Biology subjects

Tzoulaki, I.

Publications and source records attributed to Tzoulaki, I..

4 recordsLinked to original sources

bioRxiv2018

Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort

Markers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p<0.0025) with overweight/obesity and depression and nominally associated (p<0.05) with high alcohol use and low income. DNA methylation age acceleration (N=1,102) was nominally associated (p<0.05) with high alcohol use, anxiety and post-traumatic stress disorder, but not correlated with mAA. Biological age acceleration may present an important mechanism linking psycho-social stress to age-related disease.

epidemiology↗

bioRxiv2018

Importance of vitamin D in critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis

BackgroundCritical care and sepsis remain high priority concerns in children. Observational studies report high prevalence of vitamin D deficiency and present mixed results regarding the correlation between vitamin D status and adverse outcomes. Associations between deficiency and mortality, particularly in children with sepsis, remain unclear. We performed a systematic review and meta-analysis to address this uncertainty.\n\nMethodsPubMed, OVID and Google Scholar were searched for observational studies in critically ill children. We obtained pooled prevalence estimates for vitamin D deficiency and odds ratios for the association of mortality in critically ill children treated in intensive care units, with subgroup analysis for children with sepsis. Meta-regression and sensitivity analyses were used to investigate heterogeneity.\n\nFindingsForty-eight studies were included. The total sample size was 7,199, with 1,679 (23%) children acting as controls in case-control studies. Of 5,520 critically ill children, 2,664 (48%) were vitamin D deficient (< 50 nmol/L). Results of the random effects model demonstrated a pooled prevalence of vitamin D deficiency of 54.9% (95% CI 48.0-61.6, I2=95.0%, 95% CI 94.0-95.8, p < 0.0001). In subgroup analysis of children with sepsis (16 studies, 788 total individuals) we observed higher prevalence of deficiency (63.8%, 95% CI 49.9-75.7, I2=90.5%, 95% CI 86.2-93.5%, p < 0.0001). In patients admitted to intensive care for respiratory tract infections (24 studies, 1,683 total individuals), prevalence was 49.9% (95% CI 37.6-62.2; I2 = 93.9%, 95% CI 92.1-95.3, p < 0.0001). Only one identified study assessed vitamin D levels in sepsis and mortality. The meta-regression model with all available variables (year of publication, total study sample size, quality score, study design, country group and clinical setting) explained 37.52% of I2 (F = 5.1119, p = 0.0005) with clinical setting and country groups being significant predictors for prevalence.\n\nOur meta-analysis (18 studies, 2,463 total individuals) showed an increased risk of death in vitamin D deficient critically ill children both with the random (OR 1.81, 95% CI 1.24-2.64, p-value = 0.002) and fixed effects (OR 1.72, 95% CI 1.27-2.33, p= 0.0005) models with low heterogeneity (I2 = 25.7%, 95% CI 0.0-58.0, p = 0.153) and low evidence of publication bias (p = 0.084, Eggers test).\n\nInterpretationCirculating vitamin D deficiency is common amongst critically ill children, particularly in those with sepsis. Our results suggest that vitamin D deficiency in critically ill children is associated with increased mortality. Clinical trials, studies with larger sample sizes and standardized approaches are needed to further assess associations between circulating levels of vitamin D and mortality or other outcomes in the pediatric population.\n\nFundingNone\n\nRegistrationPROSPERO (CRD42016050638)\n\nCopyrightOpen access article under terms of CC BY

epidemiology↗

bioRxiv2018

Neutrophil counts and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies

OBJECTIVETo evaluate the strength and validity of evidence on the association between the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis.\n\nDESIGNUmbrella review of systematic reviews and meta-analyses of observational studies.\n\nDATA SOURCESMedline, EMBASE, and Cochrane Database of Systematic Reviews.\n\nELIGIBILITY CRITERIASystematic reviews or meta-analyses of observational studies evaluating the association between NLR or TAN and specific cancer outcomes related to disease progression or survival.\n\nDATA SYNTHESISThe available evidence was graded as strong, highly suggestive, suggestive, or weak through the application of pre-set grading criteria. For each included meta-analysis, the grading criteria considered the significance of the random effects estimate, the significance of the largest included study, the number of studies and individuals included, the heterogeneity between included studies, the 95% prediction intervals, presence of small study effects, excess significance and credibility ceilings.\n\nRESULTS239 meta-analyses investigating the association between NLR or TAN and cancer outcomes were identified from 57 published studies meeting the eligibility criteria, with 81 meta-analyses from 36 studies meeting the criteria for inclusion. No meta-analyses found a hazard ratio (HR) in the opposite direction of effect (HR<1). When assessed for significance and bias related to heterogeneity and small study effects, only three (4%) associations between NLR and outcomes in gastrointestinal and nasopharyngeal cancers were supported by strong evidence.\n\nCONCLUSIONDespite many publications exploring the association between NLR and cancer prognosis, the evidence is limited by significant heterogeneity and small study effects. There is a lack of evidence on the association between TAN and cancer prognosis, with all nine associations identified arising from the same study. Further research is required to provide strong evidence for associations between both TAN and NLR and poor cancer prognosis.\n\nREGISTRATIONThis umbrella review is registered on PROSPERO (CRD42017069131)\n\nFUNDINGMedical Research Council\n\nCOPYRIGHTOpen access article under terms of CC BY\n\nSHORT TITLENeutrophils and cancer prognosis: an umbrella review\n\nKEY RESULTWhen assessed for significance and bias related to heterogeneity and small study effects, only three (4%) associations between NLR and overall survival and progression-free survival in gastrointestinal and nasopharyngeal cancers were supported by strong evidence.\n\nWHAT THIS PAPER ADDS\n\nWHAT IS ALREADY KNOWN ON THE TOPICO_LINeutrophil counts have been linked to the progression of cancer due to their tumourigenic role in the cancer microenvironment.\nC_LIO_LINumerous meta-analyses and individual studies have explored the association between neutrophil counts and cancer outcomes for a variety of cancer sites, leading to a large body of evidence with variable strength and validity.\nC_LIO_LIUncertainty exists around the association between neutrophils and cancer outcomes, depending on the site, outcome and treatments considered.\nC_LI\n\nWHAT THIS STUDY ADDSO_LIAll meta-analyses included in this review indicated an association between high neutrophil counts and poor cancer prognosis.\nC_LIO_LIThere is strong evidence supporting the association between the neutrophil to lymphocyte ratio and poor cancer prognosis in some respiratory and gastrointestinal cancers.\nC_LIO_LIFurther research is required to strengthen the existing body of evidence, particularly for the association between tumour-associated neutrophils and cancer outcomes.\nC_LI

epidemiology↗

bioRxiv2018

Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention

BackgroundCoronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention.\n\nMethodsUsing a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank.\n\nFindingsIn UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68-1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97-4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615-0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61- 3.07) between the top and bottom 20% of the metaGRS distribution.\n\nInterpretationRecent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification.\n\nFundingNational Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.

genetics↗