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Revealing potential drug-disease-gene association patterns for precision medicine

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Abstract

Precision medicine means giving patients the right treatment at the right dose at the right time with minimum ill consequences and maximum efficacy. It is medicine personalized to the individual’s genes, environment, and lifestyle and, ultimately, its widespread use will require a deep understanding of the genomic variations that create predispositions or resistances to various diseases. Some of the links between genes and diseases are already known, and more are being discovered every day. Similarly, much is known about which drugs are efficacious for treating which diseases, but there is still more to learn. The issue now is how to extract this information from the biomedical literature in way that can keep pace with today’s rapid discoveries in medical research. Efforts to assemble an organized database of such knowledge to data have focused on mathematical statistic methods, computer-aided methods, etc. Success has been mixed as previous methods usually result in false positive or depend on training sample sets, lacking of generality in different research fields, which have choked advancements in precision medicine. To break through this bottleneck, we need novel methods that can extract and leverage the valuable information locked within the constraints of the data we have. Hence, in this paper, we present a new text-based computational framework for extracting full three-way drug-disease-gene triplet information related to colorectal cancer from biomedical texts. The framework consists of two main steps. The first is to construct an integrated drug-disease-gene network by extracting pair-wise associations between diseases, drugs, and genes, and then store unique drug-disease-gene triplets for further analysis. Since the constructed network is highly likely to be too sparse, the next step is to complete the incomplete links in the network, i.e., to predict novel links from genes to diseases to drugs. To validate our framework, we conducted a case study on colorectal cancer, mining the literature for drug-disease and disease-gene associations. An analysis of the subsequent inferences drawn between the two shows that this approach can help to inform novel research hypotheses and identify new knowledge triplets about various diseases, both of which are significant for the advancement and implementation of precision medicine.

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Notes

  1. A bi-clique is a network motif in which two sets of nodes all mutually interact with each other (Simone et al. 2012).

  2. UMLS Semantic Network has 54 semantic types and 133 semantic relations.

  3. To confirm predicated links from the results, the literature is mined for disease-gene and drug-disease links respectively.

  4. https://www.businesswire.com/news/home/20170921005188/en/.

References

  • Ahnen, D. J., et al. (2014). The increasing incidence of young-onset colorectal cancer: a call to action. Mayo Clinic Proceedings, 89(2), 216–224.

    Article  Google Scholar 

  • Agrawal, R., Carey, M., Faloutsos, C., Ghosh, S., & Swami, A. (1994). Quest: A project on database mining. Acm Sigmod Record, 23(2), 514.

    Article  Google Scholar 

  • Arenas, A., Diaz-Guilera, A., & Pérez-Vicente, C. J. (2006). Synchronization reveals topological scales in complex networks. Physical review letters, 96(11), 114102.

    Article  Google Scholar 

  • Ashley, E. A., et al. (2010). Clinical assessment incorporating a personal genome. The Lancet, 375(9725), 1525–1535.

    Article  Google Scholar 

  • Assi, H., & Wilson, K. S. (2013). Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases. Current Oncology, 20(2), 165–169.

    Article  Google Scholar 

  • Bachmann, C., et al. (2006). Targeting mucosal addressin cellular adhesion molecule (MAdCAM)-1 to noninvasively image experimental Crohn’s Disease. Gastroenterology, 130(1), 8–16.

    Article  Google Scholar 

  • Boyd, A. J., Sherman, I. A., & Saibil, F. G. (1995). Effects of plain and controlled-ileal-release budesonide formulations in experimental ileitis. Scandinavian Journal of Gastroenterology, 30(10), 974–981.

    Article  Google Scholar 

  • Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer Journal For Clinicians, 68(6), 394–424.

    Article  Google Scholar 

  • Bui, Q. C., Sloot, P. M., Van Mulligen, E. M., & Kors, J. A. (2014). A novel feature-based approach to extract drug–drug interactions from biomedical text. Bioinformatics, 30(23), 3365–3371.

    Article  Google Scholar 

  • Chen, A. J., Li, F., Zhang, Y., Gong, E. C., & Shi, X. Y. (2009). Expression of co-stimulatory molecule CD86 and its inducible co-stimulator in Crohn disease and their pathologic significance. Journal of Peking University. Health Sciences, 41(6), 620–624.

    Google Scholar 

  • Chen, C. C., et al. (2011). Chitinase 3-like-1 expression in colonic epithelial cells as a potentially novel marker for colitis-associated neoplasia. American Journal of Pathology, 179(3), 1494–1503.

    Article  Google Scholar 

  • Chen, G., Cao, S., Liu, F., & Liu, Y. (2015). Mir-195 plays a role in steroid resistance of ulcerative colitis by targeting smad7. Biochemical Journal, 471(3), 357–367.

    Article  Google Scholar 

  • Cheung, W. Y., & Liu, G. (2009). Genetic variations in esophageal cancer risk and prognosis. Gastroenterology Clinics of North America, 38(1), 75–91.

    Article  Google Scholar 

  • Christos, A., Anuj, S., Vassilis, V., Spyros, D., & Aris, P. (2011). Literature mining, ontologies and information visualization for drug repurposing. Briefings in Bioinformatics, 12(4), 357–368.

    Article  Google Scholar 

  • Collins, F. S., & Varmus, H. (2015). A new initiative on precision medicine. New England Journal of Medicine, 372(9), 793–795.

    Article  Google Scholar 

  • Cunningham, M. F., Docherty, N. G., Burke, J. P., & O’Connell, P. R. (2010). S100A4 expression is increased in stricture fibroblasts from patients with fibrostenosing Crohn’s disease and promotes intestinal fibroblast migration. American Journal of Physiology Gastrointestinal & Liver Physiology, 299(2), G457.

    Article  Google Scholar 

  • Cutting, D., Kupiec, J., Pedersen, J., & Sibun, P A. (1992). A practical part of speech tagger. In Third conference on applied natural language processing, 133-140.

  • Dewey, F. E., et al. (2014). Clinical interpretation and implications of Whole-Genome Sequencing. Journal of the American Medical Association, 311(10), 1035–1045.

    Article  Google Scholar 

  • Duke, J. D., et al. (2012). Literature based drug Interaction prediction with clinical assessment using electronic medical records: novel myopathy associated drug interactions. Plos Computational Biology, 8(8), e1002614.

    Article  Google Scholar 

  • Dulbecco, R. (1986). A turning point in cancer research: equencing the human genome. Science, 231(4742), 1055–1056.

    Article  Google Scholar 

  • Eaden, J. A., Abrams, K., Ekbom, A., Jackson, E., & Mayberry, J. (2000). Colorectal cancer prevention in ulcerative colitis: a case-control study. Alimentary Pharmacology and Therapeutics, 14(2), 145–153.

    Article  Google Scholar 

  • Egger, G., Liang, G., Aparicio, A., & Jones, P. A. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature, 429, 457–463.

    Article  Google Scholar 

  • Fodil, N., et al. (2017). CCDC88B is required for pathogenesis of inflammatory bowel disease. Nature Communications, 8(1), 1–12.

    Article  Google Scholar 

  • Freeman, H. J. (2001). Colorectal cancer complicating Crohn’s disease. Canadian Journal of Gastroenterology, 15(4), 231–236.

    Article  MathSciNet  Google Scholar 

  • Fundel, K., Küffner, R., Zimmer, R. (2007). RelEx—Relation extraction using dependency parse trees. Bioinformatics, 23(3), 365–371.

    Article  Google Scholar 

  • Greenman, C., et al. (2007). Patterns of somatic mutation in human cancer genomes. Nature, 446(7132), 153–158.

    Article  Google Scholar 

  • Hristovski, D., Peterlin, B., Mitchell, J. A., & Humphrey, S. M. (2005). Using literature-based discovery to identify disease candidate genes. International Journal of Medical Informatics, 74(2/4), 289–298.

    Article  Google Scholar 

  • Hu, G., & Agarwal, P. (2009). Human disease-drug network based on genomic expression profiles. PLoS ONE, 4(8), e6536.

    Article  Google Scholar 

  • Huang, J., Ellinghaus, D., Franke, A., Howie, B., & Li, Y. (2012). 1000 genomes-based imputation identifies novel and refined associations for the wellcome trust case control consortium phase 1 data. European Journal of Human Genetics, 20(7), 801–805.

    Article  Google Scholar 

  • Huynh, D., et al. (2009). CSF-1 Dependence of paneth cell development in the mouse small intestine. Gastroenterology, 137(1), 136–144.

    Article  Google Scholar 

  • Jimeno-Yepes, A., & Verspoor, K. (2014). Literature mining of genetic variants for curation quantifying the importance of supplementary material. Database The Journal of Biological Database, 3.

