Bootstrap-based testing approaches for the assessment of the diagnostic accuracy of biomarkers subject to a limit of detection

Abstract

Assessment of the diagnostic accuracy of biomarkers through receiver operating characteristic curve analysis frequently involves a limit of detection imposed by the laboratory analytical system precision. As a consequence, measurements below a certain level are undetectable and ignoring these is known to lead to negatively biased estimates of the area under the receiver operating characteristic curve. In this article, we introduce two receiver operating characteristic curve-based parametric approaches that tackle the issue of correct assessment of diagnostic markers in the presence of a limit of detection. Proposed approaches are simulation-based utilising bootstrap methodology. Non-parametric alternatives that are naively used in the literature do not solve the inherent problem of limit of detection values which are treated as censored observations. However, the latter seems to perform adequately well in our simulation study. Nonparametric bootstrap was consistently used throughout, while other bootstrap alternatives performed similarly in our pilot simulation study. The simulation study involves the comparison of parametric and non-parametric options described here versus alternative strategies that are routinely used in the literature. We apply all methods to a study-setting resembling a chemical quasi-standard situation, where compound tumour biomarkers were searched within a multi-variable set of measurements to discriminate between two groups, namely colorectal cancer and controls. We focus in the assessment of glutamine and methionine.