title: Bias and efficiency in family-based gene-characterization studies: conditional, prospective, retrospective, and joint likelihoods.
abstract: We revisit the usual conditional likelihood for stratum-matched case-control studies and consider three alternatives that may be more appropriate for family-based gene-characterization studies: First, the prospective likelihood, that is, Pr(D/G,A second, the retrospective likelihood, Pr(G/D); and third, the ascertainment-corrected joint likelihood, Pr(D,G/A). These likelihoods provide unbiased estimators of genetic relative risk parameters, as well as population allele frequencies and baseline risks. The parameter estimates based on the retrospective likelihood remain unbiased even when the ascertainment scheme cannot be modeled, as long as ascertainment only depends on families' phenotypes. Despite the need to estimate additional parameters, the prospective, retrospective, and joint likelihoods can lead to considerable gains in efficiency, relative to the conditional likelihood, when estimating genetic relative risk. This is true if baseline risks and allele frequencies can be assumed to be homogeneous. In the presence of heterogeneity, however, the parameter estimates assuming homogeneity can be seriously biased. We discuss the extent of this problem and present a mixed models approach for providing consistent parameter estimates when baseline risks and allele frequencies are heterogeneous. The efficiency gains of the mixed-model prospective, retrospective, and joint likelihoods relative to the efficiency of conditional likelihood are small in the situations presented here.
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA, 90033, USA. pkraft@hsc.usc.edu
authors.forename: P
authors.initials: P
authors.lastname: Kraft
authors.forename: D C
authors.initials: DC
authors.lastname: Thomas
mesh_terms: D000483:Alleles; D015982:Bias; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D005192:Family Health; D005787:Gene Frequency / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D005808:Genes, Recessive / Q000235:genetics; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D016555:Matched-Pair Analysis; D008957:Models, Genetic; D009679:Nuclear Family; D016017:Odds Ratio; D019683:Penetrance; D011446:Prospective Studies; D012189:Retrospective Studies