Non‐parametric interval estimation for the partial area under the ROC curve

Accurate diagnosis of disease is a critical part of health care. New diagnostic and screening tests must be evaluated based on their abilities to discriminate diseased conditions from non‐diseased conditions. For a continuous‐scale diagnostic test, a popular summary index of the receiver operating characteristic (ROC) curve is the area under the curve (AUC). However, when our focus is on a certain region of false positive rates, we often use the partial AUC instead. In this paper we have derived the asymptotic normal distribution for the non‐parametric estimator of the partial AUC with an explicit variance formula. The empirical likelihood (EL) ratio for the partial AUC is defined and it is shown that its limiting distribution is a scaled chi‐square distribution. Hybrid bootstrap and EL confidence intervals for the partial AUC are proposed by using the newly developed EL theory. We also conduct extensive simulation studies to compare the relative performance of the proposed intervals and existing intervals for the partial AUC. A real example is used to illustrate the application of the recommended intervals. The Canadian Journal of Statistics 39: 17–33; 2011 © 2011 Statistical Society of Canada     

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.     

A modified area under the ROC curve and its application to marker selection and classification

The area under the ROC curve (AUC) can be interpreted as the probability that the classification scores of a diseased subject is larger than that of a non-diseased subject for a randomly sampled pair of subjects. From the perspective of classification, we want to find a way to separate two groups as distinctly as possible via AUC. When the difference of the scores of a marker is small, its impact on classification is less important. Thus, a new diagnostic/classification measure based on a modified area under the ROC curve (mAUC) is proposed, which is defined as a weighted sum of two AUCs, where the AUC with the smaller difference is assigned a lower weight, and vice versa. Using mAUC is robust in the sense that mAUC gets larger as AUC gets larger as long as they are not equal. Moreover, in many diagnostic situations, only a specific range of specificity is of interest. Under normal distributions, we show that if the AUCs of two markers are within similar ranges, the larger mAUC implies the larger partial AUC for a given specificity. This property of mAUC will help to identify the marker with the higher partial AUC, even when the AUCs are similar. Two nonparametric estimates of an mAUC and their variances are given. We also suggest the use of mAUC as the objective function for classification, and the use of the gradient Lasso algorithm for classifier construction and marker selection. Application to simulation datasets and real microarray gene expression datasets show that our method finds a linear classifier with a higher ROC curve than some other existing linear classifiers, especially in the range of low false positive rates.     

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.     

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.     

Generalized Confidence Interval Estimation for the Difference in Paired Areas Under the ROC Curves in the Absence of a Gold Standard

Receiver operating characteristic (ROC) curves can be used to assess the accuracy of tests measured on ordinal or continuous scales. The most commonly used measure for the overall diagnostic accuracy of diagnostic tests is the area under the ROC curve (AUC). A gold standard (GS) test on the true disease status is required to estimate the AUC. However, a GS test may be too expensive or infeasible. In many medical researches, the true disease status of the subjects may remain unknown. Under the normality assumption on test results from each disease group of subjects, we propose a heuristic method of estimating confidence intervals for the difference in paired AUCs of two diagnostic tests in the absence of a GS reference. This heuristic method is a three-stage method by combining the expectation-maximization (EM) algorithm, bootstrap method, and an estimation based on asymptotic generalized pivotal quantities (GPQs) to construct generalized confidence intervals for the difference in paired AUCs in the absence of a GS. Simulation results show that the proposed interval estimation procedure yields satisfactory coverage probabilities and expected interval lengths. The numerical example using a published dataset illustrates the proposed method.     

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.     

Two transformation models for estimating an ROC curve derived from continuous data

A receiver operating characteristic (ROC) curve is a plot of two survival functions, derived separately from the diseased and healthy samples. A special feature is that the ROC curve is invariant to any monotone transformation of the measurement scale. We propose and analyse semiparametric and parametric transformation models for this two-sample problem. Following an unspecified or specified monotone transformation, we assume that the healthy and diseased measurements have two normal distributions with different means and variances. Maximum likelihood algorithms for estimating ROC curve parameters are developed. The proposed methods are illustrated on the marker CA125 in the diagnosis of gastric cancer.     

