- Email: [email protected]
Internet resources cataloguing inherited disorders in dogs
The Veterinary Journal 189 (2011) 132–135
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Review
Internet resources cataloguing inherited disorders in dogs Frank W. Nicholas a,⇑, Alice Crook b, David R. Sargan c a
Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia Sir James Dunn Animal Welfare Centre, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3 c Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK b
a r t i c l e
i n f o
Keywords: Canine Inherited disorders Internet resources
a b s t r a c t Up-to-date annotated catalogues of known inherited disorders in dogs are freely available on the Internet, providing vital information to existing and prospective dog owners, dog breeders, veterinarians, geneticists and others interested in the occurrence and control of inherited disorders. These resources are the Canine Inherited Disorders Database (CIDD),1 Inherited Diseases in Dogs (IDID)2 and Online Mendelian Inheritance in Animals (OMIA)3 the latter associated with Listing of Inherited Disorders in Animals (LIDA).4 The history and features of these resources are summarised. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction
Canine Inherited Disorders Database (CIDD)
When the late Dr Victor McKusick began to assemble his catalogue of X-linked inherited human disorders in the early 1960s, the Internet was not even a glint in anyone’s eye. It took nearly three decades before, in 1987, McKusick’s catalogue (long since expanded to include autosomal disorders) became searchable on-line as Online Mendelian Inheritance in Man (OMIM). Today, the Internet is a uniquely powerful means of providing global access to continually-updated information, including information on inherited disorders of dogs. There are many single-disease and open-test registries, but these are not referred to here. Rather, the purpose of this review is to summarise the history and features of Internet resources cataloguing known inherited disorders of dogs. Each resource is freely available globally, providing a wealth of invaluable information to dog owners (present and prospective), breeders, veterinarians and geneticists. In presenting this summary, we are pleased to acknowledge the pioneering leadership of Dr Donald Patterson in the collation of global knowledge on inherited disorders in dogs. During many years in the Section of Medical Genetics at the University of Pennsylvania School of Veterinary Medicine, he led a team that summarised much of the then existing knowledge in this area. The present authors are pleased to dedicate this review to Dr Patterson and to hope that one day the fruits of his labours will become fully available.
The Canine Inherited Disorders Database (CIDD)5 (Crook et al., 2011) is a joint initiative of the Sir James Dunn Animal Welfare Centre at the Atlantic Veterinary College, University of Prince Edward Island, Canada, and the Canadian Veterinary Medical Association. It was originally developed between 1998 and 2001 and is currently being completely revised and updated (projected date of completion 2011). CIDD serves as an accurate and easily accessible source of information for current and prospective dog owners, veterinarians and breeders, using primarily non-technical language. It provides current, readily accessible and comprehensive information both for well-known and more obscure inherited disorders, including diagnostic and therapeutic information. A summary, in non-technical terms, can be printed for concerned clients. The goals are to reduce the occurrence and impact of inherited disorders through education of dog owners and breeders and to facilitate the best management of these conditions by providing readily accessible and up-to-date information for veterinary practitioners. Veterinary practitioners can help to address the problem of inherited disorders in dogs by diagnosing such disorders in their patients as early and as accurately as possible, to help owners with decisions and to ensure that information is relayed back to breeders. In addition to veterinarians, CIDD is intended for dog owners whose pet has been found to have an inherited condition, potential dog owners who want help in avoiding these problems when choosing a pet and dog breeders who are looking for suggestions on how to avoid these conditions in their lines of dogs. The breed pages are used by breeders and breed clubs looking for ways to
⇑ Corresponding author. Tel.: +61 412 825761. 1 2 3 4
E-mail address: [email protected] (F.W. Nicholas). See: www.upei.ca/cidd. See: www.vet.cam.ac.uk/idid. See: omia.angis.org.au. See: www.sydney.edu.au/vetscience/lida.
1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.06.009
5
See: www.upei.ca/cidd.
