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The computational speed of many gene set analysis methods can be slow due to the computationally demanding permutation step. This article introduces GSA-Lightning, a fast implementation of permutation-based gene set analysis. GSA-Lightning achieves significant speedup compared with existing methods, particularly when the number of gene sets and permutations are large. Availability and implementation: The GSA-Lightning R package is available on Github at https:// github.com/billyhw/GSALightningdoi:10.1093/bioinformatics/btw349 pmid:27296982 fatcat:dplqkzcwj5gxpbbep53qzg43je