Metabolomic data is usually interpreted in the context of metabolic pathways. There are two types of approaches in pathway analysis – conventional and integrated approaches. The conventional approach is carried out in two major steps – researchers first obtain a list of metabolites of interest and then map them to known metabolic pathways. Important pathways are identified primarily through visual inspection of the pathway images. In contrast, the integrated approach directly uses the metabolite concentration data and produces more quantitative measures on which pathways are likely to be involved. In both approaches, a necessary preliminary step is to map the compound names from user data to names used in the underlying pathway databases. For the conventional approach, the focus is on displaying matched pathways intuitively to facilitate visual examination whereas the integrated approach focuses on using proper statistical algorithms to rank the matched pathways. Pathway visualization is not as essential as in the conventional approach.

In this issue, I will introduce two freely available pathway analysis tools for each category. The first one, MetScape (http://www.ncibi.org/gateway/metscape.html), uses the conventional approach for pathway analysis. The second tool, MetPA (http://metpa.metabolomics.ca), uses the integrated approach. Both tools support compound mapping and intuitive pathway visualization. The main differences are the allowed data inputs and outputs produced.

MetScape

MetScape was implemented in the form of a Cytoscape plugin. To use MetScape, users first need to install Cytoscape with the MetScape plugin on their local computer. The easiest way is to use the one-click Java Web Start technology (http://portal.ncibi.org/cytoscape/cytoscape.jnlp) from the MetScape 2 website (http://metscape.ncibi.org/metscape2/). When the application is installed successfully, start the Cytoscape application.

MetScape supports mammalian (human, rat, mouse) metabolic pathways mapping and visualization. It accepts either a list of compound names (Figure 1A) or an experimental result (Figure 1B). The program first tries to map the compound names to KEGG compound IDs (Figure 2). Only compounds with matches can be used to build metabolic pathways. MetScape can create four types of pathways: Compound-Reaction-Enzyme-Gene, Compound-Reaction, Compound-Gene, and Compound only. Figure 3 shows the first type of pathways. When users upload experimental results, MetScape allows users to use different filters (i.e., p-values, fold change) to exclude or include compounds for building the networks. Once the network has been displayed, users can import (normalized) concentration data for display. For time series data, users can use MetScape to build an animation to show temporal changes. Detailed instructions can be found in the comprehensive user manual available (http://metscape.ncibi.org/metscape2/Metscape2_User_Manual.pdf) on the MetScape 2 Help & Support page (http://metscape.ncibi.org/metscape2/help.html).



Figure 1. Data Inputs for MetScape. Either a list of compound names (Panel A) or experimental results (Panel B) can be used.




Figure 2. Mapping compound names from user data to KEGG compound IDs.




Figure 3. Building metabolic pathways from matched compounds. All matched pathways are displayed in the right panel. Users can zoom or navigate to different parts of the pathway using the mouse and the control panel on the lower left corner. Click on each node to display more details on the side panel.


MetPA

MetPA was implemented as a user-friendly web application. It currently supports metabolic pathway analysis for 15 different organisms based on the KEGG pathway database.

This web application accepts either a list of significant compounds (Figure 1A) or a compound concentration table (Figure 4). After uploading the data, the program will first map the compound names to underlying KEGG compound IDs. Users then need to specify which of the 15 available organism-specific pathway libraries to use. Next, users set parameters to perform statistical analysis to calculate which pathways are more likely to be involved in the experimental condition (Figure 5). MetPA combines functional enrichment analysis and pathway topology analysis for this purpose. Detailed explanations about these approaches and parameters are beyond this brief introduction. Users should visit the "Help" page (http://metpa.metabolomics.ca/MetPA/faces/FAQs.jsp) to obtain more information. The results are displayed both graphically (Figure 6) and in a table (Figure 7). Users should spend more time to explore the Google Maps style network visualization system to get more details on the compounds and pathways. Upon completion, a comprehensive PDF analysis report will be generated.




Figure 4. Compound concentration data table supported by MetPA.




Figure 5. Parameter selection for pathway analysis.




Figure 6. Pathway analysis results and visualization. The left panel is the "metabolome view" which displays all the matched pathways as circles. Clicking on any circle will launch the "pathway view" on the right panel. Clicking on any matched compound node (highlighted with different colors) within the pathway will launch the "compound view" in the form of box plots showing the corresponding concentration ranges.




Figure 7. Detailed results table from pathway analysis using MetPA.


Summary

Free software is available for both the conventional approach and the integrated approach to pathway analysis. While MetScape uses the conventional approach, MetPA supports an integrated approach to pathway analysis. Although the conventional approach is widely used and very flexible, the process is time-consuming and somewhat subjective (i.e., using different filtering thresholds may change the results). Using the integrated approach could potentially produce more accurate results since it relies on underlying metabolite concentration data and produces more quantitative measures.


