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Journal of Inherited Metabolic Disease

Erschienen in:

13.03.2018 | Metabolomics

Promises and pitfalls of untargeted metabolomics

verfasst von: Ilya Gertsman, Bruce A. Barshop

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 3/2018

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Abstract

Metabolomics is one of the newer omics fields, and has enabled researchers to complement genomic and protein level analysis of disease with both semi-quantitative and quantitative metabolite levels, which are the chemical mediators that constitute a given phenotype. Over more than a decade, methodologies have advanced for both targeted (quantification of specific analytes) as well as untargeted metabolomics (biomarker discovery and global metabolite profiling). Untargeted metabolomics is especially useful when there is no a priori metabolic hypothesis. Liquid chromatography coupled to mass spectrometry (LC-MS) has been the preferred choice for untargeted metabolomics, given the versatility in metabolite coverage and sensitivity of these instruments. Resolving and profiling many hundreds to thousands of metabolites with varying chemical properties in a biological sample presents unique challenges, or pitfalls. In this review, we address the various obstacles and corrective measures available in four major aspects associated with an untargeted metabolomics experiment: (1) experimental design, (2) pre-analytical (sample collection and preparation), (3) analytical (chromatography and detection), and (4) post-analytical (data processing).

Alvarez-Sanchez B, Priego-Capote F, Luque de Castro MD (2010) Metabolomics analysis. I. Selection of biological samples and practical aspects preceding sample preparation. Trends Anal Chem 29:111–119

Aragon AD, Quinones GA, Allen C et al (2006) An automated, pressure-driven sampling device for harvesting from liquid cultures for genomic and biochemical analyses. J Microbiol Methods 65:357–360CrossRefPubMed

Barker M, Rayens W (2003) Partial least squares for discrimination. J Chemom 17:166–173CrossRef

Barri T, Dragsted LO (2013) UPLC-ESI-QTOF/MS and multivariate data analysis for blood plasma and serum metabolomics: effect of experimental artefacts and anticoagulant. Anal Chim Acta 768:118–128CrossRefPubMed

Belanger MP, Askin N, Wittnich C (2002) Multiple in vivo liver biopsies using a freeze-clamping technique. J Investig Surg 15:109–112CrossRef

Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate - a practical and powerful approach to multiple testing. J Roy Stat Soc B Met 57:289–300

Benton HP, Wong DM, Trauger SA et al (2008) XCMS2: processing tandem mass spectrometry data for metabolite identification and structural characterization. Anal Chem 80:6382-6389

Benton HP, Ivanisevic J, Mahieu NG et al (2015) Autonomous metabolomics for rapid metabolite identification in global profiling. Anal Chem 87:884–891CrossRefPubMed

Blank LM, Kuepfer L, Sauer U (2005) Large-scale 13C-flux analysis reveals mechanistic principles of metabolic network robustness to null mutations in yeast. Genome Biol 6:R49CrossRefPubMedPubMedCentral

Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917CrossRefPubMed

Bylesjö M, Rantalainen M, Cloarec O, Nicholson JK, Holmes E, Trygg J (2006) OPLS discriminant analysis: combining the strengths of PLS-DA and SIMCA classification. J Chemom 20:341–351CrossRef

Canelas AB, ten Pierick A, Ras C et al (2009) Quantitative evaluation of intracellular metabolite extraction techniques for yeast metabolomics. Anal Chem 81:7379–7389

Caspi R, Altman T, Billington R et al (2014) The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res 42:D459–D471CrossRefPubMed

Chapman AG, Miller AL, Atkinson DE (1976) Role of the adenylate deaminase reaction in regulation of adenine nucleotide metabolism in Ehrlich ascites tumor cells. Cancer Res 36:1144–1150PubMed

Chen S, Hoene M, Li J et al (2013) Simultaneous extraction of metabolome and lipidome with methyl tert-butyl ether from a single small tissue sample for ultra-high performance liquid chromatography/mass spectrometry. J Chromatogr A 1298:9–16CrossRefPubMed

