Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy

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dc.contributor.advisor Murray, Deirdre M. en
dc.contributor.advisor Boylan, Geraldine B. en
dc.contributor.advisor Kirwan, Jennifer A. en Denihan, Niamh Marie 2016-08-30T11:15:14Z 2016 2016
dc.identifier.citation Denihan, N. M. 2016. Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy. PhD Thesis, University College Cork. en
dc.identifier.endpage 311 en
dc.description.abstract Background An early objective biomarker to predict the severity of hypoxic-ischaemic encephalopathy (HIE) and identify infants suitable for intervention remains elusive. This thesis aims to progress metabolomic markers of HIE through a pipeline of biomarker discovery and validation by employing a novel untargeted mass spectrometry metabolomic method. Methodology Term infants with perinatal asphyxia were recruited, all having umbilical cord blood (UCB) drawn and biobanked within three hours of birth. HIE was defined by Sarnat score at 24hours and continuous multichannel-EEG. Infant neurodevelopment was assessed at 36-42 months using the Bayley Scales of Infant and Toddler Development Ed. III (BSID-III). Untargeted metabolomic analysis of UCB was performed using direct injection FT-ICR mass spectrometry (DI FT-ICR MS). Putative metabolite annotations and lipid classes were assigned and pathway analysis was performed. Results Untargeted metabolomic analysis: Thirty enrolled infants were diagnosed with HIE, including 17 mild, 8 moderate, and 5 severe cases. Pathway analysis revealed that ΔHIE was associated with a 50% and 75% perturbation of tryptophan and pyrimidine metabolism respectively, alongside alterations in amino acid pathways. Significant metabolite alterations were detected from six putatively identified lipid classes including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids and prenol lipids. Outcome prediction: Metabolite model scores significantly correlated with outcome R=0.429 (model A) and R=0.549 (model B) respectively. Model B demonstrates the potential to predict both severe outcome (AUROC of 0.915) and intact survival (AUROC of 0.800). The effect of haemolysis: On average 5% of polar and 1.5% of non-polar features were altered between paired haemolysed and clean samples. However unsupervised multivariate analysis concluded that the preanalytical variability introduced by haemolysis was negligible compared with the inherent biological inter-individual variability. Conclusion This research has employed untargeted metabolomics to identify potential early cord blood biomarkers of HIE and has performed the technical validation of previously proposed markers. en
dc.description.sponsorship Molecular Medicine Ireland (PRTLI cycle 5 of the Higher Education Authority of Ireland) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2016, Niamh Marie Denihan. en
dc.rights.uri en
dc.subject Metabolomics en
dc.subject Biomarker en
dc.subject Haemolysis en
dc.subject Neurodevelopmental outcome en
dc.subject Hypoxic ischaemic encephaolpathy en
dc.subject Perinatal asphyxia en
dc.title Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.description.version Accepted Version
dc.contributor.funder Molecular Medicine Ireland en
dc.contributor.funder Higher Education Authority en
dc.description.status Not peer reviewed en Paediatrics and Child Health en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.chapterOfThesis 3,4,5,7
dc.check.embargoformat Both hard copy thesis and e-thesis en
dc.internal.conferring Autumn 2016 en

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© 2016, Niamh Marie Denihan. Except where otherwise noted, this item's license is described as © 2016, Niamh Marie Denihan.
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