Imputation of canine genotype array data using 365 whole-genome sequences improves power of genome-wide association studies.

Genomic resources for the domestic dog have improved with the widespread adoption of a 173k SNP array platform and updated reference genome. SNP arrays of this density are sufficient for detecting genetic associations within breeds but are underpowered for finding associations across multiple breeds or in mixed-breed dogs, where linkage disequilibrium rapidly decays between markers, even though such studies would hold particular promise for mapping complex diseases and traits. Here we introduce an imputation reference panel, consisting of 365 diverse, whole-genome sequenced dogs and wolves, which increases the number of markers that can be queried in genome-wide association studies approximately 130-fold. Using previously genotyped dogs, we show the utility of this reference panel in identifying potentially novel associations, including a locus on CFA20 significantly associated with cranial cruciate ligament disease, and fine-mapping for canine body size and blood phenotypes, even when causal loci are not in strong linkage disequilibrium with any single array marker. This reference panel resource will improve future genome-wide association studies for canine complex diseases and other phenotypes.

Decreased incidence of perioperative inadvertent hypothermia and faster anesthesia recovery with increased environmental temperature: A nonrandomized controlled study.

OBJECTIVE: To determine perioperative inadvertent hypothermia (PIH) incidence, risk factors, prevention methods, and effect of PIH prevention on anesthesia recovery times. STUDY DESIGN: Nonrandomized controlled before-and-after trial. ANIMALS: Dogs (n = 277) and cats (n = 20) undergoing open surgery. METHODS: Incidence and risk factors for PIH (core temperature <96.8°F), existing thermal care practices, and recovery times were documented at baseline. For group 1, a thermal care bundle consisting of protocol-driven active warming combined with raised environmental temperatures (75°F) in induction rooms (IR) and operating rooms (OR) was implemented. Perioperative inadvertent hypothermia incidence and recovery times were recorded. For group 2, baseline active warming practices were resumed while environmental temperatures remained elevated. RESULTS: Perioperative inadvertent hypothermia was associated with preoperative imaging (P = .039) and percentage clip area (P = .037). Perioperative inadvertent hypothermia decreased in group 1 (13.5%, n = 96, P < .001) and group 2 (13.0%, n = 100, P < .001) compared with baseline (35.6%, n = 101). Median time from anesthesia withdrawal to extubation decreased in group 1 (5 minutes, P = .028) and group 2 (5 minutes, P = .018) compared with baseline (7 minutes). Median time from anesthesia recovery to spontaneous food intake decreased in group 1 (6 hours, n = 92, P = .016) but not in group 2 (6.0 hours, n = 88, P = .060) compared with baseline (n = 94, 6.7 hours). No group differences in PIH risk factors were identified. CONCLUSION: Perioperative inadvertent hypothermia incidence was high but reducible by raising environmental temperatures alone or in combination with increased focus on active warming. Reductions in PIH shortened recovery times. CLINICAL SIGNIFICANCE: Maintaining IR and OR temperatures at the standard-of-care for human pediatric surgery reduces PIH and may improve outcomes.

Genetic structure in village dogs reveals a Central Asian domestication origin.

Dogs were the first domesticated species, originating at least 15,000 y ago from Eurasian gray wolves. Dogs today consist primarily of two specialized groups--a diverse set of nearly 400 pure breeds and a far more populous group of free-ranging animals adapted to a human commensal lifestyle (village dogs). Village dogs are more genetically diverse and geographically widespread than purebred dogs making them vital for unraveling dog population history. Using a semicustom 185,805-marker genotyping array, we conducted a large-scale survey of autosomal, mitochondrial, and Y chromosome diversity in 4,676 purebred dogs from 161 breeds and 549 village dogs from 38 countries. Geographic structure shows both isolation and gene flow have shaped genetic diversity in village dog populations. Some populations (notably those in the Neotropics and the South Pacific) are almost completely derived from European stock, whereas others are clearly admixed between indigenous and European dogs. Importantly, many populations--including those of Vietnam, India, and Egypt-show minimal evidence of European admixture. These populations exhibit a clear gradient of short--range linkage disequilibrium consistent with a Central Asian domestication origin.

