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

• Published in: PLoS genetics Vol. 2; no. 8; p. e123
• Main Authors: Evangelou, Evangelos, Trikalinos, Thomas A, Salanti, Georgia, Ioannidis, John P A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2006; Public Library of Science (PLoS)
• Subjects: Case-Control Studies; Confidence Intervals; Disease; Family; Genetic disorders; Genetic Predisposition to Disease; Genetics, Population; Genomes; Humans; Pedigree; Population; Research Design; Sample size; Studies; Theory; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.0020123

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.