F.W. Nicholas et al. / The Veterinary Journal 189 (2011) 132–135
reduce the incidence of inherited conditions in their breeds. Since the database went on line in 1999, many breeders and breed clubs have requested and received permission to reprint the information on disease pages relevant to their breed on their website or in their newsletter. Some veterinary hospitals have also added links to CIDD on their websites. The database has three main sections. The first is general information: What is a genetic disorder?, How are defects inherited? and Responsible breeding. The second section, which forms the bulk of the database, consists of approximately 175 disease pages, divided into systems: Inherited cardiovascular, nervous system, blood, endocrine, eye, skin, gastrointestinal, immune, respiratory, urinary and reproductive and musculoskeletal disorders. The page for each condition includes a description of the disorder, information about how the disorder is inherited, consequences for the dog, therapeutic and diagnostic information for veterinarians and recommended or required care by the owner and veterinarian. The disease pages are written in non-technical language, except for the section on diagnostic and therapeutic considerations, which is specifically for veterinarians. Owners may look up these diseases on their own and/or veterinarians may print these pages for their clients when an inherited disorder is diagnosed in a pet. The third section contains individual breed pages on which are listed disorders of concern in each breed, divided into four categories. Disorders listed in the first category are those that are relatively common and significant in each breed. It is suggested that potential owners ask the breeder about these disorders in their breeding lines. The second category lists disorders that are known to occur in each breed, but are less common or have less serious consequences for the dog. The third category includes disorders associated with conformation, such as respiratory disorders in brachycephalic breeds (breeds with shortened heads, e.g. English bulldog) and eye disorders such as entropion and ectropion in breeds with excessive skin (e.g., Basset hound, Saint Bernard). Disorders that occur sporadically in a breed and may be inherited are listed in the fourth category. Each disorder listed on a breed page is linked to the relevant disease page. The breed pages are not meant to catalogue every suspected inherited disorder that has ever been reported in a breed, but to provide a list of disorders that veterinarians and other experts agree are significant in the particular breed. The goal is to present useful information to potential dog owners considering a particular breed to give them an idea of informed questions to ask breeders. This should reduce their chances of acquiring a dog with an inherited disorder and also increase the pressure on breeders to breed dogs responsibly. Long-term maintenance and current status of CIDD In 2009, the entire content was extracted from the original CIDD database and inserted into a widely-used, fully searchable content management system. CIDD users may search for a particular dog breed or a specific condition or medical term, or may view a list of conditions under the relevant organ system. The full site is being reviewed and updated in 2010–2011 and a section on Responsible breeding has been added. The web-based format lends itself well to periodic updating, as new information becomes available (such as information that a particular disorder is inherited or confirmation about modes of inheritance). The disease pages are written so as to stay current as much as possible. For example, since the most rapid changes are in the realm of genetic testing, a link is provided on relevant disease pages to a commercial company that provides testing so that the reader may receive the most current information. The goal of the database remains the same: To provide primarily non-technical information on canine inherited disorders to
133
breeders, veterinarians and owners for educational purposes and to help all concerned make the best decisions for individual dogs and for breeds affected by inherited conditions. Inherited Diseases in Dogs (IDID)6 In the early 2000s, after working for some time on mutation finding in the dog and also on developing chromosome paint resources that would contribute to the genome mapping and characterisation going on at that time, Marjory Brooks (James A. Baker Institute, Cornell) and David Sargan contributed a chapter on genetic disease to the book ‘Genetics of the Dog’ edited by Jeff Sampson and Anatoly Ruvinsky (Brooks and Sargan, 2001). In putting this chapter together, the authors catalogued a large number of genetic diseases by organ system and were forcibly reminded of the lack of criticality in the approach to inherited disorders of the dog in most textbook sources. At that point, researchers in the field had been aware for some time of the attempt of Dr Donald Patterson to put together a definitive resource for both geneticists and veterinarians on inherited diseases of dogs. This project had been delayed several times, largely due to Dr Patterson’s efforts to render the resource self-funding. David Sargan was aware of the need to co-ordinate the molecular genetic resources that were coming to fruition in the dog with the extensive disease catalogue in that species. It was already clear that the breed structures would provide a particularly fruitful resource for the genetic dissection of disease, so a resource that classified diseases by breed was going to be useful to scientists, veterinarians and breeders. It was recognised that there was room for a resource with a less clinical approach than the CIDD and which also included rarer defects. Data collection for the tables in the Genetics of the Dog had already formed the foundation for the production of a small database, the first version of Inherited Diseases in Dogs (IDID). In deciding on inclusions in the database, the major criteria are that the database should summarise peer-reviewed evidence and that single-case studies would not be acceptable as evidence of inheritance, although groups of cases or multiple single-case reports could be acceptable in some circumstances. Single reports would, however, be acceptable if there is clear mechanistic evidence suggesting the disease must be inherited. Breed specificity should either be demonstrated statistically in case series, or be demonstrable in large-scale clinical data, such as from insurance databases or open registries, e.g. Canine Eye Registration Foundation (CERF), Orthopedic Foundation for Animals (OFA) or the UK Kennel Club/BVA health scheme. For the user, the database should be searchable by disease, breed or keyword, it should link the user to the available literature and it should be easy to use and curate. It should contain information on the disease in a few tens of words, together with any information available on inheritance patterns or mutations. Initially, there was very little attempt to provide species-comparative data. After consulting with Helen Sargan, David Sargan set up the database with two underlying Filemaker Pro databases, one containing disease listings and the other containing references to these diseases. These were connected to web front pages with both scrollable drop-down and standard keyword-search tools to allow two different methods of searching (Sargan, 2004). The original database was established unfunded and, as a result, was run on an old desktop Apple computer running Filemaker Pro 2.0, even then an old programme. Since then, a first update added brief summary texts for each of the diseases, allowing rapid scanning for relevant entries, together 6
See: www.vet.cam.ac.uk/idid.
