Abstract
The interaction between biological systems and their environments is complex and often involves mechanisms beyond changes in the genome and/or the proteome at the metabolome level. Metabolomics is a field of science, which involves the comprehensive quantitative and qualitative profiling of multiple metabolites and their interactions with environmental variables of interest such as diet, disease, environment, or exposure to chemicals. Monitoring these metabolites represents the closest end-point to understand the cell dynamics at the functional level as compared to genomics or proteomics. Metabolomics is heavily applied in the identification of biomarkers for disease diagnosis and prognosis, drug toxicity and efficacy, genetic polymorphisms, drug metabolism, and fluxomics. These applications are discussed in detail in this chapter.
There are at least 3,000 metabolites in the human body and up to 200,000 metabolites in the plant kingdom, which are very different in their physical and chemical properties such as pK a, polarity, solubility, and size. The comprehensive quantitative analyses of the metabolome and handling the amount of data generated from such analyses pose substantial challenges. Therefore, metabolomics is a technique-driven enterprise that heavily relies on the analytical and bioinformatics support of data generation and analysis.
There is no single global analytical technique that combines all the characteristics required for comprehensive quantitative analyses of the metabolome. However, mass spectrometry (MS) and nuclear magmatic resonance (NMR) represent the analytical techniques of choice in metabolomics. The theory, application, and experimental considerations of these techniques, which are relevant to metabolomics, are presented in this chapter.
Finally, the raw data generated from the quantitative analysis of the metabolome requires several stages of processing to improve its quality, reduce its size, and convert it to a format that can be subject to statistical analysis. Different strategies of data processing and statistical analysis are discussed in this chapter.
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Alpert AJ (1990) Hydrophilic-interaction chromatography for the separation of peptides, nucleic acids and other polar compounds. J Chromatogr 499:177–196
Anderle M, Roy S, Lin H, Becker C, Joho K (2004) Quantifying reproducibility for differential proteomics: noise analysis for protein liquid chromatography-mass spectrometry of human serum. Bioinformatics 20:3575–3582
Baggerly KA, Morris JS, Wang J, Gold D, Xiao LC, Coombes KR (2003) A comprehensive approach to the analysis of matrix-assisted laser desorption/ionization-time of flight proteomics spectra from serum samples. Proteomics 3:1667–1672
Beger RD, Hansen DK, Schnackenberg LK, Cross BM, Fatollahi JJ, Lagunero FT, Sarnyai Z, Boros LG (2009) Single valproic acid treatment inhibits glycogen and RNA ribose turnover while disrupting glucose-derived cholesterol synthesis in liver as revealed by the [U-C-13(6)]-d-glucose tracer in mice. Metabolomics 5:336–345
Bender K, Walsh S, Evans ACO, Fair T, Brennan L (2010) Metabolite concentrations in follicular fluid may explain differences in fertility between heifers and lactating cows. Reproduction 139:1047–1055
Bijlsma S, Bobeldijk I, Verheij ER, Ramaker R, Kochhar S, Macdonald IA, van Ommen B, Smilde AK (2006) Large-scale human metabolomics studies: a strategy for data (pre-) processing and validation. Anal Chem 78:567–574
Boros LG, Brackett DJ, Harrigan GG (2003) Metabolic biomarker and kinase drug target discovery in cancer using stable isotope-based dynamic metabolic profiling (SIDMAP). Curr Cancer Drug Targets 3:445–453
Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HWL, Clarke S, Schofield PM, McKilligin E, Mosedale DE, Grainger DJ (2002) Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using H-1-NMR-based metabonomics. Nat Med 8:1439–1444
Campbell S, Rodgers MT, Marzluff EM, Beauchamp JL (1995) Deuterium exchange reactions as a probe of biomolecule structure. Fundamental studies of cas phase H/D exchange reactions of protonated glycine oligomers with D2O, CD3OD, CD3CO2D, and ND3. J Am Chem Soc 117:12840–12854
Cho JY, Matsubara T, Kang DW, Ahn SH, Krausz KW, Idle JR, Luecke H, Gonzalez FJ (2010) Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge. J Lipid Res 51:1063–1074
Claudino WM, Quattrone A, Biganzoli L, Pestrin M, Bertini I, Di Leo A (2007) Metabolomics: available results, current research projects in breast cancer, and future applications. J Clin Oncol 25:2840–2846
Clayton TA, Lindon JC, Cloarec O, Antti H, Charuel C, Hanton G, Provost JP, Le Net JL, Baker D, Walley RJ, Everett JR, Nicholson JK (2006) Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 440:1073–1077
Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A 106:14728–14733
Coen M, O’Sullivan M, Bubb WA, Kuchel PW, Sorrell T (2005) Proton nuclear magnetic resonance-based metabonomics for rapid diagnosis of meningitis and ventriculitis. Clin Infect Dis 41:1582–1590
Connor SC, Hansen MK, Corner A, Smith RF, Ryan TE (2010) Integration of metabolomics and transcriptomics data to aid biomarker discovery in type 2 diabetes. Mol Biosyst 6:909–921
Cubbon S, Antonio C, Wilson J, Thomas-Oates J (2010) Metabolomic applications of HILIC-LC-MS. Mass Spectrom Rev 29:671–684
Dalgliesh CE, Horning EC, Horning MG, Knox KL, Yarger K (1966) A gas–liquid-chromatographic procedure for separating a wide range of metabolites occuring in urine or tissue extracts. Biochem J 101:792–810
Deprez S, Sweatman BC, Connor SC, Haselden JN, Waterfield CJ (2002) Optimisation of collection, storage and preparation of rat plasma for 1H NMR spectroscopic analysis in toxicology studies to determine inherent variation in biochemical profiles. J Pharm Biomed Anal 30:1297–1310
Dixon E, Clubb C, Pittman S, Ammann L, Rasheed Z, Kazmi N, Keshavarzian A, Gillevet P, Rangwala H, Couch RD (2011) Solid-phase microextraction and the human fecal VOC metabolome. PLoS One 6:e18471
Drexler DM, Reily MD, Shipkova PA (2011) Advances in mass spectrometry applied to pharmaceutical metabolomics. Anal Bioanal Chem 399:2645–2653
Du P, Kibbe WA, Lin SM (2006) Improved peak detection in mass spectrum by incorporating continuous wavelet transform-based pattern matching. Bioinformatics 22:2059–2065
Duarte IF, Stanley EG, Holmes E, Lindon JC, Gil AM, Tang HR, Ferdinand R, McKee CG, Nicholson JK, Vilca-Melendez H, Heaton N, Murphy GM (2005) Metabolic assessment of human liver transplants from biopsy samples at the donor and recipient stages using high-resolution magic angle spinning H-1 NMR spectroscopy. Anal Chem 77:5570–5578
Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, Srivas R, Palsson BO (2007) Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci U S A 104:1777–1782
Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC, Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK (2006) Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc Natl Acad Sci U S A 103:12511–12516
Dunn WB, Bailey NJ, Johnson HE (2005) Measuring the metabolome: current analytical technologies. Analyst 130:606–625
Ebbels TMD, Keun HC, Beckonert OP, Bollard ME, Lindon JC, Holmes E, Nicholson JK (2007) Prediction and classification of drug toxicity using probabilistic modeling of temporal metabolic data: the consortium on metabonomic toxicology screening approach. J Proteome Res 6:4407–4422
