Abstract
Comprehensive gene expression analysis has been applied to investigate the molecular mechanism of toxicity, which is generally known as toxicogenomics (TGx). When analyzing large-scale gene expression data obtained by microarray analysis, typical multivariate data analysis methods performed with commercial software such as hierarchical clustering or principal component analysis usually do not provide conclusive outputs by themselves. To best utilize the TGx data for toxicity evaluation in the drug development process, fit-for-purpose customization of the analytical algorithm with user-friendly interface and intuitive outputs are required to practically address the toxicologists’ demands. However, commercial software is usually not very flexible in the customization of their functions or outputs. Owing to the recent advancement and accumulation of open-source software contributed by bioinformaticians all over the world, it becomes easier for us to develop practical and fit-for-purpose analytical software by ourselves with fairly low cost and efforts. The aim of this article is to present an example of developing an automated TGx data processing system (ATP system), which implements gene set-level analysis toxicogenomic profiling by D-score method and generates straightforward output that makes it easy to interpret the biological and toxicological significance of the TGx data. Our example will provide basic clues for readers to develop and customize their own TGx data analysis system which complements the function of existing commercial software.
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References
Bass AS, Cartwright ME, Mahon C, Morrison R, Snyder R, McNamara P, Bradley P, Zhou YY, Hunter J (2009) Exploratory drug safety: a discovery strategy to reduce attrition in development. J Pharmacol Toxicol Methods 60:69–78
Kiyosawa N, Ando Y, Watanabe K, Niino N, Manabe S, Yamoto T (2009) Scoring multiple toxicological endpoints using a toxicogenomic database. Toxicol Lett 188:91–97
R Development Core Team (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, http://www.R-project.org
Kiyosawa N, Ando Y, Manabe S, Yamoto T (2009) Toxicogenomic biomarkers for liver toxicity. J Toxicol Pathol 22:35–52
Grewal A, Lambert P, Stockton J (2007) Analysis of expression data: an overview. Curr Protoc Bioinformatics. Chapter 7, Unit 7.1
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80
Berthold MR, Borgelt C, Hoppner F, Klawonn F (2010) KNIME. In: Gries D, Schneider FB (eds) Guide to intelligent data analysis. Springer, London, pp 375–382
Gansner ER, North SC (1999) An open graph visualization system and its applications to software engineering. Softw Pract Exper 0:1–5
Carey VJ, Gentry J, Whalen E, Gentleman R (2005) Network structures and algorithms in Bioconductor. Bioinformatics 21:135–136
Hubbell E, Liu WM, Mei R (2002) Robust estimators for expression analysis. Bioinformatics 18:1585–1592
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29
Ogata H, Goto S, Sato K, Fujibuchi W, Bono H, Kanehisa M (1999) KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res 27:29–34
Dahlquist KD, Salomonis N, Vranizan K, Lawlor SC, Conklin BR (2002) GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways. Nat Genet 31:19–20
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550
Kiyosawa N, Manabe S, Yamoto T, Sanbuissho A (2010) Practical application of toxicogenomics for profiling toxicant-induced biological perturbations. Int J Mol Sci 11:3397–3412
Lau SS, Monks TJ (1988) The contribution of bromobenzene to our current understanding of chemically-induced toxicities. Life Sci 42:1259–1269
Kiyosawa N, Manabe S, Sanbuissho A, Yamoto T (2010) Gene set-level network analysis using a toxicogenomics database. Genomics 96:39–49
Acknowledgments
The authors would like to acknowledge the people who have contributed to developing the open-source software and publicly available databases used herein. The authors are grateful to Dr. Kazumi Ito, Dr. Takashi Yamoto, Kyoko Watanabe, Noriyo Niino, and Miyuki Kanbori of Medicinal Safety Research Laboratories for their devotion to the TGx research activity in Daiichi Sankyo. Also, Drs. Masatoshi Nishimura, Koichi Tazaki, and Kazuhiko Mori for their productive discussion and advice; Drs. Atsushi Sanbuissho, Yuichi Kubo, Hideyuki Haruyama, and Sunao Manabe for their continuous support of the toxicoinformatic research activity in Daiichi Sankyo.
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Hirai, T., Kiyosawa, N. (2013). Developing a Practical Toxicogenomics Data Analysis System Utilizing Open-Source Software. In: Reisfeld, B., Mayeno, A. (eds) Computational Toxicology. Methods in Molecular Biology, vol 930. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-059-5_16
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DOI: https://doi.org/10.1007/978-1-62703-059-5_16
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