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F.W. Nicholas et al. / The Veterinary Journal 189 (2011) 132–135
with information on DNA tests and on comparisons of disorders with those in the OMIM (human) database, along with an ability to handle much larger numbers of references and links. However, this update (to Filemaker 6) was not able to handle large numbers of clients at once and, as a result, the site suffered instability. The server has now been updated to Filemaker 11.0 (server version) to allow much higher numbers of users. The other major change is that photographs have been added to illustrate most breeds and the database is now being populated with photographs of different disease conditions. This update, sponsored by the Kennel Club Charitable Trust, has made the database more robust. As at 11 May 2011, the database contained entries on 1461 disease and breed combinations, representative of over 280 breeds. After a search, the user is led to a set of concise entries fitting the search term (for instance, all the diseases of a breed or all the breeds in which a given disease is known). A short statement and set of brief references is given for each entry. The user is then invited to go to a further page on each entry, which has a longer statement, with more technical clinical details, as well as details of mode of inheritance and mutation where known, links to comparative information in the OMIM database, where appropriate, and with DNA testing information and links to all references. The database is still curated by David Sargan. Online Mendelian Inheritance in Animals (OMIA)7 The need for a single catalogue of inherited disorders and other traits in domestic animals first became evident to Frank Nicholas in 1974 when he commenced working as a Lecturer in Animal Genetics in the Faculties of Agriculture and Veterinary Science at the University of Sydney. There was a steady stream of queries from stud breeders and veterinarians, each wanting to know whether a particular trait (usually a disorder) was inherited. Each query necessitated a labour-intensive trip to the library to locate relevant reviews, many of which were out of date. It soon became evident that there was a serious need for a single catalogue of inherited disorders and other traits that was regularly updated and readily available. From the beginning, it was clear that such a catalogue should have a strong comparative emphasis, because many similar, if not identical, disorders/traits occur in more than one species and many of the disorders/traits recorded in veterinary species also occur in humans. Given that Victor McKusick’s continually-updated catalogue of human disorders (Mendelian Inheritance in Man, MIM) was by then well established as the global source of information on inherited disorders in humans, the obvious strategy was to model the animal catalogue on MIM. In a conversation with Frank Nicholas during the International Congress of Genetics in Moscow in 1978, Dr McKusick enthusiastically supported this strategy. To highlight the fact that the animal catalogue was to be modelled on (and complementary to) MIM, it was named Mendelian Inheritance in Animals (MIA). A small grant was obtained and MIA was born in 1980 (in a relational database, first on a mainframe and later on a laptop computer). Younger readers may be surprised to learn that this was ten years before the World Wide Web (WWW) was created. Consequently, the continually-updated versions of MIM and MIA were not then readily accessible. Instead, MIM was available as a book (editions were published in 1966, 1968, 1971, 1975, 1978, 1983, 1986 and 1988) and MIA had to be queried on request to Frank Nicholas. In 1995, both MIM and MIA were made freely available on the WWW, using the same search engine (kindly provided by the Na7
See: omia.angis.org.au.
tional Center for Biotechnology Information, NCBI, which by then was hosting MIM) (Nicholas and Harper, 1996; Nicholas, 1998). Not surprisingly, the online versions were called OMIM and OMIA. Two years later, reciprocal hyperlinks were established between OMIM and OMIA, providing direct access to comparative information across the whole vertebrate kingdom (Leslie, 2002; Nicholas, 2003). In 2002, Paul McGreevy, a colleague of Frank Nicholas in the Faculty of Veterinary Science at the University of Sydney, organised an assessment exercise for first-year Veterinary Science students to prepare text entries for some of the clinical fields (in lay terms) that had laid blank for so long in the canine entries of OMIA. Because of input limitations of the OMIA master database then in use, it was not possible to add the student’s text to the OMIA fields. Instead, a separate database called Listing of Inherited Disorders in Animals (LIDA)8 was created by a team comprising Paul McGreevy, Federico Costa, Paul Della Torre, Peter Thomson and Frank Nicholas. This database also contains lists of breeds affected by each disorder, obtained from the then web site of the Association of Veterinarians for Animal Rights. In the future, when real-time collection of epidemiological data has become a reality, the plan is to expand LIDA to become a means for collecting, analysing and presenting real-time genetic epidemiology data on the incidence of inherited disorders in various animal species. In 2004, the OMIA master database was transferred to a MySQL database on a server, which enabled the launching in 2005 of the present interactive OMIA web site, with hyperlinks to PubMed references. At the same time, a mirror of OMIA was created alongside OMIM at NCBI, providing a regularly-updated version of OMIA in exactly the same format as OMIM (Lenffer et al., 2006). Of all the animal species included in OMIA, dogs are by far the best documented (Nicholas, 2001). At the time of writing, there are 187 single-locus disorders/traits, 120 of which have been characterised at the DNA level. In addition, there are 364 disorders/traits for which there are published claims of inheritance, but insufficient evidence to support single-locus inheritance. Some of the disorders in this category are classic multifactorial disorders, such as hip dysplasia and syringomyelia. Each OMIA entry presents a list of relevant publications, arranged in reverse-chronological order (to place the newest papers at the top and to provide a feel for the development of knowledge of that disorder/trait). If relevant, information is also provided on the human homologue (via a hyperlink to OMIM) and the mutated gene (with hyperlinks to the major genome databases in the US (NCBI) and Europe (Ensembl). In addition, the entry presents any text that may have been entered in any of the numerous database text fields for that entry, covering issues such as cross-species summary, dog-specific description, breed(s), clinical features, pathology, control, prevalence, history, inheritance, mapping, known markers and molecular basis. While colleagues of Frank Nicholas have, from time to time, curated some entries, the vast majority of the entries in OMIA have been and are still curated by Frank Nicholas. Since this is not sustainable, considerable effort is now being devoted to developing the Internet interface of the MySQL database to the stage where specialists in particular areas can take on curatorial responsibility for that area, from anywhere in the world. In addition, a project with NCBI is developing the means of automating the accession of new publications. However, since the actual list of entries is forever changing (existing entries being altered, split or merged, as new information becomes available and new entries are being created), it will never be possible to develop a completely automated system for updating publications. This may not be such a bad thing!