 

Metabolomics is an emerging field that is complementary to other omics sciences and that is gaining increasing interest across all disciplines. Because of metabolomics' unique advantages, it is now being applied in functional genomics, integrative and systems biology, pharmacogenomics, and biomarker discovery for drug development and therapy monitoring. More than 95% of today's biomarkers are small molecules or metabolites (MW <1500 Da), which can be used for disease testing, drug testing, toxic exposure testing, and food consumption tracking. While standard clinical assays are limited in the number and type of compounds that can be detected, metabolomics measures many more compounds. Since a single compound is not always the best biomarker (diagnostic, prognostic or predictive), the use of metabolomics allows information about multiple compounds to be used together to make better medical decisions. Global metabolic profiling has now been used to determine clinical biomarkers in assessing the pathophysiological health status of patients.

In the following two recent studies, metabolomics approaches were used to develop biomarker tools for the identification of biomarkers associated with stroke and Alzheimer's disease, respectively.

1. Jee Youn Jung, Ho-Sub Lee, Dae-Gill Kang, No Soo Kim, Min Ho Cha, Ok-Sun Bang, Do Hyun Ryu and Geum-Sook Hwang, ¹H-NMR-Based Metabolomics Study of Cerebral Infarction, Stroke, 2011 May, 42(5):1282-8. Epub 2011 Apr 7. [PMID: 21474802]

This paper presents a ¹H-NMR-based metabolomics approach for identifying metabolic biomarkers associated with stroke. Plasma and urine samples from patients with cerebral infarctions and normal healthy volunteers were studied by using NMR spectroscopy followed by multivariate statistical analysis. Metabolic profiling of both plasma and urine samples showed a clear separation between the patients and normal controls. An increased level of lactate, pyruvate, glycolate, and formate and decreased level of glutamine and methanol were observed in the plasma samples of stroke patients, whereas the levels of citrate, hippurate, and glycine were decreased in the urine samples of the patients. This noninvasive NMR-based metabolomics approach has potential to be used as diagnostic tool for cerebral infarction.

2. Xianlin Han, Steve Rozen, Stephen H. Boyle, Caroline Hellegers, Hua Cheng, James R. Burke, Kathleen A. Welsh-Bohmer, P. Murali Doraiswamy and Rima Kaddurah-Daouk, Metabolomics in Early Alzheimer’s Disease: Identification of Altered Plasma Sphingolipidome Using Shotgun Lipidomics, PLoS ONE, 2011;6(7):e21643. Epub 2011 Jul 11. [PMID: 21779331]

A non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics was applied to measure the lipid species in plasma from 26 Alzheimer’s disease (AD) patients and 26 normal controls. The main objective of this study was to examine whether plasma lipidome altered in early AD. This study showed that the sphingolipids were significantly altered in plasma samples from AD patients compared to normal controls. Sphingomyelin species with long aliphatic chains (such as C22 and C24) were significantly lower in AD patients compared to controls. This study provides useful information about the AD sphingolipidome and could be used to identify potential new biomarkers.

3) Metabolomics Current Contents

Recently published papers in metabolomics:

• Metabolomics makes a mark: early changes associated with autoimmune diabetes.
• Metabolomics in the study of kidney diseases.
• Magnetic resonance spectroscopy detectable metabolomic fingerprint of response to antineoplastic treatment.
• Diverting the Flux of the JA Pathway in Nicotiana attenuata Compromises the Plant's Defense Metabolism and Fitness in Nature and Glasshouse.
• Enteric microbiome metabolites correlate with response to simvastatin treatment.
• Targeted metabolomic analysis of plasma samples for the diagnosis of inherited metabolic disorders.
• Nuclear Magnetic Resonance-Based Metabolomics Enables Detection of the Effects of a Whole Grain Rye and Rye Bran Diet on the Metabolic Profile of Plasma in Prostate Cancer Patients.
• Metabolomic profiling to identify potential serum biomarkers for schizophrenia and risperidone action.
• Pathos: A web facility that uses metabolic maps to display experimental changes in metabolites identified by mass spectrometry.
• MetaboHunter: an automatic approach for identification of metabolites from 1H-NMR spectra of complex mixtures.
  

