An insight into brachycephalic dog health from The Kennel Club

The Kennel Club has hosted a unique webcast to discuss brachycephalic health and what can be done collaboratively to ensure a healthier future for dogs. Chaired by Kennel Club Chairman, Tony Allcock OBE, the webcast panel comprised Dr Jane Ladlow, European and Royal College Specialist in Small Animal Surgery and leading BOAS researcher; Bill Lambert, Head of Health and Welfare at the Kennel Club; and Charlotte McNamara, Health and Welfare Development Manager at the Kennel Club.

The panel discussed brachycephalic health, approaches across Europe, the need for a collaborative, evidence-based approach, including how the Respiratory Function Grading Scheme can help protect and improve the health of brachycephalic dogs now and in the future, and the importance of data collection and ongoing research into the complex Brachycephalic Obstructive Airways Syndrome (BOAS).

Further information about brachycephalic dog health, what the Kennel Club is doing and which tools and health screening is available to breeders can be found at: https://www.thekennelclub.org.uk/flatfaceddoghealth

To donate and support further research into brachycephalic dog health and BOAS, visit: https://uk.virginmoneygiving.com/charity-web/charity/displayCharityCampaignPage.action?charityCampaignUrl=BDH

Nearly 20 years of DNA testing – what can we learn?

Doctors Tom Lewis (KC) and Cathryn Mellersh (AHT) recently published an Open Access paper where they analysed trends in DNA testing for 8 autosomally recessive conditions in 8 breeds. A headline in the Vet Times said “Study reveals ‘fantastic work’ of DNA testing”. The sub-headline stated that “A study has revealed responsible breeders are reducing the number of pedigree dogs at risk of often painful and debilitating inherited diseases by around 90%”.

This paper is exactly the sort of great work we have come to expect from the KC’s Health Team and their partners at the Animal Health Trust. I believe it could be one of the most influential papers that might be published this year because of its potential to influence breed health policy and strategy, as well as the behaviour of breeders and buyers.

I don’t want to dwell on the detail of the research; you can read that for yourself, here: https://goo.gl/PiQmMF – I want to discuss how and why this paper might be important. The study covers the results of 8 DNA tests in 8 breeds for the period 2000 to 2017. 2 of the DNA tests applied to 2 breeds, resulting in 10 test+breed combinations. The key metric used to measure progress was the Mutation Frequency which is more useful than simply counting the number or calculating the proportions of Clear, Carrier and Affected dogs. It is calculated as [(2 x No. of Affected) + No. of Carriers]/(2 x No. of dogs with a known result).

Measures of progress

Previously, many reports on the progress of DNA testing have simply shown the proportion of Clear, Carrier and Affected dogs tested each year and that’s what we used to report in our Dachshund Annual Health Report. However, as tests become more established, the KC is able to deduce the status of untested dogs and assign their hereditary status. For many tests we are now able to identify Hereditary Clear, Hereditary Carrier and Hereditary Affected dogs based on test results from their parents. That still leaves a proportion of dogs in the KC database without known or deduced status and the researchers acknowledged this in their analysis but were able to calculate a “worst case” view of mutation frequency in each breed. Those of us reporting on DNA testing in our breed should be asking the KC Health Team for Hereditary results so we can give a more accurate picture of the impact being made. The difference can be quite significant, for example 50% of the test results for PRA-rcd4 in Gordon Setters were “Clear” in 2017 but, when hereditary status is taken into account, 95% of the breed was “Clear”. When you’re telling the story of what’s been achieved, that’s a big difference.

Another aspect of the paper is the data on trends in uptake and usage of DNA tests. For most breeds, unsurprisingly, the peak uptake of DNA tests was around the time it became commercially available and subsequently tailing off. The one exception to this was Exercise Induced Collapse in Labradors where use of the test has grown steadily since its launch. The peak around launch may reflect the fact that breed club communities are often actively involved in developing a test and are therefore keen to make use of it as soon as it becomes available. The challenge for all of us in breed clubs is how to educate and influence those outside our community to make use of these tests.

