title: 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.
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Trikalinos
authors.forename: Georgia
authors.initials: G
authors.lastname: Salanti
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D016022:Case-Control Studies; D016001:Confidence Intervals; D005190:Family; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D010375:Pedigree; D012107:Research Design