El Rammouz R, Letisse F, Durand S, Portais JC, Moussa ZW, Fernandez X (2010) Analysis of skeletal muscle metabolome: evaluation of extraction methods for targeted metabolite quantification using liquid chromatography tandem mass spectrometry. Anal Biochem 398:169–177
Enot DP, Lin W, Beckmann M, Parker D, Overy DP, Draper J (2008) Preprocessing, classification modeling and feature selection using flow injection electrospray mass spectrometry metabolite fingerprint data. Nat Protoc 3:446–470
Fiehn O (2001) Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp Funct Genomics 2:155–168
Forshed J, Schuppe-Koistinen I, Jacobsson SP (2003) Peak alignment of NMR signals by means of a genetic algorithm. Anal Chim Acta 487:189–199
Forshed J, Torgrip RJ, Aberg KM, Karlberg B, Lindberg J, Jacobsson SP (2005) A comparison of methods for alignment of NMR peaks in the context of cluster analysis. J Pharm Biomed Anal 38:824–832
Fredriksson M, Petersson P, Jornten-Karlsson M, Axelsson BO, Bylund D (2007) An objective comparison of pre-processing methods for enhancement of liquid chromatography-mass spectrometry data. J Chromatogr A 1172:135–150
Gamache PH, Meyer DF, Granger MC, Acworth IN (2004) Metabolomic applications of electrochemistry/mass spectrometry. J Am Soc Mass Spectrom 15:1717–1726
Gika HG, Macpherson E, Theodoridis GA, Wilson ID (2008) Evaluation of the repeatability of ultra-performance liquid chromatography-TOF-MS for global metabolic profiling of human urine samples. J Chromatogr B Analyt Technol Biomed Life Sci 871:299–305
Gika HG, Theodoridis GA, Earll M, Snyder RW, Sumner SJ, Wilson ID (2010) Does the mass spectrometer define the marker? A comparison of global metabolite profiling data generated simultaneously via UPLC-MS on two different mass spectrometers. Anal Chem 82:8226–8234
Gottschalk M, Ivanova G, Collins DM, Eustace A, O’Connor R, Brougham DF (2008) Metabolomic studies of human lung carcinoma cell lines using in vitro H-1 NMR of whole cells and cellular extracts. NMR Biomed 21:809–819
Gowda GAN (2010) Human bile as a rich source of biomarkers for hepatopancreatobiliary cancers. Biomark Med 4:299–314
Granger J, Plumb R, Castro-Perez J, Wilson ID (2005) Metabonomic studies comparing capillary and conventional HPLC-oa-TOF MS for the analysis of urine from Zucker obese rats. Chromatographia 61:375–380
Griffiths WJ (2008) Metabolomics, metabonomics and metabolite profiling. RSC, Cambridge
Halket JM, Waterman D, Przyborowska AM, Patel RK, Fraser PD, Bramley PM (2005) Chemical derivatization and mass spectral libraries in metabolic profiling by GC/MS and LC/MS/MS. J Exp Bot 56:219–243
Han J, Danell RM, Patel JR, Gumerov DR, Scarlett CO, Speir JP, Parker CE, Rusyn I, Zeisel S, Borchers CH (2008) Towards high-throughput metabolomics using ultrahigh-field Fourier transform ion cyclotron resonance mass spectrometry. Metabolomics 4:128–140
Han J, Datla R, Chan S, Borchers CH (2009) Mass spectrometry-based technologies for high-throughput metabolomics. Bioanalysis 1:1665–1684
Hastings CA, Norton SM, Roy S (2002) New algorithms for processing and peak detection in liquid chromatography/mass spectrometry data. Rapid Commun Mass Spectrom 16:462–467
Heijne WHM, Lamers RJAN, van Bladeren PJ, Groten JP, van Nesselrooij JHJ, van Ommen B (2005) Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis. Toxicol Pathol 33:425–433
Hermansson M, Uphoff A, Kakela R, Somerharju P (2005) Automated quantitative analysis of complex lipidomes by liquid chromatography/mass spectrometry. Anal Chem 77:2166–2175
Holland NT, Pfleger L, Berger E, Ho A, Bastaki M (2005) Molecular epidemiology biomarkers—sample collection and processing considerations. Toxicol Appl Pharmacol 206:261–268
Horning MG, Chambaz EM, Brooks CJ, Moss AM, Boucher EA, Horning EC, Hill RM (1969) Characterization and estimation of urinary steroids of the newborn human by gas-phase analytical methods. Anal Biochem 31:512–531
