, but because we're looking multiple analytes using a particular technology, we might find other things that are important in addition to what we're screening for. And if so, do we report that? That's a question that is becoming more and more difficult to answer, especially when we start using molecular assays for this. So, newborn screening means healthy babies in Wisconsin. I wish I knew the number of healthy babies that there are in Wisconsin today that are healthy today because we were able to do the screening and identify this early on. And, with that, I'd like to acknowledge Gary Hoffman, Jan Clouder, Dr. Baker and Dr. Held, and our entire newborn screening staff who provided much of the information that I shared with you tonight. With that, I'd like to ask Dr. Baker and Dr. Held, they're here, and between the three of us, if you have any questions, we'd be happy to answer those for you. [APPLAUSE]