The paper also shows that there is an inverse relationship between the size of a breed and the take-up rate of tests. The slowest rate of increase occurred in the 2 numerically largest breeds, Labradors and Cockers. In smaller breeds, it’s more likely that breed clubs have influence over a higher proportion of breeders. The Labrador/Cocker effect may also be related to the split of working, show and pet breeders, making it more difficult to reach a more diverse group of owners. It may also be the case that, in breeds where multiple DNA tests exist, like Labradors (5 tests according to the KC) and Cockers (4 tests), it is more difficult to persuade breeders to make use of what might be seen as “yet another test”.

Another consideration related to uptake of a test is breeders’ perception of the need to use it. The severity of the condition, its age of onset and how widespread affected dogs are in the population are all factors that individual breeders will consider when prioritising whether or not to use a test. In some cases, breeders simply don’t want to know despite the seriousness of a condition and prefer to bury their heads in the sand. All of this gets me back on my change management hobby-horse; it’s important to communicate much more than just the launch or availability of a new test.

Wider implications?

In some cases, the launch of a new test could actually make things worse in a breed. The paper notes the evidence of selection – breeders intentionally avoiding producing affected puppies. In some breeds we have seen unhelpful selection strategies such as Affecteds or Carriers being removed from the breeding population completely, when they could quite safely be mated to Clear dogs. Another unhelpful approach is when people rush to use the small number of Clear stud dogs available and we may end up with the so-called Popular Sire Syndrome and all the adverse consequences that go with that. So, while DNA tests do indeed have the potential to prevent the breeding of more affected puppies, breeders must consider the bigger picture of genetic diversity. Reducing the gene pool makes it even more likely that hitherto unseen recessive mutations will “pop up” as undesirable health problems.

There are over 700 inherited disorders and traits in dogs, of which around 300 have a genetically simple mode of inheritance and around 150 available DNA tests. This tells us that we should not rely on DNA testing to solve the “problem” of diseases in pedigree dogs.

This new paper therefore gives the KC and breed clubs an opportunity to educate (or re-educate) owners and breeders on how DNA tests can be used within an overall breed health strategy. As well as celebrating the fantastic work done by so many committed breed enthusiasts, the messaging needs to be wider than “DNA testing improves dog health”.

I also wonder to what extent this paper might cause the KC to review its policies on the registration system, particularly given that there have long been calls for responsible breeders to be recognised for their commitment. It’s no good saying that’s what the ABS is for when so many good breeders have chosen not to join. Last year, Our Dogs wrote “A Manifesto for Change”, directed at the KC Board. Among other things, it said there was a need to address (or justify clearly) long-standing issues related to the registration system such as the ABS, DNA identification and the requirements for health testing. I hope the Lewis & Mellersh paper provides part of the evidence-base for those discussions.

Blue is the colour; CNR is the name…

Blue is the colour; CNR is the name…

Recently, we had the misfortune to discover that Johanna Konta (Tennis player) has bought a Blue Dachshund and was proudly sharing pictures on her Instagram page. The picture received over 4000 “Likes” and generated lots of discussion among Dachshund Facebook Group members.

Blue is a colour that occurs legitimately in the genetics of Dachshunds but is a “Colour Not Recognised” (CNR) as far as Kennel Club registration is concerned. Our survey data suggests that between a third and half of Blue Dachshunds can suffer a skin condition – Colour Dilution Alopecia (CDA – and there is no DNA test for this condition). Hence, we have been working hard on social media to educate potential owners not to buy dilute coloured Dachshunds (we also have Isabella – sometimes referred to as “Lilac”). We also encourage owners of these dogs not to breed from them.Blue

In the past year there has been a significant increase in the number of dilute coloured Dachshunds being sold in the UK. The majority are being bred by French Bulldog and English Bulldog extreme-colour breeders; many using dogs imported from the USA or Eastern Europe, presumably as they see an opportunity to make significant money from “rare-coloured” Dachshunds.

I suppose we can be thankful that, unlike in some other breeds, blue hasn’t been introduced recently by cross-breeding from another breed.

The KC created a CNR Working Group to look at this issue because it has caused much concern among other breeds. I understand they are due to report soon. We raised the CDA and CNR issue with the KC when we met to discuss our Breed Health and Conservation Plan.

