Metabolomics

, Volume 9, Issue 5, pp 1048–1072 | Cite as

NMR-based metabolomics in human disease diagnosis: applications, limitations, and recommendations

  • Abdul-Hamid M. Emwas
  • Reza M. Salek
  • Julian L. Griffin
  • Jasmeen Merzaban
Review Article

Abstract

Metabolomics is a dynamic and emerging research field, similar to proteomics, transcriptomics and genomics in affording global understanding of biological systems. It is particularly useful in functional genomic studies in which metabolism is thought to be perturbed. Metabolomics provides a snapshot of the metabolic dynamics that reflect the response of living systems to both pathophysiological stimuli and/or genetic modification. Because this approach makes possible the examination of interactions between an organism and its diet or environment, it is particularly useful for identifying biomarkers of disease processes that involve the environment. For example, the interaction of a high fat diet with cardiovascular disease can be studied via such a metabolomics approach by modeling the interaction between genes and diet. The high reproducibility of NMR-based techniques gives this method a number of advantages over other analytical techniques in large-scale and long-term metabolomic studies, such as epidemiological studies. This approach has been used to study a wide range of diseases, through the examination of biofluids, including blood plasma/serum, urine, blister fluid, saliva and semen, as well as tissue extracts and intact tissue biopsies. However, complicating the use of NMR spectroscopy in biomarker discovery is the fact that numerous variables can effect metabolic composition including, fasting, stress, drug administration, diet, gender, age, physical activity, life style and the subject’s health condition. To minimize the influence of these variations in the datasets, all experimental conditions including sample collection, storage, preparation as well as NMR spectroscopic parameters and data analysis should be optimized carefully and conducted in an identical manner as described by the local standard operating protocol . This review highlights the potential applications of NMR-based metabolomics studies and gives some recommendations to improve sample collection, sample preparation and data analysis in using this approach.

Keywords

Diagnosis Prognosis NMR spectroscopy Metabolomics Metabonomics Biomarkers Metabolic fingerprinting 

References

  1. Aboagye, E. O., & Bhujwalla, Z. M. (1999). Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Research, 59, 80–84.PubMedGoogle Scholar
  2. Abuhijleh, A. L., Abu Ali, H., & Emwas, A.-H. (2009). Synthesis, spectral and structural characterization of dinuclear rhodium (II) complexes of the anticonvulsant drug valproate with theophylline and caffeine. Journal of Organometallic Chemistry, 694, 3590–3596. doi:10.1016/j.jorganchem.2009.07.031.CrossRefGoogle Scholar
  3. Agnolet, S., Wiese, S., Verpoorte, R., & Staerk, D. (2012). Comprehensive analysis of commercial willow bark extracts by new technology platform: Combined use of metabolomics, high-performance liquid chromatography-solid-phase extraction-nuclear magnetic resonance spectroscopy and high-resolution radical scavenging assay. Journal of Chromatography A, 1262, 130–137. doi:10.1016/j.chroma.2012.09.013.PubMedCrossRefGoogle Scholar
  4. Ahmed, A. E. S. I., et al. (2011). Metabolomic profiling can differentiate between bactericidal effects of free and polymer bound halogen. Journal of Applied Polymer Science, 119, 709–718.CrossRefGoogle Scholar
  5. Ala-Korpela, M. (2007). Potential role of body fluid H-1 NMR metabonomics as a prognostic and diagnostic tool. Expert Review of Molecular Diagnostics, 7, 761–773. doi:10.1586/14737159.7.6.761.PubMedCrossRefGoogle Scholar
  6. Al-Talla, Z. A., Akrawi, S. H., & Emwas, A. H. M. (2011). Solid state NMR and bioequivalence comparison of the pharmacokinetic parameters of two formulations of clindamycin. International Journal of Clinical Pharmacology and Therapeutics, 49, 469–476. doi:10.5414/cp201478.PubMedCrossRefGoogle Scholar
  7. Antoniewicz, M. R., Stephanopoulos, G., & Kelleher, J. K. (2006). Evaluation of regression models in metabolic physiology: Predicting fluxes from isotopic data without knowledge of the pathway. Metabolomics, 2, 41–52. doi:10.1007/s11306-06-0018-2.PubMedCrossRefGoogle Scholar
  8. Ardenkjær-Larsen, J. H., et al. (2003). Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proceedings of the National Academy of Sciences, 100, 10158–10163.CrossRefGoogle Scholar
  9. Atzori, L., Griffin, J. L., Noto, A., & Fanos, V. (2012). Review metabolomics: A new approach to drug delivery in perinatology. Current Medicinal Chemistry, 19, 4654–4661.PubMedCrossRefGoogle Scholar
  10. Aue, W., Karhan, J., & Ernst, R. (1976). Homonuclear broad band decoupling and two-dimensional J-resolved NMR spectroscopy. Journal of Chemical Physics, 64, 4226–4227.CrossRefGoogle Scholar
  11. Backshall, A., Sharma, R., Clarke, S. J., & Keun, H. C. (2011). Pharmacometabonomic profiling as a predictor of toxicity in patients with inoperable colorectal cancer treated with capecitabine. Clinical Cancer Research, 17, 3019–3028. doi:10.1158/1078-0432.ccr-10-2474.PubMedCrossRefGoogle Scholar
  12. Balog, C. I. A., et al. (2011). Metabonomic investigation of human Schistosoma mansoni infection. Molecular Biosystems, 7, 1473–1480. doi:10.1039/c0mb00262c.PubMedCrossRefGoogle Scholar
  13. Bankefors, J., et al. (2011). A comparison of the metabolic profile on intact tissue and extracts of muscle and liver of juvenile Atlantic salmon (Salmo salar L.)—Application to a short feeding study. Food Chemistry, 129, 1397–1405. doi:10.1016/j.foodchem.2011.05.081.CrossRefGoogle Scholar
  14. Barton, R. H., Nicholson, J. K., Elliott, P., & Holmes, E. (2008). High-throughput 1H NMR-based metabolic analysis of human serum and urine for large-scale epidemiological studies: Validation study. International Journal of Epidemiology, 37, i31–i40.PubMedCrossRefGoogle Scholar
  15. Barzilai, A., Horowitz, A., Geier, A., & Degani, H. (1991). Phosphate metabolites and steroid-hormone receptors of benign and malignant breast-tumors—a nuclear-magnetic-resonance study. Cancer, 67, 2919–2925. doi:10.1002/1097-0142(19910601)67:11<2919.PubMedCrossRefGoogle Scholar
  16. Basant, A., Rege, M., Sharma, S., & Sonawat, H. M. (2010). Alterations in urine, serum and brain metabolomic profiles exhibit sexual dimorphism during malaria disease progression. Malaria Journal, 9, 110. doi:10.1186/1475-2875-9-110.PubMedCrossRefGoogle Scholar
  17. Baumgart, D. C., & Carding, S. R. (2007). Inflammatory bowel disease: Cause and immunobiology. The Lancet, 369, 1627–1640.CrossRefGoogle Scholar
  18. Beckonert, O., et al. (2007). Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nature Protocols, 2, 2692–2703.PubMedCrossRefGoogle Scholar
  19. Beloueche-Babari, M., et al. (2006). Identification of magnetic resonance detectable metabolic changes associated with inhibition of phosphoinositide 3-kinase signaling in human breast cancer cells. Molecular Cancer Therapeutics, 5, 187–196. doi:10.1158/1535-7163.mct-03-0220.PubMedCrossRefGoogle Scholar
  20. Beneduci, A., Cuccurullo, M., Pontoni, G., Chidichimo, G., & Capasso, G. (2010). Perspectives of H-1-NMR-based urinary metabonomics in Fabry disease. Journal of Nephrology, 23, S213–S220.PubMedGoogle Scholar
  21. Bernini, P., Bertini, I., Luchinat, C., Nincheri, P., Staderini, S., & Turano, P. (2011). Standard operating procedures for pre-analytical handling of blood and urine for metabolomic studies and biobanks. Journal of Biomolecular NMR, 49, 231–243. doi:10.1007/s10858-011-9489-1.PubMedCrossRefGoogle Scholar
  22. Bertini, I., et al. (2008). The metabonomic signature of celiac disease. Journal of Proteome Research, 8, 170–177.CrossRefGoogle Scholar
  23. Beyoglu, D., & Idle, J. R. (2013). Metabolomics and its potential in drug development. Biochemical Pharmacology, 85, 12–20. doi:10.1016/j.bcp.2012.08.013.PubMedCrossRefGoogle Scholar
