Confidence intervals for differences between volumes under receiver operating characteristic surfaces (VUS) and generalized Youden indices (GYIs)

This article explores both existing and new methods for the construction of confidence intervals for differences of indices of diagnostic accuracy of competing pairs of biomarkers in three-class classification problems and fills the methodological gaps for both parametric and non-parametric approaches in the receiver operating characteristic surface framework. The most widely used such indices are the volume under the receiver operating characteristic surface and the generalized Youden index. We describe implementation of all methods and offer insight regarding the appropriateness of their use through a large simulation study with different distributional and sample size scenarios. Methods are illustrated using data from the Alzheimer's Disease Neuroimaging Initiative study, where assessment of cognitive function naturally results in a three-class classification setting.