Issaq HJ, Abbott E, Veenstra TD (2008) Utility of separation science in metabolomic studies. J Sep Sci 31:1936–1947
Jackson AU, Werner SR, Talaty N, Song Y, Campbell K, Cooks RG, Morgan JA (2008) Targeted metabolomic analysis of Escherichia coli by desorption electrospray ionization and extractive electrospray ionization mass spectrometry. Anal Biochem 375:272–281
Jiye A, Trygg J, Gullberg J, Johansson AI, Jonsson P, Antti H, Marklund SL, Moritz T (2005) Extraction and GC/MS analysis of the human blood plasma metabolome. Anal Chem 77:8086–8094
Junot C, Madalinski G, Tabet JC, Ezan E (2010) Fourier transform mass spectrometry for metabolome analysis. Analyst 135:2203–2219
Kaddurah-Daouk R, Kristal BS, Weinshilboum RM (2008) Metabolomics: a global biochemical approach to drug response and disease. Annu Rev Pharmacol 48:653–683
Kaderbhai NN, Broadhurst DI, Ellis DI, Goodacre R, Kell DB (2003) Functional genomics via metabolic footprinting: monitoring metabolite secretion by Escherichia coli tryptophan metabolism mutants using FT-IR and direct injection electrospray mass spectrometry. Comp Funct Genomics 4:376–391
Kamel AM, Zandi KS, Massefski WW (2003) Identification of the degradation product of ezlopitant, a non-peptidic substance P antagonist receptor, by hydrogen deuterium exchange, electrospray ionization tandem mass spectrometry (ESI/MS/MS) and nuclear magnetic resonance (NMR) spectroscopy. J Pharm Biomed Anal 31:1211–1222
Kanani H, Chrysanthopoulos PK, Klapa MI (2008) Standardizing GC-MS metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci 871:191–201
Katajamaa M, Oresic M (2005) Processing methods for differential analysis of LC/MS profile data. BMC Bioinformatics 6:179
Katajamaa M, Oresic M (2007) Data processing for mass spectrometry-based metabolomics. J Chromatogr A 1158:318–328
Keun HC, Ebbels TM, Antti H, Bollard ME, Beckonert O, Schlotterbeck G, Senn H, Niederhauser U, Holmes E, Lindon JC, Nicholson JK (2002) Analytical reproducibility in (1)H NMR-based metabonomic urinalysis. Chem Res Toxicol 15:1380–1386
Kiefer P, Portais JC, Vorholt JA (2008) Quantitative metabolome analysis using liquid chromatography-high-resolution mass spectrometry. Anal Biochem 382:94–100
Kim JK, Harada K, Bamba T, Fukusaki E, Kobayashi A (2005) Stable isotope dilution-based accurate comparative quantification of nitrogen-containing metabolites in Arabidopsis thaliana T87 cells using in vivo N-15-isotope enrichment. Biosci Biotechnol Biochem 69:1331–1340
Kim HK, Choi YH, Verpoorte R (2010) NMR-based metabolomic analysis of plants. Nat Protoc 5:536–549
Knapp JS, Cabrera WL (2009) Metabolomics: metabolites, metabonomics, and analytical technologies. Nova, Hauppauge, NY
Kopp SJ, Glonek T, Erlanger M, Perry EF, Barany M, Perry HM Jr (1980) Altered metabolism and function of rat heart following chronic low level cadmium/lead feeding. J Mol Cell Cardiol 12:1407–1425
Koulman A, Cao M, Faville M, Lane G, Mace W, Rasmussen S (2009) Semi-quantitative and structural metabolic phenotyping by direct infusion ion trap mass spectrometry and its application in genetical metabolomics. Rapid Commun Mass Spectrom 23:2253–2263
Lange E, Tautenhahn R, Neumann S, Gropl C (2008) Critical assessment of alignment procedures for LC-MS proteomics and metabolomics measurements. BMC Bioinformatics 9:375
Lee R, Britz-McKibbin P (2010) Metabolomic studies of radiation-induced apoptosis of human leukocytes by capillary electrophoresis-mass spectrometry and flow cytometry: adaptive cellular responses to ionizing radiation. Electrophoresis 31:2328–2337
Lei Z, Huhman D, Sumner LW (2011) Mass spectrometry strategies in metabolomics. J Biol Chem 286:25435–25442
Lenz EM, Wilson ID (2007) Analytical strategies in metabonomics. J Proteome Res 6:443–458