  24. Bhakoo, K. K., Williams, S. R., Florian, C. L., Land, H., & Noble, M. D. (1996). Immortalization and transformation are associated with specific alterations in choline metabolism. Cancer Research, 56, 4630–4635.PubMedGoogle Scholar
  25. Bharti, S. K., Behari, A., Kapoor, V. K., Kumari, N., Krishnani, N., & Roy, R. (2013). Magic angle spinning NMR spectroscopic metabolic profiling of gall bladder tissues for differentiating malignant from benign disease. Metabolomics, 9, 101–118. doi:10.1007/s11306-012-0431-7.CrossRefGoogle Scholar
  26. Bird, S. S., et al. (2012). Structural characterization of plasma metabolites detected via LC-electrochemical coulometric array using LC-UV fractionation, MS, and NMR. Analytical Chemistry, 84, 9889–9898. doi:10.1021/ac302278u.PubMedCrossRefGoogle Scholar
  27. Blaise, B. J., et al. (2010). Two-dimensional statistical recoup ling for the identification of perturbed metabolic networks from NMR spectroscopy. Journal of Proteome Research, 9, 4513–4520. doi:10.1021/pr1002615.PubMedCrossRefGoogle Scholar
  28. Blasco, H., et al. (2010). 1H-NMR-based metabolomic profiling of CSF in early amyotrophic lateral sclerosis. PLoS One, 5, e13223.PubMedCrossRefGoogle Scholar
  29. Blindauer, C. A., Emwas, A. H., Holy, A., Dvorakova, H., Sletten, E., & Sigel, H. (1997). Complex formation of the antiviral 9-2-(phosphonomethoxy)ethyl adenine (PMEA) and of its N1, N3, and N7 deaza derivatives with copper(II) in aqueous solution. Chemistry—A European Journal, 3, 1526–1536. doi:10.1002/chem.19970030922.CrossRefGoogle Scholar
  30. Bolan, P. J., et al. (2003). In vivo quantification of choline compounds in the breast with H-1 MR spectroscopy. Magnetic Resonance in Medicine, 50, 1134–1143. doi:10.1002/mrm.10654.PubMedCrossRefGoogle Scholar
  31. Bollard, M. E., Stanley, E. G., Lindon, J. C., Nicholson, J. K., & Holmes, E. (2005). NMR-based metabonomic approaches for evaluating physiological influences on biofluid composition. NMR in Biomedicine, 18, 143–162.PubMedCrossRefGoogle Scholar
  32. Boyle, P., & Levin, B. (2008). World cancer report 2008 (1st ed.). Lyon: International Agency for Research on Cancer (IARC).Google Scholar
  33. Brindle, J. T., et al. (2002a). Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nature Medicine, 8, 1439–1445.PubMedCrossRefGoogle Scholar
  34. Brindle, J. T., Nicholson, J. K., Schofield, P. M., Grainger, D. J., & Holmes, E. (2002b). Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. Analyst, 128, 32–36.CrossRefGoogle Scholar
  35. Cai, H.-L., et al. (2012). Metabolomic analysis of biochemical changes in the plasma and urine of first-episode neuroleptic-naive schizophrenia patients after treatment with risperidone. Journal of Proteome Research, 11, 4338–4350. doi:10.1021/pr300459d.PubMedCrossRefGoogle Scholar
  36. Carrola, J., et al. (2011). Metabolic signatures of lung cancer in biofluids: NMR-based metabonomics of urine. Journal of Proteome Research, 10, 221–230.PubMedCrossRefGoogle Scholar
  37. Cascante, M., Boros, L. G., Comin-Anduix, B., de Atauri, P., Centelles, J. J., & Lee, P. W. N. (2002). Metabolic control analysis in drug discovery and disease. Nature Biotechnology, 20, 243–249.PubMedCrossRefGoogle Scholar
  38. Chan, M. K., Tsang, T. M., Harris, L. W., Guest, P. C., Holmes, E., & Bahn, S. (2011). Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Molecular Psychiatry, 16, 1189–1202. doi:10.1038/mp.2010.100.PubMedCrossRefGoogle Scholar
  39. Chekmenev, E. Y., Norton, V. A., Weitekamp, D. P., & Bhattacharya, P. (2009). Hyperpolarized 1H-NMR employing low γ nucleus for spin polarization storage. Journal of the American Chemical Society, 131, 3164–3165.PubMedCrossRefGoogle Scholar
  40. Cheng, L. L., Chang, I. W., Smith, B. L., & Gonzalez, R. G. (1998). Evaluating human breast ductal carcinomas with high-resolution magic-angle spinning proton magnetic resonance spectroscopy. Journal of Magnetic Resonance, 135, 194–202. doi:10.1006/jmre.1998.1578.PubMedCrossRefGoogle Scholar
  41. Cheng, L. L., Anthony, D. C., Comite, A. R., Black, P. M., Tzika, A. A., & Gonzalez, R. G. (2000). Quantification of microheterogeneity in glioblastoma multiforme with ex vivo high-resolution magic-angle spinning (HRMAS) proton magnetic resonance spectroscopy. Neuro-Oncology, 2, 87–95.PubMedGoogle Scholar
  42. Cloarec, O., et al. (2005). Statistical total correlation spectroscopy: An exploratory approach for latent biomarker identification from metabolic 1H-NMR data sets. Analytical Chemistry, 77, 1282–1289.PubMedCrossRefGoogle Scholar
  43. Coen, M., et al. (2012). Pharmacometabonomic investigation of dynamic metabolic phenotypes associated with variability in response to galactosamine hepatotoxicity. Journal of Proteome Research, 11, 2427–2440. doi:10.1021/pr201161f.PubMedCrossRefGoogle Scholar
  44. Connor, S. C., et al. (2004). Effects of feeding and body weight loss on the 1H-NMR-based urine metabolic profiles of male Wistar Han rats: Implications for biomarker discovery. Biomarkers, 9, 156–179.PubMedCrossRefGoogle Scholar
  45. Connor, S. C., Hansen, M. K., Corner, A., Smith, R. F., & Ryan, T. E. (2010). Integration of metabolomics and transcriptomics data to aid biomarker discovery in type 2 diabetes. Molecular Biosystems, 6, 909–921. doi:10.1039/b914182k.PubMedCrossRefGoogle Scholar
  46. Constantinou, M. A., et al. (2005). 1H NMR-based metabonomics for the diagnosis of inborn errors of metabolism in urine. Analytica Chimica Acta, 542, 169–177.CrossRefGoogle Scholar
  47. Corte, L., Rellini, P., Roscini, L., Fatichenti, F., & Cardinali, G. (2010). Development of a novel, FTIR (Fourier transform infrared spectroscopy) based, yeast bioassay for toxicity testing and stress response study. Analytica Chimica Acta, 659, 258–265.PubMedCrossRefGoogle Scholar
  48. Craig, A., Cloarec, O., Holmes, E., Nicholson, J. K., & Lindon, J. C. (2006). Scaling and normalization effects in NMR spectroscopic metabonomic data sets. Analytical Chemistry, 78, 2262–2267.PubMedCrossRefGoogle Scholar
  49. Crockford, D., Keun, H., Smith, L., Holmes, E., & Nicholson, J. (2005). Curve-fitting method for direct quantitation of compounds in complex biological mixtures using 1H NMR: Application in metabonomic toxicology studies. Analytical Chemistry, 77, 4556–4562.PubMedCrossRefGoogle Scholar
  50. Culeddu, N., et al. (2012). NMR-based metabolomic study of type 1 diabetes. Metabolomics, 8, 1162–1169. doi:10.1007/s11306-012-0420-x.CrossRefGoogle Scholar
  51. Davis, V. W., Bathe, O. F., Schiller, D. E., Slupsky, C. M., & Sawyer, M. B. (2011). Metabolomics and surgical oncology: Potential role for small molecule biomarkers. Journal of Surgical Oncology, 103, 451–459. doi:10.1002/jso.21831.PubMedCrossRefGoogle Scholar
  52. Day, S. E., et al. (2007). Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nature Medicine, 13, 1382–1387.PubMedCrossRefGoogle Scholar
  53. Daykin, C. A., Foxall, P. J. D., Connor, S. C., Lindon, J. C., & Nicholson, J. K. (2002). The comparison of plasma deproteinization methods for the detection of low-molecular-weight metabolites by 1H nuclear magnetic resonance spectroscopy. Analytical Biochemistry, 304, 220–230.PubMedCrossRefGoogle Scholar
  54. Defernez, M., Gunning, Y. M., Parr, A. J., Shepherd, L. V. T., Davies, H. V., & Colquhoun, I. J. (2004). NMR and HPLC-UV profiling of potatoes with genetic modifications to metabolic pathways. Journal of Agricultural and Food Chemistry, 52, 6075–6085.PubMedCrossRefGoogle Scholar
  55. Delikatny, E. J., et al. (1996). Tetraphenylphosphonium chloride induced mr-visible lipid accumulation in a malignant human breast cell line. International Journal of Cancer, 67, 72–79.CrossRefGoogle Scholar
  56. Deng, L., Cheng, K–. K., Dong, J., Griffin, J. L., & Chen, Z. (2012). Non-negative principal component analysis for NMR-based metabolomic data analysis. Chemometrics and Intelligent Laboratory Systems, 118, 51–61. doi:10.1016/j.chemolab.2012.07.011.CrossRefGoogle Scholar
  57. Devaux, P., Horning, M., & Horning, E. (1971). Benzyloxime derivatives of steroids. A new metabolic profile procedure for human urinary steroids human urinary steroids. Analytical Letters, 4, 151–160.Google Scholar