8
See: www.sydney.edu.au/vetscience/lida/.
F.W. Nicholas et al. / The Veterinary Journal 189 (2011) 132–135
135
Conclusions
Acknowledgements
From the above accounts, it is evident that the three Internet resources are complementary in many ways. To provide maximum exploitation of this complementarity, an obvious step is for hyperlinks to be created between relevant sections of the three databases. The three curators have agreed to work towards this development. The biggest challenge facing the curators of all three resources is keeping them up to date and this reflects the difficulty in gaining financial support for the creation and publication of catalogues. Many otherwise suitable funding sources are not inclined to provide financial support for projects that do not involve the creation of new knowledge. However, the packaging and dissemination of existing knowledge in a form that is readily accessible to a wide range of end-users is vitally important. Convincing funding bodies of this argument is not easy. In the fullness of time, it may be possible to devise a division of labour, where each resource concentrates on a subset of issues, providing ready access (via hyperlinks) to issues that are the province of other resources. In the meantime, the main message for anyone concerned with inherited disorders in dogs is that there are freely-available resources on the web, the combined knowledge of which provides a comprehensive account of global knowledge of inherited disorders in dogs.
Development of the Canine Inherited Disorders Database was funded jointly by the Canadian Veterinary Medical Association and the Sir James Dunn Animal Welfare Centre, Atlantic Veterinary College, University of Prince Edward Island, Canada. The web site structure for IDID was put in place by Helen Sargan and Janet Smith helped to populate the databases. David Sargan thanks both and the many users who have made useful suggestions. The contributions of the many people who have worked on MIA and then OMIA over the decades are recorded on-line.9
Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.
References Brooks, M., Sargan, D.R., 2001. Genetic aspects of disease in dogs. In: Ruvinsky, A., Sampson, J. (Eds.), The Genetics of the Dog. CABI, Wallingford, UK, pp. 191–266. Crook, A., Dawson, S., Côté E., Berry, J., MacDonald S., 2011. Canine Inherited Disorders Database. www.upei.ca/cidd (accessed 4 April 2011). Lenffer, J., Nicholas, F.W., Castle, K., Rao, A., Gregory, S., Poidinger, M., Mailman, M.D., Ranganathan, S., 2006. OMIA (Online Mendelian Inheritance in Animals): An enhanced platform and integration into the Entrez search interface at NCBI. Nucleic Acids Research 34, D599–D601. Leslie, M., 2002. Database: Gene farm. Science 298, 2097. Nicholas, F.W., Harper, P.A.W., 1996. Inherited disorders: The comparative picture. Australian Veterinary Journal 73, 64–66. Nicholas, F.W., 1998. Genetic databases: Online catalogues of inherited disorders. In: Muller, M., Brem, G. (Eds.), Genetic Resistance to Animal Diseases. Office International des Epizooties (OIE), Paris, France. OIE Scientific and Technical Review, vol. 17, pp. 346–350. Nicholas, F.W., 2001. Genetics of morphological traits and inherited disorders. In: Ruvinsky, A., Sampson, J. (Eds.), The Genetics of the Dog. CABI, Wallingford, UK, pp. 87–116. Nicholas, F.W., 2003. Online Mendelian Inheritance in Animals (OMIA): A comparative knowledgebase of genetic disorders and other familial traits in non-laboratory animals. Nucleic Acids Research 31, 275–277. Sargan, D.R., 2004. IDID: Inherited diseases in dogs: Web-based information for canine inherited disease genetics. Mammalian Genome 15, 503–506.
