The probability that a given pathway with certain mean up- and down-regulated genes would be identified by chance was calculated using simulations as follows: The up- or down-regulation was represented as a mean log fold ratio and was calculated separately for each pathway after noise filtering (genes with fold change of less than 0.25 were not considered; other thresholds resulted in the same trend). In cases where multiple probes existed for a gene, their average were taken. P values were determined after 5000 repeated calculations of the same measurements of mean log fold ratios for each pathway after shuffling all genes in the pathways in the analysis while keeping pathway size and gene expression distributions intact. The fraction of times the mean log fold change of the down-regulated genes exceeded that of the down-regulated genes in a pathway was considered the P value of down-regulation. P values for up-regulated genes were calculated in the same manner, and the P values for both pathways were the joint probability. KEGG pathway genes were downloaded using the package “EnrichmentBrowser” version 2.10.6 (77).

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