  58. Dieterle, F., Ross, A., Schlotterbeck, G., & Senn, H. (2006). Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H-NMR metabonomics. Analytical Chemistry, 78, 4281–4290.PubMedCrossRefGoogle Scholar
  59. Duarte, N. C., et al. (2007). Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proceedings of the National Academy of Sciences, 104, 1777–1782.CrossRefGoogle Scholar
  60. Dumas, M. E., Canlet, C., André, F., Vercauteren, J., & Paris, A. (2002). Metabonomic assessment of physiological disruptions using 1H–13C HMBC-NMR spectroscopy combined with pattern recognition procedures performed on filtered variables. Analytical Chemistry, 74, 2261–2273.PubMedCrossRefGoogle Scholar
  61. Dunn, W. B., Broadhurst, D. I., Atherton, H. J., Goodacre, R., & Griffin, J. L. (2010). Systems level studies of mammalian metabolomes: The roles of mass spectrometry and nuclear magnetic resonance spectroscopy. Chemical Society Reviews, 40, 387–426.PubMedCrossRefGoogle Scholar
  62. Eggleston, J. C., Saryan, L. A., & Hollis, D. P. (1975). Nuclear magnetic resonance investigations of human neoplastic and abnormal nonneoplastic tissues. Cancer Research, 35, 1326–1332.PubMedGoogle Scholar
  63. Ekman, D. R., Keun, H. C., Eads, C. D., Furnish, C. M., Rockett, J. C., & Dix, D. J. (2006). Metabolomic evaluation of rat liver and testis to characterize the toxicity of triazole fungicides. Metabolomics, 2, 63–73. doi:10.1007/s11306-006-0020-8.CrossRefGoogle Scholar
  64. Emwas, A. H., Saunders, M., Ludwig, C., & Günther, U. (2008). Determinants for optimal enhancement in ex situ DNP experiments. Applied Magnetic Resonance, 34, 483–494.CrossRefGoogle Scholar
  65. Engelke, U. F. H., Wehrens, R., & Wevers, R. A. (2011). 1H NMR-based metabolomics: Chemometric methods for the diagnosis of inborn errors of metabolism. Journal of Inherited Metabolic Disease, 34, S269.Google Scholar
  66. Eriksson, L., Johansson, E., Kettaneh-Wold, N., & Wold, S. (2006). Multi- and megavariate data analysis. Umea: Umetrics Academy.Google Scholar
  67. Fan, T. W. M. (1996). Metabolite profiling by one- and two-dimensional NMR analysis of complex mixtures. Progress in Nuclear Magnetic Resonance Spectroscopy, 28, 161–219.Google Scholar
  68. Fan, T. W. M., Lorkiewicz, P. K., Sellers, K., Moseley, H. N. B., Higashi, R. M., & Lane, A. N. (2012). Stable isotope-resolved metabolomics and applications for drug development. Pharmacology & Therapeutics, 133, 366–391. doi:10.1016/j.pharmthera.2011.12.007.CrossRefGoogle Scholar
  69. Feller, M., Huwiler, K., Schoepfer, A., Shang, A., Furrer, H., & Egger, M. (2010). Long-term antibiotic treatment for Crohn’s disease: Systematic review and meta-analysis of placebo-controlled trials. Clinical Infectious Diseases, 50, 473–480.PubMedCrossRefGoogle Scholar
  70. Fonville, J. M., Maher, A. D., Coen, M., Holmes, E., Lindon, J. C., & Nicholson, J. K. (2010). Evaluation of full-resolution J-resolved 1H NMR projections of biofluids for metabonomics information retrieval and biomarker identification. Analytical Chemistry, 82, 1811–1821.PubMedCrossRefGoogle Scholar
  71. Gao, H., et al. (2009). Application of 1H-NMR-based metabonomics in the study of metabolic profiling of human hepatocellular carcinoma and liver cirrhosis. Cancer Science, 100, 782–785.PubMedCrossRefGoogle Scholar
  72. Garcia, E., et al. (2011). Diagnosis of early stage ovarian cancer by 1H-NMR metabonomics of serum explored by use of a microflow NMR probe. Journal of Proteome Research, 10, 1765–1771.PubMedCrossRefGoogle Scholar
  73. Garrod, S., et al. (1999). High-resolution magic angle spinning 1H NMR spectroscopic studies on intact rat renal cortex and medulla. Magnetic Resonance in Medicine, 41, 1108–1118.PubMedCrossRefGoogle Scholar
  74. Gartland, K., Beddell, C., Lindon, J., & Nicholson, J. (1991). Application of pattern recognition methods to the analysis and classification of toxicological data derived from proton nuclear magnetic resonance spectroscopy of urine. Molecular Pharmacology, 39, 629–642.PubMedGoogle Scholar
  75. Gebregiworgis, T., & Powers, R. (2012). Application of NMR metabolomics to search for human disease biomarkers. Combinatorial Chemistry & High Throughput Screening, 15, 595–610.CrossRefGoogle Scholar
  76. Ghosh, S., Sengupta, A., Sharma, S., & Sonawat, H. M. (2011). Multivariate modelling with H-1 NMR of pleural effusion in murine cerebral malaria. Malaria Journal, 10, 330. doi:10.1186/1475-2875-10-330.PubMedCrossRefGoogle Scholar
  77. Gidman, E., Goodacre, R., Emmett, B., Smith, A. R., & Gwynn-Jones, D. (2003). Investigating plant–plant interference by metabolic fingerprinting. Phytochemistry, 63, 705–710.PubMedCrossRefGoogle Scholar
  78. Gika, H. G., Theodoridis, G. A., Wingate, J. E., & Wilson, I. D. (2007). Within-day reproducibility of an HPLC-MS-based method for metabonomic analysis: Application to human urine. Journal of Proteome Research, 6, 3291–3303.PubMedCrossRefGoogle Scholar
  79. Giskeodegard, G. F., et al. (2010). Multivariate modeling and prediction of breast cancer prognostic factors using MR metabolomics. Journal of Proteome Research, 9, 972–979. doi:10.1021/pr9008783.PubMedCrossRefGoogle Scholar
  80. Godoy, M. M. G., et al. (2010). Hepatitis C virus infection diagnosis using metabonomics. Journal of Viral Hepatitis, 17, 854–858. doi:10.1111/j.1365-2893.2009.01252.x.PubMedCrossRefGoogle Scholar
  81. Goodacre, R. (2007). Metabolomics of a superorganism. The Journal of Nutrition, 137, 259S–266S.PubMedGoogle Scholar
  82. Goodacre, R., et al. (2007). Proposed minimum reporting standards for data analysis in metabolomics. Metabolomics, 3, 231–241. doi:10.1007/s11306-007-0081-3.CrossRefGoogle Scholar
  83. Goodpaster, A. M., Ramadas, E. H., & Kennedy, M. A. (2011). Potential effect of diaper and cotton ball contamination on NMR- and LC/MS-based metabonomics studies of urine from newborn babies. Analytical Chemistry, 83, 896–902. doi:10.1021/ac102572b.PubMedCrossRefGoogle Scholar
  84. Gowda, G. A. N., et al. (2010). Quantitative analysis of blood plasma metabolites using isotope enhanced NMR methods. Analytical Chemistry, 82, 8983–8990. doi:10.1021/ac101938w.CrossRefGoogle Scholar
  85. Graham, S. F., Chevallier, O. P., Roberts, D., Holscher, C., Elliott, C. T., & Green, B. D. (2013). Investigation of the human brain metabolome to identify potential markers for early diagnosis and therapeutic targets of Alzheimer’s disease. Analytical Chemistry, 85, 1803–1811. doi:10.1021/ac303163f.PubMedCrossRefGoogle Scholar
  86. Gribbestad, I. S., et al. (1993). In-vitro proton nmr-spectroscopy of extracts from human breast-tumors and noninvolved breast-tissue. Anticancer Research, 13, 1973–1980.PubMedGoogle Scholar
  87. Gribbestad, I. S., Sitter, B., Lundgren, S., Krane, J., & Axelson, D. (1999). Metabolite composition in breast tumors examined by proton nuclear magnetic resonance spectroscopy. Anticancer Research, 19, 1737–1746.PubMedGoogle Scholar
  88. Griffin, J. L. (2004). Metabolic profiles to define the genome: Can we hear the phenotypes? Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 359, 857–871.PubMedCrossRefGoogle Scholar
  89. Griffin, J. L. (2006). The Cinderella story of metabolic profiling: Does metabolomics get to go to the functional genomics ball? Philosophical Transactions of the Royal Society B: Biological Sciences, 361, 147–161.CrossRefGoogle Scholar
  90. Griffin, J., Walker, L., Garrod, S., Holmes, E., Shore, R., & Nicholson, J. (2000a). NMR spectroscopy based metabonomic studies on the comparative biochemistry of the kidney and urine of the bank vole (〈i〉 Clethrionomys glareolus 〈/i〉), wood mouse (〈i〉 Apodemus sylvaticus 〈/i〉), white toothed shrew (〈i〉 Crocidura suaveolens 〈/i〉) and the laboratory rat. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 127, 357–367.CrossRefGoogle Scholar
  91. Griffin, J. L., Troke, J., Walker, L. A., Shore, R. F., Lindon, J. C., & Nicholson, J. K. (2000b). The biochemical profile of rat testicular tissue as measured by magic angle spinning H-1 NMR spectroscopy. FEBS Letters, 486, 225–229. doi:10.1016/s0014-5793(00)02307-3.PubMedCrossRefGoogle Scholar