  • Karaderi, T., et al. (2009). Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series. Rheumatology, 48(4), 386–389.

    Article  Google Scholar 

  • Keane, J., et al. (2001). Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. New England Journal of Medicine, 345(15), 1098–1104.

    Article  Google Scholar 

  • Kyo, K., Muto, T., Nagawa, H., Lathrop, G. M., & Nakamura, Y. (2001). Associations of distinct variants of the intestinal mucin gene MUC3A with ulcerative colitis and Crohn’s disease. Journal of Human Genetics, 46(1), 5–20.

    Article  Google Scholar 

  • Laszlo, L., et al. (2006). Risk factors for ulcerative colitis-associated colorectal cancer in a hungarian cohort of patients with ulcerative colitis: results of a population-based study. Inflammatory Bowel Diseases, 12(3), 205–211.

    Article  MathSciNet  Google Scholar 

  • Lee, J. H., et al. (2017). Treatment of recalcitrant pyoderma gangrenosum with ulcerative colitis by adalimumab injection. Annals of Dermatology, 29(2), 260–262.

    Article  Google Scholar 

  • Lombardi, C., Salmi, A., Savio, A., & Passalacqua, G. (2010). Localized eosinophilic ileitis with mastocytosis successfully treated with oral budesonide. Allergy, 62(11), 1343–1345.

    Article  Google Scholar 

  • Lopetuso, L. R., Jia, R., Wang, X. M., Jia, L. G., Petito, V., Goodman, W. A., & Pizarro, T. T. (2017). Epithelial-specific Toll-like receptor (TLR) 5 activation mediates barrier dysfunction in experimental ileitis. Inflammatory bowel diseases, 23(3), 392–403.

    Article  Google Scholar 

  • Lü, L., Jin, C. H., & Zhou, T. (2009). Similarity index based on local paths for link prediction of complex networks. Physical Review E, 80(4), 046122.

    Article  Google Scholar 

  • Ma, S., Sun, Q., & Guo, B. (2018). Expression of Sirt1 in the lung tissue of rats with ulcerative colitis and its relationship with oxidative stress and inflammatory reaction. Anatomy Research, 40(6), 489–493.

    Google Scholar 

  • Marcil, V., et al. (2012). Association between genetic variants in the HNF4A gene and childhood-onset Crohn’s disease. Genes & Immunity, 13(7), 556–565.

    Article  Google Scholar 

  • Mason, O., & Verwoerd, M. (2007). Graph theory and networks in biology. IET systems biology, 1(2), 89–119.

    Article  Google Scholar 

  • Matsuzaki, K., Hokari, R., Kato, S., Tsuzuki, Y., Tanaka, H., & Kurihara, C., et al. (2003). Differential expression of CCR 5 and CRTH 2 on infiltrated cells in colonic mucosa of patients with ulcerative colitis. Journal of Gastroenterology & Hepatology, 18(9), 1081–1088.  

    Article  Google Scholar 

  • McGovern, D. P. B., et al. (2010). Genetic epistasis of IL23/IL17 pathway genes in Crohn’s disease. Inflammatory Bowel Diseases, 15(6), 883–889.

    Article  Google Scholar 

  • McLaughlin, S. D., Bell, A. J., Clark, S. K., Tekkis, P. P., Ciclitira, P. J., & Nicholls, R. J. (2008). T1313 combined ciprofloxacin and metronidazole is highly effective for the treatment of pre-pouch ileitis following restorative proctocolectomy. Gastroenterology, 4(134), 529.

    Google Scholar 

  • Mcnamee, E. N., Masterson, J. C., Jedlicka, P., Collins, C. B., Williams, I. R., & Rivera-Nieves, J. (2013). Ectopic lymphoid tissue alters the chemokine gradient, increases lymphocyte retention and exacerbates murine ileitis. Gut, 62(1), 53–62.

    Article  Google Scholar 

  • Mirnezami, R., Nicholson, J., & Darzi, A. (2012). Preparing for precision medicine. New England Journal of Medicine, 366(6), 489–491.

    Article  Google Scholar 

  • Mitsuyama, K. (2006). STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Gut, 55(9), 1263–1269.

    Article  Google Scholar 

  • Narimatsu, K., et al. (2015). Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling. Journal of Gastroenterology & Hepatology, 30(11), 1610–1617.

