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Null diffusion-based enrichment for metabolomics data.

ABSTRACT: Metabolomics experiments identify metabolites whose abundance varies as the conditions under study change. Pathway enrichment tools help in the identification of key metabolic processes and in building a plausible biological explanation for these variations. Although several methods are available for pathway enrichment using experimental evidence, metabolomics does not yet have a comprehensive overview in a network layout at multiple molecular levels. We propose a novel pathway enrichment procedure for analysing summary metabolomics data based on sub-network analysis in a graph representation of a reference database. Relevant entries are extracted from the database according to statistical measures over a null diffusive process that accounts for network topology and pathway crosstalk. Entries are reported as a sub-pathway network, including not only pathways, but also modules, enzymes, reactions and possibly other compound candidates for further analyses. This provides a richer biological context, suitable for generating new study hypotheses and potential enzymatic targets. Using this method, we report results from cells depleted for an uncharacterised mitochondrial gene using GC and LC-MS data and employing KEGG as a knowledge base. Partial validation is provided with NMR-based tracking of 13C glucose labelling of these cells.

SUBMITTER: Picart-Armada S

PROVIDER: S-EPMC5718512 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Null diffusion-based enrichment for metabolomics data.

Picart-Armada Sergio S Fernández-Albert Francesc F Vinaixa Maria M Rodríguez Miguel A MA Aivio Suvi S Stracker Travis H TH Yanes Oscar O Perera-Lluna Alexandre A

PloS one 20171206 12

Metabolomics experiments identify metabolites whose abundance varies as the conditions under study change. Pathway enrichment tools help in the identification of key metabolic processes and in building a plausible biological explanation for these variations. Although several methods are available for pathway enrichment using experimental evidence, metabolomics does not yet have a comprehensive overview in a network layout at multiple molecular levels. We propose a novel pathway enrichment proced ...[more]

PMID: 29211807

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Project description:BackgroundBioinformatic tools for the enrichment of 'omics' datasets facilitate interpretation and understanding of data. To date few are suitable for metabolomics datasets. The main objective of this work is to give a critical overview, for the first time, of the performance of these tools. To that aim, datasets from metabolomic repositories were selected and enriched data were created. Both types of data were analysed with these tools and outputs were thoroughly examined.ResultsAn exploratory multivariate analysis of the most used tools for the enrichment of metabolite sets, based on a non-metric multidimensional scaling (NMDS) of Jaccard's distances, was performed and mirrored their diversity. Codes (identifiers) of the metabolites of the datasets were searched in different metabolite databases (HMDB, KEGG, PubChem, ChEBI, BioCyc/HumanCyc, LipidMAPS, ChemSpider, METLIN and Recon2). The databases that presented more identifiers of the metabolites of the dataset were PubChem, followed by METLIN and ChEBI. However, these databases had duplicated entries and might present false positives. The performance of over-representation analysis (ORA) tools, including BioCyc/HumanCyc, ConsensusPathDB, IMPaLA, MBRole, MetaboAnalyst, Metabox, MetExplore, MPEA, PathVisio and Reactome and the mapping tool KEGGREST, was examined. Results were mostly consistent among tools and between real and enriched data despite the variability of the tools. Nevertheless, a few controversial results such as differences in the total number of metabolites were also found. Disease-based enrichment analyses were also assessed, but they were not found to be accurate probably due to the fact that metabolite disease sets are not up-to-date and the difficulty of predicting diseases from a list of metabolites.ConclusionsWe have extensively reviewed the state-of-the-art of the available range of tools for metabolomic datasets, the completeness of metabolite databases, the performance of ORA methods and disease-based analyses. Despite the variability of the tools, they provided consistent results independent of their analytic approach. However, more work on the completeness of metabolite and pathway databases is required, which strongly affects the accuracy of enrichment analyses. Improvements will be translated into more accurate and global insights of the metabolome.

