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.

Common risk variants identified in autism spectrum disorder

Abstract: Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls that identifies five genome-wide significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), seven additional loci shared with other traits are identified at equally strict significance levels. Dissecting the polygenic architecture we find both quantitative and qualitative polygenic heterogeneity across ASD subtypes, in contrast to what is typically seen in other complex disorders. These results highlight biological insights, particularly relating to neuronal function and corticogenesis and establish that GWAS performed at scale will be much more productive in the near term in ASD, just as it has been in a broad range of important psychiatric and diverse medical phenotypes.

The Aberdeen Children of the 1950s cohort study: background, methods and follow-up information on a new resource for the study of life course and intergenerational influences on health

Abstract: In this paper we introduce and describe in detail an addition to the UK's population-based resources for the investigation of biological and social influences on health across the life course and between generations: the Aberdeen Children of the 1950s study. We also provide an account of postwar Aberdeen when study members were growing up, report on findings of analyses of data from the original survey on which this study is based and its follow-up, assess the strengths and limitations of the study, and outline current and future research directions. This cohort comprises individuals born in Aberdeen, Scotland (UK) between 1950 and 1956, and is derived from 15 thousand subjects who took part in the Aberdeen Child Development Survey, a cross-sectional study of 'mental subnormality' (learning disability) in a population of all children who were attending Aberdeen primary schools in December 1962. Data collection included information on birthweight, gestational age, childhood height and weight, tests of cognition and behavioural disorder, and a range of multilevel socio-economic indicators. In 1998 we began the process of revitalising this cohort (now termed the Aberdeen Children of the 1950s study). We have been successful in ascertaining the current vital status and whereabouts of 98.5% of a target population of 12 150 subjects (6276 males, 5874 females) with full baseline data. The large majority (81%) of study participants still reside in Scotland and many (73%) have remained in the Grampian region which incorporates Aberdeen. At the present time, a total of almost 500 subjects are known to have died. Linkages to hospital admissions and other health endpoints captured through the Scottish Morbidity Records system have been completed. This includes an intergenerational linkage to approximately eight thousand deliveries in Scotland occurring to female members of the study population. A postal questionnaire to all traced surviving cohort members has also been distributed.

Fetal Alcohol Exposure and IQ at Age 8: Evidence from a Population-Based Birth-Cohort Study

Abstract: Background Observational studies have generated conflicting evidence on the effects of moderate maternal alcohol consumption during pregnancy on offspring cognition mainly reflecting problems of confounding. Among mothers who drink during pregnancy fetal alcohol exposure is influenced not only by mother’s intake but also by genetic variants carried by both the mother and the fetus. Associations between children’s cognitive function and both maternal and child genotype at these loci can shed light on the effects of maternal alcohol consumption on offspring cognitive development.

A multiagent model of the UK market in electricity generation

Abstract: The deregulation of electricity markets has continued apace around the globe. The best structure for deregulated markets is a subject of much debate, and the consequences of poor structural choices can be dramatic. Understanding the effect of structure on behavior is essential, but the traditional economics approaches of field studies and experimental studies are particularly hard to conduct in relation to electricity markets. This paper describes an agent based computational economics approach for studying the effect of alternative structures and mechanisms on behavior in electricity markets. Autonomous adaptive agents, using hierarchical learning classifier systems, learn through competition in a simulated model of the UK market in electricity generation. The complex agent structure was developed through a sequence of experimentation to test whether it was capable of meeting the following requirements: first, that the agents are able to learn optimal strategies when competing against nonadaptive agents; second, that the agents are able to learn strategies observable in the real world when competing against other adaptive agents; and third, that cooperation without explicit communication can evolve in certain market situations. The potential benefit of an evolutionary economics approach to market modeling is demonstrated by examining the effects of alternative payment mechanisms on the behavior of agents.

Inequalities in mortality by social class measured at 3 stages of the lifecourse.

Abstract: OBJECTIVES: This study examined how social class, measured at 3 staged of life, contributes to mortality risk. METHODS: A cohort of employed Scottish men (n = 5567) provided their fathers' occupation and their own first and current occupations, from which social class in childhood, at labor-market entry, and at screening (1970 to 1973) was determined. Relative rates of mortality and relative indices of inequality were calculated from 21 years of follow-up. RESULTS: Mortality risk was similar at each stage of life, with men in the higher social classes having the lowest risk. Social class at screening produced the greatest relative indices of inequality. CONCLUSIONS: The widening of inequalities in mortality in adulthood suggests the importance of the accumulation of poor socioeconomic circumstances throughout life.

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