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October 10, 2018 – Join Dr. Kelly Diehl in Fresh Scoop's debut episode as she interviews Missy Simpson, Morris Animal Foundation Veterinary Epidemiologist, about the Foundation's Golden Retriever Lifetime Study. This is the most comprehensive, prospective canine health study in the United States, and follows more than 3,000 golden retrievers, throughout their lives, to identify the nutritional, environmental, lifestyle and genetic risk factors for cancer and other diseases in dogs. 

00:17 Dr. Kelly Diehl: Hi, I am Dr. Kelly Diehl, the Senior Scientific Programs and Communications Advisor at Morris Animal Foundation. And I'm really excited to announce a new podcast series that will feature many of our funded researchers as well as staff members, and they'll be discussing their work in advancing animal health. However, before we start, I'd like to begin with a little history about us for those who may be new to Morris Animal Foundation. Well, to start, our Foundation was the brain child of Dr. Mark Morris Senior, who was really a pioneer in small animal medicine. And Dr. Morris used royalties from the development of his specialty formulated diets, now familiar really to all of us as, of course, Hill's Prescription Diets, to provide the seed money for what eventually evolved into Morris Animal Foundation as it is today.

01:13 DD: When Dr. Morris created the Foundation in 1948, he had a vision of supporting research projects that would directly benefit the health of animals. And here we are, 70 years later, and we're still going strong. We've funded now roughly over 2,600 studies and invested more than $118 million in studies that benefit dogs, cats, horses, llamas, alpacas and a large variety of wildlife species. Just to give you an example of where Morris Animal Foundation has played a role in animal health that you may not know about, we were very instrumental in some of the early studies of canine parvovirus and the development of the first feline leukemia virus vaccine. We also were instrumental in the development of diagnostic tests for combined immunodeficiency and lavender foal syndrome, obviously in horses. We just completed a very large study studying the effects of the Deepwater Horizon oil spill on a variety of gulf species. We did a lot of the funding that resulted in assisted reproductive techniques that helped re-establish, this is going to sound like a sneeze, Przewalski's horse, one of the last wild horses. And we also did some of the initial studies that led to the development of the Penn HIP evaluation, which a lot of veterinarians out there probably use for predicting osteoarthritis in dogs.

02:51 DD: However, in addition to funding studies, education also was a part of Dr. Morris's vision for the Foundation, and we're continuing that founding principle through this podcast series. And our hope is that we can provide interesting new information in a fun and informal atmosphere. So without further ado, we'd like to start our podcast series by discussing one of the Foundation's largest projects. Many of you may have heard of it, it's the Golden Retriever Lifetime Study. And to tell us more about that study, joining me is my teammate and friend, Dr. Missy Simpson, the Morris Animal Foundation epidemiologist. So first, Missy, for those who may not know, what exactly is an epidemiologist?

03:37 Dr. Missy Simpson: An epidemiologist is someone who studies patterns of diseases in populations. So, for example, on this Study, our population of interest is our 3,000 golden retrievers. But you can really study any population, it just depends on how you want to define it.

04:00 DD: Cool. And here's a personal question. And I know this answer, but you can tell our audience. Why did you decide to become an epidemiologist after four grueling years in vet school and subjecting yourself to a PhD program?

04:14 DS: Well, I really enjoy research, and I especially enjoy the quantitative and mathematical side of research, and I'm a bit of an introvert, so this was the perfect opportunity to combine all of my interests.

04:32 DD: So, because you're an introvert, we're now subjecting you to a podcast, but also, what brought you to Morris Animal Foundation?

04:40 DS: This study, the Golden Retriever Lifetime Study brought me to Morris Animal Foundation. So, after I finished my PhD and post-doc, I was working at Marshfield Clinic Research Foundation in human health research, and when this opportunity presented itself, I was really excited to be the one that Morris picked, yay.

05:04 DD: And we're happy to have Missy here with us. So, let's talk a little bit more about the Golden Retriever Lifetime Study. First, why don't we talk about the historical background a little bit for folks. How did this study come to be?