Leo GC, Darrow AL (2009) NMR-based metabolomics of urine for the atherosclerotic mouse model using apolipoprotein-E deficient mice. Magn Reson Chem 47:S20–S25
Lin CY, Wu HF, Tjeerdema RS, Viant MR (2007) Evaluation of metabolite extraction strategies from tissue samples using NMR metabolomics. Metabolomics 3:55–67
Lindon JC, Holmes E, Nicholson JK (2001) Pattern recognition methods and applications in biomedical magnetic resonance. Prog Nucl Mag Res Spectrosc 39:1–40
Lindon JC et al (2003) Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicol Appl Pharmacol 187:137–146
Lindon JC, Nicholson JK, Holmes E (2007) The handbook of metabonomics and metabolomics, 1st edn. Elsevier, Amsterdam
Liu DQ, Hop CECA (2005) Strategies for characterization of drug metabolites using liquid chromatography-tandem mass spectrometry in conjunction with chemical derivatization and on-line H/D exchange approaches. J Pharm Biomed Anal 37:1–18
Loftus N, Miseki K, Iida J, Gika HG, Theodoridis G, Wilson ID (2008) Profiling and biomarker identification in plasma from different Zucker rat strains via high mass accuracy multistage mass spectrometric analysis using liquid chromatography/mass spectrometry with a quadrupole ion trap-time of flight mass spectrometer. Rapid Commun Mass Spectrom 22:2547–2554
Lu X, Zhao X, Bai C, Zhao C, Lu G, Xu G (2008) LC-MS-based metabonomics analysis. J Chromatogr B Analyt Technol Biomed Life Sci 866:64–76
Maddox JF, Luyendyk JP, Cosma GN, Breau AP, Bible RH Jr, Harrigan GG, Goodacre R, Ganey PE, Cantor GH, Cockerell GL, Roth RA (2006) Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide. Toxicol Appl Pharmacol 212:35–44
Mahadevan S, Shah SL, Marrie TJ, Slupsky CM (2008) Analysis of metabolomic data using support vector machines. Anal Chem 80:7562–7570
Marx A, deGraaf AA, Wiechert W, Eggeling L, Sahm H (1996) Determination of the fluxes in the central metabolism of Corynebacterium glutamicum by nuclear magnetic resonance spectroscopy combined with metabolite balancing. Biotechnol Bioeng 49:111–129
Matuszewski BK, Constanzer ML, Chavez-Eng CM (2003) Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. Anal Chem 75:3019–3030
Meadows AL, Kong B, Berdichevsky M, Roy S, Rosiva R, Blanch HW, Clark DS (2008) Metabolic and morphological differences between rapidly proliferating cancerous and normal breast epithelial cells. Biotechnol Prog 24:334–341
Millington DS, Kodo N, Norwood DL, Roe CR (1990) Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J Inherit Metab Dis 13:321–324
Moka D, Vorreuther R, Schicha H, Spraul M, Humpfer E, Lipinski M, Foxall PJD, Nicholson JK, Lindon JC (1998) Biochemical classification of kidney carcinoma biopsy samples using magic-angle-spinning H-1 nuclear magnetic resonance spectroscopy. J Pharm Biomed Anal 17:125–132
Monton MR, Soga T (2007) Metabolome analysis by capillary electrophoresis-mass spectrometry. J Chromatogr A 1168:237–246, discussion 236
Nicholson JK, Lindon JC, Holmes E (1999) “Metabonomics”: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29:1181–1189
Nielsen JH, Jewett MC (2007) Metabolomics: a powerful tool in systems biology. Springer, Berlin
Nielsen NPV, Carstensen JM, Smedsgaard J (1998) Aligning of single and multiple wavelength chromatographic profiles for chemometric data analysis using correlation optimised warping. J Chromatogr A 805:17–35
Nordstrom A, Want E, Northen T, Lehtio J, Siuzdak G (2008) Multiple ionization mass spectrometry strategy used to reveal the complexity of metabolomics. Anal Chem 80:421–429
Oakman C, Tenori L, Biganzoli L, Santarpia L, Cappadona S, Luchinat C, Di Leo A (2011) Uncovering the metabolomic fingerprint of breast cancer. Int J Biochem Cell Biol 43(7):1010–1020
