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pmid:28856086
Identification of novel targets for multiple myeloma through integrative approach with Monte Carlo cross-validation analysis.
Congjian Liu · Xiang Gu · Zhenxian Jiang
Journal of bone oncology · 2017 doi:10.1016/j.jbo.2017.08.001
Paper
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Experiment
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Data
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Analysis
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Execution
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Complete file
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Thus, identifying cross-talk among pathways is necessary to understand the molecular mechanisms of multiple myeloma (MM). Based on this, this paper looked at extracting potential pathway cross-talk in MM through an integrative approach using Monte Carlo cross-validation analysis. The gene expression library of MM (accession number: GSE6477) was downloaded from the Gene Expression Omnibus (GEO) database. The integrative approach was then used to identify potential pathway cross-talk, and included four steps: Firstly, differential expression analysis was conducted to identify differentially expressed genes (DEGs). Secondly, the DEGs obtained were mapped to the pathways downloaded from an ingenuity pathways analysis (IPA), to reveal the underlying relationship between the DEGs and pathways enriched by these DEGs. A subset of pathways enriched by the DEGs was then obtained. Thirdly, a discriminating score (DS) value for each paired pathway was computed. Lastly, random forest (RF) classification was used to identify the paired pathways based on area under the curve (AUC) and Monte Carlo cross-validation, which was repeated 50 times to explore the best paired pathways. These paired pathways were tested with another independently published MM microarray data (GSE85837), using in silico validation. Overall, 60 DEGs and 19 differential pathways enriched by DEGs were extracted. Each pathway was sorted based on their AUC values. The paired pathways, inhibition of matrix metalloproteases and EIF2 signaling pathway, indicated the best AUC value of 1.000. Paired pathways consisting of IL-8 and EIF2 signaling pathways with higher AUC of 0.975, were involved in 7 runs. Furthermore, it was validated consistently in separate microarray data sets (GSE85837). Paired pathways (inhibition of matrix metalloproteases and EIF2 signaling, IL-8 signaling and EIF2 signaling) exhibited the best AUC values and higher frequency of validation. Two paired pathways (inhibition of matrix metalloproteases and EIF2 signaling, IL-8 signaling and EIF2 signaling) were used to accurately classify MM and control samples. 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{"label": "Table 1", "caption": "List of differentially expressed genes (DEGs).", "rows": [["Genes", "LogFC", "FDR", "Genes", "LogFC", "FDR"], ["RNASE2", "−4.2668", "1.25E-24", "LMO2", "−2.02467", "1.26E-04"], ["CLC", "−4.94929", "1.05E-13", "CD24", "−2.24512", "1.65E-04"], ["PRG3", "−3.90837", "2.93E-12", "MRC1", "−2.06384", "2.36E-04"], ["RNASE3", "−4.31871", "5.08E-12", "CRISP3", "−2.73151", "2.55E-04"], ["PRG2", "−5.93443", "1.01E-09", "MS4A3", "−2.17214", "2.61E-04"], ["MPO", "−2.52454", "8.15E-09", "ZNF358", "2.042213", "2.66E-04"], ["DEFA4", "−2.22389", "1.70E-08", "MS4A6A", "−2.21587", "3.54E-04"], ["ELANE", "−4.39842", "1.94E-08", "IL