Scientists have developed Met4DX, a four-dimensional metabolomics precision analysis technology

Zhu Zhengjiang’s research group, a researcher at the Interdisciplinary Research Center for Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, published a research paper entitled A mass spectrum-oriented computational method for ion mobility-resolved untargeted metabolomics online in Nature Communications. This work developed an end-to-end accurate data analysis technology Met4DX for four-dimensional metabolomics technology based on ion mobility mass spectrometry, which is used for four-dimensional peak detection, peak alignment and peak quantification of four-dimensional metabolomics data, and combines four-dimensional database to achieve four-dimensional accurate matching and identification of metabolites (Figure 1).

Figure 1.Met4DX, a four-dimensional metabolomics precision data analysis technology

Compared with traditional mass spectrometry, ion mobility mass spectrometry increases the ion mobility according to ion size, shape and charge, effectively improves the separation ability of mass spectrometry, especially the resolution ability of metabolite isomers, and its combination with liquid chromatography to form a multi-dimensional separation analysis technology can further improve the resolution and peak capacity of complex biological sample analysis. A four-dimensional metabolomic analysis can simultaneously characterize metabolite ions in four dimensions, including precise mass (MS1), secondary mass spectrometry (MS/MS), chromatographic retention time (RT), and ion mobility collision cross-sectional area (CCS), which can effectively improve the coverage and accuracy of qualitative and quantitative analysis of metabolites in complex biological samples. However, the high complexity of four-dimensional metabolome data poses challenges to the efficient and accurate analysis of data, especially the detection of four-dimensional mass spectral peaks. Therefore, four-dimensional metabolome data analysis techniques and tools are relatively limited. At present, a small number of tools, such as MS-DIAL and MZmine, use the dimensionality reduction strategy of top-down compressed data for peak detection. This dimensionality reduction strategy can reduce the dimensionality and complexity of the data, but the dimensionality reduction process inevitably introduces signal masking and interference, which significantly reduces the sensitivity of four-dimensional peak detection.

Liquid chromatography-ion mobility-mass spectrometry achieves multidimensional separation of metabolites from the dimensions of liquid phase, ion mobility and mass spectrometry, and the time required is gradually reduced. Inspired by this separation method, a mass spectrum oriented bottom-up assembly algorithm was developed for the detection of four-dimensional peaks in four-dimensional metabolomics data (Figure 2). This technique features each mass spectrum as the smallest data unit in four-dimensional data, using a reverse engineering strategy to construct its peak shape sequentially on ion mobility and liquid chromatography. Specifically, for each mass spectrum, the algorithm will perform five steps: search for precursor ions, assembly and detection of ion mobility outflow peaks, expansion of ion mobility outflow peaks, assembly and detection of chromatographic outflow peaks, and four-dimensional peak integration to achieve four-dimensional metabolic peak detection and peak quantification. The bottom-up peak assembly algorithm developed in this work avoids data compression and dimensionality reduction, and effectively improves the coverage and sensitivity of four-dimensional peak detection. With the above algorithm as the core, the researchers further developed Met4DX, an end-to-end accurate data analysis technology suitable for four-dimensional metabolomics, and achieved accurate qualitative and accurate quantitative analysis of four-dimensional complex metabolomes through the two-stage spectrum deredundancy module, bottom-up peak assembly module, four-dimensional peak alignment and grouping module, and multi-dimensional matching and identification module of metabolites.

Figure 2: Bottom-up peak assembly algorithm and Met4DX data analysis process (image adapted from Nature Communication)

Met4DX technology enables high-coverage four-dimensional mass peak detection with high quantitative precision. Compared to comparable technologies such as MS-DIAL and MetaboScape, Met4DX can improve the coverage of 4D peak detection by 2-3 times and increase the number of accurately quantified metabolites by 2-5 times. Met4DX has excellent performance in metabolite isomer recognition. Taking the mouse liver metabolome as an example, Met4DX accurately identified 3033 pairs of metabolite isomers, which was significantly 3.6 times higher than similar technologies, and could accurately identify coeluting isomers with CCS differences of 1%. At the same time, the study also collected more than 130,000 metabolites in HMDB and KEGG, and established the most comprehensive four-dimensional metabolite database for multi-dimensional matching and identification of metabolites.

Currently, Met4DX supports 4D metabolomics data acquired by instrument platforms including Bruker timsTOF and Agilent DTIM-MS. In order to facilitate the application of this tool in related fields, the research group provides docker for academic users to use Met4DX ( for free. The four-dimensional metabolomics precision analysis technology M4dx-ret4DX developed by this work has applied for national invention patents and national software copyrights. The research work has been supported by the National Natural Science Foundation of China, the Ministry of Science and Technology, the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Commission. (Source: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences)

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