Odunsi K, Wollman RM, Ambrosone CB, Hutson A, McCann SE, Tammela J, Geisler JP, Miller G, Sellers T, Cliby W, Qian F, Keitz B, Intengan M, Lele S, Alderfer JL (2005) Detection of epithelial ovarian cancer using H-1-NMR-based metabonomics. Int J Cancer 113:782–788
Oresic M (2010) Systems biology strategy to study lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801:235–239
Overy DP, Enot DP, Tailliart K, Jenkins H, Parker D, Beckmann M, Draper J (2008) Explanatory signal interpretation and metabolite identification strategies for nominal mass FIE-MS metabolite fingerprints. Nat Protoc 3:471–485
Parida SK, Kaufmann SH (2010) The quest for biomarkers in tuberculosis. Drug Discov Today 15:148–157
Pasikanti KK, Ho PC, Chan EC (2008) Gas chromatography/mass spectrometry in metabolic profiling of biological fluids. J Chromatogr B Analyt Technol Biomed Life Sci 871:202–211
Patterson AD, Gonzalez FJ, Idle JR (2010) Xenobiotic metabolism: a view through the metabolometer. Chem Res Toxicol 23:851–860
Plumb RS, Stumpf CL, Granger JH, Castro-Perez J, Haselden JN, Dear GJ (2003) Use of liquid chromatography/time-of-flight mass spectrometry and multivariate statistical analysis shows promise for the detection of drug metabolites in biological fluids. Rapid Commun Mass Spectrom 17:2632–2638
Plumb RS, Granger JH, Stumpf CL, Johnson KA, Smith BW, Gaulitz S, Wilson ID, Castro-Perez J (2005) A rapid screening approach to metabonomics using UPLC and oa-TOF mass spectrometry: application to age, gender and diurnal variation in normal/Zucker obese rats and black, white and nude mice. Analyst 130:844–849
Plumb R, Mazzeo JR, Grumbach ES, Rainville P, Jones M, Wheat T, Neue UD, Smith B, Johnson KA (2007) The application of small porous particles, high temperatures, and high pressures to generate very high resolution LC and LC/MS separations. J Sep Sci 30:1158–1166
Powers R (2009) NMR metabolomics and drug discovery. Magn Reson Chem 47(suppl 1):S2–S11
Quinones MP, Kaddurah-Daouk R (2009) Metabolomics tools for identifying biomarkers for neuropsychiatric diseases. Neurobiol Dis 35:165–176
Raamsdonk LM, Teusink B, Broadhurst D, Zhang NS, Hayes A, Walsh MC, Berden JA, Brindle KM, Kell DB, Rowland JJ, Westerhoff HV, van Dam K, Oliver SG (2001) A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nat Biotechnol 19:45–50
Rabinowitz JD, Kimball E (2007) Acidic acetonitrile for cellular metabolome extraction from Escherichia coli. Anal Chem 79:6167–6173
Radulovic D, Jelveh S, Ryu S, Hamilton TG, Foss E, Mao YY, Emili A (2004) Informatics platform for global proteomic profiling and biomarker discovery using liquid chromatography-tandem mass spectrometry. Mol Cell Proteomics 3:984–997
Ramautar R, Mayboroda OA, Deelder AM, Somsen GW, de Jong GJ (2008) Metabolic analysis of body fluids by capillary electrophoresis using noncovalently coated capillaries. J Chromatogr B 871:370–374
Ramautar R, Mayboroda OA, Somsen GW, de Jong GJ (2011) CE-MS for metabolomics: developments and applications in the period 2008–2010. Electrophoresis 32:52–65
Robertson DG (2005) Metabonomics in toxicology: a review. Toxicol Sci 85:809–822
Robertson DG, Lindon JC (2005) Metabonomics in toxicity assessment. Taylor & Francis, Boca Raton, FL
Roy SM, Anderle M, Lin H, Becker CH (2004) Differential expression profiling of serum proteins and metabolites for biomarker discovery. Int J Mass Spectrom 238:163–171
Sana TR, Waddell K, Fischer SM (2008) A sample extraction and chromatographic strategy for increasing LC/MS detection coverage of the erythrocyte metabolome. J Chromatogr B 871:314–321
Sauer U, Lasko DR, Fiaux J, Hochuli M, Glaser R, Szyperski T, Wuthrich K, Bailey JE (1999) Metabolic flux ratio analysis of genetic and environmental modulations of Escherichia coli central carbon metabolism. J Bacteriol 181:6679–6688