No simple solutions

The CNR issue is a classic example of what’s known as a “Wicked Problem”. Lots of people have lots of different views on, and interests in, the problem; it’s not the same problem in every breed; there is no single, simple solution and any actions have the potential to result in unintended consequences. This is the realm of Systems Thinking where lots of factors are interconnected. Logical, cause and effect (reductionist) thinking is unlikely to help us understand how the “CNR system” works nor how to intervene to improve things.

The first step in identifying how to change the system is to understand the forces at play. Wicked problems benefit from being examined in a more holistic way and one of the tools to do that is a Causal Loop Diagram (CLD). It’s a pictorial way to link variables (e.g. Demand for “rare” colours, Registration income) and to tell the story of what’s happening in the system. The example CLD tells the story of what might be happening in Dachshunds (it may be different in other breeds). CNR System Causal Loop Diagram PDF

cnr sd model

In the model, if 2 variables are linked with a “plus” arrow, it means they increase together (e.g. the more demand there is, the more dogs are bred). A “minus” arrow means that, as one variable increases, the other decreases (e.g. the better educated buyers are, the lower the demand for rare colours). This Causal Loop Diagram also shows us that there are 4 distinct perspectives on the CNR problem in Dachshunds:

  • Demand
  • Supply
  • KC Registration Policy
  • The health and welfare of Dachshunds

These perspectives help us to see that, if we want to change what happens as a result of the system, multiple actions will be needed.  

How to change the system

Once you can see the systemic forces at play, you can then consider the conditions that either enable or hinder change. That way, you can reduce the chances of cherry-picking “simple but wrong” solutions. We need to look for “leverage points” but it’s important to understand that some of these will have minimal impact or might actually make things worse.

There are plenty of models describing how to change systems and, generally, they highlight 3 levels at which interventions can be made. Of course, being a system, the interventions and the levels are interdependent.

The biggest leverage and impact usually results from challenging the system by understanding its goals, the mindsets that created it and the current narratives. For CNR Dachshunds, these could include:

  • Only register Breed Standard colours of dogs with a known pedigree vs. Register any dog that looks like a Dachshund, whatever its colour/pattern
  • Keep the breed “pure” vs. Recognise that cross-breeding has always happened
  • KC registration is “exclusive” vs. KC registration is “inclusive”
  • “Greeders” vs “Breeders”

The next most effective areas to look for leverage points are the relationships and the power dynamics in the system. These could include:

  • Groups working in isolation vs. Engaging with campaigners (e.g. RSPCA, DBRG, CRUFFA, CARIAD)
  • One-size fits all solutions vs. Open source, marginal gains solutions
  • Individual communication & education campaigns vs. Joined-up campaigns
  • The KC sets the registration rules vs. Collaborative rule-setting
  • The show community shapes the rules vs. Breeders, owners & others shape the rules

People who don’t think about the system tend to start by looking for actions which, typically, have the lowest leverage and impact. Often, these relate to the policies, practices and resources that exist in the system, such as:

  • Registration rules & “acceptable” colour lists
  • Registration pricing policies
  • Data sharing on numbers of CNR dogs and how many have health issues (vs. non-CNR)
  • Legislation on imports & enforcement of this
  • Licencing regulations
  • ABS rules & guidance
  • Breed Club Codes of Ethics
  • Availability of alternative registries
  • Colour/pattern clauses in Breed Standards
  • Breed Club resources for communication & education

Some, or many, will need to be changed, but only after addressing the higher-leverage issues. Starting with these is like looking through the wrong end of a telescope!

Light at the end of the tunnel?

One of the other useful features of the Causal Loop Diagram is that we can identify 2 types of feedback loop. Reinforcing loops occur when an initial action is reinvested to create more of the same type of change. For example, the more a celebrity’s Instagram picture of a blue Dachshund is liked and shared, the more people see it and the more demand it creates for blue Dachshunds. Growth can’t continue forever so, wherever there is a reinforcing loop, there is typically a balancing loop to stabilise the system. However, this might not be as strong as the reinforcing loop or it might take time to kick-in. In our case, a balancing loop is owners finding their blue Dachshunds have health issues, which more people become aware of and which then reduces demand. Another balancing loop might be that unsuitable owners discover that Dachshunds were bred to work and aren’t suitable to live life as “fur-babies” or fashion accessories, and when they share their problems on social media other people become less likely to want one.

Behind every growth in demand is at least one reinforcing loop but there are also, invariably, balancing loops which come into play to resist further increases in demand. In the case of dog health and welfare, the question is whether those balancing loops kick-in soon enough to avoid a crisis for the dogs and their owners.

In a way, we’re lucky that the demand for, and supply of, blue and other “rare”coloured Dachshunds is still quite low compared with the CNR (and other colour) challenges facing the French Bulldogs, Bulldogs, Pugs and Staffordshire Bull Terriers (to name just 4 breeds). We have time to look at our particular CNR system and identify workable solutions. What works for us may well not work in other breeds and vice versa. However, we can and should all learn from each other.

For every complex problem there is an answer that is clear, simple, and wrong”.
L. Mencken

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Making sure the obvious really is obvious!

Some people are caught out and surprised at the “unintended consequences” of a decision or action to improve breed health. For others, these are entirely predictable outcomes which are merely minor blips on the journey towards a more significant strategic goal. The world of breed health improvement has plenty of examples and, this month, I want to discuss some of these and see if we can draw any conclusions about why “the obvious” may not be so obvious to some people.

The term “unintended consequences” originated in the world of social sciences and first appeared as “unanticipated consequences”. It is credited to Robert Merton in 1936 when he described the possible causes of unanticipated consequences as ignorance, error, over-riding of long-term interest by immediate interest and self-defeating prophecy.

Of course, it is important to recognise that “unintended” is different from “unanticipated”. It is perfectly possible that a decision in relation to breed health, such as introducing a new DNA test, could result in consequences that, while unintended, are not unanticipated! Anticipating the consequences of a particular policy decision or course of action should be a core responsibility of the people making the decision or taking the action.

Consequences grid
A good example of unanticipated AND unintended consequences is the introduction of the Cord1 PRA DNA test for Miniature Longhaired Dachshunds around 2005. Breeders had long known there was a problem with PRA and had diligently used the BVA/KC/ISDS Eye Scheme to identify clinical problems in their dogs. Breed Clubs regularly ran eye-testing sessions and the results were published by the KC as the condition was on Schedule A (inherited diseases). The development of the DNA test led to a commercially available “solution” which gave breeders the possibility of eliminating the risk of dogs going blind at a young age. Unfortunately, it also meant most breeders stopped doing the clinical eye screening test.

However, back in the day, very few breeders understood much about genetics and even less about genetic diversity. The language of Clear, Carrier and Affected was new to them, as were terms like homozygous and heterozygous. Jeff Sampson and Cathryn Mellersh did some amazing work educating breeders and trying to help them understand how to interpret and use DNA test results for individual matings as well as the wider implications for the breed. Despite this, messages like “it’s OK to breed with Carriers and Affecteds as long as you use a Clear dog” really didn’t sink in. What we saw, instead, was the stigmatisation of Affected dogs (and to some extent, Carriers) to the point where these dogs were removed from the breeding population. The unintended consequences were that the gene pool was further depleted and there was more selection pressure on Clear Stud Dogs, adding to the Popular Sire Syndrome and its associated risks. Being one of the first DNA tests, these were also probably unanticipated consequences; there was very little history to learn from and most messages were either not heard or not understood.

Fast forward 10+ years and we have data from our 2015 Breed Health Survey of 2000 Dachshunds that shows Miniature Longhaired Dachshunds have several health issues seen with higher prevalence than in the other 5 varieties of Dachshund. They have, for example, four times the rate of Idiopathic Epilepsy and a clinical eye examination of a sample of dogs showed around three quarters had some degree of Distichiasis. Over the past year we have also had a cluster of reports of early-onset lymphomas which our Health Committee is concerned about. When the KC published its Genetic Diversity reports in 2015 we concluded “Declining registrations and the overall trend in COI, when taken with extensive use of “popular sires”, are points of concern for the Miniature Long-haired variety”.

