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      Dog breeds and body conformations with predisposition to osteosarcoma in the UK: a case-control study

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          Abstract

          Background

          Osteosarcoma is an aggressive and painful bone neoplasm in dogs. Previous studies have reported epidemiological associations suggesting that large body mass, long bone length and the genetics of certain breeds including the Rottweiler are associated with elevated osteosarcoma risk. However, these studies were often limited by selection bias and confounding factors, and have rarely offered insights into breed-associated protection for osteosarcoma. The current study includes 1756 appendicular and axial osteosarcoma cases presenting to VPG Histology (Bristol, UK) compared against a control population of 905,211 dogs without osteosarcoma from primary care electronic patient records in the VetCompass™ dataset.

          Methods and study design

          Retrospective, case-control study. Multivariable logistic regression analysis explored associations between demographic risk factors (including breed, chondrodystrophy, age, sex/neuter status, skull-shape, and body mass) and osteosarcoma of all anatomical sites.

          Results

          We identified several breeds with increased and reduced odds of osteosarcoma. At highest risk were the Rottweiler and Great Dane, with > 10 times the odds of osteosarcoma compared with crossbreds, and the Rhodesian Ridgeback, which has not featured in previous lists of at-risk breeds for osteosarcoma, and had an odds ratio of 11.31 (95% confidence interval 7.37–17.35). Breeds at lowest risk of osteosarcoma (protected breeds) included the Bichon Frise, the French Bulldog and the Cavalier King Charles Spaniel, all with odd ratios of less than 0.30 compared with crossbreds. Body mass was strongly associated with osteosarcoma risk; dogs over 40 kg exhibited osteosarcoma odds of 45.44 (95% confidence interval 33.74–61.20) compared with dogs less than 10 kg. Chondrodystrophic breeds had an osteosarcoma odds ratio of 0.13 (95% confidence interval 0.11–0.16) compared with non-chondrodystrophic breeds.

          Conclusions

          This study provides evidence of strong breed-associated osteosarcoma risk and protection, suggesting a genetic basis for osteosarcoma pathogenesis. It highlights that breeds selected for long legs/large body mass are generally overrepresented amongst at-risk breeds, whilst those selected for short leg length/small body mass are generally protected. These findings could inform genetic studies to identify osteosarcoma risk alleles in canines and humans; as well as increasing awareness amongst veterinarians and owners, resulting in improved breeding practices and clinical management of osteosarcoma in dogs.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s40575-021-00100-7.

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          Most cited references74

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            pROC: an open-source package for R and S+ to analyze and compare ROC curves

            Background Receiver operating characteristic (ROC) curves are useful tools to evaluate classifiers in biomedical and bioinformatics applications. However, conclusions are often reached through inconsistent use or insufficient statistical analysis. To support researchers in their ROC curves analysis we developed pROC, a package for R and S+ that contains a set of tools displaying, analyzing, smoothing and comparing ROC curves in a user-friendly, object-oriented and flexible interface. Results With data previously imported into the R or S+ environment, the pROC package builds ROC curves and includes functions for computing confidence intervals, statistical tests for comparing total or partial area under the curve or the operating points of different classifiers, and methods for smoothing ROC curves. Intermediary and final results are visualised in user-friendly interfaces. A case study based on published clinical and biomarker data shows how to perform a typical ROC analysis with pROC. Conclusions pROC is a package for R and S+ specifically dedicated to ROC analysis. It proposes multiple statistical tests to compare ROC curves, and in particular partial areas under the curve, allowing proper ROC interpretation. pROC is available in two versions: in the R programming language or with a graphical user interface in the S+ statistical software. It is accessible at http://expasy.org/tools/pROC/ under the GNU General Public License. It is also distributed through the CRAN and CSAN public repositories, facilitating its installation.
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              Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases

              Horizontal pleiotropy occurs when the variant has an effect on disease outside of its effect on the exposure in Mendelian randomization (MR). Violation of the ‘no horizontal pleiotropy’ assumption can cause severe bias in MR. We developed the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test to identify horizontal pleiotropic outliers in multi-instrument summary-level MR testing. We showed using simulations that MR-PRESSO is best suited when horizontal pleiotropy occurs in <50% of instruments. Next, we applied MR-PRESSO, along with several other MR tests to complex traits and diseases, and found that horizontal pleiotropy: (i) was detectable in over 48% of significant causal relationships in MR; (ii) introduced distortions in the causal estimates in MR that ranged on average from −131% to 201%; (iii) induced false positive causal relationships in up to 10% of relationships; and (iv) can be corrected in some but not all instances.
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                Author and article information

                Contributors
                ge8793@bristol.ac.uk
                SmalleyMJ@Cardiff.ac.uk
                sam.beck@synlab.co.uk
                sg16003@bristol.ac.uk
                helen.winter@uhbw.nhs.uk
                dbrodbelt@rvc.ac.uk
                doneill@rvc.ac.uk
                Journal
                Canine Med Genet
                Canine Med Genet
                Canine Medicine and Genetics
                BioMed Central (London )
                2662-9380
                10 March 2021
                10 March 2021
                2021
                : 8
                : 2
                Affiliations
                [1 ]Bristol Veterinary School, Langford House, Langford, Bristol, BS40 5DU UK
                [2 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, European Cancer Stem Cell Research Institute and School of Biosciences, Cardiff University, ; Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ UK
                [3 ]VPG Histology (formerly Bridge), Horner Court, 637 Gloucester Road, Horfield, Bristol, BS7 0BJ UK
                [4 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, Division of Cancer and Genetics, School of Medicine, Academic Avenue, , Cardiff University, ; Cardiff, CF62 3LF UK
                [5 ]Langford Veterinary Services, Langford House Langford, Bristol, BS40 5DU UK
                [6 ]Bristol Cancer Institute, Bristol, BS2 8ED UK
                [7 ]GRID grid.20931.39, ISNI 0000 0004 0425 573X, Pathobiology and Population Sciences, The Royal Veterinary College, ; Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA UK
                Author information
                http://orcid.org/0000-0001-9188-7345
                Article
                100
                10.1186/s40575-021-00100-7
                7944903
                33750475
                93790b96-b28f-4d33-a79d-4032f648e151
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 6 October 2020
                : 30 January 2021
                Funding
                Funded by: Elizabeth Blackwell Institute
                Award ID: R105121-142
                Award Recipient :
                Funded by: Wellcome Trust Institutional Strategic Support Fund
                Award ID: 204813/Z/16/Z
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                vetcompass,electronic patient record,epr,breed,dog,epidemiology,primary-care,veterinary,pedigree,purebred,osteosarcoma,bone tumour,cancer,neoplasia

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