title: Integrated Analytical and Statistical Two-Dimensional Spectroscopy Strategy for Metabolite Identification: Application to Dietary Biomarkers.
abstract: A major purpose of exploratory metabolic profiling is for the identification of molecular species that are statistically associated with specific biological or medical outcomes; unfortunately, the structure elucidation process of unknowns is often a major bottleneck in this process. We present here new holistic strategies that combine different statistical spectroscopic and analytical techniques to improve and simplify the process of metabolite identification. We exemplify these strategies using study data collected as part of a dietary intervention to improve health and which elicits a relatively subtle suite of changes from complex molecular profiles. We identify three new dietary biomarkers related to the consumption of peas (N-methyl nicotinic acid), apples (rhamnitol), and onions (N-acetyl-S-(1Z)-propenyl-cysteine-sulfoxide) that can be used to enhance dietary assessment and assess adherence to diet. As part of the strategy, we introduce a new probabilistic statistical spectroscopy tool, RED-STORM (Resolution EnhanceD SubseT Optimization by Reference Matching), that uses 2D J-resolved1H NMR spectra for enhanced information recovery using the Bayesian paradigm to extract a subset of spectra with similar spectral signatures to a reference. RED-STORM provided new information for subsequent experiments (e.g., 2D-NMR spectroscopy, solid-phase extraction, liquid chromatography prefaced mass spectrometry) used to ultimately identify an unknown compound. In summary, we illustrate the benefit of acquiring J-resolved experiments alongside conventional 1D1H NMR as part of routine metabolic profiling in large data sets and show that application of complementary statistical and analytical techniques for the identification of unknown metabolites can be used to save valuable time and resources.
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.
authors.forename: Joram M
authors.identifier: 0000-0002-4971-9003
authors.initials: JM
authors.lastname: Posma
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.|Nutrition and Dietetic Research Group, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Hammersmith Campus, Imperial College London , London W12 ONN, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Garcia-Perez
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.
authors.forename: James C
authors.initials: JC
authors.lastname: Heaton
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.
authors.forename: Paula
authors.initials: P
authors.lastname: Burdisso
authors.affiliation: Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle University , Newcastle upon Tyne NE4 5PL, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.affiliation: Institute of Biological, Environmental and Rural Sciences, Aberystwyth University , Aberystwyth SY23 3DA, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Draper
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.|MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Faculty of Medicine, Hammersmith Campus, Imperial College London , London W12 0NN, United Kingdom.
authors.forename: Matt
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.affiliation: Nutrition and Dietetic Research Group, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Hammersmith Campus, Imperial College London , London W12 ONN, United Kingdom.
authors.forename: Gary
authors.initials: G
authors.lastname: Frost
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.|MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Faculty of Medicine, Hammersmith Campus, Imperial College London , London W12 0NN, United Kingdom.
authors.forename: Elaine
authors.identifier: 0000-0002-0556-8389
authors.initials: E
authors.lastname: Holmes
authors.affiliation: Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, South Kensington Campus, Imperial College London , London SW7 2AZ, United Kingdom.|MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Faculty of Medicine, Hammersmith Campus, Imperial College London , London W12 0NN, United Kingdom.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D027845:Malus / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000032:analysis* / Q000378:metabolism; D019697:Onions / Q000737:chemistry / Q000378:metabolism*; D018532:Pisum sativum / Q000737:chemistry / Q000378:metabolism*; D012210:Rhamnose / Q000031:analogs & derivatives / Q000032:analysis* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D009539:Nicotinic Acids; D012210:Rhamnose