Untargeted high-resolution paired mass distance data mining for retrieving general chemical relationships.

Untargeted metabolomics analysis captures chemical reactions among small molecules. Common mass spectrometry-based metabolomics workflows first identify the small molecules significantly associated with the outcome of interest, then begin exploring their biochemical relationships to understand biological fate or impact. We suggest an alternative by which general chemical relationships including abiotic reactions can be directly retrieved through untargeted high-resolution paired mass distance (PMD) analysis without a priori knowledge of the identities of participating compounds. PMDs calculated from the mass spectrometry data are linked to chemical reactions obtained via data mining of small molecule and reaction databases, i.e. 'PMD-based reactomics'. We demonstrate applications of PMD-based reactomics including PMD network analysis, source appointment of unknown compounds, and biomarker reaction discovery as complements to compound discovery analyses used in traditional untargeted workflows. An R implementation of reactomics analysis and the reaction/PMD databases is available as the pmd package.