Equivalent change enrichment analysis: assessing equivalent and inverse change in biological pathways between diverse...

In silico functional genomics have become a driving force in the way we interpret and use gene expression data, enabling researchers to understand which biological pathways are likely to be affected by the treatments or conditions being studied. There are many approaches to functional genomics, but a number of popular methods determine if a set of modified genes has a higher than expected overlap with genes known to function as part of a pathway (functional enrichment testing). Recently, researchers have started to apply such analyses in a new way: to ask if the data they are collecting show similar disruptions to biological functions compared to reference data. Examples include studying whether similar pathways are perturbed in smokers vs. users of e-cigarettes, or whether a new mouse model of schizophrenia is justified, based on its similarity in cytokine expression to a previously published model. However, there is a dearth of robust statistical methods for testing hypotheses related to these questions and most researchers resort to ad hoc approaches. The goal of this work is to develop a statistical approach to identifying gene pathways that are equivalently (or inversely) changed across two experimental conditions.

We developed Equivalent Change Enrichment Analysis (ECEA). This is a new type of gene enrichment analysis based on a statistic that we call the equivalent change index (ECI). An ECI of 1 represents a gene that was over or under-expressed (compared to control) to the same degree across two experiments. Using this statistic, we present an approach to identifying pathways that are changed in similar or opposing ways across experiments. We compare our approach to current methods on simulated data and show that ECEA is able to recover pathways exhibiting such changes even when they exhibit complex patterns of regulation, which other approaches are unable to do. On biological data, our approach recovered pathways that appear directly connected to the condition being studied.

ECEA provides a new way to perform gene enrichment analysis that allows researchers to compare their data to existing datasets and determine if a treatment will cause similar or opposing genomic perturbations.