Institut für Med. Informatik, Statistik und Dokumentation
Medizinische Universität Graz

Most previous sample size calculations for case-control studies to detect genetic associations with disease have assumed that the disease gene locus is known, whereas, in fact, markers are used. We calculated sample sizes for unmatched case-control and sibling case-control studies to detect associations between a biallelic marker and a disease governed by a biallelic disease locus. We evaluated the sample size requirements for two-sided trend tests with additive scores applied to marker genotypes, for both designs. The main factors influencing sample size apart from alpha-levels and relative risk parameters are:
1) the degree of agreement between marker allele and disease allele frequencies, which determine the maximal linkage disequilibrium;
2) the percent of maximal linkage disequilibrium present;
3) the attributable risk from the disease allele.
Type of inheritance also plays a role. For a fixed attributable risk, disease prevalence, and, in the sibling case-control design, residual familial aggregation and recombination have much smaller impact. Qualitatively similar results have been found for the transmission disequilibrium test. We found that additive scores, which do not require knowing which marker allele is in positive linkage disequilibrium with the putative disease allele, are not very inefficient, and can even be advantageous in some settings. The large sample size requirements represent a formidable challenge to studies of this type and may partly explain why many genetic associations based on SNPs have not been confirmed in subsequent studies.

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Prof. Dr. Andrea Berghold