4) MetaboNews

26 Oct 2011	Study identifies genetic basis of human metabolic individuality - Led by researchers from Weill Cornell Medical College in Qatar and published in a recent edition of the journal Nature, the study provides details on the genetics behind many diseases, including cardiovascular and kidney disorders, diabetes, cancer, gout, thrombosis and Crohn's disease, and elucidates the role that individual differences in metabolism play in these disorders. Disturbances in metabolism are at the root of a variety of human afflictions and complex diseases. Although many of the genes that contribute to these conditions have been identified since the completion of the Human Genome Project in 2003, it is still not known how metabolic disorders related to these genetic aberrations disrupt cellular processes. Nature paper: Suhre K et al., Human metabolic individuality in biomedical and pharmaceutical research. Nature. 2011 Aug 31;477(7362):54-60. doi: 10.1038/nature10354. [PMID: 21886157] Source: Medical Xpress
17 Oct 2011	Metabolon and Shanghai Jiao Tong University Open Metabolomics Lab in China - Metabolon, Inc., a diagnostics and services company offering the industry's leading biochemical profiling technology, announced today that it has opened a new metabolomics lab in Shanghai, China in collaboration with Shanghai Jiao Tong University (SJTU). The SJTU-Metabolon Joint Metabolomics Laboratory is a partnership with Shanghai Jiao Tong University, one of the oldest and most prestigious public research universities in China. Metabolon has licensed its proprietary metabolomics platform technology to SJTU to enable a world class biochemical profiling laboratory at the university. SJTU has funded the laboratory and personnel already trained by Metabolon and will work with academic and commercial scientists within China or other Asian countries to perform biochemical profiling experiments with Metabolon's technology. "We are very pleased to be bringing the science of metabolomics to a large untapped market such as China and the Asian continent as a whole," said Metabolon president and CEO John Ryals, Ph.D. "Our partnership with Shanghai Jiao Tong University is further proof of Metabolon's efforts to bring personalized medicine and metabolic biomarker research to all parts of the globe." Source: MarketWatch
16 Oct 2011	Gut Bacteria May Keep Statin Response in Check - Various bacterial-derived bile acids appear to influence the response to statin treatment, researchers found. Pretreatment levels of several primary and secondary bile acids were strongly associated with the low-density lipoprotein (LDL) cholesterol-lowering ability of simvastatin in healthy individuals, according to Rima Kaddurah-Daouk, PhD, of Duke University, and colleagues. The findings, reported online in PLoS ONE, "warrant further evaluation of interactions of specific markers for gut microbiota and therapeutic response to statins," the researchers wrote. "Identification of the basis for such interactions may in turn lead to dietary or other interventions that can improve statin efficacy by altering gut microflora." There is variability among individuals in the therapeutic response to statins, and previous studies have shown that genetics can only account for part of it. Kaddurah-Daouk and colleagues turned to the field of metabolomics, which incorporates the interactions between a person's genome, microbiome, and environment in explaining response to treatments. PLoS ONE paper: Kaddurah-Daouk R et al., Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS One. 2011;6(10):e25482. Epub 2011 Oct 13. [PMID: 22022402] Source: MedPage Today

Please note: If you know of any metabolomics news that we should feature in future issues of this newsletter, please email Ian Forsythe (metabolomics.innovation@gmail.com).