  92. Griffin, J., Williams, H., Sang, E., & Nicholson, J. (2001). Abnormal lipid profile of dystrophic cardiac tissue as demonstrated by one-and two-dimensional magic-angle spinning 1H NMR spectroscopy. Magnetic Resonance in Medicine, 46, 249–255.PubMedCrossRefGoogle Scholar
  93. Griffin, J. L., Atherton, H. J., Steinbeck, C., & Salek, R. M. (2011). A Metadata description of the data in “A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human.”. BMC Research Notes, 4, 272.PubMedCrossRefGoogle Scholar
  94. Grimes, J. H., & O’Connell, T. M. (2011). The application of micro-coil NMR probe technology to metabolomics of urine and serum. Journal of Biomolecular NMR, 49(3–4), 297–305.PubMedCrossRefGoogle Scholar
  95. Gruetter, R., et al. (1998). Resolution improvements in in vivo 1H NMR spectra with increased magnetic field strength. Journal of Magnetic Resonance, 135, 260–264.PubMedCrossRefGoogle Scholar
  96. Harris, T., Giraudeau, P., & Frydman, L. (2011). Kinetics from indirectly detected hyperpolarized NMR spectroscopy by using spatially selective coherence transfers. Chemistry—A European Journal, 17, 697–703.CrossRefGoogle Scholar
  97. Harrison, P. J. (1999). The neuropathological effects of antipsychotic drugs. Schizophrenia Research, 40, 87–99. doi:10.1016/s0920-9964(99)00065-1.PubMedCrossRefGoogle Scholar
  98. Hasim, A., Ali, M., Mamtimin, B., Ma, J.-Q., Li, Q.-Z., & Abudula, A. (2012). Metabonomic signature analysis of cervical carcinoma and precancerous lesions in women by H-1 NMR spectroscopy. Experimental and Therapeutic Medicine, 3, 945–951. doi:10.3892/etm.2012.509.PubMedGoogle Scholar
  99. Haug, K., et al. (2013). MetaboLights-an open-access general-purpose repository for metabolomics studies and associated meta-data. Nucleic Acids Research, 41, D781–D786. doi:10.1093/nar/gks1004.PubMedCrossRefGoogle Scholar
  100. Holmes, E., Foxall, P. J. D., Spraul, M., Duncan Farrant, R., Nicholson, J. K., & Lindon, J. C. (1997). 750 MHz 1H NMR spectroscopy characterisation of the complex metabolic pattern of urine from patients with inborn errors of metabolism: 2-hydroxyglutaric aciduria and maple syrup urine disease. Journal of Pharmaceutical and Biomedical Analysis, 15, 1647–1659.PubMedCrossRefGoogle Scholar
  101. Holmes, E., et al. (2000). Chemometric models for toxicity classification based on NMR spectra of biofluids. Chemical Research in Toxicology, 13, 471–478.PubMedCrossRefGoogle Scholar
  102. Holmes, E., et al. (2006). Metabolic profiling of CSF: Evidence that early intervention may impact on disease progression and outcome in schizophrenia. Plos Medicine, 3, 1420. doi:10.1371/journal.pmed.0030327.Google Scholar
  103. Holmes, E., Tsang, T. M., & Tabrizi, S. J. (2006c). The application of NMR-based metabonomics in neurological disorders. NeuroRx, 3, 358–372.PubMedCrossRefGoogle Scholar
  104. Hotelling, H. (1933). Analysis of a complex of statistical variables into principal components. Journal of Educational Psychology, 24, 417–441.CrossRefGoogle Scholar
  105. Houze, P., Bellik, B., Extra, J. M., Bouro, F., & Bousquet, B. (1999). Urinary carboxyterminal telopeptide of collagen I as a potential marker of bone metastases chemotherapy monitoring in breast cancer. Clinica Chimica Acta, 281, 77–88. doi:10.1016/s0009-8981(98)00209-5.CrossRefGoogle Scholar
  106. Huang, Z., et al. (2013). Holistic metabonomic profiling of urine affords potential early diagnosis for bladder and kidney cancers. Metabolomics, 9, 119–129. doi:10.1007/s11306-012-0433-5.CrossRefGoogle Scholar
  107. Hwang, G.-S., Yang, J.-Y., Ryu, D. H., & Kwon, T.-H. (2010). Metabolic profiling of kidney and urine in rats with lithium-induced nephrogenic diabetes insipidus by H-1-NMR-based metabonomics. American Journal of Physiology-Renal Physiology, 298, F461–F470. doi:10.1152/ajprenal.00389.2009.PubMedCrossRefGoogle Scholar
  108. Hyberts, S. G., et al. (2007). Ultrahigh-resolution 1H–13C HSQC spectra of metabolite mixtures using nonlinear sampling and forward maximum entropy reconstruction. Journal of the American Chemical Society, 129, 5108–5116.PubMedCrossRefGoogle Scholar
  109. Issaq, H. J., Van, Q. N., Waybright, T. J., Muschik, G. M., & Veenstra, T. D. (2009). Analytical and statistical approaches to metabolomics research. Journal of Separation Science, 32, 2183–2199.PubMedCrossRefGoogle Scholar
  110. Jarvis, R. M., & Goodacre, R. (2005). Genetic algorithm optimization for pre-processing and variable selection of spectroscopic data. Bioinformatics, 21, 860–868. doi:10.1093/bioinformatics/bti102.PubMedCrossRefGoogle Scholar
  111. Jimenez, B., et al. (2013). (1)H HR-MAS NMR spectroscopy of tumor-induced local metabolic “field-effects” enables colorectal cancer staging and prognostication. Journal of Proteome Research, 12, 959–968. doi:10.1021/pr3010106.PubMedCrossRefGoogle Scholar
  112. Jordan, K., et al. (2010). Comparison of squamous cell carcinoma and adenocarcinoma of the lung by metabolomic analysis of tissue–serum pairs. Lung Cancer, 68, 44–50.PubMedCrossRefGoogle Scholar
  113. Joseph, J. W., et al. (2006). The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion. Journal of Biological Chemistry, 281, 35624–35632. doi:10.1074/jbc.M602606200.PubMedCrossRefGoogle Scholar
  114. Kaddurah-Daouk, R., et al. (2007). Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Molecular Psychiatry, 12, 934–945. doi:10.1038/sj.mp.4002000.PubMedCrossRefGoogle Scholar
  115. Kaplan, O., van Zijl, P., & Cohen, J. S. (1990). Information from combined 1H and 31P NMR studies of cell extracts: Differences in metabolism between drug-sensitive and drug-resistant MCF-7 human breast cancer cells. Biochemical and Biophysical Research Communications, 169, 383–390.PubMedCrossRefGoogle Scholar
  116. Katz-Brull, R., Seger, D., Rivenson-Segal, D., Rushkin, E., & Degani, H. (2002). Metabolic markers of breast cancer: Enhanced choline metabolism and reduced choline-ether-phospholipid synthesis. Cancer Research, 62, 1966–1970.PubMedGoogle Scholar
  117. Kell, D. B. (2006). Systems biology, metabolic modelling and metabolomics in drug discovery and development. Drug Discovery Today, 11, 1085–1092.PubMedCrossRefGoogle Scholar
  118. Keun, H. C., et al. (2002a). Cryogenic probe 13C NMR spectroscopy of urine for metabonomic studies. Analytical Chemistry, 74, 4588–4593.PubMedCrossRefGoogle Scholar
  119. Keun, H. C., et al. (2002b). Analytical reproducibility in 1H NMR-based metabonomic urinalysis. Chemical Research in Toxicology, 15, 1380–1386.PubMedCrossRefGoogle Scholar
  120. Kim, O. Y., Lee, J. H., & Sweeney, G. (2013). Metabolomic profiling as a useful tool for diagnosis and treatment of chronic disease: Focus on obesity, diabetes and cardiovascular diseases. Expert Review of Cardiovascular Therapy, 11, 61–68. doi:10.1586/erc.12.121.PubMedCrossRefGoogle Scholar
  121. Kirschenlohr, H. L., et al. (2006). Proton NMR analysis of plasma is a weak predictor of coronary artery disease. Nature Medicine, 12, 705–710.PubMedCrossRefGoogle Scholar
  122. Kork, F., et al. (2009). A possible new diagnostic biomarker in early diagnosis of Alzheimer’s disease. Current Alzheimer Research, 6, 519–524.PubMedCrossRefGoogle Scholar
  123. Kwon, H. N., et al. (2011). Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach. Kidney International, 79, 529–537. doi:10.1038/ki.2010.440.PubMedCrossRefGoogle Scholar
  124. Lachenbruch, P. A., & Goldstein, M. (1979). Discriminant analysis. Biometrics, 35, 69–85.CrossRefGoogle Scholar
  125. Lauridsen, M., Hansen, S. H., Jaroszewski, J. W., & Cornett, C. (2007). Human urine as test material in 1H NMR-based metabonomics: Recommendations for sample preparation and storage. Analytical Chemistry, 79, 1181–1186.PubMedCrossRefGoogle Scholar
  126. Lehnert, W., & Hunkler, D. (1986). Possibilities of selective screening for inborn errors of metabolism using high-resolution 1H-FT-NMR spectrometry. European Journal of Pediatrics, 145, 260–266.PubMedCrossRefGoogle Scholar
  127. Lenz, E. M. (2011). Nuclear magnetic resonance (NMR)-based drug metabolite profiling. In: T. O. Metz (Ed.), Metabolic profiling: Methods and protocols. Methods in molecular biology, (pp. 299–319).Google Scholar
  128. Leo, G. C., van Hoogdalem, E. J., & van Doorn, M. (2006). NMR-based metabonomics of urine from an exploratory study of ciprofibrate in healthy volunteers and patients with type 2 diabetes mellitus. Frontiers in Drug Design and Discovery, 2, 175–191.Google Scholar
  129. Lewis, I. A., et al. (2007). Method for determining molar concentrations of metabolites in complex solutions from two-dimensional 1H–13C NMR spectra. Analytical Chemistry, 79, 9385–9390.PubMedCrossRefGoogle Scholar
  130. Li, H., et al. (2011a). A proton nuclear magnetic resonance metabonomics approach for biomarker discovery in nonalcoholic fatty liver disease. Journal of Proteome Research, 10, 2797–2806. doi:10.1021/pr200047c.PubMedCrossRefGoogle Scholar
  131. Li, M., et al. (2011b). An HR-MAS MR metabolomics study on breast tissues obtained with core needle biopsy. PLoS One, 6, e25563. doi:10.1371/journal.pone.0025563.PubMedCrossRefGoogle Scholar
  132. Lin, Z. Y., et al. (2009). A metabonomic approach to early prognostic evaluation of experimental sepsis by H-1 NMR and pattern recognition. NMR in Biomedicine, 22, 601–608. doi:10.1002/nbm.1373.PubMedCrossRefGoogle Scholar
  133. Lin, S., et al. (2010). GC/MS-based metabolomics reveals fatty acid biosynthesis and cholesterol metabolism in cell lines infected with influenza A virus. Talanta, 83, 262–268.PubMedCrossRefGoogle Scholar
  134. Lindon, J. C., Nicholson, J. K., Holmes, E., & Everett, J. R. (2000). Metabonomics: Metabolic processes studied by NMR spectroscopy of biofluids. Concepts in Magnetic Resonance, 12, 289–320.CrossRefGoogle Scholar
  135. Lindon, J. C., Holmes, E., & Nicholson, J. K. (2006). Metabonomics techniques and applications to pharmaceutical research & development. Pharmaceutical Research, 23, 1075–1088.PubMedCrossRefGoogle Scholar
  136. Lindon, J. C., Beckonert, O. P., Holmes, E., & Nicholson, J. K. (2009). High-resolution magic angle spinning NMR spectroscopy: Application to biomedical studies. Progress in Nuclear Magnetic Resonance Spectroscopy, 55, 79–100. doi:10.1016/j.pnmrs.2008.11.004.CrossRefGoogle Scholar
  137. Lu, D. H., et al. (2002). C-13 NMR isotopomer analysis reveals a connection between pyruvate cycling and glucose-stimulated insulin secretion (GSIS). Proceedings of the National Academy of Sciences of the United States of America, 99, 2708–2713. doi:10.1073/pnas.052005699.PubMedCrossRefGoogle Scholar
  138. Ludwig, C., & Viant, M. R. (2010). Two-dimensional J-resolved NMR spectroscopy: Review of a key methodology in the metabolomics toolbox. Phytochemical Analysis, 21, 22–32.PubMedCrossRefGoogle Scholar
  139. Ludwig, C., et al. (2010). Application of ex situ dynamic nuclear polarization in studying small molecules. Physical Chemistry Chemical Physics: PCCP, 12, 5868–5871.PubMedCrossRefGoogle Scholar
  140. Lutz, N. W., Franks, S. E., Frank, M. H., Pomer, S., & Hull, W. E. (2005). Investigation of multidrug resistance in cultured human renal cell carcinoma cells by P-31-NMR spectroscopy and treatment survival assays. Magnetic Resonance Materials in Physics, Biology and Medicine, 18, 144–161. doi:10.1007/s10334-005-0107-7.CrossRefGoogle Scholar
  141. Mackinnon, W. B., et al. (1997). Fine-needle biopsy specimens of benign breast lesions distinguished from invasive cancer ex vivo with proton MR spectroscopy. Radiology, 204, 661–666.PubMedGoogle Scholar
  142. MacKinnon, N., Khan, A. P., Chinnaiyan, A. M., Rajendiran, T. M., & Ramamoorthy, A. (2012). Androgen receptor activation results in metabolite signatures of an aggressive prostate cancer phenotype: An NMR-based metabonomics study. Metabolomics, 8, 1026–1036. doi:10.1007/s11306-012-0398-4.CrossRefGoogle Scholar
  143. Makinen, V.-P., et al. (2008). (1)H NMR metabonomics approach to the disease continuum of diabetic complications and premature death. Molecular Systems Biology, 4, 1–12. doi:10.1038/msb4100205.CrossRefGoogle Scholar
  144. Mannina, L., et al. (2008). NMR metabolic profiling of organic and aqueous sea bass extracts: Implications in the discrimination of wild and cultured sea bass. Talanta, 77, 433–444.PubMedCrossRefGoogle Scholar
  145. Marchesi, J. R., et al. (2007). Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. Journal of Proteome Research, 6, 546–551.PubMedCrossRefGoogle Scholar
  146. Maxwell, R. J., et al. (1998). Pattern recognition analysis of H-1 NMR spectra from perchloric acid extracts of human brain tumor biopsies. Magnetic Resonance in Medicine, 39, 869–877. doi:10.1002/mrm.1910390604.PubMedCrossRefGoogle Scholar
  147. Mills, S. E., & Carter, D. (2004). Sternberg’s diagnostic surgical pathology. Philadelphia: Lippincott Williams & Wilkins.Google Scholar
  148. Monleon, D., et al. (2008). Benign and atypical meningioma metabolic signatures by high-resolution magic-angle spinning molecular profiling. Journal of Proteome Research, 7, 2882–2888. doi:10.1021/pr800110a.PubMedCrossRefGoogle Scholar
  149. Mortishire-Smith, R. J., et al. (2004). Use of metabonomics to identify impaired fatty acid metabolism as the mechanism of a drug-induced toxicity. Chemical Research in Toxicology, 17, 165–173.PubMedCrossRefGoogle Scholar
  150. Morvan, D., & Demidem, A. (2007). Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways. Cancer Research, 67, 2150–2159. doi:10.1158/0008-5472.can-06-2346.PubMedCrossRefGoogle Scholar
  151. Morvan, D., Demidem, A., Papon, J., De Latour, M., & Madelmont, J. C. (2002). Melanoma tumors acquire a new phospholipid metabolism phenotype under cystemustine as revealed by high-resolution magic angle spinning proton nuclear magnetic resonance spectroscopy of intact tumor samples. Cancer Research, 62, 1890–1897.PubMedGoogle Scholar
  152. Nahon, P., et al. (2012). Identification of serum proton NMR metabolomic fingerprints associated with hepatocellular carcinoma in patients with alcoholic cirrhosis. Clinical Cancer Research, 18, 6714–6722. doi:10.1158/1078-0432.ccr-12-1099.PubMedCrossRefGoogle Scholar
  153. Nambiar, P. R., Gupta, R. R., & Misra, V. (2010). An “Omics” based survey of human colon cancer. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis, 693, 3–18.PubMedCrossRefGoogle Scholar
  154. Nevedomskaya, E., et al. (2012). H-1 NMR-based metabolic profiling of urinary tract infection: Combining multiple statistical models and clinical data. Metabolomics, 8, 1227–1235. doi:10.1007/s11306-012-0411-y.PubMedCrossRefGoogle Scholar
  155. Nicholson, J. K., & Wilson, I. D. (1989). High resolution proton magnetic resonance spectroscopy of biological fluids. Progress in Nuclear Magnetic Resonance Spectroscopy, 21, 449–501.CrossRefGoogle Scholar
  156. Nicholson, J. K., & Wilson, I. D. (2003). Understanding ‘global’ systems biology: Metabonomics and the continuum of metabolism. Nature Reviews Drug Discovery, 2, 668–676.PubMedCrossRefGoogle Scholar
  157. Nicholson, J. K., Oflynn, M. P., Sadler, P. J., Macleod, A. F., Juul, S. M., & Sonksen, P. H. (1984). Proton-nuclear-magnetic-resonance studies of serum, plasma and urine from fasting normal and diabetic subjects. Biochemical Journal, 217, 365–375.PubMedGoogle Scholar
  158. Nicholson, J. K., Foxall, P. J. D., Spraul, M., Farrant, R. D., & Lindon, J. C. (1995). 750 MHz 1H and 1H–13C NMR spectroscopy of human blood plasma. Analytical Chemistry, 67, 793–811.PubMedCrossRefGoogle Scholar
  159. Nicholson, J., Lindon, J., & 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.PubMedCrossRefGoogle Scholar
  160. Nicholson, J. K., Wilson, I. D., & Lindon, J. C. (2011). Pharmacometabonomics as an effector for personalized medicine. Pharmacogenomics, 12, 103–111. doi:10.2217/pgs.10.157.PubMedCrossRefGoogle Scholar
  161. Nissen, P. M., Nebel, C., Oksbjerg, N., & Bertram H. C. (2011). Metabolomics reveals relationship between plasma inositols and birth weight: Possible markers for fetal programming of type 2 diabetes. Journal of Biomedicine & Biotechnology. doi:10.1155/2011/378268.