Project description:BackgroundAssessing the reproducibility of measurements is an important first step for improving the reliability of downstream analyses of high-throughput metabolomics experiments. We define a metabolite to be reproducible when it demonstrates consistency across replicate experiments. Similarly, metabolites which are not consistent across replicates can be labeled as irreproducible. In this work, we introduce and evaluate the use (Ma)ximum (R)ank (R)eproducibility (MaRR) to examine reproducibility in mass spectrometry-based metabolomics experiments. We examine reproducibility across technical or biological samples in three different mass spectrometry metabolomics (MS-Metabolomics) data sets.ResultsWe apply MaRR, a nonparametric approach that detects the change from reproducible to irreproducible signals using a maximal rank statistic. The advantage of using MaRR over model-based methods that it does not make parametric assumptions on the underlying distributions or dependence structures of reproducible metabolites. Using three MS Metabolomics data sets generated in the multi-center Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPD) study, we applied the MaRR procedure after data processing to explore reproducibility across technical or biological samples. Under realistic settings of MS-Metabolomics data, the MaRR procedure effectively controls the False Discovery Rate (FDR) when there was a gradual reduction in correlation between replicate pairs for less highly ranked signals. Simulation studies also show that the MaRR procedure tends to have high power for detecting reproducible metabolites in most situations except for smaller values of proportion of reproducible metabolites. Bias (i.e., the difference between the estimated and the true value of reproducible signal proportions) values for simulations are also close to zero. The results reported from the real data show a higher level of reproducibility for technical replicates compared to biological replicates across all the three different datasets. In summary, we demonstrate that the MaRR procedure application can be adapted to various experimental designs, and that the nonparametric approach performs consistently well.ConclusionsThis research was motivated by reproducibility, which has proven to be a major obstacle in the use of genomic findings to advance clinical practice. In this paper, we developed a data-driven approach to assess the reproducibility of MS-Metabolomics data sets. The methods described in this paper are implemented in the open-source R package marr, which is freely available from Bioconductor at http://bioconductor.org/packages/marr .

Project description:Membranous glomerulonephritis (MGN) is one of the most frequent causes of nephrotic syndrome in adults. It is characterized by the thickening of the glomerular basement membrane in the renal tissue. The current diagnosis of MGN is based on renal biopsy and the detection of antibodies to the few podocyte antigens. Due to the limitations of the current diagnostic methods, including invasiveness and the lack of sensitivity of the current biomarkers, there is a requirement to identify more applicable biomarkers. The present study aimed to identify diagnostic metabolites that are involved in the development of the disease using topological features in the component‑reaction‑enzyme‑gene (CREG) network for MGN. Significant differential metabolites in MGN compared with healthy controls were identified using proton nuclear magnetic resonance and gas chromatography‑mass spectrometry techniques, and multivariate analysis. The CREG network for MGN was constructed, and metabolites with a high centrality and a striking fold‑change in patients, compared with healthy controls, were introduced as putative diagnostic biomarkers. In addition, a protein‑protein interaction (PPI) network, which was based on proteins associated with MGN, was built and analyzed using PPI analysis methods, including molecular complex detection and ClueGene Ontology. A total of 26 metabolites were identified as hub nodes in the CREG network, 13 of which had salient centrality and fold‑changes: Dopamine, carnosine, fumarate, nicotinamide D‑ribonucleotide, adenosine monophosphate, pyridoxal, deoxyguanosine triphosphate, L‑citrulline, nicotinamide, phenylalanine, deoxyuridine, tryptamine and succinate. A total of 13 subnetworks were identified using PPI analysis. In total, two of the clusters contained seed proteins (phenylalanine‑4‑hydroxlylase and cystathionine γ‑lyase) that were associated with MGN based on the CREG network. The following biological processes associated with MGN were identified using gene ontology analysis: 'Pyrimidine‑containing compound biosynthetic process', 'purine ribonucleoside metabolic process', 'nucleoside catabolic process', 'ribonucleoside metabolic process' and 'aromatic amino acid family metabolic process'. The results of the present study may be helpful in the diagnostic and therapeutic procedures of MGN. However, validation is required in the future.

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Null diffusion-based enrichment for metabolomics data.

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Null diffusion-based enrichment for metabolomics data.

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