9
See: www.omia.angis.org.au/acknowledgements.shtml.
Contents lists available at ScienceDirect
The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Review
Internet resources cataloguing inherited disorders in dogs Frank W. Nicholas a,⇑, Alice Crook b, David R. Sargan c a
Faculty of Veterinary Science, University of Sydney, NSW 2006, Australia Sir James Dunn Animal Welfare Centre, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3 c Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK b
a r t i c l e
i n f o
Keywords: Canine Inherited disorders Internet resources
a b s t r a c t Up-to-date annotated catalogues of known inherited disorders in dogs are freely available on the Internet, providing vital information to existing and prospective dog owners, dog breeders, veterinarians, geneticists and others interested in the occurrence and control of inherited disorders. These resources are the Canine Inherited Disorders Database (CIDD),1 Inherited Diseases in Dogs (IDID)2 and Online Mendelian Inheritance in Animals (OMIA)3 the latter associated with Listing of Inherited Disorders in Animals (LIDA).4 The history and features of these resources are summarised. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction
Canine Inherited Disorders Database (CIDD)
When the late Dr Victor McKusick began to assemble his catalogue of X-linked inherited human disorders in the early 1960s, the Internet was not even a glint in anyone’s eye. It took nearly three decades before, in 1987, McKusick’s catalogue (long since expanded to include autosomal disorders) became searchable on-line as Online Mendelian Inheritance in Man (OMIM). Today, the Internet is a uniquely powerful means of providing global access to continually-updated information, including information on inherited disorders of dogs. There are many single-disease and open-test registries, but these are not referred to here. Rather, the purpose of this review is to summarise the history and features of Internet resources cataloguing known inherited disorders of dogs. Each resource is freely available globally, providing a wealth of invaluable information to dog owners (present and prospective), breeders, veterinarians and geneticists. In presenting this summary, we are pleased to acknowledge the pioneering leadership of Dr Donald Patterson in the collation of global knowledge on inherited disorders in dogs. During many years in the Section of Medical Genetics at the University of Pennsylvania School of Veterinary Medicine, he led a team that summarised much of the then existing knowledge in this area. The present authors are pleased to dedicate this review to Dr Patterson and to hope that one day the fruits of his labours will become fully available.
The Canine Inherited Disorders Database (CIDD)5 (Crook et al., 2011) is a joint initiative of the Sir James Dunn Animal Welfare Centre at the Atlantic Veterinary College, University of Prince Edward Island, Canada, and the Canadian Veterinary Medical Association. It was originally developed between 1998 and 2001 and is currently being completely revised and updated (projected date of completion 2011). CIDD serves as an accurate and easily accessible source of information for current and prospective dog owners, veterinarians and breeders, using primarily non-technical language. It provides current, readily accessible and comprehensive information both for well-known and more obscure inherited disorders, including diagnostic and therapeutic information. A summary, in non-technical terms, can be printed for concerned clients. The goals are to reduce the occurrence and impact of inherited disorders through education of dog owners and breeders and to facilitate the best management of these conditions by providing readily accessible and up-to-date information for veterinary practitioners. Veterinary practitioners can help to address the problem of inherited disorders in dogs by diagnosing such disorders in their patients as early and as accurately as possible, to help owners with decisions and to ensure that information is relayed back to breeders. In addition to veterinarians, CIDD is intended for dog owners whose pet has been found to have an inherited condition, potential dog owners who want help in avoiding these problems when choosing a pet and dog breeders who are looking for suggestions on how to avoid these conditions in their lines of dogs. The breed pages are used by breeders and breed clubs looking for ways to
⇑ Corresponding author. Tel.: +61 412 825761. 1 2 3 4
E-mail address: [email protected] (F.W. Nicholas). See: www.upei.ca/cidd. See: www.vet.cam.ac.uk/idid. See: omia.angis.org.au. See: www.sydney.edu.au/vetscience/lida.
1090-0233/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tvjl.2011.06.009
5
See: www.upei.ca/cidd.