Long Term Functional Outcome of Tibial Tuberosity Advancement vs. Tibial Plateau Leveling Osteotomy and Extracapsular Repair in a Heterogeneous Population of Dogs.

OBJECTIVE: To determine a long term function of tibial tuberosity advancement (TTA) for treatment of ruptured cranial cruciate ligament (CCL) in dogs, and to compare this to the long term function of previously reported tibial plateau leveling osteotomy (TPLO), extracapsular reconstruction (ECR), and a population of normal dogs. STUDY DESIGN: Prospective clinical trial. ANIMALS: Dogs with unilateral ruptured CCL treated with TTA (n = 14), TPLO (n = 15), and ECR (n = 23), and normal adult dogs (control, n = 80). MATERIALS AND METHODS: Force plate gait analysis was performed at 1 time point for the normal control group and preoperatively, and at 2 and 8 weeks and 6 and 12 months postoperatively for the treatment groups. Using serial force plates, symmetry indices (SI) were calculated between the operated and unoperated pelvic limbs for peak vertical force (PVF), contact time (CT), and vertical impulse (VI). Ground reaction forces (GRF) of the treatment and control group were compared using a general linear model. RESULTS: Walk SI for dogs with TTA were not significantly different from the control group at 12 months postoperatively. At the trot, neither TTA nor ECR achieved normal GRF. SI of the TPLO group were not different from the normal control group by 6-12 months postoperatively. CONCLUSION: At the walk, TTA achieves normal function by 12 months; however, at the trot TTA is indistinguishable from ECR. TPLO resulted in operated limb function that was similar to the control population by 6-12 months postoperatively at the walk and the trot.

Enrichment of statistical power for genome-wide association studies.

BACKGROUND: The inheritance of most human diseases and agriculturally important traits is controlled by many genes with small effects. Identifying these genes, while simultaneously controlling false positives, is challenging. Among available statistical methods, the mixed linear model (MLM) has been the most flexible and powerful for controlling population structure and individual unequal relatedness (kinship), the two common causes of spurious associations. The introduction of the compressed MLM (CMLM) method provided additional opportunities for optimization by adding two new model parameters: grouping algorithms and number of groups. RESULTS: This study introduces another model parameter to develop an enriched CMLM (ECMLM). The parameter involves algorithms to define kinship between groups (that is, kinship algorithms). The ECMLM calculates kinship using several different algorithms and then chooses the best combination between kinship algorithms and grouping algorithms. CONCLUSION: Simulations show that the ECMLM increases statistical power. In some cases, the magnitude of power gained by using ECMLM instead of CMLM is larger than the improvement found by using CMLM instead of MLM.

Genomic analysis establishes correlation between growth and laryngeal neuropathy in Thoroughbreds.

BACKGROUND: Equine recurrent laryngeal neuropathy (RLN) is a bilateral mononeuropathy with an unknown pathogenesis that significantly affects performance in Thoroughbreds. A genetic contribution to the pathogenesis of RLN is suggested by the higher prevalence of the condition in offspring of RLN-affected than unaffected stallions. To better understand RLN pathogenesis and its genetic basis, we performed a genome-wide association (GWAS) of 282 RLN-affected and 268 control Thoroughbreds. RESULTS: We found a significant association of RLN with the LCORL/NCAPG locus on ECA3 previously shown to affect body size in horses. Using height at the withers of 505 of these horses, we confirmed the strong association of this locus with body size, and demonstrated a significant phenotypic and genetic correlation between height and RLN grade in this cohort. Secondary genetic associations for RLN on ECA18 and X did not correlate with withers height in our cohort, but did contain candidate genes likely influencing muscle physiology and growth: myostatin (MSTN) and integral membrane protein 2A (ITM2A). CONCLUSIONS: This linkage between body size and RLN suggests that selective breeding to reduce RLN prevalence would likely reduce adult size in this population. However, our results do not preclude the possibility of modifier loci that attenuate RLN risk without reducing size or performance, or that the RLN risk allele is distinct but tightly linked to the body size locus on ECA3. This study is both the largest body size GWAS and the largest RLN GWAS within Thoroughbred horses to date, and suggests that improved understanding of the relationship between genetics, equine growth rate, and RLN prevalence may significantly advance our understanding and management of this disease.

