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This study leveraged differential network enrichment analysis methodology to identify and validate lipid subnetworks that potentially differentiate chronic kidney disease (CKD) by severity or progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We built a partial correlation interaction network, identified highly connected network components, applied network-based gene-set analysis to identify differentially enriched subnetworks, and compared the subnetworks in patients with early-stage versus late-stage CKD. We identified two subnetworks \u2018triacylglycerols\u2019 and \u2018cardiolipins-phosphatidylethanolamines (CL-PE)\u2019 characterized by lower connectivity, and a higher abundance of longer polyunsaturated triacylglycerols in patients with severe CKD (stage \u22654) from the Clinical Phenotyping Resource and Biobank Core. These finding were replicated in an independent cohort, the Chronic Renal Insufficiency Cohort. Using an innovative method for elucidating biological alterations in lipid networks, we demonstrated alterations in triacylglycerols and cardiolipins-phosphatidylethanolamines that precede the clinical outcome of end-stage kidney disease by several years.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>A complete list of NetGSA results in HTML format can be found at http:\/\/metscape.ncibi.org\/netgsa\/12345-022118\/cric_cprobe\/022118\/results_cric_cprobe\/main.html. The DNEA is freely available at https:\/\/github.com\/wiggie\/DNEA. Java wrapper leveraging the cytoscape.js framework is available at http:\/\/js.cytoscape.org.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btz114","type":"journal-article","created":{"date-parts":[[2019,2,14]],"date-time":"2019-02-14T13:00:45Z","timestamp":1550149245000},"page":"3441-3452","source":"Crossref","is-referenced-by-count":30,"title":["Differential network enrichment analysis reveals novel lipid pathways in chronic kidney disease"],"prefix":"10.1093","volume":"35","author":[{"given":"Jing","family":"Ma","sequence":"first","affiliation":[{"name":"Division of Public Health Sciences, Fred Hutchinson Cancer Research Center , Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alla","family":"Karnovsky","sequence":"additional","affiliation":[{"name":"Department of Computational Medicine & 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