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Untargeted metabolomics of childhood asthma exacerbations from retrospectively collected serum samples

Mendez, Kevin Milton (2017) Untargeted metabolomics of childhood asthma exacerbations from retrospectively collected serum samples. Honours thesis, Murdoch University.

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Embargoed until January 2020.

Abstract

Asthma is a common chronic inflammatory disease of the airways, affecting 360 million people globally. It is characterised by chronic inflammation, recurrent episodes of bronchoconstriction and mucosal hypersecretion. Symptoms include chest tightness, shortness of breath, coughing and wheezing. Oral corticosteroids used for the treatment of asthma have adverse effects, including bone mineralisation and adrenal suppression. Not all children with acute asthma-like symptoms will have persistent asthma in the future. This is particularly common at a pre-school age. This persistence is only known retrospectively. Identifying children early in their disease course can better direct treatment. Additionally, further understanding of the underlying disease mechanisms can direct novel therapies.

Metabolomics is the systematic study of metabolites in a biological system. Metabolites are low molecular weight biochemical that are reactants, intermediates and end products of biological reactions. They are highly sensitive and are a snapshot of a particular biochemistry and/or pathophysiology. However, they are also highly sensitive to analytical variation. Thus, there were three aims in this study: to assess the impact of potentially limiting factors of retrospectively collected serum samples on metabolomic analysis; to determine whether metabolomics can identify potential biomarkers to distinguish wheeze/asthma exacerbation and control groups; and to determine whether metabolomics-derived biomarkers can identify differences between preschool-aged and school-aged phenotypes.

Serum samples were curated from the Mechanisms of Acute Viral Respiratory Infections in Children (MAVRIC) study. This cohort study recruited children upon presentation to the emergency department at Princess Margaret Hospital with acute lower respiratory illnesses including wheeze/asthma. One–hundred and sixty-one samples were from children with acute wheeze/asthma, and 51 were from healthy controls. Samples were previously stored between 0.8 to 7.9 years at −80 °C. Samples were extracted, derivatised and subsequently analysed using GC-QTOF-MS. SpectralWorks’ AnalyzerPro® was used for the deconvolution and untargeted processing of the metabolite data. The quality control-robust spline correction (QC-RSC) algorithm was used for inter- and intra- batch correction. Putative identification of metabolites was made using the NIST (v2.0) library.

Fifty-two metabolites were included in the data analysis, with 24 putatively identified metabolites. The effects of storage time on metabolites were determined via Spearman’s correlation. There was a significant difference (p-value < 0.05) in metabolite abundances for succinate, serine and tryptophan; however, the correlation was weak. A two-way Analysis of Variance was performed to compare acute wheeze/asthma vs. healthy, pre-school vs. school age and the associated interactions. Twenty-nine metabolites were found to be significantly different (p-value < 0.05) between the acute wheeze/asthma and the control group. The sub-classes of metabolites include amino acids, fatty acids and sugars. Principal Component Analysis showed a difference in spread between the acute wheeze/asthma and control group. However, there was no clear difference between preschool and school-aged brackets for each group. Arabinofuranose and creatinine were significantly different (p-value < 0.05) between pre-school and school-aged subjects with acute wheeze/asthma. Creatinine is potentially being indicative of higher ASM stress and damage in the school-aged subjects with acute wheeze/asthma.

Publication Type: Thesis (Honours)
Murdoch Affiliation: School of Veterinary and Life Sciences
UNSD Goals: Goal 3: Good Health and Well-being
Supervisor: Reinke, Stacey, Abbiss, Hayley, Laing, Ingrid and Trengrove, Robert
URI: http://researchrepository.murdoch.edu.au/id/eprint/40063
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