Exploring and accounting for publication bias in mental health: a brief overview of methods

Objective Publication bias undermines the integrity of published research. The aim of this paper is to present a synopsis of methods for exploring and accounting for publication bias. Methods We discussed the main features of the following methods to assess publication bias: funnel plot analysis; trim-and-fill methods; regression techniques and selection models. We applied these methods to a well-known example of antidepressants trials that compared trials submitted to the Food and Drug Administration (FDA) for regulatory approval. Results The funnel plot-related methods (visual inspection, trim-andfill, regression models) revealed an association between effect size and SE. Contours of statistical significance showed that asymmetry in the funnel plot is probably due to publication bias. Selection model found a significant correlation between effect size and propensity for publication. Conclusions Researchers should always consider the possible impact of publication bias. Funnel plot-related methods should be seen as a means of examining for small-study effects and not be directly equated with publication bias. Possible causes for funnel plot asymmetry should be explored. Contours of statistical significance may help disentangle whether asymmetry in a funnel plot is caused by publication bias or not. Selection models, although underused, could be useful resource when publication bias and heterogeneity are suspected because they address directly the problem of publication bias and not that of smallstudy effects. INTRODUCTION Synthesis of evidence via meta-analysis of published studies only might produce misleading results as the published set of data may not be a representative sample of the overall evidence. It has also been found that publicly funded research is more likely to be published irrespective of its results, whereas commercially sponsored research is more likely to be published if research findings are positive. A thorough review of causes and examples of publication bias in medicine and psychiatry can be found elsewhere. Publication bias undermines the credibility of meta-analysis results and may misinform clinical practice. A typical example of the influence of publication bias was given by Turner et al on the exaggerated efficacy of antidepressants in the published literature. The authors compared antidepressant placebo-controlled trials in the Food and Drug Administration (FDA) registry with its subset of trials that were subsequently published and found that publication bias inflated the apparent efficacy of antidepressants. Subsequently, Turner also compared antipsychotic placebo-controlled trials submitted to the FDA for regulatory approval to the related journal publications. In this case, publication bias was not so eminent probably due to their greater superiority compared with placebo. To overcome publication bias, mandatory registration of trials has been advocated irrespective of publication status; however, most of the medicines prescribed today were in the market more than a decade ago and the results of old studies are not available to the public. Prospective registration of studies and public disclosure of their results are the only viable solutions to the publication problem, but there are still clear gaps in the trial registration system, and the risk of having biased estimates in meta-analysis is still high. Therefore, a number of data-based visual and statistical methods have been developed to explore and account for publication bias in a set of trials. In this paper, we reviewed the most frequently used methods to assess publication bias and we used the antidepressant trials dataset by Turner to illustrate the main characteristics of this series of visual and statistical methods. METHODS There are two different categories of methods for publication bias: methods based on funnel plots and selection models. Methods were applied to the FDA registered and the published trials to explore the differences between the two datasets. Methods based on funnel plots Funnel plot A funnel plot is a useful graph to detect small-study effects. An asymmetric scatter of studies around the summary estimate of the meta-analysis is often mistakenly equated with publication bias. However, asymmetry should not be attributed to publication bias but should be seen as a means of examining for small-study effects. 12 Asymmetry may be caused by other reasons such as true heterogeneity in the underlying treatment effects, selective outcome reporting or chance. Clinical heterogeneity among patients may result in an asymmetric funnel plot. An intervention may be more effective in high-risk populations which are harder to recruit, but studies involving such patients are very few. Also, studies conducted at high-risk populations require small sample size to achieve adequate levels of power. Lack of observed studies at certain regions of the plot that correspond to non-significant results may indicate that nonpositive studies have not been published. It has been suggested to add contour lines indicating conventional milestones in levels of statistical significance (eg,<0.01, <0.05, <0.1) to the funnel plot as an aid to differentiate asymmetry due to publication bias from that due to other factors. Trim-and-fill method The trim-and-fill is a method that attempts to identify and adjust results for publication bias. The method starts by omitting small studies (trimming) until the plot becomes symmetrical and an adjusted summary effect is estimated from the remaining studies. Then, the funnel plot is replicated with the omitted studies replaced plus their ‘missing’ counterparts around the adjusted summary estimate (filling). The funnel plot becomes now symmetrical around the adjusted summary estimate. The trim-and-fill method provides a summary effect adjusted for publication bias and also estimates the number of unpublished studies. However, it makes the strong assumption that asymmetry in the funnel plot is solely caused by publication bias. The mechanism causing publication bias is unknown and we do not know whether the ‘filled’ studies would have been observed in the absence of publication bias. Simulation studies have shown that the method performs poorly in the presence of substantial between-study variation 16 as heterogeneity may be responsible for funnel plot asymmetry. Finally, the adjusted intervention effect is based on unobserved data and the method should account for increased uncertainty. Evid Based Mental Health February 2014 Vol 17 No 1 11 Statistics in practice group.bmj.com on June 17, 2017 Published by http://ebmh.bmj.com/ Downloaded from