Issues and solutions in biomarker evaluation when subclasses are involved under binary classification.

In practice, it is common to evaluate biomarkers in binary classification settings (e.g. non-cancer vs. cancer) where one or both main classes involve multiple subclasses. For example, non-cancer class might consist of healthy subjects and benign cases, while cancer class might consist of subjects at early and late stages. The standard practice is pooling within each main class, i.e. all non-cancer subclasses are pooled together to create a control group, and all cancer subclasses are pooled together to create a case group. Based on the pooled data, the area under ROC curve () and other characteristics are estimated under binary classification for the purpose of biomarker evaluation. Despite the popularity of this pooling strategy in practice, its validity and implication in biomarker evaluation have never been carefully inspected. This paper aims to demonstrate that pooling strategy can be seriously misleading in biomarker evaluation. Furthermore, we present a new diagnostic framework as well as new accuracy measures appropriate for biomaker evaluation under such settings. In the end, an ovarian cancer data set is analyzed.