05:20 DS: The Study started because a lot of really smart, really innovative people recognized an unmet need in veterinary medicine for a robust prospective study such as this. Up to this point, a lot of veterinary research has been piecemeal. I don't mean to discount what's been done, but there was a very real need for a large and extensive study like this. So, Bette Morris and Rod Page and a lot of other really smart people got together and decided that this study should happen.

06:03 DD: Cool. And can you give a little bit background on how the Study was designed and modeled after?

06:12 DS: Sure. The best correlation, the best comparison that people will probably be familiar with is the Framingham Heart Study. So basically, the structure is that we established a cohort of golden retrievers and are following them throughout their life to try to identify risk factors for cancer. The important part about a prospective study and one of the things that makes it really robust is that we enroll our cohort naïve to disease status and we collect exposures in real time, so it minimizes the potential for some kinds of bias.

07:00 DD: Okay. So can you describe, to go a little deeper, a little bit about the... More detail about the structure of what samples we're collecting, and what owners have to do as part of the Study?

07:16 DS: Sure. This is a big commitment for the owners who have enrolled their dogs. So every year, the owner completes an online questionnaire that asks them everything from the food that they feed their dog to lifestyle and physical activity and travel history. We also ask them for the health history of their dog's mom and dad, if they know it, as well as health history of litter mates, and there's also a behavioral questionnaire. So in total, the owner fills out about 120 pages worth of information about their dog each year. After that, they go to the veterinarian, and the veterinarian does a really extensive physical exam and collects blood, urine, feces, hair, and toenails. And then we ask the veterinarian to also fill out quite a long questionnaire that includes the dog's health history for the prior year, any medications that the dog is on, vaccines, as well as a physical exam report. The samples that the veterinarian collects for us get... We run clinical pathology, routine clin-path, heartworm test, fecal exam, and we also bank blood, whole blood, serum, feces, urine, hair and toenails for future studies, which in the epidemiology biz, we call "freezer studies." If there are veterinarians or Study participants listening and, heaven forbid, your dog gets diagnosed with lymphoma, grab a lymph node for us please. [chuckle]

09:14 DD: Tissue is important, that's something that is one big part of this study as well. I know that we talked about... You mentioned there were 3,000... I know there are 3,044 dogs precisely that were enrolled in the Study. Can you elaborate on why that number was chosen in regards to our primary endpoints and explain to everyone what our primary endpoints are?

09:42 DS: Sure. I'll start with our primary endpoints. We have four of them, they are osteosarcoma, high grade mast cell tumor, lymphoma, and hemangiosarcoma.

09:55 DD: And I'm going to interrupt Missy for a second to say those are diagnoses of those diseases, not death or... That's... We'll talk about death as a different endpoint, but just so... Sorry, I just wanted to interrupt for that.

10:09 DS: Yeah, that's a good point. Those are first diagnosis of any of those endpoints. So the number 3,000 was chosen because based on the literature that was available, the actuarial calculations indicated that we would need 3,000 dogs in order to get 500 diagnoses of those four main endpoints. So it's an estimate, but it's based on a lot of data that has been collected previously. The reason we need 500 endpoints is that's a number that we can use so that we have stability in statistical models. So what that means is we'll have enough diagnoses that we can estimate risk with a reasonable level of precision.

11:13 DD: Okay. So we also measure secondary endpoints, and you talked about all the data that we collect. I think sometimes we hear from folks they think it's a cancer study, which is certainly a big focus of the Study, but can you elaborate on the secondary endpoints that we have?

11:36 DS: Yeah. So we have quite a long list of secondary endpoints, and most of them are diagnoses that are common in golden retrievers, such as hypothyroidism and atopy, things like that. Osteoarthritis is another one. And then certainly, the endpoint... The secondary endpoint that's common to everyone is death, so that is an endpoint we're definitely tracking.

12:13 DD: I have a question on... If you could tell everyone a little bit about the demographics of the people and the dogs, where they're located, just a little of the general stuff we published in the second paper that you wrote.

12:30 DS: Sure. So the the human participants in the Study are... The vast majority are white females. Our dogs live all over the lower 48 states, California has the most dogs enrolled. However, Colorado has the most dogs per capita. And I was just looking at study compliance, and Colorado has the best compliance of any other state, so yay for us. [chuckle] Otherwise, our dogs are kind of a mixed bag, so about 50% of our dogs are female, about 50% of our dogs are spayed or neutered. The range of things that our dogs do ranges from just being a pet and a couch potato, all the way to very high-performance hunting and obedience dogs.

