PAIRUP-MS: Pathway analysis and imputation to relate unknowns in profiles from mass spectrometry-based metabolite data
Year: 2019
Type: article
Abstract: Metabolomics is a powerful approach for discovering biomarkers and for characterizing the biochemical consequences of genetic variation. While untargeted metabolite profiling can measure thousands of signals in a single experiment, many biologically meaningful signals cannot be readily identified as known metabolites nor compared across datasets, making it difficult to infer biology and to conduct well-powered meta-analyses across studies. To overcome these challenges, we developed a suite of computational methods, PAIRUP-MS, to match metabolite signals across mass spectrometry-based profiling datasets and to generate metabolic pathway annotations for these signals. To pair up signals measured in different datasets, where retention times (RT) are often not comparable or even available, we implemented an imputation-based approach that only requires mass-to-charge ratios (m/z). As validation, we treated each shared known metabolite as an unmatched signal and showed that PAIRUP-MS correctly matched 70-88% of these metabolites from among thousands of signals, equaling or outperforming a standard m/z- and RT-based approach. We performed further validation using genetic data: the most stringent set of matched signals and shared knowns showed comparable consistency of genetic associations across datasets. Next, we developed a pathway reconstitution method to annotate unknown signals using curated metabolic pathways containing known metabolites. We performed genetic validation for the generated annotations, showing that annotated signals associated with gene variants were more likely to be enriched for pathways functionally related to the genes compared to random expectation. Finally, we applied PAIRUP-MS to study associations between metabolites and genetic variants or body mass index (BMI) across multiple datasets, identifying up to ~6 times more significant signals and many more BMI-associated pathways compared to the standard practice of only analyzing known metabolites. These results demonstrate that PAIRUP-MS enables analysis of unknown signals in a robust, biologically meaningful manner and provides a path to more comprehensive, well-powered studies of untargeted metabolomics data.
Source: PLoS Computational Biology
Institutions: Broad Institute, Boston Children's Hospital, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Massachusetts Institute of Technology, Statens Serum Institut, University of Copenhagen, Novo Nordisk Foundation, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Tartu, Instituto Nacional de Salud Pública
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,350
Funders: Doris Duke Charitable Foundation, European Commission, Eesti Teadusagentuur, Lundbeckfonden, Novo Nordisk Fonden, H. Lundbeck A/S, Horizon 2020, European Regional Development Fund, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Omics for health: an integrated approach to understand and predict human disease, G1888088267, G1953887145, G2975900969, G3527974372, G391091299, G434337789, G4579096045, G4898532384, G5316693180, G5567028926, Developing integrative methods to improve GWAS inference using epigenomic data, Harvard Training Program in Bioinformatics Applied to Diabetes, Obesity and Metabolism., G6318795230, G6766900198, Genetic and epidemiological predictors for all-cause and cause-specific mortality in the Estonian population., G6880312390, G753227631, Utilising special human populations to quantify the impact of rare DNA sequence variants in human health, G8337069619, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia, Biological Insights from Genetic Investigation of ANthropometric Traits (GIANT) Across the Allelic Spectrum, Training in Bioinformatics and Integrative Genomics, G959094345
OpenAlex ID: W2951026398