Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy

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dc.check.chapterOfThesis3,4,5,7
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.opt-outNot applicableen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorMurray, Deirdre M.en
dc.contributor.advisorBoylan, Geraldine B.en
dc.contributor.advisorKirwan, Jennifer A.en
dc.contributor.authorDenihan, Niamh Marie
dc.contributor.funderMolecular Medicine Irelanden
dc.contributor.funderHigher Education Authorityen
dc.date.accessioned2016-08-30T11:15:14Z
dc.date.issued2016
dc.date.submitted2016
dc.description.abstractBackground 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.sponsorshipMolecular Medicine Ireland (PRTLI cycle 5 of the Higher Education Authority of Ireland)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationDenihan, N. M. 2016. Investigating metabolomic biomarkers of hypoxic ischaemic encephalopathy. PhD Thesis, University College Cork.en
dc.identifier.endpage311en
dc.identifier.urihttps://hdl.handle.net/10468/3037
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2016, Niamh Marie Denihan.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectMetabolomicsen
dc.subjectBiomarkeren
dc.subjectHaemolysisen
dc.subjectNeurodevelopmental outcomeen
dc.subjectHypoxic ischaemic encephaolpathyen
dc.subjectPerinatal asphyxiaen
dc.thesis.opt-outfalse
dc.titleInvestigating metabolomic biomarkers of hypoxic ischaemic encephalopathyen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisord.murray@ucc.ie
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