The case-combined-control design was efficient in detecting gene-environment interactions.
OBJECTIVE
The interest in studying gene-environment (GxE) interaction is increasing for complex diseases. A design combining both related and unrelated controls (e.g., population-based and siblings) is proposed to increase the power to detect GxE interaction.


METHODS
We used simulations to assess the efficiency of the case-combined-control design relative to a classical case-control study under a variety of assumptions.


RESULTS
The case-combined-control design appears more efficient and feasible than a classical case-control study for detecting interaction involving rare exposures and/or genetic factors. The number of available sibling controls per case and the frequencies of the risk factors are the most important parameters for determining relative efficiency. Relative efficiencies decrease as the frequency of the gene (G) increases. A positive correlation in exposure (E) between siblings decreases relative efficiency.


CONCLUSIONS
Although the case-combined-control design may not be efficient for common genes with moderate effects, it appears to be a useful alternative in certain situations where classical approaches remain unrealistic.
Andrieu
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Inserm EMI00-06, Tour Evry 2, 523 Place des Terrasses de l'Agora, 91034 Evry Cedex, France. nadine.andrieu@curie.net
Goldstein
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AM
D001943:Breast Neoplasms / Q000235:genetics; D016022:Case-Control Studies; D004777:Environment; D004781:Environmental Exposure / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D012107:Research Design; D035781:Siblings