title: Bias in the case-only design applied to studies of gene-environment and gene-gene interaction: a systematic review and meta-analysis.
abstract: BACKGROUND
  The case-only study, proposed as a design specifically for assessing departure from multiplicative gene-environment and gene-gene interactions, is of considerable potential value but there are concerns about its validity. The objective of this study was to evaluate the extent and sources of bias in the case-only design by means of a systematic review and meta-regression 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 (IOR(CC)/IOR(CO)) of the case-control (IOR(CC)) and case-only (IOR(CO)) 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 IOR(CC)/IOR(CO) 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, ON, Canada. dennis.jessica@gmail.com
authors: Jessica
authors: J
authors: Dennis
authors: Steven
authors: S
authors: Hawken
authors: Daniel
authors: D
authors: Krewski
authors: Nick
authors: N
authors: Birkett
authors: Mihaela
authors: M
authors: Gheorghe
authors: Julia
authors: J
authors: Frei
authors: Gail
authors: G
authors: McKeown-Eyssen
authors: Julian
authors: J
authors: Little
mesh_terms: D015982:Bias; D016022:Case-Control Studies; D003627:Data Interpretation, Statistical; D004781:Environmental Exposure / Q000009:adverse effects; D004843:Epistasis, Genetic; D015870:Gene Expression; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D012044:Regression Analysis