I'm reading Subramanian et. al's (2005) original GSEA [paper][1]. In the paper, the authors mention the following: > We noticed that the use of > weighted steps could cause the distribution of observed ES scores to > be asymmetric in cases where many more genes are correlated with one > of the two phenotypes. We therefore estimate the significance levels > by considering separately the positively and negatively scoring gene > sets I understand what they're saying, but I simply don't understand why it's a problem. Basically, they're saying that in some cases, most genes in the list we're testing could appear mostly at the top or bottom of the list. But I don't understand why having asymmetric distributions is a problem. What is the issue here? EDIT: Here are some example GSEA plots I found via a web search with such gene sets. Where is the problem? [![enter image description here][2]][2] One thing I don't get though is why this problem would be introduced through "weighting" of the steps. I feel like it would also be a problem without weighting. The way it is phrased in the paper seems to suggest that it's the weighting that causes an issue. [1]: https://www.pnas.org/doi/10.1073/pnas.0506580102 [2]: https://i.sstatic.net/qJdzT.jpg