Csató E, Fülöp N, Szabó G (1990) Preparation and comparison of a pentafluorophenyl stationary phase for reversed-phase liquid chromatography. J Chromatogr A 511:79–88CrossRef

Denery JR, Nunes AA, Dickerson TJ (2011) Characterization of differences between blood sample matrices in untargeted metabolomics. Anal Chem 83:1040–1047CrossRefPubMed

Dietmair S, Timmins NE, Gray PP, Nielsen LK, Kromer JO (2010) Towards quantitative metabolomics of mammalian cells: development of a metabolite extraction protocol. Anal Biochem 404:155–164CrossRefPubMed

Dietz C, Ehret F, Palmas F, et al (2017) Applications of high-resolution magic angle spinning MRS in biomedical studies II-human diseases. NMR Biomed 30:e3784

Dorn GW 2nd (2013) MicroRNAs and the butterfly effect. Cell cycle (Georgetown, Tex) 12:707–708CrossRef

Dudzik D, Barbas-Bernardos C, Garcia A, Barbas C (2017) Quality assurance procedures for mass spectrometry untargeted metabolomics. A review. J Pharma Biomed Anal 147:149-173

Dunn OJ (1961) Multiple Comparisons among Means. J Am Stat Assoc 56:52CrossRef

Dunn WB, Broadhurst D, Begley P et al (2011) Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc 6:1060–1083CrossRefPubMed

Fan TW, Lane AN (2016) Applications of NMR spectroscopy to systems biochemistry. Prog Nucl Magn Reson Spectrosc 92-93:18–53CrossRefPubMedPubMedCentral

Fan TW, Lane AN, Higashi RM et al (2009) Altered regulation of metabolic pathways in human lung cancer discerned by (13)C stable isotope-resolved metabolomics (SIRM). Mol Cancer 8:41CrossRefPubMedPubMedCentral

FDA (2001) Guidance for Industry: Bioanalytical Method Validation (Fda.Gov/cder/guidance/index.htm)

Fiehn O, Robertson D, Griffin J et al (2007) The metabolomics standards initiative (MSI). Metabolomics 3:175–178CrossRef

Fischer EH (2013) Cellular regulation by protein phosphorylation. Biochem Biophys Res Commun 430:865–867CrossRefPubMed

Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509PubMed

Fuhrer T, Heer D, Begemann B, Zamboni N (2011) High-throughput, accurate mass metabolome profiling of cellular extracts by flow injection-time-of-flight mass spectrometry. Anal Chem 83:7074–7080CrossRefPubMed

Genovese C, Wasserman L (2002) Operating characteristics and extensions of the false discovery rate procedure. J Roy Stat Soc B 64:499–517CrossRef

Gertsman I, Gangoiti J, Barshop B (2014) Validation of a dual LC–HRMS platform for clinical metabolic diagnosis in serum, bridging quantitative analysis and untargeted metabolomics. Metabolomics 10:312–323CrossRefPubMed

Gertsman I, Gangoiti JA, Nyhan WL, Barshop BA (2015) Perturbations of tyrosine metabolism promote the indolepyruvate pathway via tryptophan in host and microbiome. Mol Genet Metab 114:431–437CrossRefPubMed

Golland P, Fischl B (2003) Permutation tests for classification: towards statistical significance in image-based studies. Inf Process Med Imaging 18:330–341CrossRefPubMed

Guillarme D, Ruta J, Rudaz S, Veuthey JL (2010) New trends in fast and high-resolution liquid chromatography: a critical comparison of existing approaches. Anal Bioanal Chem 397:1069–1082CrossRefPubMed

Hill C, Drolet J, Kellogg MD, Tolstikov V, Narain NR, Kiebish MA (2017) Blood sampled through dried blood spots (DBS) exhibits diminished ex vivo metabolism compared to whole blood through use of a kinetic isotope-labeling metabolomics approach. Biochem Anal Biochem 6:325–330

Horai H, Arita M, Kanaya S et al (2010) MassBank: a public repository for sharing mass spectral data for life sciences. J Mass Spectrom 45:703–714CrossRefPubMed