13:37 DD: So I am going to ask you another question about why goldens were chosen.

13:44 DS: Goldens, we chose golden retrievers for a few reasons. Unfortunately, cancer is really common in golden retrievers. So that's one of the big reasons we chose that breed. But then also they tend to be pretty happy-go-lucky dogs. So they're amenable to all of the rigors of study participation, and they're also a really popular breed. So we knew we could hit our recruiting goals using this breed.

14:20 DD: Do you think, realizing goldens have high instances of cancer, that this, the information we find will actually benefit other dog breeds as well?

14:32 DS: Potentially it can. The epidemiologist answer is we don't know, because it is a highly selected cohort, so we don't know if the results will be generalizable to other dog breeds, but we certainly hope so. And there are... There will be components that are applicable to other breeds, and there will be other parts that are only true for golden retrievers. For example, maybe some of our genetic risk factors will be unique to goldens, but some of the exposures we identify could be generalized to all dogs.

15:16 DD: Right. And as Missy just alluded to, we have DNA on all these dogs, and one of the areas we're very intensely interested in is looking for genetic markers of disease because we know they could be developed into diagnostic tests for biomarkers. I think all of us are familiar with the breast cancer risk factors in women and how those are really informing how women's healthcare is delivered to people; again, that idea of personalized medicine. And what we do know about genetics is even though some of these biomarkers may be specific to goldens, what a lot of geneticists and really smart people who look at this have told me is sometimes it helps them cone down where to look in the future in a different... So okay, you find it here in a golden retriever; well, a cocker spaniel might not be in exactly the same genetic location, but it can cone down, because as everyone knows, there's lots and lots and lots and lots of genes in dogs and lots of genetic material, but if we can cone down where researchers can look, that can accelerate future development. And again, maybe you look here and you develop one diagnostic test for goldens, but it's different for cocker spaniels versus miniature poodles, but the idea, again, that the techniques and the basic underpinnings of what we find could translate to other dog breeds. Is there any applicability or translational component for humans or even other animals?

16:51 DS: Sure. Certainly, with osteosarcoma, the biological behavior in dogs is almost identical to that of children. So some of what we learn about osteosarcoma could quite easily translate to human healthcare. Bigger picture, one of the ways that dogs are such a great model for disease is because they share almost all of the exposures that they get with their human family. Dogs basically live right next to us. So what they're exposed to, we're exposed to. So there is potential for identifying some potential risk factors in humans as well.

17:42 DD: Okay. I heard a researcher talk, just to give everyone perspective, for example, we all know about the wildfires in California last year and there are some, I've heard, estimates that the most tonnage of fire retardant ever used was used to quell those fires. So really important. And we have, as Missy mentioned, a lot of dogs that have been exposed, and I know that there are some thoughts about, well, what's the exposure going to do, because... And because we know where these dogs live, we obviously can GPS track them, we actually have made models where we know they're by this reservoir, or they live in the desert, or they live here or there, is we have a very good sense of their environmental exposures, right? That they share with people. And one of the reasons dogs in general are becoming an interesting model for human disease, as naturally occurring disease, is also because their lifespan, for those of us who have dogs, is really a bummer, but, right? We all know their lifespan is much compressed compared to people. So we can find out information in a shorter period of time that may impact human health and other animals that live in that same environment. We learn... What we learn from these guys can also translate to even the wildlife that are in these areas. The Study's now been running for six years, and how many dogs and owners are still in this study? How many dogs have... If you can comment on how many are withdrawn, how many passed away?

19:24 DS: Sure, so currently in the Study, we have about 2,900 dogs, 90 of which have passed away, so that leaves about 60 dogs whose owners withdrew them from the Study for different reasons. Some owners have more than one dog in the Study, so those 2,900 dogs come with about 2,700 owners. The owner who has the most dogs in the Study has six in the Study. So as if it's not enough to have six dogs in the house, they go through this study process six times a year. [chuckle]

20:11 DD: And as you alluded, it's not just the owners and the dogs, of course we have a lot of veterinarians who play a pivotal role in this. And can you tell me... You talked a little bit about our sample collection which is fairly extensive. Once the samples are taken from a patient when they're in for their visit, can you speak a little bit to what the veterinarian then has to do with the samples that we've asked them to collect and also what they have to do on their end for the Study?

