[Large-scale sequencing by nested deletions].

Association studies using diseased cases and their parents avoid biases due to population stratification, and the transmission/disequilibrium test (TDT) is a popular method of analysis. Sample size and power calculations for the TDT method have been reported, but often for the special situation of multiplicative effects of alleles on the genotype relative risks. Furthermore, some of the proposed calculations ignore the dependence of transmitted alleles from a pair of heterozygous parents when the effects are not multiplicative, which can lead to erroneous sample size calculations. We demonstrate how to calculate sample size and power for the TDT method for general genotype relative risks. As an alternative to the TDT method, we present likelihood methods for a variety of genotype relative risk models. Exact likelihood methods are presented to allow for accurate small-sample analyses. We demonstrate by numerical comparisons: (1) that the TDT method is inefficient for recessive patterns of relative risks, (2) for alleles that are not rare, falsely assuming a multiplicative model can lead to gross underestimation of the required sample size for the TDT statistic, and (3) for common alleles, if the true genotype relative risks have an approximately dominant pattern, then the TDT method can be grossly inefficient compared to likelihood methods. An alternative likelihood ratio statistic, based on two degrees of freedom, tends to be robust for a wide range of genotype relative risk models. Finally, we discuss how to use standard software for conditional logistic regression to accurately assess effects of alleles as well as genotype-environment interaction.

Genome, Human↗

PubMed1999

Now what do we do with all these genes? Yeast-based two-hybrid analysis: an emerging technology for molecular urology in the post-genome era.

By the year 2005, the Human Genome Project is expected to have mapped and sequenced all of the estimated 100,000 genes that encode the various proteins found in human cells. Defining the role of each gene, and using that information to redirect its action when therapeutic intervention is required, is one of the major assignments for molecular medicine and molecular urology in the post-genome era. This challenge to determine gene function, and to do it cost-effectively and on a large scale, has driven development of new technologies that can more efficiently flag genes that are likely targets for therapeutic intervention. Yeast-based genetic assays that detect protein-protein interactions in vivo offer many of the features required of a practical "gene-flagging" strategy for identifying genes that might be functionally manipulated to achieve therapeutic goals. In the past few years, the yeast-based assays collectively referred to as "two-hybrid interaction traps" or simply "two-hybrid systems" have become increasingly important tools for experimental analysis of gene function. This review presents an overview of the principles of yeast-based two-hybrid analysis, examines some specific applications of the technique of interest to urologic investigators, and discusses some key points that a basic urologic investigator new to the technology would want to consider when designing or evaluating a yeast-based two-hybrid project.

Genome, Human↗