It was documented that a number of genes in the TOR pathway play important roles in ALL development and drug resistance [41]. More importantly, synergistic effect was found between mTOR inhibitors and MTX in clinical trial [42]. This gene set was not significant in the GSA result, which supports the argument that GSDCA extracts additional useful results from the data by utilizing different information than regular gene set analysis. The second most significant gene set found by our method, nonprotein amino acid metabolic process (Table 2; superscript 3), involves the metabolism of citrulline, ornithine and beta-alanine. The concentrations of ornithine and citrulline in gut tissues were found to be impacted by MTX treatment [43]. Among the other top gene sets, we also RNA Synthesis inhibitor found many connections with MTX and/or ALL development. We briefly list some examples here. A few genes in collagen metabolism were found to be associated with leukemia [44], and the overall expression level of collagen increases with MTX treatment (superscript 4) [45]. Several cellular adhesion molecules are known to be influenced by MTX (superscript 5) [40]. In addition, diversity in adhesion molecule levels was observed in other types of leukemia [46]. A number of proteins in the membrane organization process are influenced by leukemia (superscript 6) [44] and [47]. Pyrimidine metabolism is known to be affected by MTX due to its inhibition of the related purine metabolic pathway (superscript 7) [48]. Genes in the ATP biosynthesis pathway were found to be differentially expressed in a combination therapy involving MTX (superscript 8) [49]. We then identified gene sets that showed differential coordination (p-value < 0.005) with those listed in Table 2 (Fig. 5). With the increase of MTX response, seven of the top 25 gene sets, six of which belonging to the stimulus response system, showed decreased coordination (red dashed edges) with other gene sets. A large proportion of the pairs showed clear functional relationships. For example, 76.7% of the stimulus response and cytokine production gene sets associated with any of the top 25 gene sets were actually associated with one of the 12 stimulus response and cytokine production gene sets. The full list of the gene set pairs is provided in Supporting Table 6. We further identified major gene contributors to the top differentially coordinated gene sets (Supporting Table 7). Interleukins and their receptors, especially IL10, appeared to contribute to the differential coordination of multiple gene sets. The gene set “acid secretion” was differentially coordinated (Table 1, superscript 9), yet no clear functional link to ALL or MTX was documented. The gene-level result provided an explanation — among the 8 genes of the gene set, 2 were shared with inflammatory response. One of these two genes, ANXA1, was highly significant in the test of single gene contributors (p-value 0.002).