F.W. Nicholas et al. / The Veterinary Journal 189 (2011) 132–135
reduce the incidence of inherited conditions in their breeds. Since the database went on line in 1999, many breeders and breed clubs have requested and received permission to reprint the information on disease pages relevant to their breed on their website or in their newsletter. Some veterinary hospitals have also added links to CIDD on their websites. The database has three main sections. The first is general information: What is a genetic disorder?, How are defects inherited? and Responsible breeding. The second section, which forms the bulk of the database, consists of approximately 175 disease pages, divided into systems: Inherited cardiovascular, nervous system, blood, endocrine, eye, skin, gastrointestinal, immune, respiratory, urinary and reproductive and musculoskeletal disorders. The page for each condition includes a description of the disorder, information about how the disorder is inherited, consequences for the dog, therapeutic and diagnostic information for veterinarians and recommended or required care by the owner and veterinarian. The disease pages are written in non-technical language, except for the section on diagnostic and therapeutic considerations, which is specifically for veterinarians. Owners may look up these diseases on their own and/or veterinarians may print these pages for their clients when an inherited disorder is diagnosed in a pet. The third section contains individual breed pages on which are listed disorders of concern in each breed, divided into four categories. Disorders listed in the first category are those that are relatively common and significant in each breed. It is suggested that potential owners ask the breeder about these disorders in their breeding lines. The second category lists disorders that are known to occur in each breed, but are less common or have less serious consequences for the dog. The third category includes disorders associated with conformation, such as respiratory disorders in brachycephalic breeds (breeds with shortened heads, e.g. English bulldog) and eye disorders such as entropion and ectropion in breeds with excessive skin (e.g., Basset hound, Saint Bernard). Disorders that occur sporadically in a breed and may be inherited are listed in the fourth category. Each disorder listed on a breed page is linked to the relevant disease page. The breed pages are not meant to catalogue every suspected inherited disorder that has ever been reported in a breed, but to provide a list of disorders that veterinarians and other experts agree are significant in the particular breed. The goal is to present useful information to potential dog owners considering a particular breed to give them an idea of informed questions to ask breeders. This should reduce their chances of acquiring a dog with an inherited disorder and also increase the pressure on breeders to breed dogs responsibly. Long-term maintenance and current status of CIDD In 2009, the entire content was extracted from the original CIDD database and inserted into a widely-used, fully searchable content management system. CIDD users may search for a particular dog breed or a specific condition or medical term, or may view a list of conditions under the relevant organ system. The full site is being reviewed and updated in 2010–2011 and a section on Responsible breeding has been added. The web-based format lends itself well to periodic updating, as new information becomes available (such as information that a particular disorder is inherited or confirmation about modes of inheritance). The disease pages are written so as to stay current as much as possible. For example, since the most rapid changes are in the realm of genetic testing, a link is provided on relevant disease pages to a commercial company that provides testing so that the reader may receive the most current information. The goal of the database remains the same: To provide primarily non-technical information on canine inherited disorders to
133
breeders, veterinarians and owners for educational purposes and to help all concerned make the best decisions for individual dogs and for breeds affected by inherited conditions. Inherited Diseases in Dogs (IDID)6 In the early 2000s, after working for some time on mutation finding in the dog and also on developing chromosome paint resources that would contribute to the genome mapping and characterisation going on at that time, Marjory Brooks (James A. Baker Institute, Cornell) and David Sargan contributed a chapter on genetic disease to the book ‘Genetics of the Dog’ edited by Jeff Sampson and Anatoly Ruvinsky (Brooks and Sargan, 2001). In putting this chapter together, the authors catalogued a large number of genetic diseases by organ system and were forcibly reminded of the lack of criticality in the approach to inherited disorders of the dog in most textbook sources. At that point, researchers in the field had been aware for some time of the attempt of Dr Donald Patterson to put together a definitive resource for both geneticists and veterinarians on inherited diseases of dogs. This project had been delayed several times, largely due to Dr Patterson’s efforts to render the resource self-funding. David Sargan was aware of the need to co-ordinate the molecular genetic resources that were coming to fruition in the dog with the extensive disease catalogue in that species. It was already clear that the breed structures would provide a particularly fruitful resource for the genetic dissection of disease, so a resource that classified diseases by breed was going to be useful to scientists, veterinarians and breeders. It was recognised that there was room for a resource with a less clinical approach than the CIDD and which also included rarer defects. Data collection for the tables in the Genetics of the Dog had already formed the foundation for the production of a small database, the first version of Inherited Diseases in Dogs (IDID). In deciding on inclusions in the database, the major criteria are that the database should summarise peer-reviewed evidence and that single-case studies would not be acceptable as evidence of inheritance, although groups of cases or multiple single-case reports could be acceptable in some circumstances. Single reports would, however, be acceptable if there is clear mechanistic evidence suggesting the disease must be inherited. Breed specificity should either be demonstrated statistically in case series, or be demonstrable in large-scale clinical data, such as from insurance databases or open registries, e.g. Canine Eye Registration Foundation (CERF), Orthopedic Foundation for Animals (OFA) or the UK Kennel Club/BVA health scheme. For the user, the database should be searchable by disease, breed or keyword, it should link the user to the available literature and it should be easy to use and curate. It should contain information on the disease in a few tens of words, together with any information available on inheritance patterns or mutations. Initially, there was very little attempt to provide species-comparative data. After consulting with Helen Sargan, David Sargan set up the database with two underlying Filemaker Pro databases, one containing disease listings and the other containing references to these diseases. These were connected to web front pages with both scrollable drop-down and standard keyword-search tools to allow two different methods of searching (Sargan, 2004). The original database was established unfunded and, as a result, was run on an old desktop Apple computer running Filemaker Pro 2.0, even then an old programme. Since then, a first update added brief summary texts for each of the diseases, allowing rapid scanning for relevant entries, together 6
See: www.vet.cam.ac.uk/idid.
