Breath analysis by two-dimensional gas chromatography with dual flame ionisation and mass spectrometric detection – Method optimisation and integration within a large-scale clinical study

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Highlights

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New method for the analysis of exhaled breath VOCs by TD-GC × GC-FID/qMS.
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Optimisation of flow modulation and dual detection alongside clinical requirements.
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Addresses key challenges of using GC × GC for large-scale breath metabolomics.

Abstract

Precision medicine has spurred new innovations in molecular pathology leading to recent advances in the analysis of exhaled breath as a non-invasive diagnostic tool. Volatile organic compounds (VOCs) detected in exhaled breath have the potential to reveal a wealth of chemical and metabolomic information. This study describes the development of a method for the analysis of breath, based on automated thermal desorption (TD) combined with flow modulated comprehensive two-dimensional gas chromatography (GC×GC) with dual flame ionisation and quadrupole mass spectrometric detection (FID and qMS). The constrained optimisation and analytical protocol was designed to meet the practical demands of a large-scale multi-site clinical study, while maintaining analytical rigour to produce high fidelity data. The results demonstrate a comprehensive method optimisation for the collection and analysis of breath VOCs by GC×GC, integral to the standardisation and integration of breath analysis within large clinical studies.

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Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

Matej Orešič, Satu Simell, Marko Sysi-Aho … (2008)

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward β cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.

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Breath gas aldehydes as biomarkers of lung cancer.

Wolfram Miekisch, Jochen K. Schubert, Patricia Fuchs … (2010)

There is experimental evidence that volatile substances in human breath can reflect presence of neoplasma. Volatile aldehydes were determined in exhaled breath of 12 lung cancer patients, 12 smokers and 12 healthy volunteers. Alveolar breath samples were collected under control of expired CO(2). Reactive aldehydes were transformed into stable oximes by means of on-fiber-derivatization (SPME-OFD). Aldehyde concentrations in the ppt and ppb level were determined by means of gas chromatography-mass spectrometry (GC-MS). Exhaled concentrations were corrected for inspired values. Exhaled C(1)-C(10) aldehydes could be detected in all healthy volunteers, smokers and lung cancer patients. Concentrations ranged from 7 pmol/l (161 pptV) for butanal to 71 nmol/l (1,582 ppbV) for formaldehyde. Highest inspired concentrations were found for formaldehyde and acetaldehyde (0-55 nmol/l and 0-13 nmol/l, respectively). Acetaldehyde, propanal, butanal, heptanal and decanal concentrations showed no significant differences for cancer patients, smokers and healthy volunteers. Exhaled pentanal, hexanal, octanal and nonanal concentrations were significantly higher in lung cancer patients than in smokers and healthy controls (p(pentanal) = 0.001; p(hexanal) = 0.006; p(octanal) = 0.014; p(nonanal) = 0.025). Sensitivity and specificity of this method were comparable to the diagnostic certitude of conventional serum markers and CT imaging. Lung cancer patients could be identified by means of exhaled pentanal, hexanal, octanal and nonanal concentrations. Exhaled aldehydes reflect aspects of oxidative stress and tumor-specific tissue composition and metabolism. Noninvasive recognition of lung malignancies may be realized if analytical skills, biochemical knowledge and medical expertise are combined into a joint effort.

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Mitochondrial energy metabolism and ageing.

Ivana Bratic, Aleksandra Trifunovic (2010)

Ageing can be defined as "a progressive, generalized impairment of function, resulting in an increased vulnerability to environmental challenge and a growing risk of disease and death". Ageing is likely a multifactorial process caused by accumulated damage to a variety of cellular components. During the last 20 years, gerontological studies have revealed different molecular pathways involved in the ageing process and pointed out mitochondria as one of the key regulators of longevity. Increasing age in mammals correlates with increased levels of mitochondrial DNA (mtDNA) mutations and a deteriorating respiratory chain function. Experimental evidence in the mouse has linked increased levels of somatic mtDNA mutations to a variety of ageing phenotypes, such as osteoporosis, hair loss, graying of the hair, weight reduction and decreased fertility. A mosaic respiratory chain deficiency in a subset of cells in various tissues, such as heart, skeletal muscle, colonic crypts and neurons, is typically found in aged humans. It has been known for a long time that respiratory chain-deficient cells are more prone to undergo apoptosis and an increased cell loss is therefore likely of importance in the age-associated mitochondrial dysfunction. In this review, we would like to point out the link between the mitochondrial energy balance and ageing, as well as a possible connection between the mitochondrial metabolism and molecular pathways important for the lifespan extension. Copyright © 2010 Elsevier B.V. All rights reserved.

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Author and article information

Contributors

Paul S. Monks

Journal

Journal ID (nlm-ta): J Chromatogr A

Journal ID (iso-abbrev): J Chromatogr A

Title: Journal of Chromatography. a

Publisher: Elsevier

ISSN (Print): 0021-9673

ISSN (Electronic): 1873-3778

Publication date PMC-release: 07 June 2019

Publication date (Print): 07 June 2019

Volume: 1594

Pages: 160-172

Affiliations

[a ]Department of Chemistry, University of Leicester, University Road, Leicester, LE1 7RH, UK

[b ]Centre of Analytical Science, Loughborough University, Epinal Way, Loughborough, LE11 3TU, UK

[c ]Leicester NIHR Biomedical Research Centre (Respiratory theme), Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK

[d ]College of Life Sciences, Department of Infection, Immunity and Inflammation, University of Leicester, University Road, Leicester, LE1 7RH, UK

[e ]Paediatric Clinical Investigation Centre, Leicester NIHR Biomedical Research Centre (Respiratory theme), University of Leicester, Leicester Royal Infirmary, Leicester, LE2 7LX, UK

Author notes

[* ]Corresponding author. paul.monks@ 123456leicester.ac.uk

Article

Publisher ID: S0021-9673(19)30131-1

DOI: 10.1016/j.chroma.2019.02.001

PMC ID: 6491496

PubMed ID: 30755317

SO-VID: b07b1102-4e65-4a23-9b6b-6f07e766b7a7

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 13 September 2018

Date revision received : 24 December 2018

Date accepted : 1 February 2019

Breath analysis by two-dimensional gas chromatography with dual flame ionisation and mass spectrometric detection – Method optimisation and integration within a large-scale clinical study

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Most cited references 38

Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

Breath gas aldehydes as biomarkers of lung cancer.

Mitochondrial energy metabolism and ageing.

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