CONFIDENCE INTERVALS FOR THE DIFFERENCE BETWEEN TWO PARTIAL AUCS

As new diagnostic tests are developed and marketed, it is very important to be able to compare the accuracy of a given two continuous‐scale diagnostic tests. An effective method to evaluate the difference between the diagnostic accuracy of two tests is to compare partial areas under the receiver operating characteristic curves (AUCs). In this paper, we review existing parametric methods. Then, we propose a new semiparametric method and a new nonparametric method to investigate the difference between two partial AUCs. For the difference between two partial AUCs under each method, we derive a normal approximation, define an empirical log‐likelihood ratio, and show that the empirical log‐likelihood ratio follows a scaled chi‐square distribution. We construct five confidence intervals for the difference based on normal approximation, bootstrap, and empirical likelihood methods. Finally, extensive simulation studies are conducted to compare the finite‐sample performances of these intervals, and a real example is used as an application of our recommended intervals. The simulation results indicate that the proposed hybrid bootstrap and empirical likelihood intervals outperform other existing intervals in most cases.     

A Framework for Random-Effects ROC Analysis: Biases with the Bootstrap and Other Variance Estimators

In this article, we analyze the three-way bootstrap estimate of the variance of the reader-averaged nonparametric area under the receiver operating characteristic (ROC) curve. The setting for this work is medical imaging, and the experimental design involves sampling from three distributions: a set of normal and diseased cases (patients), and a set of readers (doctors). The experiment we consider is fully crossed in that each reader reads each case. A reading generates a score that indicates the reader's level of suspicion that the patient is diseased. The distribution of scores for the normal patients is compared to the distribution of scores for the diseased patients via an ROC curve, and the area under the ROC curve (AUC) summarizes the reader's diagnostic ability to separate the normal patients from the diseased ones. We find that the bootstrap estimate of the variance of the reader-averaged AUC is biased, and we represent this bias in terms of moments of success outcomes. This representation helps unify and improve several current methods for multi-reader multi-case (MRMC) ROC analysis.     

Nonparametric and semiparametric estimation of the three way receiver operating characteristic surface

In many situations the diagnostic decision is not limited to a binary choice. Binary statistical tools such as receiver operating characteristic (ROC) curve and area under the ROC curve (AUC) need to be expanded to address three-category classification problem. Previous authors have suggest various ways to model the extension of AUC but not the ROC surface. Only simple parametric approaches are proposed for modeling the ROC measure under the assumption that test results all follow normal distributions. We study the estimation methods of three-dimensional ROC surfaces with nonparametric and semiparametric estimators. Asymptotical results are provided as a basis for statistical inference. Simulation studies are performed to assess the validity of our proposed methods in finite samples. We consider an Alzheimer's disease example from a clinical study in the US as an illustration. The nonparametric and semiparametric modelling approaches for the three way ROC analysis can be readily generalized to diagnostic problems with more than three classes.     

Semi-empirical likelihood inference for the ROC curve with missing data

The receiver operating characteristic (ROC) curve is one of the most commonly used methods to compare the diagnostic performance of two or more laboratory or diagnostic tests. In this paper, we propose semi-empirical likelihood based confidence intervals for ROC curves of two populations, where one population is parametric and the other one is non-parametric and both have missing data. After imputing missing values, we derive the semi-empirical likelihood ratio statistic and the corresponding likelihood equations. It is shown that the log-semi-empirical likelihood ratio statistic is asymptotically scaled chi-squared. The estimating equations are solved simultaneously to obtain the estimated lower and upper bounds of semi-empirical likelihood confidence intervals. We conduct extensive simulation studies to evaluate the finite sample performance of the proposed empirical likelihood confidence intervals with various sample sizes and different missing probabilities.     

A sequential conditional probability ratio test procedure for comparing diagnostic tests

In this paper, we derive sequential conditional probability ratio tests to compare diagnostic tests without distributional assumptions on test results. The test statistics in our method are nonparametric weighted areas under the receiver-operating characteristic curves. By using the new method, the decision of stopping the diagnostic trial early is unlikely to be reversed should the trials continue to the planned end. The conservatism reflected in this approach to have more conservative stopping boundaries during the course of the trial is especially appealing for diagnostic trials since the end point is not death. In addition, the maximum sample size of our method is not greater than a fixed sample test with similar power functions. Simulation studies are performed to evaluate the properties of the proposed sequential procedure. We illustrate the method using data from a thoracic aorta imaging study.     