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with information on DNA tests and on comparisons of disorders with those in the OMIM (human) database, along with an ability to handle much larger numbers of references and links. However, this update (to Filemaker 6) was not able to handle large numbers of clients at once and, as a result, the site suffered instability. The server has now been updated to Filemaker 11.0 (server version) to allow much higher numbers of users. The other major change is that photographs have been added to illustrate most breeds and the database is now being populated with photographs of different disease conditions. This update, sponsored by the Kennel Club Charitable Trust, has made the database more robust. As at 11 May 2011, the database contained entries on 1461 disease and breed combinations, representative of over 280 breeds. After a search, the user is led to a set of concise entries fitting the search term (for instance, all the diseases of a breed or all the breeds in which a given disease is known). A short statement and set of brief references is given for each entry. The user is then invited to go to a further page on each entry, which has a longer statement, with more technical clinical details, as well as details of mode of inheritance and mutation where known, links to comparative information in the OMIM database, where appropriate, and with DNA testing information and links to all references. The database is still curated by David Sargan. Online Mendelian Inheritance in Animals (OMIA)7 The need for a single catalogue of inherited disorders and other traits in domestic animals first became evident to Frank Nicholas in 1974 when he commenced working as a Lecturer in Animal Genetics in the Faculties of Agriculture and Veterinary Science at the University of Sydney. There was a steady stream of queries from stud breeders and veterinarians, each wanting to know whether a particular trait (usually a disorder) was inherited. Each query necessitated a labour-intensive trip to the library to locate relevant reviews, many of which were out of date. It soon became evident that there was a serious need for a single catalogue of inherited disorders and other traits that was regularly updated and readily available. From the beginning, it was clear that such a catalogue should have a strong comparative emphasis, because many similar, if not identical, disorders/traits occur in more than one species and many of the disorders/traits recorded in veterinary species also occur in humans. Given that Victor McKusick’s continually-updated catalogue of human disorders (Mendelian Inheritance in Man, MIM) was by then well established as the global source of information on inherited disorders in humans, the obvious strategy was to model the animal catalogue on MIM. In a conversation with Frank Nicholas during the International Congress of Genetics in Moscow in 1978, Dr McKusick enthusiastically supported this strategy. To highlight the fact that the animal catalogue was to be modelled on (and complementary to) MIM, it was named Mendelian Inheritance in Animals (MIA). A small grant was obtained and MIA was born in 1980 (in a relational database, first on a mainframe and later on a laptop computer). Younger readers may be surprised to learn that this was ten years before the World Wide Web (WWW) was created. Consequently, the continually-updated versions of MIM and MIA were not then readily accessible. Instead, MIM was available as a book (editions were published in 1966, 1968, 1971, 1975, 1978, 1983, 1986 and 1988) and MIA had to be queried on request to Frank Nicholas. In 1995, both MIM and MIA were made freely available on the WWW, using the same search engine (kindly provided by the Na7
See: omia.angis.org.au.
tional Center for Biotechnology Information, NCBI, which by then was hosting MIM) (Nicholas and Harper, 1996; Nicholas, 1998). Not surprisingly, the online versions were called OMIM and OMIA. Two years later, reciprocal hyperlinks were established between OMIM and OMIA, providing direct access to comparative information across the whole vertebrate kingdom (Leslie, 2002; Nicholas, 2003). In 2002, Paul McGreevy, a colleague of Frank Nicholas in the Faculty of Veterinary Science at the University of Sydney, organised an assessment exercise for first-year Veterinary Science students to prepare text entries for some of the clinical fields (in lay terms) that had laid blank for so long in the canine entries of OMIA. Because of input limitations of the OMIA master database then in use, it was not possible to add the student’s text to the OMIA fields. Instead, a separate database called Listing of Inherited Disorders in Animals (LIDA)8 was created by a team comprising Paul McGreevy, Federico Costa, Paul Della Torre, Peter Thomson and Frank Nicholas. This database also contains lists of breeds affected by each disorder, obtained from the then web site of the Association of Veterinarians for Animal Rights. In the future, when real-time collection of epidemiological data has become a reality, the plan is to expand LIDA to become a means for collecting, analysing and presenting real-time genetic epidemiology data on the incidence of inherited disorders in various animal species. In 2004, the OMIA master database was transferred to a MySQL database on a server, which enabled the launching in 2005 of the present interactive OMIA web site, with hyperlinks to PubMed references. At the same time, a mirror of OMIA was created alongside OMIM at NCBI, providing a regularly-updated version of OMIA in exactly the same format as OMIM (Lenffer et al., 2006). Of all the animal species included in OMIA, dogs are by far the best documented (Nicholas, 2001). At the time of writing, there are 187 single-locus disorders/traits, 120 of which have been characterised at the DNA level. In addition, there are 364 disorders/traits for which there are published claims of inheritance, but insufficient evidence to support single-locus inheritance. Some of the disorders in this category are classic multifactorial disorders, such as hip dysplasia and syringomyelia. Each OMIA entry presents a list of relevant publications, arranged in reverse-chronological order (to place the newest papers at the top and to provide a feel for the development of knowledge of that disorder/trait). If relevant, information is also provided on the human homologue (via a hyperlink to OMIM) and the mutated gene (with hyperlinks to the major genome databases in the US (NCBI) and Europe (Ensembl). In addition, the entry presents any text that may have been entered in any of the numerous database text fields for that entry, covering issues such as cross-species summary, dog-specific description, breed(s), clinical features, pathology, control, prevalence, history, inheritance, mapping, known markers and molecular basis. While colleagues of Frank Nicholas have, from time to time, curated some entries, the vast majority of the entries in OMIA have been and are still curated by Frank Nicholas. Since this is not sustainable, considerable effort is now being devoted to developing the Internet interface of the MySQL database to the stage where specialists in particular areas can take on curatorial responsibility for that area, from anywhere in the world. In addition, a project with NCBI is developing the means of automating the accession of new publications. However, since the actual list of entries is forever changing (existing entries being altered, split or merged, as new information becomes available and new entries are being created), it will never be possible to develop a completely automated system for updating publications. This may not be such a bad thing!