Precision and accuracy of ground reaction force normalization in a heterogeneous population of dogs.

OBJECTIVE: To determine if currently used ground reaction force (GRF) normalization methods are accurate and precise enough to be used on a single-limb basis. STUDY DESIGN: Prospective clinical trial. ANIMALS: Clinically normal (n = 69) dogs and 40 dogs with unilateral ruptured cranial cruciate ligaments (CCL). METHODS: Pelvic limb GRFs of orthopedically normal dogs and those with unilateral ruptured CCL were collected. Normalization methods included none, body weight (BW), withers height (WH), WH and relative velocity (WH*F) and principal component 1 (PC1). Normalization methods were evaluated both by individual GRFs and additively. Binary logistic regression was performed for all normalization methods; sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) calculated. Stepwise backward logistic regression was used; significant values were retained in the final model. P < .05 was significant. RESULTS: Normalization of contact time (CT) by BW uniformly increased sensitivity, specificity, PPV, NPV, and accuracy. SI was the most accurate at both the walk and trot (accuracy 80-96%). Normalization by BW, WH, and WH*F all achieved similar results. When normalized GRFs were added, the accuracy increased only at the walk. CLINICAL SIGNIFICANCE: CT should be normalized to BW. SIs remain the gold standard, if SIs cannot be used, combining GRFs normalized to BW will result in high precision (80%) and high accuracy (89.5%) at the walk. At the trot, normalization by BW, WH and WH*F results in consistent results for the individual GRFs, though not all accuracies are >80%.

Cubital subchondral joint space width and CT osteoabsorptiometry in dogs with and without fragmented medial coronoid process.

OBJECTIVE: To evaluate subchondral joint space width measurements (SJSW) and CT-osteoabsorptiometry (CTOAM) measurements in the elbow of dogs with naturally occurring fragmented medial coronoid process (FMCP) preoperatively and 6 months postoperatively, and to compare these to normal dogs. STUDY DESIGN: Prospective randomized clinical trial. ANIMALS: Large breed dogs <1 year of age (n = 15). METHODS: Arthroscopic FMCP debridement was performed, followed by randomization to a proximal ulnar ostectomy with IM pin (PUO). CTs were performed pre-operatively and 6 months post-operatively. CTOAM and SJSW measurements were acquired in 7 locations within the joint and compared to an age-matched normal control group. Pearson correlation was performed on SJSW and CTOAM measurements. A linear mixed model determined the effect of disease and treatment on SJSW and CTOAM measurements. RESULTS: Fifteen dogs (28 elbows) with FMCP participated (11 arthroscopic FMCP removal, 17 with additional PUO). Data were normally distributed. Pearson correlation between CTOAM and SJSW measurements showed moderate to strong negative correlation in the control dogs. Preoperatively, affected elbows had lower medial compartment and higher lateral coronoid process CTOAM values than normal elbows. After treatment, CTOAM values of the medial compartment increased to normal. Treatment with PUO did not affect SJSW or CTOAM. CONCLUSIONS: Our data agree with these previous studies suggesting lower subchondral plate mineralization in dogs affected by FMCP. Arthroscopy may result in higher CTOAM values secondary to increased loading.

Effect of ulnar ostectomy on intra-articular pressure mapping and contact mechanics of the congruent and incongruent canine elbow ex vivo.