  162. Odunsi, K., et al. (2005). Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics. International Journal of Cancer, 113, 782–788.CrossRefGoogle Scholar
  163. Oliver, S. (2003). Functional genomics: All the king’s horses and all the king’s men can put Humpty together again. Molecular Cell, 12, 1343–1344.PubMedCrossRefGoogle Scholar
  164. Oliver, S. G., Winson, M. K., Kell, D. B., & Baganz, F. (1998). Systematic functional analysis of the yeast genome. Trends in Biotechnology, 16, 373–378.PubMedCrossRefGoogle Scholar
  165. Ouyang, D. (2012). Metabolomic characterization of human pancreatitis by H-1-NMR spectroscopy. Hepato-Gastroenterology, 59, 2314–2317. doi:10.5754/hge11839.PubMedGoogle Scholar
  166. Pan, Z., et al. (2007). Principal component analysis of urine metabolites detected by NMR and DESI-MS in patients with inborn errors of metabolism. Analytical and Bioanalytical Chemistry, 387, 539–549. doi:10.1007/s00216-006-0546-7.PubMedCrossRefGoogle Scholar
  167. Pears, M. R., Cooper, J. D., Mitchison, H. M., Mortishire-Smith, R. J., Pearce, D. A., & Griffin, J. L. (2005). High resolution 1H NMR-based metabolomics indicates a neurotransmitter cycling deficit in cerebral tissue from a mouse model of Batten disease. Journal of Biological Chemistry, 280, 42508–42514.PubMedCrossRefGoogle Scholar
  168. Philippeos, C., Steffens, F. E., & Meyer, D. (2009). Comparative H-1 NMR-based metabonomic analysis of HIV-1 sera. Journal of Biomolecular NMR, 44, 127–137. doi:10.1007/s10858-009-9329-8.PubMedCrossRefGoogle Scholar
  169. Pirozynski, M. (2006). Retraced: 100 years of lung cancer. Respiratory Medicine, 100, 2073–2084.PubMedCrossRefGoogle Scholar
  170. Polson, C., Sarkar, P., Incledon, B., Raguvaran, V., & Grant, R. (2003). Optimization of protein precipitation based upon effectiveness of protein removal and ionization effect in liquid chromatography-tandem mass spectrometry. Journal of Chromatography B, 785, 263–275.CrossRefGoogle Scholar
  171. Prabakaran, S., et al. (2004). Mitochondrial dysfunction in schizophrenia: Evidence for compromised brain metabolism and oxidative stress. Molecular Psychiatry, 9, 684–697.PubMedCrossRefGoogle Scholar
  172. Prantera, C., & Scribano, M. L. (2009). Antibiotics and probiotics in inflammatory bowel disease: Why, when, and how. Current Opinion in Gastroenterology, 25, 329–333. doi:10.1097/MOG.0b013e32832b20bf.PubMedCrossRefGoogle Scholar
  173. Psihogios, N. G., Gazi, I. F., Elisaf, M. S., Seferiadis, K. I., & Bairaktari, E. T. (2008). Gender-related and age-related urinalysis of healthy subjects by NMR-based metabonomics. NMR in Biomedicine, 21, 195–207.PubMedCrossRefGoogle Scholar
  174. Psychogios, N., et al. (2011). The human serum metabolome. PLoS One, 6, e16957.PubMedCrossRefGoogle Scholar
  175. Puccio, G., Brambilla, P., Conti, M., Bartolini, D., Noonan, D., & Albini, A. (2013). Surface-activated chemical ionization-electrospray mass spectrometry in the analysis of urinary thiodiglycolic acid. Rapid Communications in Mass Spectrometry, 27, 476–480. doi:10.1002/rcm.6471.PubMedCrossRefGoogle Scholar
  176. Purohit, P. V., Rocke, D. M., Viant, M. R., & Woodruff, D. L. (2004). Discrimination models using variance-stabilizing transformation of metabolomic NMR data. Omics: A Journal of Integrative Biology, 8, 118–130.CrossRefGoogle Scholar
  177. Qi, S., Ouyang, X., Wang, L., Peng, W., Wen, J., & Dai, Y. (2012a). A pilot metabolic profiling study in serum of patients with chronic kidney disease based on 1H-NMR-spectroscopy. Cts-Clinical and Translational Science, 5, 379–385. doi:10.1111/j.1752-8062.2012.00437.x.CrossRefGoogle Scholar
  178. Qi, S., et al. (2012b). Comparison of the metabolic profiling of hepatitis B virus-infected cirrhosis and alcoholic cirrhosis patients by using 1H NMR-based metabonomics. Hepatology Research, 42, 677–685. doi:10.1111/j.1872-034X.2011.00964.x.PubMedCrossRefGoogle Scholar
  179. Raamsdonk, L. M., et al. (2001). A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nature Biotechnology, 19, 45–50.PubMedCrossRefGoogle Scholar
  180. Rahmioglu, N., et al. (2011). Prediction of variability in CYP3A4 induction using a combined (1)H NMR metabonomics and targeted UPLC-MS approach. Journal of Proteome Research, 10, 2807–2816. doi:10.1021/pr200077n.PubMedCrossRefGoogle Scholar
  181. Rantalainen, M., et al. (2006). Statistically integrated metabonomic-proteomic studies on a human prostate cancer xenograft model in mice. Journal of Proteome Research, 5, 2642–2655.PubMedCrossRefGoogle Scholar
  182. Rasmiena, A. A., Ng, T. W., & Meikle, P. J. (2013). Metabolomics and ischaemic heart disease. Clinical Science, 124, 289–306. doi:10.1042/cs20120268.PubMedCrossRefGoogle Scholar
  183. Rasmussen, L. G., Savorani, F., Larsen, T. M., Dragsted, L. O., Astrup, A., & Engelsen, S. B. (2011). Standardization of factors that influence human urine metabolomics. Metabolomics, 7, 71–83.CrossRefGoogle Scholar
  184. Ratai, E. M., et al. (2005). Comparisons of brain metabolites observed by HRMAS 1H NMR of intact tissue and solution 1H NMR of tissue extracts in SIV-infected macaques. NMR in Biomedicine, 18, 242–251.PubMedCrossRefGoogle Scholar
  185. Rehman, S., et al. (2012). Dupuytren’s disease metabolite analyses reveals alterations following initial short-term fibroblast culturing. Molecular Biosystems, 8, 2274–2288. doi:10.1039/c2mb25173f.PubMedCrossRefGoogle Scholar
  186. Riccio, M. F., et al. (2010). Easy mass spectrometry for metabolomics and quality control of vegetable and animal fats. European Journal of Lipid Science and Technology, 112, 434–438.CrossRefGoogle Scholar
  187. Ringeissen, S., et al. (2003). Potential urinary and plasma biomarkers of peroxisome proliferation in the rat: Identification of N-methylnicotinamide and N-methyl-4-pyridone-3-carboxamide by 1H nuclear magnetic resonance and high performance liquid chromatography. Biomarkers, 8(3), 240–271.PubMedCrossRefGoogle Scholar
  188. Rocha, C. M., et al. (2011). Metabolic signatures of lung cancer in biofluids: NMR-based metabonomics of blood plasma. Journal of Proteome Research, 10, 4314–4324.PubMedCrossRefGoogle Scholar
  189. Rochfort, S. J., Ezernieks, V., & Yen, A. L. (2009). NMR-based metabolomics using earthworms as potential indicators for soil health. Metabolomics, 5, 95–107.CrossRefGoogle Scholar
  190. Ronnebaum, S. M., et al. (2006). A pyruvate cycling pathway involving cytosolic NADP-dependent isocitrate dehydrogenase regulates glucose-stimulated insulin secretion. Journal of Biological Chemistry, 281, 30593–30602. doi:10.1074/jbc.M511908200.PubMedCrossRefGoogle Scholar
  191. Rooney, O., Troke, J., Nicholson, J., & Griffin, J. (2003). High-resolution diffusion and relaxation-edited magic angle spinning 1H NMR spectroscopy of intact liver tissue. Magnetic Resonance in Medicine, 50, 925–930.PubMedCrossRefGoogle Scholar
  192. Ross, B., Tran, T., Bhattacharya, P., Watterson, D. M., & Sailasuta, N. (2011). Application of NMR spectroscopy in medicinal chemistry and drug discovery. Current Topics in Medicinal Chemistry, 11, 93–114. doi:10.2174/156802611793611850.PubMedCrossRefGoogle Scholar
  193. Roussel, R., et al. (2007). NMR-based prediction of cardiovascular risk in diabetes. Nature Medicine, 13, 399–400.PubMedCrossRefGoogle Scholar