4R", "−2.1392", "3.74E-04"], ["EPX", "−3.18113", "9.02E-08", "PXDC1", "−2.08509", "4.67E-04"], ["ARMC7", "2.314169", "2.21E-07", "CD320", "2.241042", "4.83E-04"], ["CAMP", "−3.0549", "9.82E-07", "CD163", "−2.52643", "5.17E-04"], ["IGHG1", "−3.7307", "2.23E-06", "LUM", "−3.58203", "5.20E-04"], ["CTSH", "−2.87845", "3.55E-06", "CXCL8", "−2.40243", "5.26E-04"], ["AIF1", "−2.16656", "4.43E-06", "NOD2", "−2.95453", "5.26E-04"], ["LST1", "−2.19262", "8.38E-06", "S100A8", "−2.70373", "5.61E-04"], ["IGLJ3", "−4.49176", "1.13E-05", "CXCL2", "−2.71229", "5.61E-04"], ["CLPP", "2.32109", "1.65E-05", "IGHD", "−4.07084", "5.84E-04"], ["LTF", "−3.89554", "1.65E-05", "HMOX1", "−2.36868", "5.99E-04"], ["FABP4", "−2.79511", "3.18E-05", "MS4A4A", "−3.38126", "6.11E-04"], ["LYVE1", "−2.9819", "3.18E-05", "HIF1A", "−2.13129", "6.18E-04"], ["NRP1", "−2.08155", "3.34E-05", "VNN2", "−2.4071", "6.18E-04"], ["S100A12", "−2.16333", "3.34E-05", "MAFB", "−3.4547", "6.41E-04"], ["CEACAM8", "−3.52708", "4.20E-05", "ALDH1A3", "−2.01185", "6.80E-04"], ["IGLV1-44", "−4.8402", "6.64E-05", "LHFP", "−2.18934", "6.98E-04"], ["KCTD12", "−2.56891", "6.99E-05", "S100A9", "−2.3273", "8.20E-04"], ["CD14", "−3.15551", "7.82E-05", "MNDA", "−3.14832", "9.14E-04"], ["RPS11", "2.079562", "8.44E-05", "HLA-DPA1", "−2.64283", "9.63E-04"], ["IGK", "−3.99784", "9.70E-05", 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differentially expressed genes (DEGs).", "rows": [["Pathway", "FDR", "Genes in pathway", "Number of common genes"], ["Granulocyte Adhesion and Diapedesis", "6.09E-11", "163", "4"], ["EIF2 Signaling", "2.88E-10", "173", "6"], ["Atherosclerosis Signaling", "1.32E-07", "119", "1"], ["Hepatic Fibrosis / Hepatic Stellate Cell Activation", "1.66E-07", "137", "2"], ["LXR/RXR Activation", "1.78E-07", "121", "1"], ["T Helper Cell Differentiation", "2.91E-06", "62", "3"], ["Bladder Cancer Signaling", "5.83E-06", "86", "5"], ["Role of Macrophages", "2.23E-05", "282", "4"], ["Complement System", "4.96E-05", "32", "3"], ["Altered T Cell and B Cell Signaling in Rheumatoid Arthritis", "6.80E-05", "76", "2"], ["IL-8 Signaling", "6.96E-05", "183", "1"], ["PI3K Signaling in B Lymphocytes", "1.01E-04", "122", "3"], ["Regulation of the Epithelial-Mesenchymal Transition Pathway", "1.17E-04", "175", "1"], ["Neuroprotective Role of THOP1 in Alzheimer's Disease", "3.38E-04", "40", "1"], ["Role of 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"reader_status": "available", "identifier": "section[12]/table-wrap[1]#t0025", "version": null, "note": "Top 10 pairs of pathways with AUC value, validated using the other MM microarray data.", "structure": {"pmcid": "PMC5565744", "section_index": 12, "section_title": "In silico validation with independent MM microarray data", "row_count": 21, "column_count": 2}, "table": {"label": "Table 5", "caption": "Top 10 pairs of pathways with AUC value, validated using the other MM microarray data.", "rows": [["Pairs of pathways", "AUC"], ["(1a) Inhibition of matrix metalloproteases", "0.971"], ["(1b) EIF2 signaling"], ["(2a) TREM1 signaling", "0.968"], ["(2b) EIF2 signaling", ""], ["(3a) EIF2 signaling", "0.961"], ["(3b) IL-8 signaling", ""], ["(4a) IL-10 signaling", "0.956"], ["(4b) EIF2 signaling"], ["(5a) Antigen Presentation Pathway", "0.955"], ["(5b) LPS/IL-1 Mediated Inhibition of RXR Function"], ["(6a) Caveolar-mediated Endocytosis Signaling", "0.955"], ["(6b) Agranulocyte Adhesion and 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