George Davey Smith

Bio: George Davey Smith is an academic researcher from University of Bristol. The author has contributed to research in topics: Population & Mendelian randomization. The author has an hindex of 224, co-authored 2540 publications receiving 248373 citations. Previous affiliations of George Davey Smith include Keele University & Western Infirmary.

The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study

Abstract: Background Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma. Objective We sought to determine the natural history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study. Methods We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991. Results FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 × 10 −8 ). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 × 10 −11 ). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 × 10 −27 ). Conclusion FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the "eczema plus early wheeze" and "eczema plus asthma" phenotypes.

Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies

Abstract: Objective To investigate whether alcohol consumption and raised body mass index (BMI) act together to increase risk of liver disease. Design Analysis of data from prospective cohort studies. Setting Scotland. Participants Data were from two of the Midspan prospective cohort studies (9559 men): “Main” study 1965-8, participants from workplaces across central belt of Scotland, population of island of Tiree, and mainland relatives, and “Collaborative” study, 1970-3, participants from 27 workplaces in Glasgow, Clydebank, and Grangemouth. Follow-up was to 31 December 2007 (median 29 years, range 0.13-42). We divided participants into nine groups based on measures of body mass index (BMI) (underweight/normal weight Main outcome measures Liver disease morbidity and mortality. Results 80 (0.8%) men died with liver disease as the main cause and 146 (1.5%) with liver disease as any cause. In the Collaborative study, 196 men (3.3%) had liver disease defined by a death, admission, or cancer registration. BMI and alcohol consumption were strongly associated with liver disease mortality in analyses adjusted for other confounders (P=0.001 and P Conclusions Raised BMI and alcohol consumption are both related to liver disease, with evidence of a supra-additive interaction between the two. The occurrence of both factors in the same populations should inform health promotion and public health policies.

Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders

Abstract: Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Genetic variation in LIN28B is associated with the timing of puberty

Abstract: The timing of puberty is highly variable(1). We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor a ...

Measuring inconsistency in meta-analyses

Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice? Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis. Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4 Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted? A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …

Bias in meta-analysis detected by a simple, graphical test

Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure

The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration

Abstract: Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials

Abstract: Flaws in the design, conduct, analysis, and reporting of randomised trials can cause the effect of an intervention to be underestimated or overestimated. The Cochrane Collaboration’s tool for assessing risk of bias aims to make the process clearer and more accurate