skip to main content
10.1145/1854776.1854799acmconferencesArticle/Chapter ViewAbstractPublication PagesbcbConference Proceedingsconference-collections
research-article

Analyzing metabolite measurements for automated prediction of underlying biological mechanisms

Published: 02 August 2010 Publication History

Abstract

The emerging field of metabolomics enables researchers to measure concentrations of large numbers of metabolites in biofluids, and to interpret them in connection with the underlying metabolic network, which poses a significant challenge for manual analysis. Given a set of observations on metabolite concentration changes, our goal in this study is to employ automated reasoning, and provide researchers with possible metabolic action scenarios that may have occurred in the body to produce the observed metabolite changes. Our proposed methodology, called the Observed Metabolite Analysis, is to (1) computationally chase the implications of a given a set of metabolite concentration change observations in body fluids, relative to a control subject, (2) eliminate metabolic action scenarios, called hypothesis, that are invalid (i.e., those scenarios that could not have happened) (e.g., increased protein turnover), and (3) rank possibly valid metabolic action scenarios on the basis of pre-defined flux ratio information. We computationally evaluate the proposed methodology with typical metabolomics data, and demonstrate that (a) through consistency analysis against a small number of measured metabolite concentration changes, over 90% of the automatically generated hypotheses are invalidated with no manual analysis, (b) using summarization techniques, the entire hypothesis set is represented by a much smaller (2% of the original) hypothesis set, and (c) performing hypothesis generation and consistency checking in an interleaved manner leads to over 95% improvement in running time.

References

[1]
Daviss, B. 2005. Growing pains for metabolomics. The Scientist, 19{8}:25--28.
[2]
Wikipedia Entry (Metabolomics), http://en.wikipedia.org/wiki/ Metabolite. (Retrieved on May 13, 2008)
[3]
Oliver, SG et al. 1998. Systematic Functional Analysis of the Yeast genome. Trends BioTechnol., Vol. 16, 1998, pp. 373--378.
[4]
Harrigan, GG., and Goodacre, R. (Eds). 2003. Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis. Kluwer Academic Publishers, Boston, USA.
[5]
Fell, D. A. (1997). Understanding the control of metabolism. (Portland Press, London, UK).
[6]
Schilling, C. H., Schuster, S., Palsson, B. O., Heinrich, R. (1999). Metabolic Pathway Analysis: basic concepts and scientific applications in the post-genomic era. Biotechnol. Prog., 15, 296--303.
[7]
Stephanopoulas, G., Aristidou, A., Nielsen, J. H. (1998). Metabolic Engineering: principles and methodologies. (Academic Press, Maryland Hts, MO).
[8]
Trinh, C. T., Wlaschin, A., Srienc, F. (2009). Elementary mode analysis: a useful metabolic pathway analysis tool for characterizing cellular metabolism, Appl. Microbiol. Biotech., 81, 813--826.
[9]
Hoppe, A. et al. 2007. Including metabolite concentrations into flux balance analysis: thermodynamic realizability as a constraint on flux distributions in metabolic networks. BMC Syst Biol. 1:23.
[10]
Schuster, S., Higetag, S. (1994). On elementary flux modes in biochemical reaction systems at steady state", J. Biol. Syst., 2, 165--182.
[11]
Hoops, S., Sahle, S., Gauges, R., Lee, C., Pahle, J., Simus, N. et al. (2006). COPASI - a COmplex PAthway Simulator, Bioinformatics 22, 3067--74.
[12]
Pfeiffer, T., Sánchez-valdenebro, I., Nuño, J. C. et al. (1999). METATOOL: for studying metabolic networks, Bioinformatics, 15: 251--257.
[13]
Urbanczik, R. (2006). SNA-A toolbox for the stoichiometric analysis of metabolic networks. BMC Bioinformatics, 7: 129.
[14]
Klamt, S., Stelling J, Ginkel, M., Gilles, E. D. (2003). FluxAnalyzer: exploring structure, pathways, and flux distributions in metabolic networks on interactive flux maps. Bioinformatics, 19, 261--269.
[15]
Schwartz, J. M., Gaugain, C., Nacher, J. C., De Daruvar, A., Kanehisa, M. (2007b). Observing metabolic functions at the genome scale. Genome Biol, 8, R213.
[16]
Wlaschin, A. P., Trinh, C. T., Carlson, R., Srienc, F. (2006). The fractional contributions of elementary modes to the metabolism of Escherichia coli and their estimation from reaction entropies, Metabolic Eng., 8, 338--352.
[17]
Urbanczik, R., Wagner, C. (2005). An improved algorithm for stoichiometric network analysis: theory and applications. Bioinformatics, 21, 1203--1210.
[18]
Cakmak, A., Ozsoyoglu, G., Hanson, RW. Querying Metabolism under Different Physiological Constraints. Journal of Bioinformatics and Computational Biology, 8:(2) pp. 247--293, April 2010.
[19]
Klamt, S., Stelling, J. (2003). Two approaches for metabolic pathway analysis? Trends in Biotech., 21, 2, 64--69.
[20]
Glykys, D. J., Banta, S. (2009). Metabolic Control Analysis of an enzymatic biofuel cell. Biotechnology and Bioengineering. 102 (6), 1625--1635.
[21]
Kuipers, B. J. 1993. Reasoning with Qualitative Models. Artificial Intelligence 59, 125--132.
[22]
Kuipers B. J. 2001. Qualitative Simulation. In Encyclopedia of Physical Science and Technology, 3rd edn. Academic Press, 287--300.
[23]
Forbus, K. D. 1984. Qualitative Process Theory. Artificial Intelligence 24. 85--168.
[24]
Karp, P. D. 1993a. Design Methods for Scientific Hypothesis Formation and Their Application to Molecular Biology. Machine Learning, 12, 89--116.
[25]
Wishart, DS. 2007. Current progress in computational metabolomics. Briefings in Bioinformatics (8) 5: 279--293.
[26]
Devlin, TM. 2006. Textbook of Biochemistry with Clinical Correlations, Sixth Edition. Hoboken, NJ, John Wiley & Sons.
[27]
Salway, JG. 1999. Metabolism at a Glance, 2nd Edition. Blackwell Science.
[28]
Cakmak, A., Dsouza, A., Hanson, R. W., Ozsoyoglu, M., Ozsoyoglu, G. A Web-Based Data Source for Metabolomics. ISCIS, 2009. Available online at: http://dblab.case.edu/PathwaysMetabolomics/Web/
[29]
Cakmak, A. et al. (2010). Analyzing Metabolite Measurements for Automated Prediction of Underlying Biological Mechanisms. Technical Report. Dept. of EECS, CWRU, Cleveland, OH.
[30]
Wishart, DS et al. (2008). HMDB: a knowledgebase for the human metabolome. Nucleic Acids Research. October 25, 2008.
[31]
Cakmak, A. et al. (2010). Automated Metabolomics Data Interpretation: A Case Study on Non-Alcoholic Fatty Liver Disease. Technical Report. Dept. of EECS, CWRU, Cleveland, OH.
[32]
Kanehisa M et al. 2006. From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 34 (Database issue):D354--7.
[33]
Joshi-Tope G et al. 2005. Reactome: a knowledgebase of biological pathways. Nucleic Acids Res 33 (Database issue):D428--32.
[34]
Caspi, R et al. 2006. MetaCyc: a multiorganism database of metabolic pathways and enzymes. Nucleic Acids Res 34 (Database issue):D511--16.
[35]
Elliott, B., Kirac, M., Cakmak, A. et al. 2008. PathCase Pathways Database System. Bioinformatics 24(21): 2526--2533, November 2008.
[36]
Lawton, K. A., Berger, A., Mitchell, M. et al. (2008). Analysis of the adult human plasma metabolome. Pharmacogenomics Apr; 9(4):383--9.

