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PLoS Comput Biol. 2019 Jan 14;15(1):e1006734. doi: 10.1371/journal.pcbi.1006734. eCollection 2019 Jan.

PAIRUP-MS: Pathway analysis and imputation to relate unknowns in profiles from mass spectrometry-based metabolite data.

Author information

Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, United States of America.
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
Analytical and Translational Genomics Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia.
BioAge Labs, Richmond, CA, United States of America.
Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico.
Centro de Estudios en Diabetes, Mexico City, Mexico.


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.

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