Family-based versus unrelated case-control designs for genetic associations

Abstract

The most simple and commonly used approach for genetic associations is the case-control study design of unrelated people. This design is susceptible to population stratification. This problem is obviated in family-based studies, but it is usually difficult to accumulate large enough samples of well-characterized families. We addressed empirically whether the two designs give similar estimates of association in 93 investigations where both unrelated case-control and family-based designs had been employed. Estimated odds ratios differed beyond chance between the two designs in only four instances (4%). The summary relative odds ratio (ROR) (the ratio of odds ratios obtained from unrelated case-control and family-based studies) was close to unity (0.96 [95% confidence interval, 0.91-1.01]). There was no heterogeneity in the ROR across studies (amount of heterogeneity beyond chance I(2) = 0%). Differences on whether results were nominally statistically significant (p < 0.05) or not with the two designs were common (opposite classification rates 14% and 17%); this reflected largely differences in power. Conclusions were largely similar in diverse subgroup analyses. Unrelated case-control and family-based designs give overall similar estimates of association. We cannot rule out rare large biases or common small biases.

Figure 1. ROR and 95% CIs for Each Comparison of an Unrelated Case-Control Study versus Family-Based Study

Odds ratios have been coined in such a way so that the summary OR of the two designs would be >1. Also shown are the summary ROR and its 95% CIs (diamond). Size of the boxes represents the weight of each study i which is calculated by . ID numbers correspond to Table 1. The crosses at the end of bars mean that the 95% CI extends beyond the shown range.

Figure 2. Relative Deviation of the OR with Two Designs as a Function of the Standard Error of the Summary OR

The continuous bold line is the fit unweighted linear regression, and the shaded boundary presents the 95% CIs. Four outliers are not shown.