Schlotterbeck G, Ross A, Hochstrasser R, Senn H, Kuhn T, Marek D, Schett O (2002) High-resolution capillary tube NMR. A miniaturized 5-microL high-sensitivity TXI probe for mass-limited samples, off-line LC NMR, and HT NMR. Anal Chem 74:4464–4471
Schripsema J (2010) Application of NMR in plant metabolomics: techniques, problems and prospects. Phytochem Anal 21:14–21
Seeger K (2009) Metabolic changes in autoimmune diseases. Curr Drug Discov Technol 6:256–261
Sequeira S, So PW, Everett JR, Elcombe CR, Kelvin AS, Nicholson JK (1990) 1H-NMR spectroscopy of biofluids and the investigation of xenobiotic-induced changes in liver biochemistry. J Pharm Biomed Anal 8:945–949
Shin MH, Lee do Y, Liu KH, Fiehn O, Kim KH (2010) Evaluation of sampling and extraction methodologies for the global metabolic profiling of Saccharophagus degradans. Anal Chem 82:6660–6666
Shlomi T, Cabili MN, Ruppin E (2009) Predicting metabolic biomarkers of human inborn errors of metabolism. Mol Syst Biol 5:263
Sinha AE, Hope JL, Prazen BJ, Nilsson EJ, Jack RM, Synovec RE (2004) Algorithm for locating analytes of interest based on mass spectral similarity in GC x GC-TOF-MS data: analysis of metabolites in human infant urine. J Chromatogr A 1058:209–215
Smedsgaard J, Nielsen NPV, Carstensen JM (1998) Aligning of single and multiple wavelength chromatographic profiles for chemometric data analysis using correlation optimised warping. J Chromatogr A 805:17–35
Spagou K, Tsoukali H, Raikos N, Gika H, Wilson ID, Theodoridis G (2010) Hydrophilic interaction chromatography coupled to MS for metabonomic/metabolomic studies. J Sep Sci 33:716–727
Syage JA, Hanold KA, Lynn TC, Horner JA, Thakur RA (2004) Atmospheric pressure photoionization. II. Dual source ionization. J Chromatogr A 1050:137–149
Tang HR, Xiao CN, Wang YL (2009) Important roles of the hyphenated HPLC-DAD-MS-SPE-NMR technique in metabonomics. Magn Reson Chem 47:S157–S162
Taylor PJ (2005) Matrix effects: the Achilles heel of quantitative high-performance liquid chromatography-electrospray-tandem mass spectrometry. Clin Biochem 38:328–334
Tolstikov VV, Fiehn O, Tanaka N (2007) Application of liquid chromatography-mass spectrometry analysis in metabolomics: reversed-phase monolithic capillary chromatography and hydrophilic chromatography coupled to electrospray ionization-mass spectrometry. Methods Mol Biol 358:141–155
Tomita M, Nishioka T (2005) Metabolomics: the frontier of systems biology. Springer, Tokyo
Trygg J, Holmes E, Lundstedt T (2007) Chemometrics in metabonomics. J Proteome Res 6:469–479
Tuck MK, Chan DW, Chia D, Godwin AK, Grizzle WE, Krueger KE, Rom W, Sanda M, Sorbara L, Stass S, Wang W, Brenner DE (2009) Standard operating procedures for serum and plasma collection: early detection research network consensus statement standard operating procedure integration working group. J Proteome Res 8:113–117
Ullsten S, Danielsson R, Backstrom D, Sjoberg P, Bergquist J (2006) Urine profiling using capillary electrophoresis-mass spectrometry and multivariate data analysis. J Chromatogr A 1117:87–93
Villas-Boas SG, Mas S, Akesson M, Smedsgaard J, Nielsen J (2005) Mass spectrometry in metabolome analysis. Mass Spectrom Rev 24:613–646
Wang WX, Zhou HH, Lin H, Roy S, Shaler TA, Hill LR, Norton S, Kumar P, Anderle M, Becker CH (2003) Quantification of proteins and metabolites by mass spectrometry without isotopic labeling or spiked standards. Anal Chem 75:4818–4826
Wang YL, Holmes E, Nicholson JK, Cloarec O, Chollet J, Tanner M, Singer BH, Utzinger J (2004) Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification. Proc Natl Acad Sci U S A 101:12676–12681