20:45 DS: Yeah. So after the veterinarian does their physical exam and draws all of these samples, they have to aliquot the blood and send it to a couple of different places. So some of the blood, some of the feces, and some of the urine go to Antech, as I mentioned, for routine clinical pathology testing. The rest of those samples get sent to our biorepository for storage. Once all of that is finished, then the veterinarian has to go online and complete their questionnaire, which includes the physical exam report and health history.

21:35 DD: Cool, and I'll put in a little commercial for Antech. They're one of our major partners in this and have donated back these tests for us to our veterinarians and our owners, and we thank them for that 'cause that's helping us out tremendously because the Study is a very expensive study for us to run. And we really appreciate them pitching in in a big way to help us out. So there's our little shoutout to Antech, thanks Antech. And so to move on a little bit, can you tell us a little, this is a kind of a fun question, on what happens to the samples when they arrive at our storage biorepository which is Fisher in Maryland. So we have samples coming from all over the country that end up at Fisher in Maryland, and if you could just briefly say to the folks what happens once they get there.

22:33 DS: Yeah, so we pull quite a bit of blood from these dogs annually. Once it gets to Fisher, they aliquot it into one milliliter aliquots, so we get 10 one milliliter aliquots of whole blood, 10 of serum, 10 of urine, and then the feces, hair, and toenails are aliquoted. Then everything gets stored in freezers. Our serum is stored in liquid nitrogen. The rest of the samples are stored in negative 80 degree Celsius freezers there.

23:19 DD: So for those of you guys who are listening, these are very expensive and interesting. They're not your house freezer that goes through defrost cycles or whatever. It's really interesting. And when we send samples to Fisher, they're kept... We have our own storage, and so they're not mixed with any other samples. The idea is that there is no confusion. And can you give everyone... Remind me, what's the total number that we have samples at Fisher right now?

23:55 DS: Right now, just individual tubes, we're sitting on about 400,000 samples. So you figure 3,000 dogs, six years in the Study, that's 18,000 study visits and, what did we say? About 33 samples per visit, so yeah.

24:22 DD: Yeah, it's a lot. Just to give you guys perspective, when you think about 3,000 dogs let's say coming in for their annuals, that's an average of 10 dogs a day we're getting notified, samples are being taken and they're going to Fisher, we're getting notifications that data has been entered. And on the back end, as Missy mentioned, not only do the owners have to provide data, it's a really big questionnaire, the veterinarians also have to go in and they provide supplemental data, some complimentary to what the owners report to us, and then the owners and the veterinarians also have different data that they report to us. So lots of data points. I think we estimated over five million by the time the Study is done, and that's data points from the questionnaires as well as these biological samples. And just really quickly, 'cause I'm sure our veterinary audience may have an idea of why we want the blood samples, but can you discuss a little bit about the why we have hair and nails, which is kind of interesting?

25:26 DS: Yeah, the hair and nails are to investigate potential environmental toxins. So the things that we're exposed to outside and inside, all of those chemicals, pesticides, herbicides, everything, likes to sit in our hair and nails. So we keep those on hand to potentially look at associations between environmental pollutants and risk for cancer.

25:58 DD: Okay. So just a couple of things to finish up here. I know that you have started to look at some of the, not the biological samples, but in your role as epidemiologist, you've started to look at some of the older questionnaire information. And what have you used this information for so far, and what are your plans looking at this over the next year?