    Article  Google Scholar 

  • Natarajan, N., & Dhillon, I. S. (2014). Inductive matrix completion for predicting gene-disease associations. Bioinformatics, 30(12), 60–68.

    Article  Google Scholar 

  • Nathan, D. M., Iser, J. H., & Gibson, P. R. (2010). A single center experience of methotrexate in the treatment of crohn’s disease and ulcerative colitis: a case for subcutaneous administration. Journal of Gastroenterology & Hepatology, 23(6), 954–958.

    Article  Google Scholar 

  • Obeid, S., George, J., & Hebbard, L. (2014). P-188 the role of adiponectin in inflammatory bowel disease. Inflammatory Bowel Diseases, 20(1), S102.

    Google Scholar 

  • Oertel, S., et al. (2017). Ceramide synthase 2 deficiency aggravates AOM-DSS-induced colitis in mice: role of colon barrier integrity. Cellular & Molecular Life Sciences, 74(16), 3039–3055.

    Article  Google Scholar 

  • Ozgür, A., Vu, T., Erkan, G., & Radev, D. R. (2008). Identifying gene-disease associations using centrality on a literature mined gene-interaction network. Bioinformatics, 24(13), 277–285.

    Article  Google Scholar 

  • Pokorny, R. M., Hofmeister, A., Galandiuk, S., Dietz, A. B., & Neibergs, H. L. (1997). Crohn’s disease and ulcerative colitis are associated with the DNA repair gene MLH1. Annals of Surgery, 225(6), 718–723.

    Article  Google Scholar 

  • Rindflesch, T. C., Bean, C. A., & Sneiderman, C. A. (2000). Argument identification for arterial branching predications asserted in cardiac catheterization reports. In Proceedings of the AMIA Symposium (pp. 704–708). American Medical Informatics Association.

  • Rindflesch, T. C., & Fiszman, M. (2003). The interaction of domain knowledge and linguistic structure in natural language processing: interpreting hypernymic propositions in biomedical text. Journal of Biomedical Informatics, 36(6), 462–477.

    Article  Google Scholar 

  • Rindflesch, T. C., Rajan, J. V., & Hunter, L. (2000). Extracting molecular binding relationships from biomedical text. In Sixth Applied Natural Language Processing Conference (pp. 188–195).

  • Rindflesch, T.C. , Tanabe, L. ,Weinstein, J. N. , & Hunter, L. (2000). EDGAR: Extraction of drugs, genes and relations from the biomedical literature. Pacific Symposium on Biocomputing, 517–528.

  • Rivera-Nieves, J., et al. (2006). Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis. Gastroenterology, 131(5), 1518–1529.

    Article  Google Scholar 

  • Ross, J. S., et al. (2015). Comprehensive genomic profiling of carcinoma of unknown primary site. Jama Oncology, 1(1), 40–49.

    Article  Google Scholar 

  • Roy, N., Raj, R., Rai, S., & Varadwaj, P. K. (2019). Deciphering the novel target genes involved in the epigenetics of hepatocellular carcinoma using graph theory approach. Current Genomics, 20(8), 545–555.

    Article  Google Scholar 

  • Sandborn, W. J., Reinisch, W., Rachmilewitz, D., Hanauer, S. B., & Colombel, J. F. (2005). Infliximab induction and maintenance therapy for ulcerative colitis: the ACT2 trial. Ztschrift Für Gastroenterologie, 43(5), A104–A105.

    Google Scholar 

  • Simone, D., Joachim, H. V., Matthias, R., & Michael, S. (2012). Drug repositioning through incomplete bi-cliques in an integrated drug–target–disease network. Integrative Biology, 4(7), 778–788.

    Article  Google Scholar 

  • Singhal, A., Simmons, M., & Lu, Z. (2016). Text mining for precision medicine: automating diseasemutation relationship extraction from biomedical literature. Journal of the American Medical Association, 23(4), 766–772.

    Google Scholar 

  • Sovran, B., et al. (2013). Mo1813 homeostatic mechanisms preventing ileitis in mice with absent or deficient MUC2 production. Gastroenterology, 144(5), S-669.

  • Stappenbeck, T. S., et al. (2011). Crohn disease: a current perspective on genetics, autophagy and immunity. Autophagy, 7(4), 355–374.

