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OBJECTIVES: To determine whether more years spent in education is a causal risk factor for myopia, or whether myopia is a causal risk factor for more years in education.DESIGN: Bidirectional, two sample mendelian randomisation study.SETTING: Publically available genetic data from two consortiums applied to a large, independent population cohort. Genetic variants used as proxies for myopia and years of education were derived from two large genome wide association studies: 23andMe and Social Science Genetic Association Consortium (SSGAC), respectively.PARTICIPANTS: 67 798 men and women from England, Scotland, and Wales in the UK Biobank cohort with available information for years of completed education and refractive error.MAIN OUTCOME MEASURES: Mendelian randomisation analyses were performed in two directions: the first exposure was the genetic predisposition to myopia, measured with 44 genetic variants strongly associated with myopia in 23andMe, and the outcome was years in education; and the second exposure was the genetic predisposition to higher levels of education, measured with 69 genetic variants from SSGAC, and the outcome was refractive error.RESULTS: Conventional regression analyses of the observational data suggested that every additional year of education was associated with a more myopic refractive error of -0.18 dioptres/y (95% confidence interval -0.19 to -0.17; PCONCLUSIONS: This study shows that exposure to more years in education contributes to the rising prevalence of myopia. Increasing the length of time spent in education may inadvertently increase the prevalence of myopia and potential future visual disability.

Using genetic variants as a proxy for modifiable environmental factors that are associated with disease can circumvent some of the problems of observational studies Epidemiologists look for modifiable causes of common diseases to improve population health. However, epidemiological studies may identify spurious “causes.” For example, the epidemiological findings that hormone replacement therapy protects against coronary heart disease,w1β carotene prevents lung cancer,w2and vitamin E and vitamin C reduce risk of cardiovascular diseasew3have all been refuted by randomised controlled trials and have raised concerns about the value of epidemiological studies.1 The misleading findings were probably due to confounding by behavioural, physiological, and socioeconomic factors related both to exposures and to disease end points.2 3 One solution to these problems is mendelian randomisation.4 5 Mendelian randomisation is a recent development in genetic epidemiology6 7 based on Mendel's second law that inheritance of one trait is independent of inheritance of other traits. It uses common genetic polymorphisms that are known to influence exposure patterns (such as propensity to drink alcohol) or have effects equivalent to those produced by modifiable exposures (such as raised blood cholesterol concentration). Associations between genetic variants and outcome are not generally confounded by behavioural or environmental exposures. This means that observational studies of genetic variants have similar properties to intention to treat analyses in randomised controlled trials (fig 1). Comparison of design of mendelian randomisation studies and randomised controlled trials The simplest way of appreciating the potential of mendelian randomisation is to consider applications of the underlying principles. The inferences that can be drawn from mendelian randomisation studies depend on the different ways in which genetic variants can proxy for environmentally modifiable exposures. ### Understanding effects of health related behaviours In observational studies, alcohol consumption is related to many known and unknown confounding factors; ill health …

Inequalities in health between rich and poor areas of Britain widened in the 1980s and 1990s, and the current government has repeatedly expressed its intention to reduce these inequalities. In this article, however, the authors report that inequalities in life expectancy have continued to widen, alongside widening inequalities in income and wealth, and argue that more potent and redistributive policies are needed

Objectives: To examine the association between self perceived psychological stress and cardiovascular disease in a population where stress was not associated with social disadvantage. Design: Prospective observational study with follow up of 21 years and repeat screening of half the cohort 5 years from baseline. Measures included perceived psychological stress, coronary risk factors, self reported angina, and ischaemia detected by electrocardiography. Setting: 27 workplaces in Scotland. Participants: 5606 men (mean age 48 years) at first screening and 2623 men at second screening with complete data on all measures Main outcome measures: Prevalence of angina and ischaemia at baseline, odds ratio for incident angina and ischaemia at second screening, rate ratios for cause specific hospital admission, and hazard ratios for cause specific mortality. Results: Both prevalence and incidence of angina increased with increasing perceived stress (fully adjusted odds ratio for incident angina, high versus low stress 2.66, 95% confidence interval 1.61 to 4.41; P for trend Conclusions: The relation between higher stress, angina, and some categories of hospital admissions probably resulted from the tendency of participants reporting higher stress to also report more symptoms. The lack of a corresponding relation with objective indices of heart disease suggests that these symptoms did not reflect physical disease. The data suggest that associations between psychosocial measures and disease outcomes reported from some other studies may be spurious. What is already known on this topic Higher psychological stress has predicted coronary heart disease in several observational studies Exposure to stress and heart disease outcomes were often based on self report so that a general tendency to negative perceptions may have generated a spurious association between higher perceived stress and heart disease symptoms What this study adds Perceived stress was strongly related to subjective symptoms of heart disease, including those leading to hospital admission However, stress showed a weakly inverse relation to all objective indices of heart disease: socially advantaged men perceived themselves to be most stressed, and the “protective” effect of stress was probably attributable to residual confounding Suggestions that psychological stress is an important determinant of heart disease may be premature

This is the second in a series of four articles Studies that show a significant effect of treatment are more likely to be published, be published in English, be cited by other authors, and produce multiple publications than other studies.1–8 Such studies are therefore also more likely to be identified and included in systematic reviews, which may introduce bias.9 Low methodological quality of studies included in a systematic review is another important source of bias.10 All these biases are more likely to affect small studies than large ones. The smaller a study the larger the treatment effect necessary for the results to be significant. The greater investment of time and money in larger studies means that they are more likely to be of high methodological quality and published even if their results are negative. Bias in a systematic review may therefore become evident through an association between the size of the treatment effect and study size—such associations may be examined both graphically and statistically. #### Summary points Asymmetrical funnel plots may indicate publication bias or be due to exaggeration of treatment effects in small studies of low quality Bias is not the only explanation for funnel plot asymmetry; funnel plots should be seen as a means of examining “small study effects” (the tendency for the smaller studies in a meta-analysis to show larger treatment effects) rather than a tool for diagnosing specific types of bias Statistical methods may be used to examine the evidence for bias and to examine the robustness of the conclusions of the meta-analysis in sensitivity analyses “Correction” of treatment effect estimates for bias should be avoided as such corrections may depend heavily on the assumptions made Multivariable models may be used, with caution, to examine the relative importance of different types of bias ### Funnel plots Funnel …

Objectives: To examine the changes in blood pressure over time in a cohort of young adults attending university between 1948 and 1968. Design: Cross sectional study. Setting: Glasgow University. Participants: 12 414 students aged 16-25 years—9248 men (mean age 19.9 years) and 3164 women (19.2 years)—who participated in health screening on entering university between 1948 and 1968. Main outcome measures: Systolic and diastolic blood pressure. Results: In male students mean systolic blood pressure adjusted for age decreased from 134.5 (95% confidence interval 133.8 to 135.2) mm Hg in those born before 1929 to 125.7 (125.0 to 126.3) mm Hg in those born after 1945, and diastolic blood pressure dropped from 80.3 (79.8 to 80.8) mm Hg to 74.7 (74.2 to 75.1) mm Hg. For female students the corresponding declines were from 129.0 (127.5 to 130.5) mm Hg to 120.6 (119.8 to 121.4) mm Hg and from 79.7 (78.7 to 80.6) mm Hg to 77.0 (76.5 to 77.5) mm Hg. Adjustment for potential confounding factors made little difference to these findings. The proportion of students with hypertension declined substantially in both sexes. Conclusions: Substantial declines in systolic and diastolic blood pressure over time were occurring up to 50 years ago in young adults who were not taking antihypertensive medication. Since blood pressure tracks into adult life, the results of the cross sectional comparisons suggest that factors acting in early life may be important in determining population risk of cardiovascular disease. Changes in such factors may have made important contributions to the decline in rates of cardiovascular diseases, particularly stroke, seen in developed countries during the past century. What is already known on this topic Mortality from stroke in developed countries decreased throughout the 20th century; declines in mortality from coronary heart disease occurred more recently Explanations may include favourable trends in risk factors, including blood pressure Since blood pressure tracks into adulthood, description of the trends occurring in blood pressure in young adults may help to elucidate the critical periods involved in influencing trends in blood pressure What this study adds Declines in blood pressure over time were taking place up to 50 years ago in young adults These changes did not result from use of antihypertensive medications and point to the importance of factors in early life in determining blood pressure and risk of subsequent cardiovascular disease

The findings of medical research are often met with considerable scepticism, even when they have apparently come from studies with sound methodologies that have been subjected to appropriate statistical analysis. This is perhaps particularly the case with respect to epidemiological findings that suggest that some aspect of everyday life is bad for people. Indeed, one recent popular history, the medical journalist James Le Fanu's The Rise and Fall of Modern Medicine , went so far as to suggest that the solution to medicine's ills would be the closure of all departments of epidemiology.1 One contributory factor is that the medical literature shows a strong tendency to accentuate the positive; positive outcomes are more likely to be reported than null results.2–4 By this means alone a host of purely chance findings will be published, as by conventional reasoning examining 20 associations will produce one result that is “significant at P=0.05” by chance alone. If only positive findings are published then they may be mistakenly considered to be of importance rather than being the necessary chance results produced by the application of criteria for meaningfulness based on statistical significance. As many studies contain long questionnaires collecting information on hundreds of variables, and measure a wide range of potential outcomes, several false positive findings are virtually guaranteed. The high volume and often contradictory nature5 of medical research findings, however, is not only because of publication bias. A more fundamental problem is the widespread misunderstanding of the nature of statistical significance. #### Summary points P values, or significance levels, measure the strength of the evidence against the null hypothesis; the smaller the P value, the stronger the evidence against the null hypothesis An arbitrary division of results, into “significant” or “non-significant” according to the P value, was not the intention of the …

The limits to demand for health care {#article-title-2} There are a number of historical, political, and economic explanations for the tradition of underinvestment in the NHS, but one insidious disincentive will provide a continuing brake on expansion. This is the expectation that in a publicly funded healthcare system any increase in expenditure will be followed only by further failure, although at an increased cost. Further, the imbalance between demand and supply is assumed to be deteriorating as the population ages, new technologies appear, and expectations rise.1 This orthodoxy has become so pronounced that questioning the linkage between particular aspects of failure in healthcare delivery and an overarching mismatch between supply and demand can be dismissed as an idealistic act of denial. These problems are most commonly discussed in the idiom of rationing. In rationing the concern is to curtail access to health care through measures that may be, according to the perspective of the commentator, most likely to enhance effectiveness; be efficient, equitable, ethical, or beneficial to the independent sector; or be politically feasible. The rationing debate came to the fore during a period of recession, so that “choices” in health care involved choosing to offer less. The conventional, but implausible, insistence that the term rationing has a neutral meaning will be tested in the welcome new circumstance in which healthcare expenditure in the United Kingdom is set to expand substantially. But what are the grounds for the view that legitimate demand in most areas of provision must exceed realisable supply? #### Summary points The rationing debate has been conducted almost exclusively through assertion and political analysis Conventional assumptions of an imbalance between demand and supply are not supported by evidence Pessimism about adverse future trends in demand arising from an ageing population, the costs of innovation, and rising public expectations are similarly unsupported by good evidence Many perceived deficiencies …

Studies on the health effects of income inequality have generated great interest. The evidence on this association between countries is mixed,1–4 but income inequality and health have been linked within the United States,5–11 Britain,12 and Brazil.13 Questions remain over how to interpret these findings and the mechanisms involved. We discuss three interpretations of the association between income inequality and health: the individual income interpretation, the psychosocial environment interpretation, and the neo-material interpretation. #### Summary points Income inequality has generally been associated with differences in health A psychosocial interpretation of health inequalities, in terms of perceptions of relative disadvantage and the psychological consequences of inequality, raises several conceptual and empirical problems Income inequality is accompanied by many differences in conditions of life at the individual and population levels, which may adversely influence health Interpretation of links between income inequality and health must begin with the structural causes of inequalities, and not just focus on perceptions of that inequality Reducing health inequalities and improving public health in the 21st century requires strategic investment in neo-material conditions via more equitable distribution of public and private resources We reviewed the literature through traditional and electronic means and supplemented this with correlational analyses of gross domestic product and life expectancy and of income inequality and mortality trends based on data from the World Bank,14 the World Health Organization,15 and two British sources.16 17 According to the individual income interpretation, aggregate level associations between income inequality and health reflect only the individual level association between income and health. The curvilinear relation between income and health at the individual level 18 19 is a sufficient condition to produce health differences between populations with the same average income but different distributions of income.3 20 This interpretation assumes that determinants …

Objectives: To investigate the association between suicide and area based measures of deprivation and social fragmentation. Design: Ecological study. Setting: 633 parliamentary constituencies of Great Britain as defined in 1991. Main outcome measures: Age and sex specific mortality rates for suicide and all other causes for 1981-92. Results: Mortality from suicide and all other causes increased with increasing Townsend deprivation score, social fragmentation score, and abstention from voting in all age and sex groups. Suicide mortality was most strongly related to social fragmentation, whereas deaths from other causes were more closely associated with Townsend score. Constituencies with absolute increases in social fragmentation and Townsend scores between 1981 and 1991 tended to have greater increases in suicide rates over the same period. The relation between change in social fragmentation and suicide was largely independent of Townsend score, whereas the association with Townsend score was generally reduced after adjustment for social fragmentation. Conclusions: Suicide rates are more strongly associated with measures of social fragmentation than with poverty at a constituency level. Key messages Place of residence may affect health, and mortality from most common diseases tends to be higher in areas characterised by low socioeconomic position Research dating back over 100 years suggests that social fragmentation may influence suicide In the 1980s and 1990s, parliamentary constituencies with high levels of social fragmentation had high rates of suicide, independent of deprivation Constituencies with the greatest increases in social fragmentation between 1981 and 1991 also had the greatest increases in suicide rates over the same period Any targeting of suicide prevention may be more effective if aimed at socially fragmented rather than deprived areas

Objectives: To relate alcohol consumption to mortality. Design: Prospective cohort study. Setting: 27 workplaces in the west of Scotland. Participants: 5766 men aged 35-64 when screened in 1970-3 who answered questions on their usual weekly alcohol consumption. Main outcome measures: Mortality from all causes, coronary heart disease, stroke, and alcohol related causes over 21 years of follow up related to units of alcohol consumed per week. Results: Risk for all cause mortality was similar for non-drinkers and men drinking up to 14 units a week. Mortality risk then showed a graded association with alcohol consumption (relative rate compared with non-drinkers 1.34 (95% confidence interval 1.14 to 1.58) for 15-21 units a week, 1.49 (1.27 to 1.75) for 22-34 units, 1.74 (1.47 to 2.06) for 35 or more units). Adjustment for risk factors attenuated the increased relative risks, but they remained significantly above 1 for men drinking 22 or more units a week. There was no strong relation between alcohol consumption and mortality from coronary heart disease after adjustment. A strong positive relation was seen between alcohol consumption and risk of mortality from stroke, with men drinking 35 or more units having double the risk of non-drinkers, even after adjustment. Conclusions: The overall association between alcohol consumption and mortality is unfavourable for men drinking over 22 units a week, and there is no clear evidence of any protective effect for men drinking less than this.

Objectives: To analyse trends in rates of genital chlamydial infection and ectopic pregnancy between 1985 and 1995 in a county in Sweden. Setting: Uppsala county where screening for chlamydial infection, treatment, and contact tracing has been widespread and where ectopic pregnancies are recorded. Methods: Rates of chlamydial infections and ectopic pregnancy between 1985 and 1995 were calculated for women aged 20-39 years. Poisson and linear regression were used to examine the association between the risk of ectopic pregnancy and the current rates of chlamydial infection and rates of chlamydial infection from up to 5 years earlier. Main outcome measures: Rates of chlamydial infection per 100 examinations, rates of ectopic pregnancy per 1000 pregnancies, rate ratios and 95% confidence intervals for an increase in chlamydial infections of 5 new cases per 100 examinations. Results: 103 870 cervical samples from women aged 15-39 years were analysed; 5648 (5.4%) were positive for chlamydia. 51 630 pregnancies were analysed; 930 (1.8%) were ectopic. Both rates declined over time. For women aged 20-24 years there was a strong correlation between the rate of ectopic pregnancy and the rate of chlamydial infection in the same year (r=0.93, P Conclusions: Declining rates of genital chlamydial infections have probably led to a fall in the rate of ectopic pregnancies. The timing of the decline in the rate of ectopic pregnancies varies with age. Among young women falling rates of chlamydial infection have been accompanied by an immediate reduction in the rate of ectopic pregnancy. Key messages The effect of measures to diagnose and treat genital chlamydial infections on the risk of ectopic pregnancy was examined in a county in Sweden Rates of chlamydial infection and ectopic pregnancy both declined between 1985 and 1995 Chlamydial infections seem to be the main cause of ectopic pregnancy in young women; the risk of ectopic pregnancy decreased concurrently with the decline in chlamydial infections In older women the associations were less pronounced

Objective: To investigate the association between social circumstances in childhood and mortality from various causes of death in adulthood. \ud Design: Prospective observational study. \ud Setting: 27 workplaces in the west of Scotland. \ud Subjects: 5645 men aged 35-64 years at the time of examination. \ud Main outcome measures: Death from various causes. \ud Results: Men whose fathers had manual occupations when they were children were more likely as adults to have manual jobs and be living in deprived areas. Gradients in mortality from coronary heart disease, stroke, lung cancer, stomach cancer, and respiratory disease were seen (all PConclusions: Adverse socioeconomic circumstances in childhood have a specific influence on mortality from stroke and stomach cancer in adulthood, which is not due to the continuity of social disadvantage throughout life. Deprivation in childhood influences risk of mortality from coronary heart disease and respiratory disease in adulthood, although an additive influence of adulthood circumstances is seen in these cases. Mortality from lung cancer, other cancer, and accidents and violence is predominantly influenced by risk factors that are related to social circumstances in adulthood.

Since its recent introduction into clinical epidemiology, meta-analysis has established itself as an influential branch of biostatistics. Several books have focused mainly or entirely on meta-analysis in medicine,1 2 3 4 5 and the latest editions of relevant textbooks generally include a section on meta-analysis.6 7 8 9 Computer software entirely devoted to meta-analysis has been developed, and meta-analytic procedures have been introduced in general statistical software packages. We will soon be providing an overview of software packages on the BMJ 's website.10 Several unresolved issues concerning meta-analysis remain, and in this final article of our series we address some of the topics that are likely to feature in future discussions of the appropriate practice and domain of meta-analysis. Publication bias, discussed in detail in a previous article,11 is a major threat to the validity of meta-analysis. Obtaining and including data from unpublished studies seems to be the obvious way of avoiding this problem. Including data from unpublished studies can itself introduce bias, however. Even after extensive consultation with the research community, unpublished studies may remain hidden. The unpublished studies that can be located may thus be an unrepresentative sample of unpublished studies. Whether bias is reduced or increased by including unpublished studies cannot formally be assessed as it is impossible to be certain that all unpublished studies have been located. A further problem relates to the willingness of investigators of located unpublished studies to provide data. This may depend on the findings of the study, more favourable results being provided more readily. This could again bias the findings of a meta-analysis. ### Summary points Meta-analysis has established itself as an important technique in clinical epidemiology, but several issues remain unresolved The inclusion of unpublished, non-peer reviewed data can be problematic, particularly if these data come from interested sources, …