  194. Rubtsov, D. V., & Griffin, J. L. (2007). Time-domain Bayesian detection and estimation of noisy damped sinusoidal signals applied to NMR spectroscopy. Journal of Magnetic Resonance, 188, 367–379.PubMedCrossRefGoogle Scholar
  195. Ruiz-Cabello, J., & Cohen, J. S. (1992). Phospholipid metabolites as indicators of cancer cell function. NMR in Biomedicine, 5, 226–233.PubMedCrossRefGoogle Scholar
  196. Ryan, D., Robards, K., Prenzler, P., & Kendall, M. (2011). Recent and potential developments in the analysis of urine: A review. Analytica Chimica Acta, 684, 17–29.CrossRefGoogle Scholar
  197. Sachse, D., et al. (2012). Metabolic changes in urine during and after pregnancy in a large, multiethnic population-based cohort Study of gestational diabetes. PLoS One, 7, e52399. doi:10.1371/journal.pone.0052399.PubMedCrossRefGoogle Scholar
  198. Salek, R. M., et al. (2007). A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human. Physiological Genomics, 29, 99–108. doi:10.1152/physiolgenomics.00194.2006.PubMedCrossRefGoogle Scholar
  199. Sandusky, P., & Raftery, D. (2005). Use of selective TOCSY NMR experiments for quantifying minor components in complex mixtures: Application to the metabonomics of amino acids in honey. Analytical Chemistry, 77, 2455–2463.PubMedCrossRefGoogle Scholar
  200. Saric, J., et al. (2009). Panorganismal metabolic response modeling of an experimental echinostoma caproni infection in the mouse. Journal of Proteome Research, 8, 3899–3911. doi:10.1021/pr900185s.PubMedCrossRefGoogle Scholar
  201. Saude, E. J., & Sykes, B. D. (2007). Urine stability for metabolomic studies: Effects of preparation and storage. Metabolomics, 3, 19–27.CrossRefGoogle Scholar
  202. Saude, E. J., Adamko, D., Rowe, B. H., Marrie, T., & Sykes, B. D. (2007). Variation of metabolites in normal human urine. Metabolomics, 3, 439–451.CrossRefGoogle Scholar
  203. Scheltema, R., Decuypere, S., Dujardin, J. C., Watson, D., Jansen, R., & Breitling, R. (2009). Simple data-reduction method for high-resolution LC-MS data in metabolomics. Bioanalysis, 1, 1551–1557.PubMedCrossRefGoogle Scholar
  204. Scott, I. M., et al. (2010). Enhancement of plant metabolite fingerprinting by machine learning. Plant Physiology, 153, 1506–1520.PubMedCrossRefGoogle Scholar
  205. Sengupta, A., et al. (2011). Global host metabolic response to plasmodium vivax infection: A H-1 NMR based urinary metabonomic study. Malaria Journal, 10, 384. doi:10.1186/1475-2875-10-384.PubMedCrossRefGoogle Scholar
  206. Shanaiah, N., Desilva, M. A., Nagana Gowda, G., Raftery, M. A., Hainline, B. E., & Raftery, D. (2007). Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced 13C NMR. Proceedings of the National Academy of Sciences, 104, 11540–11544.CrossRefGoogle Scholar
  207. Sharma, U., Mehta, A., Seenu, V., & Jagannathan, N. R. (2004). Biochemical characterization of metastatic lymph nodes of breast cancer patients by in vitro H-1 magnetic resonance spectroscopy: A pilot study. Magnetic Resonance Imaging, 22, 697–706. doi:10.1016/j.mri.2004.01.037.PubMedCrossRefGoogle Scholar
  208. Sheedy, J. R., Ebeling, P. R., Gooley, P. R., & McConville, M. J. (2010). A sample preparation protocol for (1)H nuclear magnetic resonance studies of water-soluble metabolites in blood and urine. Analytical Biochemistry, 398, 263–265. doi:10.1016/j.ab.2009.11.027.PubMedCrossRefGoogle Scholar
  209. Sitter, B., Sonnewald, U., Spraul, M., Fjösne, H. E., & Gribbestad, I. S. (2002). High-resolution magic angle spinning MRS of breast cancer tissue. NMR in Biomedicine, 15, 327–337.PubMedCrossRefGoogle Scholar
  210. Smolinska, A., Blanchet, L., Buydens, L. M. C., & Wijmenga, S. S. (2012). NMR and pattern recognition methods in metabolomics: From data acquisition to biomarker discovery: A review. Analytica Chimica Acta, 750, 82–97. doi:10.1016/j.aca.2012.05.049.PubMedCrossRefGoogle Scholar
  211. Sonawat, H. M., & Sharma, S. (2012). Host responses in malaria disease evaluated through nuclear magnetic resonance-based metabonomics. Clinics in Laboratory Medicine, 32, 129. doi:10.1016/j.cll.2012.04.005.PubMedCrossRefGoogle Scholar
  212. Steinbeck, C., et al. (2012). MetaboLights: Towards a new COSMOS of metabolomics data management. Metabolomics, 8(5), 1–4.CrossRefGoogle Scholar
  213. Stretch, C., et al. (2012). Prediction of skeletal muscle and fat mass in patients with advanced cancer using a metabolomic approach. Journal of Nutrition, 142, 14–21. doi:10.3945/jn.111.147751.PubMedCrossRefGoogle Scholar
  214. Sukumaran, D. K., et al. (2009). Standard operating procedure for metabonomics studies of blood serum and plasma samples using a H-1-NMR micro-flow probe. Magnetic Resonance in Chemistry, 47, S81–S85. doi:10.1002/mrc.2469.PubMedCrossRefGoogle Scholar
  215. Sumner, L. W., et al. (2007). Proposed minimum reporting standards for chemical analysis. Metabolomics, 3, 211–221. doi:10.1007/s11306-007-0082-2.CrossRefGoogle Scholar
  216. Tang, J., Tan, C. Y., Oresic, M., & Vidal-Puig, A. (2009). Integrating post-genomic approaches as a strategy to advance our understanding of health and disease. Genome Medicine, 1, e35.CrossRefGoogle Scholar
  217. Tenori, L., et al. (2012). Exploration of serum metabolomic profiles and outcomes in women with metastatic breast cancer: A pilot study. Molecular Oncology, 6, 437–444. doi:10.1016/j.molonc.2012.05.003.PubMedCrossRefGoogle Scholar
  218. Tiziani, S., et al. (2008). Optimized metabolite extraction from blood serum for 1H nuclear magnetic resonance spectroscopy. Analytical Biochemistry, 377, 16–23.PubMedCrossRefGoogle Scholar
  219. Torgrip, R. J. O., Åberg, K., Alm, E., Schuppe-Koistinen, I., & Lindberg, J. (2008). A note on normalization of biofluid 1D 1H-NMR data. Metabolomics, 4, 114–121.CrossRefGoogle Scholar
  220. Tsang, T., Griffin, J., Haselden, J., Fish, C., & Holmes, E. (2005). Metabolic characterization of distinct neuroanatomical regions in rats by magic angle spinning 1H nuclear magnetic resonance spectroscopy. Magnetic Resonance in Medicine, 53, 1018–1024.PubMedCrossRefGoogle Scholar
  221. Urbanczyk-Wochniak, E., et al. (2003). Parallel analysis of transcript and metabolic profiles: A new approach in systems biology. EMBO Reports, 4, 989–993.PubMedCrossRefGoogle Scholar
  222. Usenius, J. P., Vainio, P., Hernesniemi, J., & Kauppinen, R. A. (1994). Choline-containing compounds in human astrocytomas studied by 1H NMR spectroscopy in vivo and in vitro. Journal of Neurochemistry, 63, 1538–1543.PubMedCrossRefGoogle Scholar
  223. van Doorn, M., et al. (2007). Evaluation of metabolite profiles as biomarkers for the pharmacological effects of thiazolidinediones in Type 2 diabetes mellitus patients and healthy volunteers. British Journal of Clinical Pharmacology, 63, 562–574. doi:10.1111/j.1365-2125.2006.02816.x.PubMedCrossRefGoogle Scholar
  224. van Jim, O. S., & Kapur, S. (2009). Schizophrenia. Lancet, 374, 635–645.CrossRefGoogle Scholar
  225. Van Oss, C. (1989). On the mechanism of the cold ethanol precipitation method of plasma protein fractionation. Journal of Protein Chemistry, 8, 661–668.PubMedCrossRefGoogle Scholar
  226. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science’s STKE, 324, 1029–1033.Google Scholar
  227. Vermathen, M., Marzorati, M., & Vermathen, P. (2012). Exploring high-resolution magic angle spinning (HR-MAS) NMR Spectroscopy for metabonomic analysis of apples. Chimia, 66, 747–751. doi:10.2533/chimia.2012.747.PubMedCrossRefGoogle Scholar