OBJECTIVE: To determine (1) the effect of elbow incongruity on contact mechanics and (2) the effect of treatment of this incongruity with 1 of 2 ulnar ostectomies in the canine elbow. STUDY DESIGN: Ex vivo biomechanical study. SAMPLE POPULATION: Unpaired cadaveric canine forelimbs (n = 17). METHODS: In a servohydraulic testing frame, thin-film pressure sensors were placed into the lateral and medial compartments of the elbow. Specimens were tested in 135° of elbow joint flexion at 200 N of cyclic axial force, followed by a 20 seconds hold. Intra-articular contact area (CA), mean contact pressure (mCP) and peak contact pressure (pCP) were measured in each compartment. After radial shortening, testing was repeated and limbs randomized into proximal ulnar ostectomy with IM pin (PUO) or sequential distal ulnar ostectomy (DUO), interosseous ligament release (DUO-L), and ulnar attachment of the abductor pollicis longus muscle and interosseous membrane release (DUO-ML). Paired t-tests were used to compare each treatment to baseline values. Differences between treatment groups were evaluated with a mixed model with random effect to adjust for the clustering of limbs within dog. P < .05 was considered significant. RESULTS: Radial shortening resulted in shift of mCP and pCP from the lateral to the medial compartment. The PUO group resulted in normalization of medial compartment mCP and decrease of pCP, whereas in the DUO group return to baseline was achieved only after DUO-ML. CONCLUSION: PUO is effective in unloading medial compartment pCP in an incongruent joint.

Long-term functional outcome of tibial plateau leveling osteotomy versus extracapsular repair in a heterogeneous population of dogs.

OBJECTIVE: To compare the long-term outcome of tibial plateau leveling osteotomy (TPLO) and extracapsular repair (ECR) for treatment of a ruptured cranial cruciate ligament (RCCL). STUDY DESIGN: Prospective clinical trial. ANIMALS: Normal adult dogs (control, n = 79); dogs with unilateral CCL disease (n = 38). METHODS: Dogs had TPLO (n = 15) or ECR (n = 23) for treatment of RCCL. Force plate gait analysis was performed for the control group at one time point and for treatment groups at serial points: preoperatively, 2 weeks, 8 weeks, 6 and 12 months postoperatively. Symmetry indices (SIs) were calculated between operated and unoperated pelvic limb for ground reaction forces (GRFs), including peak vertical force (PVF), contact time (CT), and vertical impulse (VI). GRFs of the treatment groups and control group were compared using a general linear model and Kaplan-Meier survival analysis. RESULTS: At 8 weeks, for PVF and VI, the TPLO group had more symmetric limb loading than the ECR group at the walk and trot. SIs of the TPLO group were not different from the control group by 6 months to 1 year postoperatively. SIs for the ECR group were less symmetrical than the control group at all time periods. Using survival analysis, median time to normal function was no different at the walk between groups, but was shorter for the TPLO group for VI and PVF. CONCLUSIONS: Dogs achieved normal limb loading faster after TPLO than ECR. TPLO resulted in operated limb function that was indistinguishable from the control population by 1 year postoperatively.

Common Orthopedic Traits and Screening for Breeding Programs.

Orthopedic diseases are complex traits, meaning genetics and environmental factors affect risk, making identification of genetic associations difficult. In the United States, hip and elbow scores, patellar luxation scores, Legg-Calvé-Perthes disease, and shoulder osteochondrosis affectedness are available in the Orthopedic Foundation for Animals registry. Distraction indices and extended, ventrodorsal hip conformation scores are recorded by PennHIP. Application of estimated breeding values for hip and elbow dysplasia in breeder selection reduces the severity and prevalence of these traits. Genomic prediction and whole-genome sequence technologies and methods should improve knowledge of genetics underlying orthopedic diseases, leading to improved canine orthopedic genetic quality.

