Journal
METABOLOMICS
Volume 14, Issue 10, Pages -Publisher
SPRINGER
DOI: 10.1007/s11306-018-1420-2
Keywords
Untargeted metabolomics; Missing values imputation; Limit of detection; Batch effects; MICE; K-nearest neighbor; Mass spectrometry
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Funding
- German Federal Ministry of Education and Research (BMBF)
- BMBF [01ZX1313C, 03IS2061B]
- European Union's Seventh Framework Programme [FP7-Health-F5-2012] [305280]
- European Research Council (starting grant LatentCauses)
- Biomedical Research Program funds at Weill Cornell Medical College in Qatar
- Qatar Foundation
- Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
- Medical Research Council [MC_PC_13048, MC_UU_12015/1]
- MRC [MC_UU_12015/1] Funding Source: UKRI
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BackgroundUntargeted mass spectrometry (MS)-based metabolomics data often contain missing values that reduce statistical power and can introduce bias in biomedical studies. However, a systematic assessment of the various sources of missing values and strategies to handle these data has received little attention. Missing data can occur systematically, e.g. from run day-dependent effects due to limits of detection (LOD); or it can be random as, for instance, a consequence of sample preparation.MethodsWe investigated patterns of missing data in an MS-based metabolomics experiment of serum samples from the German KORA F4 cohort (n=1750). We then evaluated 31 imputation methods in a simulation framework and biologically validated the results by applying all imputation approaches to real metabolomics data. We examined the ability of each method to reconstruct biochemical pathways from data-driven correlation networks, and the ability of the method to increase statistical power while preserving the strength of established metabolic quantitative trait loci.ResultsRun day-dependent LOD-based missing data accounts for most missing values in the metabolomics dataset. Although multiple imputation by chained equations performed well in many scenarios, it is computationally and statistically challenging. K-nearest neighbors (KNN) imputation on observations with variable pre-selection showed robust performance across all evaluation schemes and is computationally more tractable.ConclusionMissing data in untargeted MS-based metabolomics data occur for various reasons. Based on our results, we recommend that KNN-based imputation is performed on observations with variable pre-selection since it showed robust results in all evaluation schemes.
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