26:25 DS: Yeah, so far we have two papers published in peer-reviewed journals. The first one describes the structure of the Study and a little bit of the history. The second paper is descriptive and it just goes over the characteristics of our dogs at the time of enrollment. So it was just a way to get that data out there. Instead of having to revisit it in every single future publication, we can just cite that paper now. Future research plans, we are currently analyzing, looking at spayed/neuter data, and associating it with some chronic health outcomes, including overweight and obesity, and some non-traumatic orthopedic injuries, like cruciate tears and osteoarthritis. Another paper that we're working on is just describing the behavior data over time. So the behavior questionnaire that we use is the CBARQ, which is spelled C-B-A-R-Q. And it's a publicly available online behavior questionnaire, and anyone can go take it on behalf of their dog. But this is the first time anyone has been able to collect longitudinal data using that instrument, so we are going to look at whether or not the behavior constructs that come from that survey are stable within a dog over time.

28:12 DD: So that's kind of cool. So that's looking at, again, I think a lot of owners and those of us as veterinarians, when we've done behavior analysis, etcetera, it would be interesting to notice what can change in a dog, or maybe they don't change at all over time. If you're always nervous about thunder, no matter what you do, you're always going to be nervous about thunder. So that sounds really, really cool. And just to fill in for the folks listening, when we enrolled dogs, they had to be between six months of age and two years of age. So our youngest dogs are now around three and our oldest dogs are seven, in that range. So when we we're talking about this, we get questions from people about, "Can we enroll our dog?" And, "How old are these dogs?" And the idea was to try to capture them when they're really young, not older, though we have lots of dogs that live in the same houses with these dogs. And we certainly recognize that they're there, but they're not technically completely part of the Study. So once the Study is complete, what happens next?

29:25 DS: That's a great question. [chuckle] I guess I'll need to get my CV in order. [chuckle] Once the Study is complete, it will live on. The dogs in this study are really going to be immortalized because their data is so valuable, and people will be doing research on this data for many, many years to come. In addition, we will have this wonderful repository of biological samples that will continue to serve the veterinary community long after the Study is closed out. And I should also mention that in addition to the biological samples that we collect annually, we're also getting tissue samples on a lot of these dogs, both at the time of cancer diagnosis and when they pass away.

30:28 DD: Great. And I will add in that we talked a little bit about Missy being tasked to look at a lot of this data, but obviously at Morris, we don't have the opportunity to analyze, do lab data. I mean, we get some results, so we're actually beginning a process of sending out calls for proposals to our research community. So if you're a researcher and listening, we're going to make these both data, data and samples, just samples available to researchers. We'll require of course that people submit proposals to us. They'll be evaluated in pretty much the same way as we evaluate our normal grants that we've been receiving for and funding for 70 years, but that those samples will be also available. And as Missy alluded to, there's a lot of samples. And so I think this is going to fuel research for decades to come, which is cool. Which brings me to another question, which was is there technically an end date to this study?

31:30 DS: There is not. So we are currently planning to follow these dogs until we get our 500 diagnoses of those four endpoints, but depending on budget and a few other factors, we may end up following at least a sub-cohort, but hopefully the entire cohort throughout their entire life course. So we don't have a date on the calendar when things will end, but there are some predefined checkpoints along the way.

32:10 DD: Yeah, that's really cool. We know that there are other folks who are starting studies smaller in scale that we are really proud of. Some of them we've been a big brother to as they've designed their studies. And I see this as being a really pivotal study for veterinary medicine, because eventually it could extend beyond just golden retrievers to other breeds of dogs, or cats, or horses, or prairie dogs, or whatever we can do. I think it's a great model out there for other people, and I'm really excited about the collaborative efforts we can do as well. So thanks, Missy, it was great to have a chance to sit down with you and discuss the Study. And I'd like to thank everyone for listening and hope you'll join us again in the next few podcasts.

33:03 DD: We're going to cover some very different topics than we did today. So we're going to talk with Dr. Noah Cohen from the Texas A&M University, who's one of our funded researchers on foal pneumonia, which is a big problem for our equine companion animals. And we're also going to speak with Dr. Kate Meurs from North Carolina State University, and she's going to talk about mitral valve disease in dogs, which is the number one heart disease, not only of dogs, but of all animals. If you combined all the other heart diseases together in dogs and cats, mitral valve disease would beat them all. So important problem. And we're going to be speaking with Dr. Dave Edmunds from Colorado State University on chronic wasting disease, which is a hot topic, as everyone knows. It's a prion disease that is decimating a lot of our deer and elk, and has some important implications for human health as well. So thanks again for joining us and we'll see you next time.