Complex population structure in African village dogs and its implications for inferring dog domestication history.

High genetic diversity of East Asian village dogs has recently been used to argue for an East Asian origin of the domestic dog. However, global village dog genetic diversity and the extent to which semiferal village dogs represent distinct, indigenous populations instead of admixtures of various dog breeds has not been quantified. Understanding these issues is critical to properly reconstructing the timing, number, and locations of dog domestication. To address these questions, we sampled 318 village dogs from 7 regions in Egypt, Uganda, and Namibia, measuring genetic diversity >680 bp of the mitochondrial D-loop, 300 SNPs, and 89 microsatellite markers. We also analyzed breed dogs, including putatively African breeds (Afghan hounds, Basenjis, Pharaoh hounds, Rhodesian ridgebacks, and Salukis), Puerto Rican street dogs, and mixed breed dogs from the United States. Village dogs from most African regions appear genetically distinct from non-native breed and mixed-breed dogs, although some individuals cluster genetically with Puerto Rican dogs or United States breed mixes instead of with neighboring village dogs. Thus, African village dogs are a mosaic of indigenous dogs descended from early migrants to Africa, and non-native, breed-admixed individuals. Among putatively African breeds, Pharaoh hounds, and Rhodesian ridgebacks clustered with non-native rather than indigenous African dogs, suggesting they have predominantly non-African origins. Surprisingly, we find similar mtDNA haplotype diversity in African and East Asian village dogs, potentially calling into question the hypothesis of an East Asian origin for dog domestication.

The S-measurement in the diagnosis of canine hip dysplasia.

OBJECTIVE: To propose a direct measure of subluxation of the femoral head (S) in the assessment of hip joint laxity and evaluate it for clinical use. STUDY DESIGN: Method comparison study. ANIMALS: Dogs (n = 51). METHODS: Dogs were sedated or anesthetized for a dorsolateral subluxation (DLS) examination. Two sets of radiographs were acquired, 1 each by a different technologist. A calibrated measuring bar was included on the image at the height of the hip to assess magnification. The DLS was calculated for each hip and different persons unaware of these details measured the "S"-value. One person measured the S-value 3 times over 3 days. Box plots were used to determine a cut-off for the empiric (8 mm) and corrected (4 mm) S-value. RESULTS: Of 51 dogs, 33 were dysplastic based on a DLS score <55%. Magnification and body weight were strongly correlated (r = 0.4922, P = .0006). Both empiric and corrected S measurements showed good agreement with the DLS score (κ = 0.688 and κ = 0.681, respectively). The corrected S measurement produced more false negatives. Bland-Altman analysis showed interobserver and technician variance acceptable for clinical use (limits of agreement < ±3 mm). Intraobserver repeatability was acceptable for the right hip (95% of differences were ≤1.3 mm and 100% ≤ 1.9) but not for the left hip. CONCLUSION: Using a cut-off value of 5 mm, the empirical S measurement can be used to exclude hip dysplasia in young dogs of various body proportions.

Evaluation of tibial torsion in Yorkshire Terriers with and without medial patellar luxation.

OBJECTIVE: To determine if medial patellar luxation (MPL) in Yorkshire Terriers is associated with tibial torsion. STUDY DESIGN: Prospective cross-sectional study. ANIMALS: Yorkshire Terriers (n = 30; 60 tibiae). METHODS: Each MPL was graded using a categorical grading scheme. Computed tomography of the tibiae was performed and tibial torsion angle (TTA) was assessed. MPL grade was analyzed with a general linear model where the independent variables include sex, neutering status, age, weight, and TTA. RESULTS: Factors that had collective impact on MPL grade were TTA, age, and weight squared. As MPL grade increased, TTA decreased by 0.05° and age increased by 0.13 years. As weight increased, MPL decreased. There was no effect (P > .05) from scorers, side, and neutering status. CONCLUSION: Body weight squared, TTA, and age affect MPL grade, suggesting that a torsional deformity may contribute to the development of MPL in Yorkshire terriers along with weight and age.

