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dc.contributor.advisorPlevris, John
dc.contributor.advisorHayes, Peter
dc.contributor.authorSinha, Rohit
dc.date.accessioned2022-09-29T09:49:48Z
dc.date.available2022-09-29T09:49:48Z
dc.date.issued2022-11-26
dc.identifier.urihttps://hdl.handle.net/1842/39393
dc.description.abstractBACKGROUND: Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhosis and end-stage liver disease. The prevalence is increasing in line with the global obesity epidemic. There is a need to develop a non-invasive diagnostic tool that could be used as a point of care. Exhaled breath contains a vast array of volatile organic compounds (VOCs) with potential for diagnostic exploitation. METHODOLOGY: The study was a prospective single-centre cohort study (ClinicalTrials.gov: NCT02950610). In the present study, exhaled breath of 60 well-characterised NAFLD (cirrhotics and non-cirrhotic) patients was compared against that of self-declared healthy individuals. Gas chromatography - mass spectrometry and electronic signature of breath using a metal oxide semi-conductor sensor electronic nose was studied. Data were analysed using R studio (v 2.3.2) and SPSS 21. An unbiased machine learning clustering technique was applied. A 5-year longitudinal data was collected with endpoints of disease progression, liver disease-related complications and all-cause mortality. RESULTS: Combined dimethyl sulphide (DMS) and D-limonene led to better discrimination of patients with NAFLD cirrhosis from healthy volunteers (AUROC 0.98; 95% CI 0.93–1.00; p <0.001) and patients with NAFLD cirrhosis from those with non-cirrhotic NAFLD (AUROC 0.91; 95% CI 0.82–1.00; p <0.001). Breath terpinene concentrations discriminated between patients with non-cirrhotic NAFLD and healthy volunteers (AUROC 0.84; 95% CI 0.68–0.99; p = 0.002). The eNose was able to differentiate between healthy from non-cirrhotic NAFLD (p<0.001, CVV 96.8%) and NAFLD cirrhotic (p<0.001, CVV 95.1%). An unbiased clustering technique further classified the patients into three distinct clusters. Cluster 1 consists of 23 patients, cluster 2 consists of 24 patients, and cluster 3 consists of 13 patients. The clusters were comparable in clinical phenotyping. Cluster 2 was identified as a higher risk group with significant differences in serum hyaluronic acid levels (p=0.001), portal hypertension(p=0.003) and dimethyl sulphide (p=0.041) and D-limonene (p=0.015). Cluster 2 was associated with a significant 5-year odds risk of 8.5 [95%CI 1.8 – 39.7] for disease progression. A 25% decompensation rate, 12.5% variceal bleeding and 12.5% all-cause mortality were noted in cluster 2 compared with 4.3% and 0% for decompensation. No variceal bleeding and 1% all-cause mortality was observed in cluster 1 and 3, respectively. CONCLUSION: Electronic noses can differentiate between healthy and patient groups with high confidence. In addition, unbiased clustering within the NAFLD spectrum identifies three subtypes: mild, moderate, and severe disease phenotypes. These results warrant prospective studies on the potential of exhaled breath fingerprinting using eNose technology as point-of-care diagnostics and identifying high-risk disease progressors.en
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionSinha R, Lockman KA, Homer NZM, Bower E, Brinkman P, Knobel HH, Fallowfield JA, et al. Volatomic analysis identifies compounds that can stratify non-alcoholic fatty liver disease. JHEP Rep 2020;2:100137.en
dc.relation.hasversionDunne PDJ, Sinha R, Stanley AJ, Lachlan N, Ireland H, Shams A, Kasthuri R, et al. Randomised clinical trial: standard of care versus early-transjugular intrahepatic portosystemic shunt (TIPSS) in patients with cirrhosis and oesophageal variceal bleeding. Aliment Pharmacol Ther 2020;52:98-106en
dc.relation.hasversionForrest EH, Storey N, Sinha R, Atkinson SR, Vergis N, Richardson P, Masson S, et al. Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis. Aliment Pharmacol Ther 2019;50:442-453.en
dc.relation.hasversionPlevris N, Sinha R, Hay AW, McDonald N, Plevris JN, Hayes PC. Index serum hyaluronic acid independently and accurately predicts mortality in patients with liver disease. Aliment Pharmacol Ther 2018;48:423-430en
dc.relation.hasversionSinha R, Lockman KA, Mallawaarachchi N, Robertson M, Plevris JN, Hayes PC. Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites. J Hepatol 2017en
dc.relation.hasversionSinha R, Lockman KA, Church NI, Plevris JN, Hayes PC. The use of hemostatic spray as an adjunct to conventional hemostatic measures in high-risk nonvariceal upper GI bleeding (with video). Gastrointest Endosc 2016.en
dc.relation.hasversionSinha R, Lockman KA. Editorial: screening for NAFLD - a promising strategy to mitigate the future burden of liver disease. Aliment Pharmacol Ther 2016;43:163.en
dc.relation.hasversionLockman KA, Htun V, Sinha R, Treskes P, Nelson LJ, Martin SF, Rogers SM, et al. Proteomic profiling of cellular steatosis with concomitant oxidative stress in vitro. Lipids Health Dis 2016;15:114.en
dc.relation.hasversionSinha R, Gillespie S, Brinkman P, et al. O24 Unbiased clustering of breath signature in NAFLD identifies disease progression high-risk patient phenotype- 5 year study. Gut 2022;71:A13-A14en
dc.relation.hasversionSinha R, Foo J, Hayes P. Multi-frequency bioelectrical impedance output correlates to liver disease severity, nutritional status and functional capacity. Journal of Hepatology 2018;68:S382-S383.en
dc.relation.hasversionMcDonald N, Sinha R, De Vries R, Hayes PC, Chamuleau RAFM, Fallowfield JA, Plevris JN. Exhaled Breath Profiling by Electronic Nose as a Novel Non-Invasive Method for Assessment of Chronic Liver Disease: Proof of Principle Study. Journal of Hepatology 2016;64:S734–S735en
dc.relation.hasversionSinha R, Gallagher I, Lockman A, Chamuleau RAFM, Jaap A, Hayes PC, Plevris JN. Electronic-nose breath print distinguishes non-alcoholic fatty liver disease from healthy lean control: A pilot study. Journal of Hepatology 68(1):S556-S557en
dc.relation.hasversionSinha R, Lockman A, Homer N, Bower E, Brinkman P, Knobel HH, Chamuleau RAFM, Jaap A, Hayes PC, Plevris JN. A study of breath metabolome in Non-alcoholic fatty liver disease. Journal of Hepatology 68(1):S557-S558en
dc.subjectmachine learningen
dc.subjectnon-alcoholic fatty liver diseaseen
dc.subjectelectronic noseen
dc.subjectunbiased clusteringen
dc.titleBreathomics in liver diseaseen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2023-09-29en
dcterms.accessRightsRestricted Accessen


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