Exact Bootstrap Variances of the Area Under ROC Curve

The area under the Receiver Operating Characteristic (ROC) curve (AUC) and related summary indices are widely used for assessment of accuracy of an individual and comparison of performances of several diagnostic systems in many areas including studies of human perception, decision making, and the regulatory approval process for new diagnostic technologies. Many investigators have suggested implementing the bootstrap approach to estimate variability of AUC-based indices. Corresponding bootstrap quantities are typically estimated by sampling a bootstrap distribution. Such a process, frequently termed Monte Carlo bootstrap, is often computationally burdensome and imposes an additional sampling error on the resulting estimates. In this article, we demonstrate that the exact or ideal (sampling error free) bootstrap variances of the nonparametric estimator of AUC can be computed directly, i.e., avoiding resampling of the original data, and we develop easy-to-use formulas to compute them. We derive the formulas for the variances of the AUC corresponding to a single given or random reader, and to the average over several given or randomly selected readers. The derived formulas provide an algorithm for computing the ideal bootstrap variances exactly and hence improve many bootstrap methods proposed earlier for analyzing AUCs by eliminating the sampling error and sometimes burdensome computations associated with a Monte Carlo (MC) approximation. In addition, the availability of closed-form solutions provides the potential for an analytical assessment of the properties of bootstrap variance estimators. Applications of the proposed method are shown on two experimentally ascertained datasets that illustrate settings commonly encountered in diagnostic imaging. In the context of the two examples we also demonstrate the magnitude of the effect of the sampling error of the MC estimators on the resulting inferences.     

Nonparametric covariate adjustment for receiver operating characteristic curves

The accuracy of a diagnostic test is typically characterized using the receiver operating characteristic (ROC) curve. Summarizing indexes such as the area under the ROC curve (AUC) are used to compare different tests as well as to measure the difference between two populations. Often additional information is available on some of the covariates which are known to influence the accuracy of such measures. The authors propose nonparametric methods for covariate adjustment of the AUC. Models with normal errors and possibly non‐normal errors are discussed and analyzed separately. Nonparametric regression is used for estimating mean and variance functions in both scenarios. In the model that relaxes the assumption of normality, the authors propose a covariate‐adjusted Mann–Whitney estimator for AUC estimation which effectively uses available data to construct working samples at any covariate value of interest and is computationally efficient for implementation. This provides a generalization of the Mann–Whitney approach for comparing two populations by taking covariate effects into account. The authors derive asymptotic properties for the AUC estimators in both settings, including asymptotic normality, optimal strong uniform convergence rates and mean squared error (MSE) consistency. The MSE of the AUC estimators was also assessed in smaller samples by simulation. Data from an agricultural study were used to illustrate the methods of analysis. The Canadian Journal of Statistics 38:27–46; 2010 © 2009 Statistical Society of Canada     

Nonparametric estimation of the ROC curve based on smoothed empirical distribution functions

The receiver operating characteristic (ROC) curve is a graphical representation of the relationship between false positive and true positive rates. It is a widely used statistical tool for describing the accuracy of a diagnostic test. In this paper we propose a new nonparametric ROC curve estimator based on the smoothed empirical distribution functions. We prove its strong consistency and perform a simulation study to compare it with some other popular nonparametric estimators of the ROC curve. We also apply the proposed method to a real data set.     

Bounding sample size projections for the area under a ROC curve

Studies of diagnostic tests are often designed with the goal of estimating the area under the receiver operating characteristic curve (AUC) because the AUC is a natural summary of a test's overall diagnostic ability. However, sample size projections dealing with AUCs are very sensitive to assumptions about the variance of the empirical AUC estimator, which depends on two correlation parameters. While these correlation parameters can be estimated from the available data, in practice it is hard to find reliable estimates before the study is conducted. Here we derive achievable bounds on the projected sample size that are free of these two correlation parameters. The lower bound is the smallest sample size that would yield the desired level of precision for some model, while the upper bound is the smallest sample size that would yield the desired level of precision for all models. These bounds are important reference points when designing a single or multi-arm study; they are the absolute minimum and maximum sample size that would ever be required. When the study design includes multiple readers or interpreters of the test, we derive bounds pertaining to the average reader AUC and the ‘pooled’ or overall AUC for the population of readers. These upper bounds for multireader studies are not too conservative when several readers are involved.     

Applications of the Bootstrap in ROC Analysis

The problem of estimating standard errors for diagnostic accuracy measures might be challenging for many complicated models. We can address such a problem by using the Bootstrap methods to blunt its technical edge with resampled empirical distributions. We consider two cases where bootstrap methods can successfully improve our knowledge of the sampling variability of the diagnostic accuracy estimators. The first application is to make inference for the area under the ROC curve resulted from a functional logistic regression model which is a sophisticated modelling device to describe the relationship between a dichotomous response and multiple covariates. We consider using this regression method to model the predictive effects of multiple independent variables on the occurrence of a disease. The accuracy measures, such as the area under the ROC curve (AUC) are developed from the functional regression. Asymptotical results for the empirical estimators are provided to facilitate inferences. The second application is to test the difference of two weighted areas under the ROC curve (WAUC) from a paired two sample study. The correlation between the two WAUC complicates the asymptotic distribution of the test statistic. We then employ the bootstrap methods to gain satisfactory inference results. Simulations and examples are supplied in this article to confirm the merits of the bootstrap methods.     

