Characterization of non-monotonic relationships between tumor mutational burden and clinical outcomes

Potential clinical biomarkers are often assessed with Cox regressions or their ability to differentiate two groups of patients based on a single cutoff. However, both of these approaches assume a monotonic relationship between the potential biomarker and survival. Tumor mutational burden (TMB) is currently being studied as a predictive biomarker for immunotherapy, and a single cutoff is often used to divide patients. In this study we introduce a two-cutoff approach that allows splitting of patients when a non-monotonic relationship is present, and explore the use of neural networks to model more complex relationships of TMB to outcome data. Using real-world data we find that while in most cases the true relationship between TMB and survival appears monotonic, that is not always the case and researchers should be made aware of this possibility. SignificanceWhen a non-monotonic relationship to survival is present it is not possible to divide patients by a single value of a predictor. Neural networks allow for complex transformations and can be used to correctly split patients when a non-monotonic relationship is present.