Validation of Nonparametric Two-sample Bootstrap in ROC Analysis on Large Datasets

The nonparametric two-sample bootstrap is applied to computing uncertainties of measures in receiver operating characteristic (ROC) analysis on large datasets in areas such as biometrics, speaker recognition, etc. when the analytical method cannot be used. Its validation was studied by computing the standard errors of the area under ROC curve using the well-established analytical Mann–Whitney statistic method and also using the bootstrap. The analytical result is unique. The bootstrap results are expressed as a probability distribution due to its stochastic nature. The comparisons were carried out using relative errors and hypothesis testing. These match very well. This validation provides a sound foundation for such computations.     

The average area under correlated receiver operating characteristic curves: a nonparametric approach based on generalized two-sample Wilcoxon statistics

It is well known that, when sample observations are independent, the area under the receiver operating characteristic (ROC) curve corresponds to the Wilcoxon statistics if the area is calculated by the trapezoidal rule. Correlated ROC curves arise often in medical research and have been studied by various parametric methods. On the basis of the Mann–Whitney U-statistics for clustered data proposed by Rosner and Grove, we construct an average ROC curve and derive nonparametric methods to estimate the area under the average curve for correlated ROC curves obtained from multiple readers. For the more complicated case where, in addition to multiple readers examining results on the same set of individuals, two or more diagnostic tests are involved, we derive analytic methods to compare the areas under correlated average ROC curves for these diagnostic tests. We demonstrate our methods in an example and compare our results with those obtained by other methods. The nonparametric average ROC curve and the analytic methods that we propose are easy to explain and simple to implement.     

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     

Detecting diagnostic accuracy of two biomarkers through a bivariate log-normal ROC curve

In biomedical research, two or more biomarkers may be available for diagnosis of a particular disease. Selecting one single biomarker which ideally discriminate a diseased group from a healthy group is confront in a diagnostic process. Frequently, most of the people use the accuracy measure, area under the receiver operating characteristic (ROC) curve to choose the best diagnostic marker among the available markers for diagnosis. Some authors have tried to combine the multiple markers by an optimal linear combination to increase the discriminatory power. In this paper, we propose an alternative method that combines two continuous biomarkers by direct bivariate modeling of the ROC curve under log-normality assumption. The proposed method is applied to simulated data set and prostate cancer diagnostic biomarker data set.     

Semi-parametric estimation of ROC curves based on binomial regression modelling

This paper presents a method of estimating a receiver operating characteristic (ROC) curve when the underlying diagnostic variable X is continuous and fully observed. The new method is based on modelling the probability of response given X , rather than the distribution of X given response. The method offers advantages in modelling flexibility and computational simplicity. The resulting ROC curve estimates are semi-parametric and can, in principle, take an infinite variety of shapes. Moreover, model selection can be based on standard methods within the binomial regression framework. Statistical accuracy of the curve estimate is provided by a simply implemented bootstrap approach.     

Importance resampling for the smoothed bootstrap

Alternative methods of estimating properties of unknown distributions include the bootstrap and the smoothed bootstrap. In the standard bootstrap setting, Johns (1988) introduced an importance resam¬pling procedure that results in more accurate approximation to the bootstrap estimate of a distribution function or a quantile. With a suitable “exponential tilting” similar to that used by Johns, we derived a smoothed version of importance resampling in the framework of the smoothed bootstrap. Smoothed importance resampling procedures were developed for the estimation of distribution functions of the Studentized mean, the Studentized variance, and the correlation coefficient. Implementation of these procedures are presented via simulation results which concentrate on the problem of estimation of distribution functions of the Studentized mean and Studentized variance for different sample sizes and various pre-specified smoothing bandwidths for the normal data; additional simulations were conducted for the estimation of quantiles of the distribution of the Studentized mean under an optimal smoothing bandwidth when the original data were simulated from three different parent populations: lognormal, t(3) and t(10). These results suggest that in cases where it is advantageous to use the smoothed bootstrap rather than the standard bootstrap, the amount of resampling necessary might be substantially reduced by the use of importance resampling methods and the efficiency gains depend on the bandwidth used in the kernel density estimation.     