Nonparametric Predictive Inference for diagnostic accuracy

Measuring the accuracy of diagnostic tests is crucial in many application areas including medicine and health care. Good methods for determining diagnostic accuracy provide useful guidance on selection of patient treatment, and the ability to compare different diagnostic tests has a direct impact on quality of care. In this paper Nonparametric Predictive Inference (NPI) methods for accuracy of diagnostic tests with continuous test results are presented and discussed. For such tests, Receiver Operating Characteristic (ROC) curves have become popular tools for describing the performance of diagnostic tests. We present the NPI approach to ROC curves, and some important summaries of these curves. As NPI does not aim at inference for an entire population but instead explicitly considers a future observation, this provides an attractive alternative to standard methods. We show how NPI can be used to compare two continuous diagnostic tests.     

An alternative method for global and partial comparison of two diagnostic systems based on ROC curves

In this paper, an alternative method for the comparison of two diagnostic systems based on receiver operating characteristic (ROC) curves is presented. ROC curve analysis is often used as a statistical tool for the evaluation of diagnostic systems. However, in general, the comparison of ROC curves is not straightforward, in particular, when they cross each other. A similar difficulty is also observed in the multi-objective optimization field where sets of solutions defining fronts must be compared with a multi-dimensional space. Thus, the proposed methodology is based on a procedure used to compare the performance of distinct multi-objective optimization algorithms. In general, methods based on the area under the ROC curves are not sensitive to the existence of crossing points between the curves. The new approach can deal with this situation and also allows the comparison of partial portions of ROC curves according to particular values of sensitivity and specificity of practical interest. Simulations results are presented. For illustration purposes, considering real data from newborns with very low birthweight, the new method was applied in order to discriminate the better index for evaluating the risk of death.     

Compare diagnostic tests using transformation-invariant smoothed ROC curves()

Receiver operating characteristic (ROC) curve, plotting true positive rates against false positive rates as threshold varies, is an important tool for evaluating biomarkers in diagnostic medicine studies. By definition, ROC curve is monotone increasing from 0 to 1 and is invariant to any monotone transformation of test results. And it is often a curve with certain level of smoothness when test results from the diseased and non-diseased subjects follow continuous distributions. Most existing ROC curve estimation methods do not guarantee all of these properties. One of the exceptions is Du and Tang (2009) which applies certain monotone spline regression procedure to empirical ROC estimates. However, their method does not consider the inherent correlations between empirical ROC estimates. This makes the derivation of the asymptotic properties very difficult. In this paper we propose a penalized weighted least square estimation method, which incorporates the covariance between empirical ROC estimates as a weight matrix. The resulting estimator satisfies all the aforementioned properties, and we show that it is also consistent. Then a resampling approach is used to extend our method for comparisons of two or more diagnostic tests. Our simulations show a significantly improved performance over the existing method, especially for steep ROC curves. We then apply the proposed method to a cancer diagnostic study that compares several newly developed diagnostic biomarkers to a traditional one.     

Detection and Localization in Test Accuracy: A Bayesian Perspective

In assessing the area under the ROC curve for the accuracy of a diagnostic test, it is imperative to detect and locate multiple abnormalities per image. This approach takes that into account by adopting a statistical model that allows for correlation between the reader scores of several regions of interest (ROI).

The ROI method of partitioning the image is taken. The readers give a score to each ROI in the image and the statistical model takes into account the correlation between the scores of the ROI's of an image in estimating test accuracy. The test accuracy is given by Pr[Y > Z] + (1/2)Pr[Y = Z], where Y is an ordinal diagnostic measurement of an affected ROI, and Z is the diagnostic measurement of an unaffected ROI. This way of measuring test accuracy is equivalent to the area under the ROC curve. The parameters are the parameters of a multinomial distribution, then based on the multinomial distribution, a Bayesian method of inference is adopted for estimating the test accuracy.

Using a multinomial model for the test results, a Bayesian method based on the predictive distribution of future diagnostic scores is employed to find the test accuracy. By resampling from the posterior distribution of the model parameters, samples from the posterior distribution of test accuracy are also generated. Using these samples, the posterior mean, standard deviation, and credible intervals are calculated in order to estimate the area under the ROC curve. This approach is illustrated by estimating the area under the ROC curve for a study of the diagnostic accuracy of magnetic resonance angiography for diagnosis of arterial atherosclerotic stenosis. A generalization to multiple readers and/or modalities is proposed.