Complex Feline Disease Mapping Using a Dense Genotyping Array.

The current feline genotyping array of 63 k single nucleotide polymorphisms has proven its utility for mapping within breeds, and its use has led to the identification of variants associated with Mendelian traits in purebred cats. However, compared to single gene disorders, association studies of complex diseases, especially with the inclusion of random bred cats with relatively low linkage disequilibrium, require a denser genotyping array and an increased sample size to provide statistically significant associations. Here, we undertook a multi-breed study of 1,122 cats, most of which were admitted and phenotyped for nine common complex feline diseases at the Cornell University Hospital for Animals. Using a proprietary 340 k single nucleotide polymorphism mapping array, we identified significant genome-wide associations with hyperthyroidism, diabetes mellitus, and eosinophilic keratoconjunctivitis. These results provide genomic locations for variant discovery and candidate gene screening for these important complex feline diseases, which are relevant not only to feline health, but also to the development of disease models for comparative studies.

Evaluation of a fibrillin 2 gene haplotype associated with hip dysplasia and incipient osteoarthritis in dogs.

OBJECTIVE: To determine whether a mutation in the fibrillin 2 gene (FBN2) is associated with canine hip dysplasia (CHD) and osteoarthritis in dogs. ANIMALS: 1,551 dogs. Procedures-Hip conformation was measured radiographically. The FBN2 was sequenced from genomic DNA of 21 Labrador Retrievers and 2 Greyhounds, and a haplotype in intron 30 of FBN2 was sequenced in 90 additional Labrador Retrievers and 143 dogs of 6 other breeds. Steady-state values of FBN2 mRNA and control genes were measured in hip joint tissues of fourteen 8-month-old Labrador Retriever-Greyhound crossbreeds. RESULTS: The Labrador Retrievers homozygous for a 10-bp deletion haplotype in intron 30 of FBN2 had significantly worse CHD as measured via higher distraction index and extended-hip joint radiograph score and a lower Norberg angle and dorsolateral subluxation score. Among 143 dogs of 6 other breeds, those homozygous for the same deletion haplotype also had significantly worse radiographic CHD. Among the 14 crossbred dogs, as the dorsolateral subluxation score decreased, the capsular FBN2 mRNA increased significantly. Those dogs with incipient hip joint osteoarthritis had significantly increased capsular FBN2 mRNA, compared with those dogs without osteoarthritis. Dogs homozygous for the FBN2 deletion haplotype had significantly less FBN2 mRNA in their femoral head articular cartilage. CONCLUSIONS AND CLINICAL RELEVANCE: The FBN2 deletion haplotype was associated with CHD. Capsular gene expression of FBN2 was confounded by incipient secondary osteoarthritis in dysplastic hip joints. Genes influencing complex traits in dogs can be identified by genome-wide screening, fine mapping, and candidate gene screening.

Genomic Prediction of Two Complex Orthopedic Traits Across Multiple Pure and Mixed Breed Dogs.

