Design of Gene Characterization Studies: an Overview

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Abstract
This collection of papers from the Gene Characterization Panel addresses design issues in studies aimed at assessing the population characteristics of cloned genes, such as their allele frequencies, penetrance, variation in these parameters across subpopulations, and gene-environment and gene-gene interactions. This paper provides an overview of the various designs that have been suggested, including cohort and case-control designs using independent and related individuals as well as optimal multistage sampling and hybrid designs. Various statistical (bias and efficiency) and practical considerations are suggested for evaluation of the alternative designs, with the aim of posing the question, “What is the optimal design for a particular situation”? The answer to this question clearly depends on such contextual issues as nature of the outcome variable, the gene frequency and genetic relative risk, and the importance of gene-environment and gene-gene interactions. Further methodologic work might be usefully directed toward assessment of the seriousness of the population stratification problem in general as well as methods of dealing with it, the utility of registries of high-risk families, and the merits of various hybrid designs for gene discovery and gene characterization.