Survival analysis of pathway activity as a prognostic determinant in breast cancer

High throughput biology enables the measurements of relative concentrations of thousands of biomolecules from e.g. tissue samples. The process leaves the investigator with the problem of how to best interpret the potentially large numbers of differences between samples. Many activities in a cell depend on ordered reactions involving multiple biomolecules, often referred to as pathways. It hence makes sense to study differences between samples in terms of altered pathway activity, using so-called pathway analysis. Traditional pathway analysis gives significance to differences in the pathway components' concentrations between sample groups, however, less frequently used methods for estimating individual samples' pathway activities have been suggested. Here we demonstrate that such a method can be used for pathway-based survival analysis. Specifically, we investigate the pathway activities' association with patients' survival time based on the transcription profiles of the METABRIC dataset. Our implementation shows that pathway activities are better prognostic markers for survival time in METABRIC than the individual transcripts. We also demonstrate that we can regress out the effect of individual pathways on other pathways, which allows us to estimate the other pathways' residual pathway activity on survival. Furthermore, we illustrate how one can visualize the often interdependent measures over hierarchical pathway databases using sunburst plots.

Automated summary

High throughput biology allows for the measurement of relative concentrations of biomolecules from tissue samples, but interpreting the resulting differences between samples remains a challenge. Pathway analysis provides a way to study these differences in terms of altered pathway activity. In this study, we demonstrate the use of a method for pathway-based survival analysis, using the METABRIC dataset. Our findings show that pathway activities can serve as better prognostic markers for survival than individual transcripts.