Jandera P, Janas P (2017) Recent advances in stationary phases and understanding of retention in hydrophilic interaction chromatography. A review. Anal Chim Acta 967:12–32CrossRefPubMed

Jensen SK (2008) Improved Bligh and dyer extraction procedure. Lipid Technol 20:280–281CrossRef

Jolliffe IT, Cadima J (2016) Principal component analysis: a review and recent developments. Philos Trans A Math Phys Eng Sci 374:20150202CrossRefPubMedPubMedCentral

Kind T, Fiehn O (2007) Seven golden rules for heuristic filtering of molecular formulas obtained by accurate mass spectrometry. BMC Bioinformatics 8:105CrossRefPubMedPubMedCentral

Kolarovic L, Fournier NC (1986) A comparison of extraction methods for the isolation of phospholipids from biological sources. Anal Biochem 156:244–250CrossRefPubMed

Kouassi Nzoughet J, Bocca C, Simard G et al (2017) A nontargeted UHPLC-HRMS metabolomics pipeline for metabolite identification: application to cardiac remote ischemic preconditioning. Anal Chem 89:2138–2146

Koulman A, Prentice P, Wong MCY et al (2014) The development and validation of a fast and robust dried blood spot based lipid profiling method to study infant metabolism. Metabolomics 10:1018–1025CrossRefPubMedPubMedCentral

Kummel A, Panke S, Heinemann M (2006) Putative regulatory sites unraveled by network-embedded thermodynamic analysis of metabolome data. Mol Syst Biol 2:0034CrossRefPubMed

Leon Z, Garcia-Canaveras JC, Donato MT, Lahoz A (2013) Mammalian cell metabolomics: experimental design and sample preparation. Electrophoresis 34:2762–2775PubMed

Li L, Ren W, Kong H, et al (2017) An alignment algorithm for LC-MS-based metabolomics dataset assisted by MS/MS information. Analytica Chimica Acta 990:96-102

Lommen A (2009) MetAlign: interface-driven, versatile metabolomics tool for hyphenated full-scan mass spectrometry data preprocessing. Anal Chem 81:3079–3086CrossRefPubMed

Lorenz MA, Burant CF, Kennedy RT (2011) Reducing time and increasing sensitivity in sample preparation for adherent mammalian cell metabolomics. Anal Chem 83:3406–3414CrossRefPubMedPubMedCentral

Madalinski G, Godat E, Alves S et al (2008) Direct introduction of biological samples into a LTQ-Orbitrap hybrid mass spectrometer as a tool for fast metabolome analysis. Anal Chem 80:3291–3303CrossRefPubMed

Martano G, Delmotte N, Kiefer P et al (2015) Fast sampling method for mammalian cell metabolic analyses using liquid chromatography-mass spectrometry. Nat Protoc 10:1–11CrossRefPubMed

McCalley DV (2017) Understanding and manipulating the separation in hydrophilic interaction liquid chromatography-a review. J Chromatogr A 1523:49-71

McCloskey D, Gangoiti JA, King ZA et al (2014) A model-driven quantitative metabolomics analysis of aerobic and anaerobic metabolism in E. Coli K-12 MG1655 that is biochemically and thermodynamically consistent. Biotechnol Bioeng 111:803–815CrossRefPubMed

Metabolon (2017) Sample preparation and shipping guidelines.www.metabolon.com

Miller MJ, Kennedy AD, Eckhart AD et al (2015) Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism. J Inherit Metab Dis 38:1029–1039CrossRefPubMedPubMedCentral

Overmyer KA, Thonusin C, Qi NR, Burant CF, Evans CR (2015) Impact of anesthesia and euthanasia on metabolomics of mammalian tissues: studies in a C57BL/6J mouse model. PLoS One 10:e0117232CrossRefPubMedPubMedCentral

Perneger TV (1998) What's wrong with Bonferroni adjustments. Brit Med J 316:1236–1238CrossRefPubMedPubMedCentral

Reaves ML, Rabinowitz JD (2011) Metabolomics in systems microbiology. Curr Opin Biotechnol 22:17–25CrossRefPubMed