A Bayesian way to estimate test accuracy is easy to perform with standard software packages and has the advantage of employing the efficient inclusion of information from prior related imaging studies.     

Powerful nonparametric statistics to compare k independent ROC curves

The authors deal with the problem of comparing receiver operating characteristic (ROC) curves from independent samples. From a nonparametric approach, they propose and study three different statistics. Their asymptotic distributions are obtained and a resample plan is considered. In order to study the statistical power of the introduced statistics, a simulation study is carried out. The (observed) results suggest that, for the considered models, the new statistics are more powerful than the usually employed ones (the Venkatraman test and the usual area under the ROC curve criterion) in non-uniform dominance situations and quite good otherwise.     

ROC curve estimation based on local smoothing

ROC curve is a graphical representation of the relationship between sensitivity and specificity of a diagnostic test. It is a popular tool for evaluating and comparing different diagnostic tests in medical sciences. In the literature,the ROC curve is often estimated empirically based on an empirical distribution function estimator and an empirical quantile function estimator. In this paper an alternative nonparametric procedure to estimate the ROC Curve is suggested which is based on local smoothing techniques. Several numerical examples are presented to evaluate the performance of this procedure.     

Nonparametric Covariate-Adjusted Association Tests Based on the Generalized Kendall's Tau()

Identifying the risk factors for comorbidity is important in psychiatric research. Empirically, studies have shown that testing multiple, correlated traits simultaneously is more powerful than testing a single trait at a time in association analysis. Furthermore, for complex diseases, especially mental illnesses and behavioral disorders, the traits are often recorded in different scales such as dichotomous, ordinal and quantitative. In the absence of covariates, nonparametric association tests have been developed for multiple complex traits to study comorbidity. However, genetic studies generally contain measurements of some covariates that may affect the relationship between the risk factors of major interest (such as genes) and the outcomes. While it is relatively easy to adjust these covariates in a parametric model for quantitative traits, it is challenging for multiple complex traits with possibly different scales. In this article, we propose a nonparametric test for multiple complex traits that can adjust for covariate effects. The test aims to achieve an optimal scheme of adjustment by using a maximum statistic calculated from multiple adjusted test statistics. We derive the asymptotic null distribution of the maximum test statistic, and also propose a resampling approach, both of which can be used to assess the significance of our test. Simulations are conducted to compare the type I error and power of the nonparametric adjusted test to the unadjusted test and other existing adjusted tests. The empirical results suggest that our proposed test increases the power through adjustment for covariates when there exist environmental effects, and is more robust to model misspecifications than some existing parametric adjusted tests. We further demonstrate the advantage of our test by analyzing a data set on genetics of alcoholism.     

COMBINING MULTIPLE MARKERS FOR MULTI‐CATEGORY CLASSIFICATION: AN ROC SURFACE APPROACH

The Receiver Operating Characteristic (ROC) curve and the Area Under the ROC Curve (AUC) are effective statistical tools for evaluating the accuracy of diagnostic tests for binary‐class medical data. However, many real‐world biomedical problems involve more than two categories. The Volume Under the ROC Surface (VUS) and Hypervolume Under the ROC Manifold (HUM) measures are extensions for the AUC under three‐class and multiple‐class models. Inference methods for such measures have been proposed recently. We develop a method of constructing a linear combination of markers for which the VUS or HUM of the combined markers is maximized. Asymptotic validity of the estimator is justified by extending the results for maximum rank correlation estimation that are well known in econometrics. A bootstrap resampling method is then applied to estimate the sampling variability. Simulations and examples are provided to demonstrate our methods.     

An application of lomax distributions in receiver operating characteristic(roc)curve analysis

Receiver operating characteristic(ROC)curves are useful for studying the performance of diagnostic tests. ROC curves occur in many fields of applications including psychophysics, quality control and medical diagnostics. In practical situations, often the responses to a diagnostic test are classified into a number of ordered categories. Such data are referred to as ratings data. It is typically assumed that the underlying model is based on a continuous probability distribution. The ROC curve is then constructed from such data using this probability model. Properties of the ROC curve are inherited from the model. Therefore, understanding the role of different probability distributions in ROC modeling is an interesting and important area of research. In this paper the Lomax distribution is considered as a model for ratings data and the corresponding ROC curve is derived. The maximum likelihood estimation procedure for the related parameters is discussed. This procedure is then illustrated in the analysis of a neurological data example.