How to reduce negative unintended consequences

Learning from your own, or other people’s, past experience is one of the key ways to avoid or anticipate negative unintended consequences. When the Wirehaired Dachshund Club launched the DNA test for Lafora Disease in 2010, they had the benefit of learning from the Cord1 PRA experience. They recruited around 100 dogs for a heavily subsidised initial screening exercise and made the results public immediately. It was entirely predictable that some breeders would choose not to participate because of the decision to publish the results. The club felt it was important to be open and transparent about the extent of the problem in the breed. Other, new tactics were also employed, again learning from experience. Communication of the need for screening was directed at owners and potential owners, as well as at breeders. This helped to create “demand side” pressure for Lafora-screened litters. Publishing the data on the proportion of “safe” and “unsafe” litters every quarter from the Breed Records Supplement provided further evidence of progress and was a good way to recognise what was being achieved.

A second aspect of avoiding or anticipating unintended consequences is to understand the systemic impact of a decision and potential perverse responses. The “system” for canine health improvement is complex and I’ve written about this before. Decisions made in isolation invariably impact on other parts of the system. Those who cannot think systemically are doomed to make “simple” decisions that result in unintended adverse consequences. This is the realm of U-turns! Perverse responses are not that unusual. With the Lafora DNA test, we had people denying that there was a problem in Mini Wires, despite the evidence from test results showing 10% of dogs were “Affected”. Another perverse response from some people was to challenge the validity and reliability of the test. In both these cases, the team managing the Lafora screening programme responded with a series of “myth-busters”. These were short, evidence-based, statements explaining the facts and debunking the myths.

Keep the end goal in mind

We anticipated these things would happen and had responses in place so that they made only a minor impact on our overall goal of stopping the breeding of Lafora-affected puppies.

Interestingly, we also had some pleasant surprises when the Lafora test was launched. A number of Mini Wire pet owners started campaigning for wider adoption of the test by breeders. They added to the credibility of our communications with their down-to-earth stories of what it was like living with a Lafora-affected dog.

In November 2016, the Dachshund Breed Council launched an X-ray screening programme for Intervertebral Disc Disease (IVDD) which is the most significant health challenge we face. The range of reactions to this new programme are pretty much what we anticipated and we realise this will be a much longer-term project than either Cord1 PRA or Lafora Disease screening. One surprise though, has been an unintended consequence of breeders having a decade of experience with DNA tests: the expectation that a screening programme can give a “definitive” answer. X-ray screening for complex diseases (e.g. Hips, Elbows, IVDD) can never give the same “Clear” or “Affected” answer as a DNA test for a simple, recessive mutation. We will therefore have to work hard to communicate the science behind IVDD screening and how the results can be used to reduce IVDD risk.

In conclusion, in the world of breed health improvement, “the obvious” may not be so obvious to some people if they repeat the mistakes of the past, don’t think about the wider system and take a short-term, self-interest, perspective when making decisions.

I’ll end with a quote that is usually attributed to Albert Einstein: “Insanity: doing the same thing over and over again and expecting different results”.

Complex diseases; can we really “find the genes”?

Many breeds have been pinning their hopes on finding the genetic mutations responsible for diseases and health issues with the expectation that breeders will be able to test their way out of problems.

In some breeds, we have been “fortunate” to be able to identify so-called simple mutations from which DNA tests have been developed. In theory, these enable breeders to make informed decisions before breeding from a dog and bitch so that no “affected” puppies are born. It is, of course, important that we know how these single genetic mutatioons directly correlate with the clinical manifestation of the disease. There is also the potential unintended consequence of a reduction in overall genetic diversity in these breeds which may result from removing Affected (and sometimes, Carriers) from the breeding population.

I’ve written before about a couple of examples where “simple” recessive mutations may, in fact, subsequently turn out not to be so simple. One example is Cord1 PRA in Miniature Dachshunds where we now know there is a second mutation (MAP9) which influences the age of onset of blindness. This second mutation helps explain why some Cord1 Affected dogs don’t suffer retinal degeneration until old age (if at all). The other example is the POMC mutation which was associated with obesity in Labradors. The mutation is also found in Flatcoated Retrievers, but this breed is not noted for having an issue with obesity.

In the case of so-called complex diseases (e.g. Hip Dysplasia, Epilepsy, BOAS) there has been an assumption that multiple genes are involved in these conditions as well as environmental factors.

