Bias in the case-only design applied to studies of gene-environment and gene-gene interaction: a systematic review and meta-analysis

Methods The MEDLINE, CINAHL, EMBASE and PUBMED databases were searched through to 7 October 2009. Studies that assessed bias in the case-only design applied to the study of gene-environment and gene-gene interaction were identified. Qualitative comments on the sources and extent of bias were extracted. A meta-regression analysis of the ratio (IORCC/IORCO) of the case-control (IORCC) and case-only (IORCO) interaction odds ratios was conducted based on studies in which both methods were applied to the same data set. Results The search yielded 365 unique articles of which 38 met the inclusion criteria. Potential sources of bias in the case-only design included non-independence of genotype and exposure in the source population. Meta-regression analysis, based on 24 evaluations, produced a mean IORCC/IORCO of 1.06 [95% confidence interval (95% CI) 0.93-1.22], suggesting that bias in case-only designs is not common in practice. The I-2 statistic indicated that 23.9% (95% uncertainty interval 0-53.9%) of the observed variation was due to heterogeneity between studies, which was not explained by any methodological characteristics of the included studies. Conclusion As understanding of the relationships between genes and environmental exposures in the population improves, the case-only design may prove to be of considerable value.