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      Development and internal validation of a prediction tool to aid the diagnosis of Cushing's syndrome in dogs attending primary‐care practice

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          Abstract

          Background

          Novel methods to aid identification of dogs with spontaneous Cushing's syndrome are warranted to optimize case selection for diagnostics, avoid unnecessary testing, and ultimately aid decision‐making for veterinarians.

          Hypothesis/Objectives

          To develop and internally validate a prediction tool for dogs receiving a diagnosis of Cushing's syndrome using primary‐care electronic health records.

          Animals

          Three hundred and ninety‐eight dogs diagnosed with Cushing's syndrome and 541 noncase dogs, tested for but not diagnosed with Cushing's syndrome, from a cohort of 905 544 dogs attending VetCompass participating practices.

          Methods

          A cross‐sectional study design was performed. A prediction model was developed using multivariable binary logistic regression taking the demography, presenting clinical signs and some routine laboratory results into consideration. Predictive performance of each model was assessed and internally validated through bootstrap resampling. A novel clinical prediction tool was developed from the final model.

          Results

          The final model included predictor variables sex, age, breed, polydipsia, vomiting, potbelly/hepatomegaly, alopecia, pruritus, alkaline phosphatase, and urine specific gravity. The model demonstrated good discrimination (area under the receiver operating curve [AUROC] = 0.78 [95% CI = 0.75‐0.81]; optimism‐adjusted AUROC = 0.76) and calibration (C‐slope = 0.86). A tool was developed from the model which calculates the predicted likelihood of a dog having Cushing's syndrome from 0% (score = −13) to 96% (score = 10).

          Conclusions and Clinical Importance

          A tool to predict a diagnosis of Cushing's syndrome at the point of first suspicion in dogs was developed, with good predictive performance. This tool can be used in practice to support decision‐making and increase confidence in diagnosis.

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          Most cited references59

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          General cardiovascular risk profile for use in primary care: the Framingham Heart Study.

          Separate multivariable risk algorithms are commonly used to assess risk of specific atherosclerotic cardiovascular disease (CVD) events, ie, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure. The present report presents a single multivariable risk function that predicts risk of developing all CVD and of its constituents. We used Cox proportional-hazards regression to evaluate the risk of developing a first CVD event in 8491 Framingham study participants (mean age, 49 years; 4522 women) who attended a routine examination between 30 and 74 years of age and were free of CVD. Sex-specific multivariable risk functions ("general CVD" algorithms) were derived that incorporated age, total and high-density lipoprotein cholesterol, systolic blood pressure, treatment for hypertension, smoking, and diabetes status. We assessed the performance of the general CVD algorithms for predicting individual CVD events (coronary heart disease, stroke, peripheral artery disease, or heart failure). Over 12 years of follow-up, 1174 participants (456 women) developed a first CVD event. All traditional risk factors evaluated predicted CVD risk (multivariable-adjusted P<0.0001). The general CVD algorithm demonstrated good discrimination (C statistic, 0.763 [men] and 0.793 [women]) and calibration. Simple adjustments to the general CVD risk algorithms allowed estimation of the risks of each CVD component. Two simple risk scores are presented, 1 based on all traditional risk factors and the other based on non-laboratory-based predictors. A sex-specific multivariable risk factor algorithm can be conveniently used to assess general CVD risk and risk of individual CVD events (coronary, cerebrovascular, and peripheral arterial disease and heart failure). The estimated absolute CVD event rates can be used to quantify risk and to guide preventive care.
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            Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors.

            Multivariable regression models are powerful tools that are used frequently in studies of clinical outcomes. These models can use a mixture of categorical and continuous variables and can handle partially observed (censored) responses. However, uncritical application of modelling techniques can result in models that poorly fit the dataset at hand, or, even more likely, inaccurately predict outcomes on new subjects. One must know how to measure qualities of a model's fit in order to avoid poorly fitted or overfitted models. Measurement of predictive accuracy can be difficult for survival time data in the presence of censoring. We discuss an easily interpretable index of predictive discrimination as well as methods for assessing calibration of predicted survival probabilities. Both types of predictive accuracy should be unbiasedly validated using bootstrapping or cross-validation, before using predictions in a new data series. We discuss some of the hazards of poorly fitted and overfitted regression models and present one modelling strategy that avoids many of the problems discussed. The methods described are applicable to all regression models, but are particularly needed for binary, ordinal, and time-to-event outcomes. Methods are illustrated with a survival analysis in prostate cancer using Cox regression.
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              Assessing the performance of prediction models: a framework for traditional and novel measures.

              The performance of prediction models can be assessed using a variety of methods and metrics. Traditional measures for binary and survival outcomes include the Brier score to indicate overall model performance, the concordance (or c) statistic for discriminative ability (or area under the receiver operating characteristic [ROC] curve), and goodness-of-fit statistics for calibration.Several new measures have recently been proposed that can be seen as refinements of discrimination measures, including variants of the c statistic for survival, reclassification tables, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Moreover, decision-analytic measures have been proposed, including decision curves to plot the net benefit achieved by making decisions based on model predictions.We aimed to define the role of these relatively novel approaches in the evaluation of the performance of prediction models. For illustration, we present a case study of predicting the presence of residual tumor versus benign tissue in patients with testicular cancer (n = 544 for model development, n = 273 for external validation).We suggest that reporting discrimination and calibration will always be important for a prediction model. Decision-analytic measures should be reported if the predictive model is to be used for clinical decisions. Other measures of performance may be warranted in specific applications, such as reclassification metrics to gain insight into the value of adding a novel predictor to an established model.
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                Author and article information

                Contributors
                ischofield6@rvc.ac.uk
                Journal
                J Vet Intern Med
                J Vet Intern Med
                10.1111/(ISSN)1939-1676
                JVIM
                Journal of Veterinary Internal Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                0891-6640
                1939-1676
                16 September 2020
                Nov-Dec 2020
                : 34
                : 6 ( doiID: 10.1111/jvim.v34.6 )
                : 2306-2318
                Affiliations
                [ 1 ] Pathobiology and Population Sciences The Royal Veterinary College Hatfield UK
                [ 2 ] Clinical Science and Services The Royal Veterinary College Hatfield UK
                [ 3 ] The VetCT Telemedicine Hospital St John's Innovation Centre Cambridge UK
                Author notes
                [*] [* ] Correspondence

                Imogen Schofield, Pathobiology and Population Sciences, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts AL9 7TA, UK.

                Email: ischofield6@ 123456rvc.ac.uk

                Author information
                https://orcid.org/0000-0003-3169-8723
                https://orcid.org/0000-0003-1115-2723
                Article
                JVIM15851
                10.1111/jvim.15851
                7694798
                32935905
                fe00fb35-650d-468d-8517-b92fd162308e
                © 2020 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 13 March 2020
                : 23 June 2020
                : 26 June 2020
                Page count
                Figures: 2, Tables: 6, Pages: 13, Words: 9627
                Funding
                Funded by: Dechra Veterinary Products Ltd
                Categories
                Standard Article
                SMALL ANIMAL
                Standard Articles
                Endocrinology
                Custom metadata
                2.0
                November/December 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.4 mode:remove_FC converted:27.11.2020

                Veterinary medicine
                canine,diagnosis,electronic patient record,endocrinology,hyperadrenocorticism,vetcompass

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