Network-Based Approaches for Pathway Level Analysis.

Identification of impacted pathways is an important problem because it allows us to gain insights into the underlying biology beyond the detection of differentially expressed genes. In the past decade, a plethora of methods have been developed for this purpose. The last generation of pathway analysis methods are designed to take into account various aspects of pathway topology in order to increase the accuracy of the findings. Here, we cover 34 such topology-based pathway analysis methods published in the past 13 years. We compare these methods on categories related to implementation, availability, input format, graph models, and statistical approaches used to compute pathway level statistics and statistical significance. We also discuss a number of critical challenges that need to be addressed, arising both in methodology and pathway representation, including inconsistent terminology, data format, lack of meaningful benchmarks, and, more importantly, a systematic bias that is present in most existing methods.