    Article  Google Scholar 

  • Steffen, B., et al. (2014). Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a danish cohort. PLoS ONE, 9(6), e98815.

    Article  Google Scholar 

  • Sun, P., Guo, J., Winnenburg, R., & Baumbach, J. (2016). Drug repurposing by integrated literature mining and drug-gene-disease triangulation. Drug Discovery Today, 22(4), 615–619.

    Article  Google Scholar 

  • Sundaram, U., et al. (2003). Rabbit chronic ileitis leads to up-regulation of adenosine A1/A3 gene products, oxidative stress, and immune modulation. Biochemical Pharmacology, 65(9), 1529–1538.

    Article  Google Scholar 

  • Sutherland, L. R., & MacDonald, J. K. (2006). Oral 5‐aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database of Systematic Reviews, (2), CD000544.

  • Turunen, U. M., et al. (1998). Long-term treatment of ulcerative colitis with ciprofloxacin: A prospective, double-blind, placebo-controlled study. Gastroenterology, 115(5), 1072–1078.

    Article  Google Scholar 

  • Veera, H., et al. (2008). IL-23/IL-17 immunity as a hallmark of Crohn’s disease. Inflammatory Bowel Diseases, 14(9), 1175–1184.

    Article  Google Scholar 

  • Vemu, B., Selvasubramanian, S., & Pandiyan, V. (2015). Emu oil offers protection in Crohn’s disease model in rats. Bmc Complementary & Alternative Medicine, 16(1), 1–9.

    Article  Google Scholar 

  • Venditti, O., et al. (2015). Ipilimumab and immune-mediated adverse events: A case report of anti- CTLA4 induced ileitis. Bmc Cancer, 15(1), 87.

    Article  Google Scholar 

  • West, N. R., et al. (2017). Erratum: oncostatin m drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine, 23(6), 788.

    Article  Google Scholar 

  • Yamaguchi, N., Isomoto, H., Shikuwa, S., Ohnita, K., & Nakao, K. (2010). Proximal extension of backwash ileitis in ulcerative-colitis - associated colon cancer. Medical Science Monitor International Medical Journal of Experimental And Clinical Research, 16(7), 87–91.

    Google Scholar 

  • Zhang, Y., Tao, C., Jiang, G., Nair, A. A., Su, J., Chute, C. G., & Liu, H. (2014). Network-based analysis reveals distinct association patterns in a semantic MEDLINE-based drug-disease-gene network. Journal of Biomedical Semantics, 5(1), 33.

    Article  Google Scholar 

  • Zhou, H. Y., Yan, J., Fang, L., Zhang, H., Su, L. G., & Zhou, G. H. (2014). Change and significance of IL-8, IL-4, and IL-10 in the pathogenesis of terminal ileitis in sd rat. Cell Biochemistry & Biophysics, 69(2), 327–331.

    Article  Google Scholar 

  • Zhou, J., & Fu, B. (2018). The research on gene-disease association based on textmining of PubMed. BMC Bioinformatics, 19(1), 37.

    Article  Google Scholar 

  • Zhu, J., Tan, Z., Hollis-Hansen, K., Zhang, Y., Yu, C., & Li, Y. (2017). Epidemiological trends in colorectal cancer in China: an ecological study. Digestive Diseases and Sciences, 62(1), 235–243.

    Article  Google Scholar 

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Acknowledgments

This work is partly supported by the General Program of the National Natural Science Foundation of China (Grant No.71774012, 71673024) and the strategic research project of the Development Planning Bureau of the Chinese Academy of Sciences (Grant No.GHJ-ZLZX-2019-42). The findings and observations present in this paper are those of the authors and do not necessarily reflect the views of the supporters or the sponsors. The authors would like to thank the anonymous reviewers for their constructive input into this paper.

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  1. School of Management and Economics, Beijing Institute of Technology, Beijing, 100081, China

    Xuefeng Wang, Shuo Zhang & Yao Wu

  2. Institute of Medical Information, Chinese Academy of Medical Sciences, Beijing, 100005, China

    Xuemei Yang

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  1. Xuefeng Wang
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Correspondence to Xuefeng Wang.

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Table 11 Drug-disease-gene triples
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Wang, X., Zhang, S., Wu, Y. et al. Revealing potential drug-disease-gene association patterns for precision medicine. Scientometrics 126, 3723–3748 (2021). https://doi.org/10.1007/s11192-021-03892-4

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