A Workflow for Missing Values Imputation of Untargeted Metabolomics Data

Metabolites, vol. 10, pp. 486

Abstract

Metabolomics studies have seen a steady growth due to the development and implementation of affordable and high-quality metabolomics platforms. In large metabolite panels, measurement values are frequently missing and, if neglected or sub-optimally imputed, can cause biased study results. We provided a publicly available, user-friendly R script to streamline the imputation of missing endogenous, unannotated, and xenobiotic metabolites. We evaluated the multivariate imputation by chained equations (MICE) and k-nearest neighbors (kNN) analyses implemented in our script by simulations using measured metabolites data from the Netherlands Epidemiology of Obesity (NEO) study (n = 599). We simulated missing values in four unique metabolites from different pathways with different correlation structures in three sample sizes (599, 150, 50) with three missing percentages (15%, 30%, 60%), and using two missing mechanisms (completely at random and not at random). Based on the simulations, we found that for MICE, larger sample size was the primary factor decreasing bias and error. For kNN, the primary factor reducing bias and error was the metabolite correlation with its predictor metabolites. MICE provided consistently higher performance measures particularly for larger datasets (n > 50). In conclusion, we presented an imputation workflow in a publicly available R script to impute untargeted metabolomics data. Our simulations provided insight into the effects of sample size, percentage missing, and correlation structure on the accuracy of the two imputation methods.

Authors 12

1. Tariq O. Faquih Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands

2. Maarten van Smeden

   Utrecht University · University Medical Center Utrecht

   Affiliation as printed

   Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, 8, 3584 Utrecht, The Netherlands

3. Jiao Min Luo Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands

4. Saskia le Cessie Aachen Department of Biomedical Data Sciences Section Medical Statistics and Bioinformatics Department of Clinical Epidemiology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Biomedical Data Sciences, Section Medical Statistics and Bioinformatics, Leiden University Medical Center, 2, 2333 Leiden, The Netherlands

   Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands

5. Gabi Kastenmüller

   Helmholtz Munich · Institute of Bioinformatics and Systems Biology

   Affiliation as printed

   Institute of Bioinformatics and Systems Biology, Helmholtz-Zentrum München, 85764 Neuherberg, Germany

   Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany

6. Jan Krumsiek

   Weill Cornell Medicine

   Affiliation as printed

   Department of Physiology, Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10065, USA

7. Raymond Noordam Aachen Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, 2333ZA Leiden, The Netherlands

8. Diana van Heemst Aachen Department of Internal Medicine Section of Gerontology and Geriatrics

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, 2333ZA Leiden, The Netherlands

9. Frits Richard Rosendaal Aachen Department of Clinical Epidemiology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands

10. Astrid van Hylckama Vlieg Aachen Department of Clinical Epidemiology

    Leiden University Medical Center

    Affiliation as printed

    Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands

11. Ko Willems van Dijk Aachen Department of Human Genetics Department of Internal Medicine Division of Endocrinology, Leiden University Medical Center Einthoven Laboratory for Experimental Vascular Medicine

    Leiden University · Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, 2, 2333 Leiden, The Netherlands

    Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, 2, 2333 Leiden, The Netherlands

    Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2, 2333 Leiden, The Netherlands

12. Dennis Owen Mook-Kanamori corresponding Aachen Department of Clinical Epidemiology Department of Public Health and Primary Care

    Leiden University Medical Center · Metabolon (United States)

    Affiliation as printed

    Department of Clinical Epidemiology, Leiden University Medical Center, Postal Zone C7-P, PO Box 9600, 2300 RC Leiden, The Netherlands

    Department of Public Health and Primary Care, Leiden University Medical Center, 2, 233 Leiden, The Netherlands

    Metabolon Inc., Morrisville, NC 27560, USA