Righi V, Tugnoli V, Mucci A, Bacci A, Bonora S, Schenetti L (2012) MRS study of meningeal hemangiopericytoma and edema: a comparison with meningothelial meningioma. Oncol Rep 28:1461–1467CrossRefPubMed

Rojas-Cherto M, Peironcely JE, Kasper PT et al (2012) Metabolite identification using automated comparison of high-resolution multistage mass spectral trees. Anal Chem 84:5524–5534CrossRefPubMed

Rose HG, Oklander M (1965) Improved procedure for the extraction of lipids from human erythrocytes. J Lipid Res 6:428–431PubMed

Salek RM, Steinbeck C, Viant MR, Goodacre R, Dunn WB (2013) The role of reporting standards for metabolite annotation and identification in metabolomic studies. Gigascience 2:13CrossRefPubMedPubMedCentral

Salerno S Jr, Mehrmohamadi M, Liberti MV et al (2017) RRmix: a method for simultaneous batch effect correction and analysis of metabolomics data in the absence of internal standards. PLoS One 12:e0179530CrossRefPubMedPubMedCentral

Sellick CA, Hansen R, Stephens GM, Goodacre R, Dickson AJ (2011) Metabolite extraction from suspension-cultured mammalian cells for global metabolite profiling. Nat Protoc 6:1241–1249CrossRefPubMed

Shi H, Enriquez A, Rapadas M et al (2017) NAD deficiency, congenital malformations, and niacin supplementation. N Engl J Med 377:544–552CrossRefPubMed

Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100:9440–9445CrossRefPubMedPubMedCentral

Sud M, Fahy E, Cotter D et al (2016) Metabolomics workbench: an international repository for metabolomics data and metadata, metabolite standards, protocols, tutorials and training, and analysis tools. Nucleic Acids Res 44:D463–D470CrossRefPubMed

Sud M, Fahy E, Cotter D, Dennis EA, Subramaniam S (2012) LIPID MAPS-nature Lipidomics gateway: an online resource for students and educators interested in lipids. J Chem Educ 89:291–292CrossRefPubMed

Sumner LW, Amberg A, Barrett D et al (2007) Proposed minimum reporting standards for chemical analysis chemical analysis working group (CAWG) metabolomics standards initiative (MSI). Metabolomics 3:211–221

Sysi-Aho M, Katajamaa M, Yetukuri L, Oresic M (2007) Normalization method for metabolomics data using optimal selection of multiple internal standards. BMC Bioinformatics 8:93CrossRefPubMedPubMedCentral

Tautenhahn R, Cho K, Uritboonthai W, Zhu Z, Patti GJ, Siuzdak G (2012a) An accelerated workflow for untargeted metabolomics using the METLIN database. Nat Biotechnol 30:826–828CrossRefPubMedPubMedCentral

Tautenhahn R, Patti GJ, Rinehart D, Siuzdak G (2012b) XCMS online: a web-based platform to process untargeted metabolomic data. Anal Chem 84:5035–5039CrossRefPubMedPubMedCentral

Teng Q, Huang W, Collette TW, Ekman DR, Tan C (2009) A direct cell quenching method for cell-culture based metabolomics. Metabolomics 5:199–208CrossRef

Thonusin C, IglayReger HB, Soni T, Rothberg AE, Burant CF, Evans CR (2017) Evaluation of intensity drift correction strategies using MetaboDrift, a normalization tool for multi-batch metabolomics data. J Chromatogr A 1523:265-274

Tognarelli JM, Dawood M, Shariff MI et al (2015) Magnetic resonance spectroscopy: principles and techniques: lessons for clinicians. Journal of clinical and experimental hepatology 5:320–328CrossRefPubMedPubMedCentral

Trygg J, Wold S (2002) Orthogonal projections to latent structures (O-PLS). J Chemom 16:119–128CrossRef

Tugizimana F, Steenkamp PA, Piater LA, Dubery IA (2016) A conversation on sata mining strategies in LC-MS untargeted metabolomics: pre-processing and pre-treatment steps. Metabolites 6:40

