Abstract

       Metabolomics is the scientific study of chemical processes involving metabolites. Metabolomics data provide unprecedented opportunities to decipher metabolic mechanisms by analyzing hundreds to thousands of metabolites. Data quality concerns and complex batch effects in metabolomics must be appropriately addressed through statistical analysis. This study developed an integrated analysis tool for metabolomics studies to streamline the complete analysis flow from initial data preprocessing to downstream association analysis. We developed Statistical Metabolomics Analysis – An R Tool (SMART), which can analyze input files with different formats, visually represent various types of data features, implement peak alignment and annotation, conduct quality control for replicate samples and peaks, explore batch effects, perform association analysis, and accomplish peak identification. A pharmacometabolomics study of antihypertensive medication was conducted and data were analyzed using SMART. Neuromedin N was identified as a metabolite significantly associated with angiotensin-converting-enzyme inhibitors in our metabolome-wide association analysis (p = 1.56 × 10−4 in an analysis of covariance (ANCOVA) with an adjustment for unknown latent groups and p = 1.02 × 10−4 in an ANCOVA with an adjustment for hidden substructures). This endogenous neuropeptide is highly related to neurotensin and neuromedin U, which are involved in blood pressure regulation and smooth muscle contraction. The SMART software, a user guide, and example data can be downloaded from http://www.stat.sinica.edu.tw/hsinchou/metabolomics/SMART.htm.