Wang Y, Wang J, Yao M, Zhao X, Fritsche J, Schmitt-Kopplin P, Cai Z, Wan D, Lu X, Yang S, Gu J, Haring HU, Schleicher ED, Lehmann R, Xu G (2008) Metabonomics study on the effects of the ginsenoside Rg3 in a beta-cyclodextrin-based formulation on tumor-bearing rats by a fully automatic hydrophilic interaction/reversed-phase column-switching HPLC-ESI-MS approach. Anal Chem 80:4680–4688
Wang HL, Tso VK, Slupsky CM, Fedorak RN (2010) Metabolomics and detection of colorectal cancer in humans: a systematic review. Future Oncol 6:1395–1406
Want EJ, O’Maille G, Smith CA, Brandon TR, Uritboonthai W, Qin C, Trauger SA, Siuzdak G (2006) Solvent-dependent metabolite distribution, clustering, and protein extraction for serum profiling with mass spectrometry. Anal Chem 78:743–752
Want EJ, Coen M, Masson P, Keun HC, Pearce JT, Reily MD, Robertson DG, Rohde CM, Holmes E, Lindon JC, Plumb RS, Nicholson JK (2010) Ultra performance liquid chromatography-mass spectrometry profiling of bile acid metabolites in biofluids: application to experimental toxicology studies. Anal Chem 82:5282–5289
Ward ME, Politzer IR, Laseter JL, Alam SQ (1976) Gas chromatographic mass spectrometric evaluation of free organic acids in human saliva. Biomed Mass Spectrom 3:77–80
Waterman CL, Kian-Kai C, Griffin JL (2010) Metabolomic strategies to study lipotoxicity in cardiovascular disease. Biochim Biophys Acta 1801:230–234
Weckwerth W (2007) Metabolomics: methods and protocols. Humana Press, Totowa, NJ
Werner E, Heilier JF, Ducruix C, Ezan E, Junot C, Tabet JC (2008) Mass spectrometry for the identification of the discriminating signals from metabolomics: current status and future trends. J Chromatogr B Analyt Technol Biomed Life Sci 871:143–163
Wetmore DR, Joseloff E, Pilewski J, Lee DP, Lawton KA, Mitchell MW, Milburn MV, Ryals JA, Guo L (2010) Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells. J Biol Chem 285:30516–30522
Wilson ID, Nicholson JK, Castro-Perez J, Granger JH, Johnson KA, Smith BW, Plumb RS (2005) High resolution “ultra performance” liquid chromatography coupled to oa-TOF mass spectrometry as a tool for differential metabolic pathway profiling in functional genomic studies. J Proteome Res 4:591–598
Winnike JH, Li Z, Wright FA, Macdonald JM, O’Connell TM, Watkins PB (2010) Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin Pharmacol Ther 88:45–51
Wu H, Southam AD, Hines A, Viant MR (2008) High-throughput tissue extraction protocol for NMR- and MS-based metabolomics. Anal Biochem 372:204–212
Wu ZM, Huang ZQ, Lehmann R, Zhao CX, Xu GW (2009) The application of chromatography-mass spectrometry: methods to metabonomics. Chromatographia 69:S23–S32
Young SP, Wallace GR (2009) Metabolomic analysis of human disease and its application to the eye. J Ocul Biol Dis Infor 2:235–242
Zelena E, Dunn WB, Broadhurst D, Francis-McIntyre S, Carroll KM, Begley P, O’Hagan S, Knowles JD, Halsall A; HUSERMET Consortium, Wilson ID, Kell DB (2009) Development of a robust and repeatable UPLC-MS method for the long-term metabolomic study of human serum. Anal Chem 15;81(4):1357–64. doi: 10.1021/ac8019366. PMID: 19170513
Zhang S, Nagana Gowda GA, Ye T, Raftery D (2010) Advances in NMR-based biofluid analysis and metabolite profiling. Analyst 135:1490–1498
Zhang HP, Wang Y, Gu X, Zhou JY, Yan C (2011) Metabolomic profiling of human plasma in pancreatic cancer using pressurized capillary electrochromatography. Electrophoresis 32:340–347
Zhou M, McDonald JF, Fernandez FM (2010) Optimization of a direct analysis in real time/time-of-flight mass spectrometry method for rapid serum metabolomic fingerprinting. J Am Soc Mass Spectrom 21:68–75
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Alnouti, Y. (2014). Metabolomics. In: Xiong, H., Gendelman, H.E. (eds) Current Laboratory Methods in Neuroscience Research. Springer Protocols Handbooks. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8794-4_30
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