Cited By

View all
  • (2011)Computational interpretation of metabolomics measurementsProceedings of the 2nd ACM Conference on Bioinformatics, Computational Biology and Biomedicine10.1145/2147805.2147856(387-392)Online publication date: 1-Aug-2011

Recommendations

Comments

Information & Contributors

Information

Published In

cover image ACM Conferences
BCB '10: Proceedings of the First ACM International Conference on Bioinformatics and Computational Biology
August 2010
705 pages
ISBN:9781450304382
DOI:10.1145/1854776
Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than ACM must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from [email protected]

Sponsors

Publisher

Association for Computing Machinery

New York, NY, United States

Publication History

Published: 02 August 2010

Permissions

Request permissions for this article.

Check for updates

Qualifiers

  • Research-article

Funding Sources

Conference

BCB'10
Sponsor:

Acceptance Rates

Overall Acceptance Rate 254 of 885 submissions, 29%

Contributors

Other Metrics

Bibliometrics & Citations

Bibliometrics

Article Metrics

  • Downloads (Last 12 months)0
  • Downloads (Last 6 weeks)0
Reflects downloads up to 25 Feb 2025

Other Metrics

Citations

Cited By

View all
  • (2011)Computational interpretation of metabolomics measurementsProceedings of the 2nd ACM Conference on Bioinformatics, Computational Biology and Biomedicine10.1145/2147805.2147856(387-392)Online publication date: 1-Aug-2011

View Options

Login options

View options

PDF

View or Download as a PDF file.

PDF

eReader

View online with eReader.

eReader

Figures

Tables

Media

Share

Share

Share this Publication link

Share on social media