8
See: www.sydney.edu.au/vetscience/lida/.
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135
Conclusions
Acknowledgements
From the above accounts, it is evident that the three Internet resources are complementary in many ways. To provide maximum exploitation of this complementarity, an obvious step is for hyperlinks to be created between relevant sections of the three databases. The three curators have agreed to work towards this development. The biggest challenge facing the curators of all three resources is keeping them up to date and this reflects the difficulty in gaining financial support for the creation and publication of catalogues. Many otherwise suitable funding sources are not inclined to provide financial support for projects that do not involve the creation of new knowledge. However, the packaging and dissemination of existing knowledge in a form that is readily accessible to a wide range of end-users is vitally important. Convincing funding bodies of this argument is not easy. In the fullness of time, it may be possible to devise a division of labour, where each resource concentrates on a subset of issues, providing ready access (via hyperlinks) to issues that are the province of other resources. In the meantime, the main message for anyone concerned with inherited disorders in dogs is that there are freely-available resources on the web, the combined knowledge of which provides a comprehensive account of global knowledge of inherited disorders in dogs.
Development of the Canine Inherited Disorders Database was funded jointly by the Canadian Veterinary Medical Association and the Sir James Dunn Animal Welfare Centre, Atlantic Veterinary College, University of Prince Edward Island, Canada. The web site structure for IDID was put in place by Helen Sargan and Janet Smith helped to populate the databases. David Sargan thanks both and the many users who have made useful suggestions. The contributions of the many people who have worked on MIA and then OMIA over the decades are recorded on-line.9
Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.
References Brooks, M., Sargan, D.R., 2001. Genetic aspects of disease in dogs. In: Ruvinsky, A., Sampson, J. (Eds.), The Genetics of the Dog. CABI, Wallingford, UK, pp. 191–266. Crook, A., Dawson, S., Côté E., Berry, J., MacDonald S., 2011. Canine Inherited Disorders Database. www.upei.ca/cidd (accessed 4 April 2011). Lenffer, J., Nicholas, F.W., Castle, K., Rao, A., Gregory, S., Poidinger, M., Mailman, M.D., Ranganathan, S., 2006. OMIA (Online Mendelian Inheritance in Animals): An enhanced platform and integration into the Entrez search interface at NCBI. Nucleic Acids Research 34, D599–D601. Leslie, M., 2002. Database: Gene farm. Science 298, 2097. Nicholas, F.W., Harper, P.A.W., 1996. Inherited disorders: The comparative picture. Australian Veterinary Journal 73, 64–66. Nicholas, F.W., 1998. Genetic databases: Online catalogues of inherited disorders. In: Muller, M., Brem, G. (Eds.), Genetic Resistance to Animal Diseases. Office International des Epizooties (OIE), Paris, France. OIE Scientific and Technical Review, vol. 17, pp. 346–350. Nicholas, F.W., 2001. Genetics of morphological traits and inherited disorders. In: Ruvinsky, A., Sampson, J. (Eds.), The Genetics of the Dog. CABI, Wallingford, UK, pp. 87–116. Nicholas, F.W., 2003. Online Mendelian Inheritance in Animals (OMIA): A comparative knowledgebase of genetic disorders and other familial traits in non-laboratory animals. Nucleic Acids Research 31, 275–277. Sargan, D.R., 2004. IDID: Inherited diseases in dogs: Web-based information for canine inherited disease genetics. Mammalian Genome 15, 503–506.
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See: www.omia.angis.org.au/acknowledgements.shtml.