5) Metabolomics Events

8-9 Nov 2011	7th annual Advances in Metabolic Profiling Venue: Dublin, Ireland Welcome to the 7th annual Advances in Metabolic Profiling conference and exhibition. This year's event will be held in the dynamic city of Dublin, economic and cultural centre of Ireland. The conference will be co-located with Mass Spec Europe. Registered delegates will have access to both meetings ensuring a very cost-effective trip. For more information, please visit http://www.selectbiosciences.com/conferences/AMP2011/.
13-16 Nov 2011	International Conference on Natural Products (ICNP2011) - Metabolomics A New Frontier in Natural Products Science Venue: Palm Garden Hotel, Putrajaya, Malaysia On behalf of the Organising Committee you are invited to participate in the next International Conference on Natural Products (ICNP2011) - Metabolomics A New Frontier in Natural Products Science. The conference is being organised by the Universiti Putra Malaysia and Malaysian Natural Products Society. The conference will be held at Palm Garden Hotel, IOI Resort, PUTRAJAYA from 13th -16th November 2011. For more information, please visit http://www.icnp2011.upm.edu.my/.
20-22 Feb 2012	International Conference and Exhibition on Metabolomics & Systems Biology Venue: San Francisco, USA OMICS Group invites you to attend the International Conference and Exhibition on Metabolomics & Systems Biology which is going to be held during 20-22 February 2012 San Francisco, USA.    Metabolomics-2012 will serve as a catalyst for the advances in the study of Metabolomics & Systems Biology by connecting scientists within and across disciplines at sessions and exhibition held at the venue, creates an environment conducive to information exchange, generation of new ideas, and acceleration of applications that benefit Research in Metabolomics & Systems Biology.   Conference Highlights the following topics: Proteomics & Genomics      Transcriptomics & Metabolomics Bioinformatics     Gene expression Profiling Immunology     Microbiology & Biochemistry Computational Biology     Genetics and Metabolism Glycomics & Lipidomics     Avail the early bird discounts and register on/before 14 November 2011.   For more information, please visit http://omicsonline.org/metabolomics2012/.
17-20 Apr 2012	analytica Conference 2012 Venue: Munich, Germany For the classical exhibition area, the analytica Conference provides the perfect complement. It has been a decisive factor in establishing analytica as the pre-eminent meeting point for the industry. In various symposiums, leading scientists from all over the world report on the latest developments, current trends and visions of the future. Analytic, diagnostic, biochemical and molecular biological methods and procedures are discussed here. On the last occasion, 140 well-known experts gave talks in 23 different thematic symposiums. Main subject emphases/highlights of the analytica Conference 2010 Presentation of the Gerstel Award and the Bunsen-Kirchhoff Award Patient-oriented laboratory diagnostics Separation techniques in the life sciences Doping analytics Proteome research Measurement and toxicology of particulate matter Modern analytical methods for the chemical analysis of art objects Analytical contributions to the treatment of diabetes The 2012 event will focus on topics such as acute diagnostics and clinical metabolomics. For more information, please visit http://www.analytica.de/en/Home/congress/conference-program.
25-28 June 2012	METABOLOMICS 2012: Breakthroughs in plant, microbial and human biology, clinical and nutritional research, and biomarker discovery Venue: Washington Marriott Wardman Park Hotel, Washington, DC, USA The Metabolomics Society is pleased to announce the location and dates for our next annual meeting 'METABOLOMICS 2012'. We will host a program full of practical workshops and parallel sessions covering the broad range of biological and technological metabolomics topics as well as provide rich opportunities for networking. Prominent scientists will speak on the state-of-the-art in a number of leading disciplines to kick off each session, after which, we will have a full agenda of innovative speakers with specific oral presentation opportunities provided for younger researchers. We invite you to reserve the above dates in your calendar and follow our website for further details, www.metabolomics2012.org. Local Organisers: Dan Bearden, Rick Beger, Rima Kaddurah-Daouk, Lloyd W. Sumner, Don Robertson, Padma Maruvada and Donna Kimball. For more information, please visit http://www.metabolomics2012.org.

Please note: If you know of any metabolomics lectures, meetings, workshops, or training sessions that we should feature in future issues of this newsletter, please email Ian Forsythe (metabolomics.innovation@gmail.com).

6) Metabolomics Jobs

This is a resource for advertising positions in metabolomics. If you have a job you would like posted in this newsletter, please email Ian Forsythe (metabolomics.innovation@gmail.com). Job postings will be carried for a maximum of 4 issues (8 weeks) unless the position is filled prior to that date.

Jobs Offered

Job Title	Employer	Location	Date Posted	Source
Research Associate	Department of Biochemistry, University of Cambridge, UK	Cambridge, UK	24-Oct-2011	Metabolomics Society Jobs
Research Scientist (Ph.D.) – Molecular Physiology - Metabolomics	Algenol Biofuels	Bonita Springs, Florida	13-Oct-2011	Metabolomics Society Jobs
Sr. Scientist / Principal Scientist (R4-R5) – Analytical Chemistry – NMR	Pfizer	Groton, CT (New London/Norwich, Connecticut Area)	10-Oct-2011	LinkedIn Jobs
Applications Development Senior	Seattle Children's Research Institute	Greater Seattle Area	6-Oct-2011	LinkedIn Jobs
Computational Biologist - Metabolomics	Genentech	South San Francisco,CA (San Francisco Bay Area)	4-Oct-2011	LinkedIn Jobs
Business Development Manager	BASF – The Chemical Company	Florham Park, New Jersey	27-Sep-2011	Metabolomics Society Jobs
Assoc Director - Bioinformatics	Genentech	United States	16-Sep-2011	LinkedIn Jobs
Senior Scientist 208819 (NCI) Job	SAIC	Frederick, MD, US (Washington D.C. Metro Area)	12-Sep-2011	LinkedIn Jobs

Jobs Wanted
Very highly qualified individuals (e.g., lab managers, professors, directors, executives with extensive experience) seeking employment in metabolomics are encouraged to submit their position requests to Ian Forsythe (metabolomics.innovation@gmail.com). Upon review, a limited number of job submissions will be selected for publication in the Jobs Wanted section.

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Ian J. Forsythe, M.Sc. Editor MetaboNews Department of Computing Science University of Alberta 221 Athabasca Hall Edmonton, AB, T6G 2E8, Canada Email: metabolomics.innovation@gmail.com Website: http://www.metabonews.ca

This newsletter is produced by The Metabolomics Innovation Centre (TMIC, http://www.metabolomicscentre.ca/) for the benefit of the worldwide metabolomics community. MetaboNews is currently sponsored by TMIC: