Selection Bias in Meta-Analyses of Gene-Disease Associations

1226 M any studies have too small a sample size for their fi ndings to be conclusive, but large studies are expensive and time-consuming. Meta-analysis is an alternative to conducting large studies in tackling the problem of small sample size, by combining available small studies to increase the total sample size. Since the 1980s, meta-analysis has been widely used in summarizing results from clinical trials of medical interventions and has also recently gained increasing attention in studying gene-disease associations. However, selection bias may occur in meta-analyses due to the inability to identify and include all conducted and relevant studies. Such selection bias can cause exaggerated or even false-positive gene-disease associations [1]. Failure to include all relevant studies is largely caused by selective publication of studies with certain results (publication bias), and the inability to identify studies published in languages other than English (language bias). Selection bias has been well recognized in meta-analyses of clinical trials [2–4]. Less is known about selection bias in meta-analyses of studies of gene-disease associations; such studies generally address weak associations and thus are particularly vulnerable to biases. In their study published in this issue of PLoS Medicine, Pan and colleagues compared genetic studies conducted in mainland China with those from other places [5]. The researchers identifi ed 12 gene-disease associations and compared a total of 161 Chinese studies and 309 non-Chinese studies. The Chinese studies were on average smaller in sample size than non-Chinese studies and appeared in the literature a few years after the fi rst non-Chinese studies. Chinese studies in general reported a stronger gene-disease association and more frequently a statistically signifi cant result. These two characteristics were more likely to occur in Chinese studies identifi ed through PubMed than in those accessible only locally. These fi ndings suggest a variation or heterogeneity in the strength of the gene-disease association (often expressed in an odds ratio) observed between Chinese and non-Chinese studies. These studies are primarily case-control studies. Many factors may contribute to the variation in the estimate of odds ratio across such studies, such as the genetic make-up of the population studied, the type of patients included, the selection of controls, the quality of the study design, and the quality of the laboratory work. These factors could lead to either over-or underestimation of the true odds ratio. However, it is diffi cult to conceive that any single factor, or combination of these …