  228. Verwaest, K. A., et al. (2011). (1)H NMR based metabolomics of CSF and blood serum: A metabolic profile for a transgenic rat model of Huntington disease. Biochimica Et Biophysica Acta-Molecular Basis of Disease, 1812, 1371–1379. doi:10.1016/j.bbadis.2011.03.001.CrossRefGoogle Scholar
  229. Viant, M. R. (2003). Improved methods for the acquisition and interpretation of NMR metabolomic data. Biochemical and Biophysical Research Communications, 310, 943–948.PubMedCrossRefGoogle Scholar
  230. Viant, M. R., Rosenblum, E. S., & Tjeerdema, R. S. (2003). NMR-based metabolomics: A powerful approach for characterizing the effects of environmental stressors on organism health. Environmental Science and Technology, 37, 4982–4989.PubMedCrossRefGoogle Scholar
  231. Vizán, P., Mazurek, S., & Cascante, M. (2008). Robust metabolic adaptation underlying tumor progression. Metabolomics, 4, 1–12.CrossRefGoogle Scholar
  232. Walenta, S., Schroeder, T., & Mueller-Klieser, W. (2004). Lactate in solid malignant tumors: Potential basis of a metabolic classification in clinical oncology. Current Medicinal Chemistry, 11, 2195–2204.PubMedCrossRefGoogle Scholar
  233. Wang, Z., et al. (2012). H-1 NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis. Experimental and Therapeutic Medicine, 4, 165–171. doi:10.3892/etm.2012.567.PubMedGoogle Scholar
  234. Warburg, O. (1956). On the origin of cancer cells. Science, 123, 309–314.PubMedCrossRefGoogle Scholar
  235. Waters, N. J., Waterfield, C. J., Farrant, R. D., Holmes, E., & Nicholson, J. K. (2005). Metabonomic deconvolution of embedded toxicity: Application to thioacetamide hepato- and nephrotoxicity. Chemical Research in Toxicology, 18, 639–654.PubMedCrossRefGoogle Scholar
  236. Weljie, A. M., Newton, J., Mercier, P., Carlson, E., & Slupsky, C. M. (2006). Targeted profiling: Quantitative analysis of 1H NMR metabolomics data. Analytical Chemistry, 78, 4430–4442.PubMedCrossRefGoogle Scholar
  237. Wen, H., et al. (2011). identification of urinary biomarkers related to cisplatin-induced acute renal toxicity using NMR-based metabolomics. Biomolecules & Therapeutics, 19, 38–44. doi:10.4062/biomolther.2011.19.1.038.CrossRefGoogle Scholar
  238. Williams, H. R. T., et al. (2012). Serum metabolic profiling in inflammatory bowel disease. Digestive Diseases and Sciences, 57, 2157–2165. doi:10.1007/s10620-012-2127-2.PubMedCrossRefGoogle Scholar
  239. Wilson, I. D., Plumb, R., Granger, J., Major, H., Williams, R., & Lenz, E. M. (2005). HPLC-MS-based methods for the study of metabonomics. Journal of Chromatography B, 817, 67–76.CrossRefGoogle Scholar
  240. Winder, C. L., et al. (2008). Global metabolic profiling of Escherichia coli cultures: An evaluation of methods for quenching and extraction of intracellular metabolites. Analytical Chemistry, 80, 2939–2948. doi:10.1021/ac7023409.PubMedCrossRefGoogle Scholar
  241. Wishart, D. S., et al. (2007). HMDB: The human metabolome database. Nucleic Acids Research, 35, D521–D526.PubMedCrossRefGoogle Scholar
  242. Witjes, H., Melssen, W., van der Graaf, M., Heerschap, A., & Buydens, L. (2000). Automatic correction for phase shifts, frequency shifts, and lineshape distortions across a series of single resonance lines in large spectral data sets. Journal of Magnetic Resonance, 144, 35–44.PubMedCrossRefGoogle Scholar
  243. Wold, S., Sjostrom, M., & Eriksson, L. (2001). PLS-regression: A basic tool of chemometrics. Chemometrics and Intelligent Laboratory Systems, 58, 109–130. doi:10.1016/s0169-7439(01)00155-1.CrossRefGoogle Scholar
  244. Worley, B., Halouska, S., & Powers, R. (2013). Utilities for quantifying separation in PCA/PLS-DA scores plots. Analytical Biochemistry, 433, 102–104.PubMedCrossRefGoogle Scholar
  245. Xi, Y., de Ropp, J. S., Viant, M. R., Woodruff, D. L., & Yu, P. (2006). Automated screening for metabolites in complex mixtures using 2D COSY NMR spectroscopy. Metabolomics, 2, 221–233.CrossRefGoogle Scholar
  246. Xu, X.-H., Huang, Y., Wang, G., & Chen, S.-D. (2012). Metabolomics: A novel approach to identify potential diagnostic biomarkers and pathogenesis in Alzheimer’s disease. Neuroscience Bulletin, 28, 641–648. doi:10.1007/s12264-012-1272-0.PubMedCrossRefGoogle Scholar
  247. Yang, J., et al. (2004). Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases. Journal of Chromatography B, 813, 59–65.CrossRefGoogle Scholar
  248. Yizhak, K., Benyamini, T., Liebermeister, W., Ruppin, E., & Shlomi, T. (2010). Integrating quantitative proteomics and metabolomics with a genome-scale metabolic network model. Bioinformatics, 26, i255–i260.PubMedCrossRefGoogle Scholar
  249. Yuk, J., McKelvie, J. R., Simpson, M. J., Spraul, M., & Simpson, A. J. (2010). Comparison of 1-D and 2-D NMR techniques for screening earthworm responses to sub-lethal endosulfan exposure. Environmental Chemistry, 7, 524–536.CrossRefGoogle Scholar
  250. Zellner, M., et al. (2005). Quantitative validation of different protein precipitation methods in proteome analysis of blood platelets. Electrophoresis, 26, 2481–2489.PubMedCrossRefGoogle Scholar
  251. Zhang, S., Gowda, G. A. N., Asiago, V., Shanaiah, N., Barbas, C., & Raftery, D. (2008). Correlative and quantitative H-1 NMR-based metabolomics reveals specific metabolic pathway disturbances in diabetic rats. Analytical Biochemistry, 383, 76–84. doi:10.1016/j.ab.2008.07.041.PubMedCrossRefGoogle Scholar
  252. Zhang, J., et al. (2012). NMR-based metabolomics study of canine bladder cancer. Biochimica Et Biophysica Acta-Molecular Basis of Disease, 1822, 1807–1814. doi:10.1016/j.bbadis.2012.08.001.CrossRefGoogle Scholar
  253. Zhao, L., Liu, X., Xie, L., Gao, H., & Lin, D. (2010). H-1 NMR-based metabonomic analysis of metabolic changes in streptozotocin-induced diabetic rats. Analytical Sciences, 26, 1277–1282. doi:10.2116/analsci.26.1277.PubMedCrossRefGoogle Scholar
  254. Zhi, H.-J., Qin, X.-M., Sun, H.-F., Zhang, L.-Z., Guo, X.-Q., & Li, Z.-Y. (2012). Metabolic fingerprinting of Tussilago farfara L. using 1H-NMR spectroscopy and multivariate data analysis. Phytochemical Analysis, 23, 492–501. doi:10.1002/pca.2346.PubMedCrossRefGoogle Scholar
  255. Zhu, Z.-J., et al. (2013). Liquid chromatography quadrupole time-of-flight mass spectrometry characterization of metabolites guided by the METLIN database. Nature Protocols, 8, 451–460. doi:10.1038/nprot.2013.004.PubMedCrossRefGoogle Scholar
  256. Zivkovic, A. M., & German, J. B. (2009). Metabolomics for assessment of nutritional status. Current Opinion in Clinical Nutrition and Metabolic Care, 12, 501–507.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Abdul-Hamid M. Emwas
    • 1
  • Reza M. Salek
    • 3
    • 4
    • 5
  • Julian L. Griffin
    • 3
    • 4
  • Jasmeen Merzaban
    • 2
  1. 1.NMR Core LabKing Abdullah University of Science and TechnologyThuwalKingdom of Saudi Arabia
  2. 2.Biological and Environmental Sciences and EngineeringKing Abdullah University of Science and TechnologyThuwalKingdom of Saudi Arabia
  3. 3.Department of Biochemistry & Cambridge Systems Biology CentreUniversity of CambridgeCambridgeUK
  4. 4.Medical Research Council Human Nutrition ResearchCambridgeUK
  5. 5.European Bioinformatics Institute Wellcome Trust Genome Campus, Hinxton CambridgeSaffron WaldenUK

Personalised recommendations