Are there limits in explainability of prognostic biomarkers? Scrutinizing biological utility of established signatures

Prognostic biomarkers can have an important role in the clinical practice because they allow stratification of patients in terms of predicting the outcome of a disorder. Obstacles for developing such markers include lack of robustness when using different data sets and limited concordance among similar signatures. In this paper, we highlight a new problem that relates to the biological meaning of already established prognostic gene expression signatures. Specifically, it is commonly assumed that prognostic markers provide sensible biological information and molecular explanations about the underlying disorder. However, recent studies on prognostic biomarkers investigating 80 established signatures of breast and prostate cancer demonstrated that this is not the case. We will show that this surprising result is related to the distinction between causal models and predictive models and the obfuscating usage of these models in the biomedical literature. Furthermore, we suggest a falsification procedure for studies aiming to establish a prognostic signature to safeguard against false expectations with respect to biological utility.