Optimal and Robust Designs for Estimating the Concentration Curve and the AUC

The problem of interest is to estimate the concentration curve and the area under the curve (AUC) by estimating the parameters of a linear regression model with an autocorrelated error process. We introduce a simple linear unbiased estimator of the concentration curve and the AUC. We show that this estimator constructed from a sampling design generated by an appropriate density is asymptotically optimal in the sense that it has exactly the same asymptotic performance as the best linear unbiased estimator. Moreover, we prove that the optimal design is robust with respect to a minimax criterion. When repeated observations are available, this estimator is consistent and has an asymptotic normal distribution. Finally, a simulated annealing algorithm is applied to a pharmacokinetic model with correlated errors.     

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.     

Consistency of non parametric estimators of the area under the ROC curve

ABSTRACT

The area under the receiver operating characteristic (ROC) curve is a popular summary index that measures the accuracy of a continuous-scale diagnostic test to measure its accuracy. Under certain conditions on estimators of distribution functions, we prove a theorem on strong consistency of the non parametric “plugin” estimators of the area under the ROC curve. Based on this theorem, we construct some new “plugin” consistent estimators. The performance of the non parametric estimators considered is illustrated numerically and the estimators are compared in terms of bias, variance, and mean square error.     

Monte Carlo studies of bootstrap variability in ROC analysis with data dependency

ROC analysis involving two large datasets is an important method for analyzing statistics of interest for decision making of a classifier in many disciplines. And data dependency due to multiple use of the same subjects exists ubiquitously in order to generate more samples because of limited resources. Hence, a two-layer data structure is constructed and the nonparametric two-sample two-layer bootstrap is employed to estimate standard errors of statistics of interest derived from two sets of data, such as a weighted sum of two probabilities. In this article, to reduce the bootstrap variance and ensure the accuracy of computation, Monte Carlo studies of bootstrap variability were carried out to determine the appropriate number of bootstrap replications in ROC analysis with data dependency. It is suggested that with a tolerance 0.02 of the coefficient of variation, 2,000 bootstrap replications be appropriate under such circumstances.     

A non-inferiority test for diagnostic accuracy in the absence of the golden standard test based on the paired partial areas under receiver operating characteristic curves

Non-inferiority tests are often measured for the diagnostic accuracy in medical research. The area under the receiver operating characteristic (ROC) curve is a familiar diagnostic measure for the overall diagnostic accuracy. Nevertheless, since it may not differentiate the diverse shapes of the ROC curves with different diagnostic significance, the partial area under the ROC (PAUROC) curve, another summary measure emerges for such diagnostic processes that require the false-positive rate to be in the clinically interested range. Traditionally, to estimate the PAUROC, the golden standard (GS) test on the true disease status is required. Nevertheless, the GS test may sometimes be infeasible. Besides, in a lot of research fields such as the epidemiology field, the true disease status of the patients may not be known or available. Under the normality assumption on diagnostic test results, based on the expectation-maximization algorithm in combination with the bootstrap method, we propose the heuristic method to construct a non-inferiority test for the difference in the paired PAUROCs without the GS test. Through the simulation study, although the proposed method might provide a liberal test, as a whole, the empirical size of the proposed method sufficiently controls the size at the significance level, and the empirical power of the proposed method in the absence of the GS is as good as that of the non-inferiority in the presence of the GS. The proposed method is illustrated with the published data.     

Bayesian ROC curve estimation under binormality using an ordinal category likelihood

Receiver operating characteristic (ROC) curve has been widely used in medical diagnosis. Various methods are proposed to estimate ROC curve parameters under the binormal model. In this paper, we propose a Bayesian estimation method from the continuously distributed data which is constituted by the truth-state-runs in the rank-ordered data. By using an ordinal category data likelihood and following the Metropolis–Hastings (M–H) procedure, we compute the posterior distribution of the binormal parameters, as well as the group boundaries parameters. Simulation studies and real data analysis are conducted to evaluate our Bayesian estimation method.