The search for simple and complex genetic explanations for canine diseases has been accelerated by the development of Genome Wide Association Studies (GWAS). These are large-scale investigations of genetic disease that aim to identify genetic variants scattered throughout the whole canine genome. The canine genome is a sequence of 2.4 billion letters of DNA (G, A, C and T), so the scale of these studies is truly enormous and requires massive computing power. In human genetic research, the number and scale of GWAS have been growing year by year. In 2016, of more than 400 published studies, around 50 involved studying the genomes of samples of more than 100,000 people. A similar situation has occurred in dogs. Last year, a team from Cornell University published a canine GWAS paper based on a sample of more than 4200 dogs from 150 breeds as well as mixed breeds. They tracked down two loci linked to Elbow Dysplasia and one for Hip Dysplasia. They also identified loci associated with epilepsy and lymphoma.

There has, however, been some debate about the extent to which GWAS in humans has actually led to useful clinical applications. For example, they may not fully explain the genetic familial risk of common diseases and there is a small size effect for many of the identified associations. They have also proved to be of limited value in predicting disease risk. All these shortcomings, of course, would mitigate against GWAS being of much practical use to dog breeders.

A new omnigenic model

A paper published in the journal Cell in June this year adds further challenge to the idea that there are relatively simple, causal, links between genetic variation and disease. In their paper, geneticists Boyle, Li and Pritchard from Stanford University suggest that many genetic variants identified by GWAS have no specific biological relevance to diseases. Their view is that common illnesses could, in fact, be linked to hundreds of thousands of DNA variants. Their conclusion is that, for complex traits, association signals from a GWAS tend to be spread across the whole genome, including near many genes without any obvious connection to the disease. They also state that most heritability can be explained by effects on genes outside core pathways. They called this an “omnigenic model” whereby most genes matter for most things!

There’s been this notion that for every gene that’s involved in a trait, there’d be a story connecting that gene to the trait,” says Pritchard. But he thinks that’s only partly true because genes don’t work in isolation. They influence each other in networks so, if there is a variant in one gene, it could well change a whole gene network. All this suggests that the search for simple genetic causes of complex diseases will continue to be challenging and breeders are unlikely to have new DNA tests for these conditions anytime soon. Of course, GWAS may well continue to help identify simple recessive mutations and it is important to remember that the paper is critical of the value of GWAS in human studies where the population structures are likely to be rather different to pedigree dogs with their closed gene pools and high levels of inbreeding.

I recently saw a comment by Carol Beuchat (Institute of Canine Biology) that 70% of genetic disorders in dogs are caused by recessive mutations. We also need to know the extent to which these have an impact on canine welfare as many of them could be relatively trivial. Developing yet more DNA tests for some of these would actually make life more difficult for breeders. Given that many of the high welfare-impact diseases are in the remaining 30% of complex conditions, it’s going to be virtually impossible to “breed away” from the “bad genes”.

Hope for the future

The AHT’s “Give a dog a Genome” project is a current example of Whole Genome Sequencing (WGS) which has the potential to avoid some of the shortcomings of non-sequencing GWAS. Here, by sequencing the genomes of different breeds, the AHT hopes to identify the variations that exist within the canine genome. Having built a database of “neutral variants” from healthy dogs, the genomes of dogs affected by particular diseases can be compared. The different variants between healthy and unhealthy dogs potentially lead to the identification of the associated disease mutation.

The AHT can already claim some success for their WGS work; on their website, they showcase the development of the DNA tests for cerebellar ataxia in Hungarian Vizslas and primary open angle glaucoma in the PBGV. The Vizsla genome sequence can now be used as a control sequence in future studies of inherited diseases in other breeds. With more than 70 breeds participating in the Give a dog a Genome project, the AHT expects to see many more useful and practical developments like those in the Vizsla and PBGV.

I’m sure all the breeds who are participating in the GDG project will recognise the scale and complexity of this project. I hope they see it as a longer-term opportunity to address health issues. In the meantime, they need to look for and implement other strategies that address the root causes of disease in pedigree dogs; closed stud books and high levels of inbreeding.

 

[There’s a presentation – pdf- by Boyle, Li and Pritchard here]

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