title: Discriminating precursors of common fragments for large-scale metabolite profiling by triple quadrupole mass spectrometry.
abstract: BACKGROUND
  The goal of large-scale metabolite profiling is to compare the relative concentrations of as many metabolites extracted from biological samples as possible. This is typically accomplished by measuring the abundances of thousands of ions with high-resolution and high mass accuracy mass spectrometers. Although the data from these instruments provide a comprehensive fingerprint of each sample, identifying the structures of the thousands of detected ions is still challenging and time intensive. An alternative, less-comprehensive approach is to use triple quadrupole (QqQ) mass spectrometry to analyze predetermined sets of metabolites (typically fewer than several hundred). This is done using authentic standards to develop QqQ experiments that specifically detect only the targeted metabolites, with the advantage that the need for ion identification after profiling is eliminated.
  
  
  RESULTS
  Here, we propose a framework to extend the application of QqQ mass spectrometers to large-scale metabolite profiling. We aim to provide a foundation for designing QqQ multiple reaction monitoring (MRM) experiments for each of the 82 696 metabolites in the METLIN metabolite database. First, we identify common fragmentation products from the experimental fragmentation data in METLIN. Then, we model the likelihoods of each precursor structure in METLIN producing each common fragmentation product. With these likelihood estimates, we select ensembles of common fragmentation products that minimize our uncertainty about metabolite identities. We demonstrate encouraging performance and, based on our results, we suggest how our method can be integrated with future work to develop large-scale MRM experiments.
  
  
  METHODS
  Our predictions, Supplementary results, and the code for estimating likelihoods and selecting ensembles of fragmentation reactions are made available on the lab website at http://pattilab.wustl.edu/FragPred.
authors.affiliation: Department of Genetics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA, Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Nikolskiy
authors.affiliation: Department of Genetics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA, Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
authors.affiliation: Department of Genetics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA, Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry, Washington University, St. Louis, MO 63130, USA Department of Genetics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA, Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry, Washington University, St. Louis, MO 63130, USA Department of Genetics, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA, Scripps Center for Metabolomics and Mass Spectrometry, Departments of Chemistry, Molecular and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA and Department of Chemistry, Washington University, St. Louis, MO 63130, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Patti
mesh_terms: D016208:Databases, Factual; D006801:Humans; D016013:Likelihood Functions; D013058:Mass Spectrometry / Q000379:methods*; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods*