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 …

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Measuring inconsistency in meta-analyses

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

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

Systematic review and meta-analysis

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.

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

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

https://www.bmj.com/content/bmj/343/bmj.d5928.full.pdf

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

On the quantitative analysis of field-ion micrographs

Study objective To describe the relationship between risk factors, risk behaviours, symptoms and mortality from cardiorespiratory diseases in an urban area with high levels of socioeconomic deprivation. A cohort study of 15,411 men and women aged 45-64, comprising 80% of the general population of Paisley and Renfrew, Scotland. Outcomes Mortality after 15 years from coronary heart disease(ICD 410-4), stroke(ICD 430-8), respiratory disease(ICD 460-519) and all causes. Main results Mortality rates from all causes were 19% in men aged 45-49, 31% in men aged 50-54, 42% in men aged 55-59 and 57% in men aged 60-64. The rates are considerably higher than those reported in previous UK prospective studies. For women the rates were 12%, 18%, 25% and 38% respectively. In general men and women showed similar relationships between risk factor levels and mortality rates. People in manual occupations had higher mortality rates. Raised levels of systolic and diastolic blood pressure were associated with increased coronary, stroke and all cause mortality rates. Plasma cholesterol had no such association with all cause mortality rates. High and low levels of body mass index were associated with higher mortality rates than intermediate levels. A relationship between short stature and increased mortality rates was observed in men and women. FEV1 expressed as a percentage of the expected value showed the strongest relationship with mortality rates, particularly for respiratory disease, but also for deaths from coronary heart disease, stroke and all causes. Conclusions A similar pattern of relationship between risk factor levels and mortality rates exists in men and women in Renfrew and Paisley. Respiratory impairment as measured by FEV1% predicted appears to be the most likely explanation of the observed high all cause mortality rates in this population.

Risk factors for cardiorespiratory and all cause mortality in men and women in urban Scotland: 15 year follow up.

Studies in the biochemistry of micro-organisms: The metabolic products of Penicillium Charlesii G. Smith.

Editorial by Albanes 

Experiments in animals have shown that energy intake during the growth period is positively associated with the later incidence of cancer.1 Recently, direct evidence of an association between childhood energy intake and adult mortality from cancer among humans was published in a report from the Boyd Orr cohort study.2 Childhood energy intake was positively associated with mortality from cancers not related to smoking, whereas there was no association between energy intake and mortality from cancers related to smoking.2 This is to be expected as the substantial effects of tobacco would mask any effects of childhood diet on cancers related to smoking.

Height has been used in previous studies as a marker for energy intake in childhood,3 with the limited evidence indicating a positive association for …

https://www.bmj.com/content/bmj/317/7169/1351.full.pdf

George Davey Smith

Papers

On the quantitative analysis of field-ion micrographs

Risk factors for cardiorespiratory and all cause mortality in men and women in urban Scotland: 15 year follow up.

Studies in the biochemistry of micro-organisms: The metabolic products of Penicillium Charlesii G. Smith.

Height and mortality from cancer among men: prospective observational study

Commentary: William Ogilvy Kermack and the childhood origins of adult health and disease