Overview of network mapping and its application to metabolomic data.

1. Connecting Data with Context
Dmitry Grapov, PhD
FiehnLab Seminar
112013

2. Cycle of Scientific Discovery
Hypothesis
Hypothesis Generation
Data Acquisition
Data Processing
Data Analysis
Data

3. Analysis at the Metabolomic Scale

4. Network Mapping
1. Generate
Connections
2. Calculate
Mappings
3. Create
Network
Grapov D., Fiehn O., Multivariate and network tools for analysis and visualization of metabolomic data, ASMS, June 08, 2013, Minneapolis, MN

5. Connections and Contexts
Biochemical (substrate/product)
•Database lookup
•Web query
Chemical (structural or
spectral similarity )
•fingerprint generation
BMC Bioinformatics 2012, 13:99 doi:10.1186/1471-2105-13-99
Empirical (dependency)
•correlation, partial-correlation

6. Biochemical
Relationships
http://www.genome.jp/dbget-bin/www_bget?rn:R00975

7. Structural
Similarity
http://pubchem.ncbi.nlm.nih.gov//score_matrix/score_matrix.cgi

8. Linking Experimental Observations:
malignant vs. normal tissue
purine and pyrimidine metabolism
seems to be increased
select amino acid
metabolism is decreased
Question: How are these changes related?

9. Empirical Associations
How are the
variables related
given my
experiment?
Types of associations:
•Correlation
•Partial correlation
•Bayesian
•Other
association based on data

10. Correlation based relationships:
•simple to calculate
•can offer insight when the biology is unknown
Complex lipids correlation network in mouse serum

11. Correlation based relationships:
•can be difficult to interpret
•poorly discriminate between direct and indirect
associations
Complex lipids correlation network in mouse heart tissue

12. Partial correlations can
help simplify networks
and preference direct
over indirect
associations.
10.1007/978-1-4614-1689-0_17
Complex lipids partial correlation
network in human plasma

13. Combining
biochemical
and empirical
information
Are theses changes
related?

14. Learning from experiments
partial correlation network
between top predictors for cancer
A
B
The observed changes can be
summarized into three groups, A, B
and central inversely correlated
group

15. A)
1. increase in 5′-Deoxy-5′-(methylthio)adenosine (MTA) suggests deficiency of
enzyme 5'-methylthioadenosine phosphorylase (MTAP) important for Sadenosylmethionine (AdoMet) salvage shown to be decreased in cancer
• inhibits spermidine synthase [PMID:6896990, PMID:21135097] vital for cell
survival
2. increased 5,6-dihydrouracil is observed in prostate cancer [PMID:23824564]
3. increased xanthine indicates tissue depletion of ATP [PMID:3062020] and product
uric acid is a pro-oxidant (in cells) [PMID:18600514]
4. biosynthesis of UDP-GlcNAc involves glutamate
B)
1. ornithine and citrulline linked through ornithine transcarbamylase [PMID:11849441]
2. decrease in citrulline, allantoic acid and biuret may suggest reduction in urea cycle
3. nicotinamide induces L-ornithine decarboxylase [PMID: 153228, heart] which is
necessary for putrescine synthesis

16. Variable relationships can be
independently assessed for
differing experimental groups

17. Mass Spectral Connections
Watrous J et al. PNAS 2012;109:E1743-E1752

18. Linking the Known and Unknown
mass spectral similarity + empirical association

19. Network Mapping Tool
http://spark.rstudio.com/dgrapov/MetaMapR/

20. Miscellaneous 2012-2013 Projects
Data Analysis As a Service (DAAS)
over 20 studies
$20K earnings
Automated Data Analysis and Reporting

21. Primary Metabolomics
1.
Dmitry Grapov, Caitlin Campbell, Oliver Fiehn, Carol J. Chandler, Dustin J. Burnett, Elaine C.
Souza, John K. Meissen, Kohei Takeuchi, Gretchen A. Casazza, Mary B. Gustafson, Nancy L.
Keim, John W. Newman, Gary R. Hunter, Jose R. Fernandez, W. Timothy Garvey, Mary-Ellen
Harper, Charles L. Hoppel, and Sean H. Adams, Altered patterns of plasma metabolites of
endogenous and gut origin in insulin-resistant obese women following a weight loss and
fitness intervention, Nov. 2013, Plos ONE (accepted)
2.
Dmitry Grapov, Johannes Fahrmann, Manami Hara, Oliver Fiehn, Type 1 diabetes
associated metabolic perturbations. (in preparation)
3.
William R. Wikoff, Dmitry Grapov, Brian Defelice*, Oliver Fiehn*, Suzanne Miyamoto,
William Rom, Harvey Pass, Karen Kelly, David Gandara, Kyoungmi Kim, Early Stage
Adenocarcinoma Affects Multiple Metabolic Pathways in Lung Tissue. Cancer research (in
preparation)
4.
Brian D. Piccolo, Dmitry Grapov, W. Timothy Garvey, Mary-Ellen Harper, Oliver Fiehn, Sean
H. Adams, John W. Newman, Impact of a human missense UCP3 polymorphism on the
plasma metabolomic profile: support for a mitochondrial fuel-partitioning role for UCP3
(in preparation)

22. Lipidomics
1.
Dmitry Grapov, Stuart G. Snowden, Heli Nygren,Magnus Settergren, Fabio Luiz
D’Alexandri, Jesper Z. Haeggström, Tuulia Hyötyläinen, Theresa L. Pedersen, John
W. Newman, Matej Orešič, John Pernow, Craig E. Wheelock, High dose
simvastatin exhibits enhanced lipid lowering effects relative to
simvastatin/ezetimibe combination therapy. Circulation Cardiovascular Genetics,
Nov. 2013 (submitted)
2.
Schuster GU, Bratt JM, Jiang X, Pedersen TL, Grapov D, Adkins Y, Kelley DS,
Newman JW, Kenyon NJ, Stephensen CB. Dietary Long-Chain Omega-3 Fatty Acids
do not Diminish Eosinophilic Pulmonary Inflammation in Mice. Am J Respir Cell
Mol Biol. 2013 Oct 17.
3.
Denis J. Glenn, Michelle C. Cardema, Wei Ni, Yan Zhang, Yerem Yeghiazarians,
Dmitry Grapov, Oliver Fiehn and David G. Gardner, Cardiac Steatosis Potentiates
Angiotensin II Effects in the Heart. Sept. 2013, Circulation (in review)

23. Glycomics and Proteomics
1. Smilowitz, J.T., Totten S.M.,Huang J., Grapov D., Durham H.A., LammiKeefe C.J., Lebrilla C., German J.B. , Human Milk Secretory
Immunoglobulin A and Lactoferrin N-Glycans Are Altered in Women with
Gestational Diabetes Mellitus. J Nutr, 2013.
2. Dmitry Grapov, Smilowitz, J.T., Gestational diabetes related changes in
milk colostrum proteins. (in preparation)

24. Bioinformatics
1.
Dmitry Grapov, Oliver Fiehn, MetaMapR: a Metabolomic Network Generation
and Analysis Tool. Bioinformatics (in preparation)
2.
Dmitry Grapov, Oliver Fiehn, Devium: Dynamic Multivariate Data Analysis and
Visualization Platform. Bioinformatics (in development)
Method Development
1.
Dmitry Grapov, Theresa Pedersen, John W. Newman, Quantitative analysis of
Sterol Ester, Triglyceride and Phospholipid Bound Fatty Acids and Oxylipins. (in
preparation)