Vaniya A, Fiehn O (2015) Using fragmentation trees and mass spectral trees for identifying unknown compounds in metabolomics. Trends Analyt Chem 69:52–61CrossRefPubMedPubMedCentral

Vuckovic D (2012) Current trends and challenges in sample preparation for global metabolomics using liquid chromatography-mass spectrometry. Anal Bioanal Chem 403:1523–1548CrossRefPubMed

Wang M, Carver JJ, Phelan VV et al (2016) Sharing and community curation of mass spectrometry data with global natural products social molecular networking. Nat Biotechnol 34:828–837CrossRefPubMedPubMedCentral

Wang Y, Xiao J, Suzek TO, Zhang J, Wang J, Bryant SH (2009) PubChem: a public information system for analyzing bioactivities of small molecules. Nucleic Acids Res 37:W623–W633CrossRefPubMedPubMedCentral

Want EJ, Cravatt BF, Siuzdak G (2005) The expanding role of mass spectrometry in metabolite profiling and characterization. Chembiochem: a European journal of chemical biology 6:1941–1951

Want EJ, Masson P, Michopoulos F et al (2013) Global metabolic profiling of animal and human tissues via UPLC-MS. Nat Protoc 8:17–32CrossRefPubMed

Want EJ, Nordstrom A, Morita H, Siuzdak G (2007) From exogenous to endogenous: the inevitable imprint of mass spectrometry in metabolomics. J Proteome Res 6:459–468CrossRefPubMed

Warrack BM, Hnatyshyn S, Ott KH et al (2009) Normalization strategies for metabonomic analysis of urine samples. J Chromatogr B Anal Technol Biomed Life Sci 877:547–552CrossRef

Watson DG (2013) A rough guide to metabolite identification using high resolution liquid chromatography mass spectrometry in metabolomic profiling in metazoans. Comput Struct Biotechnol J 4:e201301005CrossRefPubMedPubMedCentral

Wehrens R, Hageman JA, van Eeuwijk F et al (2016) Improved batch correction in untargeted MS-based metabolomics. Metabolomics 12:88CrossRefPubMedPubMedCentral

Westerhuis JA, Hoefsloot HCJ, Smit S et al (2008) Assessment of PLSDA cross validation. Metabolomics 4:81–89CrossRef

Wheelock AM, Wheelock CE (2013) Trials and tribulations of ‘omics data analysis: assessing quality of SIMCA-based multivariate models using examples from pulmonary medicine. Mol BioSyst 9:2589–2596CrossRefPubMed

Wikoff WR, Gangoiti JA, Barshop BA, Siuzdak G (2007) Metabolomics identifies perturbations in human disorders of propionate metabolism. Clin Chem 53:2169–2176CrossRefPubMed

Williams A, Tkachenko V (2014) The Royal Society of Chemistry and the delivery of chemistry data repositories for the community. J Comput Aided Mol Des 28:1023–1030CrossRefPubMed

Wishart DS, Knox C, Guo AC et al (2009) HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res 37:D603–D610CrossRefPubMed

Xia J, Wishart DS (2016) Using MetaboAnalyst 3.0 for comprehensive metabolomics data analysis. Curr Protoc Bioinformatics 55:14 10 11–14 10 91

Yanes O, Tautenhahn R, Patti GJ, Siuzdak G (2011) Expanding coverage of the metabolome for global metabolite profiling. Anal Chem 83:2152–2161CrossRefPubMedPubMedCentral

Yin P, Lehmann R, Xu G (2015) Effects of pre-analytical processes on blood samples used in metabolomics studies. Anal Bioanal Chem 407:4879–4892CrossRefPubMedPubMedCentral

Zhou J, Liu H, Liu Y, Liu J, Zhao X, Yin Y (2016) Development and evaluation of a parallel reaction monitoring strategy for large-scale targeted metabolomics quantification. Anal Chem 88:4478–4486

Titel: Promises and pitfalls of untargeted metabolomics
verfasst von: Ilya Gertsman
Bruce A. Barshop
Publikationsdatum: 13.03.2018
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 3/2018
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-017-0130-7

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