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Application of differential mobility-mass spectrometry for untargeted human plasma metabolomic analysis

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Abstract

Differential mobility spectrometry (DMS) has been gaining popularity in small molecule analysis over the last few years due to its selectivity towards a variety of isomeric compounds. While DMS has been utilized in targeted liquid chromatography-mass spectrometry (LC-MS), its use in untargeted discovery workflows has not been systematically explored. In this contribution, we propose a novel workflow for untargeted metabolomics based solely on DMS separation in a clinically relevant chronic kidney disease (CKD) patient population. We analyzed ten plasma samples from early- and late-stage CKD patients. Peak finding, alignment, and filtering steps performed on the DMS-MS data yielded a list of 881 metabolic features (unique mass-to-charge and migration time combinations). Differential analysis by CKD patient group revealed three main features of interest. One of them was putatively identified as bilirubin based on high-accuracy MS data and comparison of its optimum compensation voltage (COV) with that of an authentic standard. The DMS-MS analysis was four times faster than a typical HPLC-MS run, which suggests a potential for the utilization of this technique in screening studies. However, its lower separation efficiency and reduced signal intensity make it less suitable for low-abundant features. Fewer features were detected by the DMS-based platform compared with an HPLC-MS-based approach, but importantly, the two approaches resulted in different features. This indicates a high degree of orthogonality between HPLC- and DMS-based approaches and demonstrates the need for larger studies comparing the two techniques. The workflow described here can be adapted for other areas of metabolomics and has a value as a prescreening method to develop semi-targeted workflows and as a faster alternative to HPLC in large biomedical studies.

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Abbreviations

ACN:

Acetonitrile

BMI:

Body mass index

CKD:

Chronic kidney disease

COV:

Compensation voltage

CPROBE:

Clinical Phenotyping Resource and Biobank Core at the University of Michigan

cps:

Counts per second

DMS:

Differential mobility spectrometry

eGFR:

Estimated glomerular filtration rate

FC:

Fold change

FDR:

False discovery rate

FOI:

Feature of interest

HPLC:

High-performance liquid chromatography

iPrOH:

Isopropanol

MS:

Mass spectrometry

PCA:

Principal component analysis

PLS-DA:

Partial least squares-discriminant analysis

PP:

Pooled plasma

RP:

Reversed-phase

(R)SD:

(Relative) standard deviation

SV:

Separation voltage

TIC:

Total ion current

UPCR:

Urinary protein-to-creatinine ratio

VIP:

Variable importance in projection (PLS-DA)

XIC:

Extracted ion chromatogram

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Acknowledgements

The authors thank Dr. Farsad Afshinnia (University of Michigan) for helping in statistical data analysis and Dr. J. Larry Campbell (Sciex) for providing access to MarkerView software. We also appreciate the assistance of the Michigan Kidney Translational Core Clinical Phenotyping Resource and Biobank Core Investigator Group. It includes Matthias Kretzler and Debbie Gipson (University of Michigan, Ann Arbor), Keith Bellovich (St. Clair Nephrology Research, Detroit), Zeenat Bhat (Wayne State University, Detroit), Crystal Gadegbeku (Temple University Health System, Philadelphia), Susan Massengill (Levin Children’s Hospital, Charlotte), and Kalyani Perumal (JH Stroger Hospital, Chicago).

Funding

This work was supported by the Postdoctoral Translational Science Program from the Michigan Institute for Clinical and Health Research UL1TR000433 (to S.W.) and National Institutes of Health grants P30DK089503, DK082841, P30DK081943, U2C ES026553, and DK097153 (to S.P.).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, MI, 48105, USA

    Stefanie Wernisch & Subramaniam Pennathur

  2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48105, USA

    Subramaniam Pennathur

Authors
  1. Stefanie Wernisch
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  2. Subramaniam Pennathur
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Correspondence to Subramaniam Pennathur.

Ethics declarations

All human studies were approved by the Institutional Review Board (IRB) for the University of Michigan and the CPROBE ancillary studies committee.

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The authors declare that they have no conflicts of interest.

Additional information

Published in the topical collection Close-Up of Current Developments in Ion Mobility Spectrometry with guest editor Gérard Hopfgartner.

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Wernisch, S., Pennathur, S. Application of differential mobility-mass spectrometry for untargeted human plasma metabolomic analysis. Anal Bioanal Chem 411, 6297–6308 (2019). https://doi.org/10.1007/s00216-019-01719-z

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