Canine hip dysplasia (CHD) and rupture of the cranial cruciate ligament (RCCL) are two complex inherited orthopedic traits of dogs. These two traits may occur concurrently in the same dog. Genomic prediction of these two diseases would benefit veterinary medicine, the dog's owner, and dog breeders because of their high prevalence, and because both traits result in painful debilitating osteoarthritis in affected joints. In this study, 842 unique dogs from 6 breeds with hip and stifle phenotypes were genotyped on a customized Illumina high density 183 k single nucleotide polymorphism (SNP) array and also analyzed using an imputed dataset of 20,487,155 SNPs. To implement genomic prediction, two different statistical methods were employed: Genomic Best Linear Unbiased Prediction (GBLUP) and a Bayesian method called BayesC. The cross-validation results showed that the two methods gave similar prediction accuracy (r = 0.3-0.4) for CHD (measured as Norberg angle) and RCCL in the multi-breed population. For CHD, the average correlation of the AUC was 0.71 (BayesC) and 0.70 (GBLUP), which is a medium level of prediction accuracy and consistent with Pearson correlation results. For RCCL, the correlation of the AUC was slightly higher. The prediction accuracy of GBLUP from the imputed genotype data was similar to the accuracy from DNA array data. We demonstrated that the genomic prediction of CHD and RCCL with DNA array genotype data is feasible in a multiple breed population if there is a genetic connection, such as breed, between the reference population and the validation population. Albeit these traits have heritability of about one-third, higher accuracy is needed to implement in a natural population and predicting a complex phenotype will require much larger number of dogs within a breed and across breeds. It is possible that with higher accuracy, genomic prediction of these orthopedic traits could be implemented in a clinical setting for early diagnosis and treatment, and the selection of dogs for breeding. These results need continuous improvement in model prediction through ongoing genotyping and data sharing. When genomic prediction indicates that a dog is susceptible to one of these orthopedic traits, it should be accompanied by clinical and radiographic screening at an acceptable age with appropriate follow-up.

Synovial fluid lubricin increases in spontaneous canine cruciate ligament rupture.

Lubricin is an important boundary lubricant and chondroprotective glycoprotein in synovial fluid. Both increased and decreased synovial fluid lubricin concentrations have been reported in experimental post-traumatic osteoarthritis (PTOA) animal models and in naturally occurring joint injuries in humans and animals, with no consensus about how lubricin is altered in different species or injury types. Increased synovial fluid lubricin has been observed following intra-articular fracture in humans and horses and in human late-stage osteoarthritis; however, it is unknown how synovial lubricin is affected by knee-destabilizing injuries in large animals. Spontaneous rupture of cranial cruciate ligament (RCCL), the anterior cruciate ligament equivalent in quadrupeds, is a common injury in dogs often accompanied by OA. Here, clinical records, radiographs, and synovial fluid samples from 30 dogs that sustained RCCL and 9 clinically healthy dogs were analyzed. Synovial fluid lubricin concentrations were nearly 16-fold greater in RCCL joints as compared to control joints, while IL-2, IL-6, IL-8, and TNF-α concentrations did not differ between groups. Synovial fluid lubricin concentrations were correlated with the presence of radiographic OA and were elevated in three animals sustaining RCCL injury prior to the radiographic manifestation of OA, indicating that lubricin may be a potential biomarker for early joint injury.

Bayesian and Machine Learning Models for Genomic Prediction of Anterior Cruciate Ligament Rupture in the Canine Model.

Anterior cruciate ligament (ACL) rupture is a common, debilitating condition that leads to early-onset osteoarthritis and reduced quality of human life. ACL rupture is a complex disease with both genetic and environmental risk factors. Characterizing the genetic basis of ACL rupture would provide the ability to identify individuals that have high genetic risk and allow the opportunity for preventative management. Spontaneous ACL rupture is also common in dogs and shows a similar clinical presentation and progression. Thus, the dog has emerged as an excellent genomic model for human ACL rupture. Genome-wide association studies (GWAS) in the dog have identified a number of candidate genetic variants, but research in genomic prediction has been limited. In this analysis, we explore several Bayesian and machine learning models for genomic prediction of ACL rupture in the Labrador Retriever dog. Our work demonstrates the feasibility of predicting ACL rupture from SNPs in the Labrador Retriever model with and without consideration of non-genetic risk factors. Genomic prediction including non-genetic risk factors approached clinical relevance using multiple linear Bayesian and non-linear models. This analysis represents the first steps toward development of a predictive algorithm for ACL rupture in the Labrador Retriever model. Future work may extend this algorithm to other high-risk breeds of dog. The ability to accurately predict individual dogs at high risk for ACL rupture would identify candidates for clinical trials that would benefit both veterinary and human medicine.