A robust linkage analysis method using combined allele sharing and transmission disequilibrium information from case-parent tetrad families.

There are two types of linkage information, the allele sharing information and transmission disequilibrium information, that can be extracted from case-parent tetrad families for deriving statistics for test of linkage. By extracting allele sharing information the mean test can be derived. By extracting transmission disequilibrium information the transmission/disequilibrium test (TDT) can be derived. The power performances of the two tests are different with respect to the extent of linkage disequilibrium. The TDT is more powerful than the mean test when the extent of linkage disequilibrium is moderate to strong, but the mean test has better power performance than the TDT when linkage disequilibrium is weak. Some previous studies have proposed several post-combination analysis methods, which combine the two tests after they are derived using the two types of linkage information respectively, to yield robust test statistics against the interference of linkage disequilibrium. Instead of adopting the post-combination approach, in this paper we investigate the approach of using the pre-combination idea to yield robust statistics for test of linkage. The pre-combination methods combine the two types of linkage information first, and then use the combined information to construct robust test statistics. Simulation studies are conducted to compare the power performances of the proposed pre-combination tests with those of the existing post-combination methods.

Identifying chromosomal fragile sites from a hierarchical-clustering point of view.

Identification of fragile sites is a way to investigate the genetic abnormalities that are the hallmark of cancer and play an important role in carcinogenesis. Manifestation of nonrandom breakage at a chromosome band is an essential criterion for determination of the fragility of the band. In this article, a new detection procedure is proposed. This new procedure takes the relationship of one site with the others into consideration and can be applied to tests of the randomness of breakpoints under either the proportional probability model (PPM) or the equiprobability model (EPM). The procedure can form a grouping structure that classifies all sites into several clusters. It is applied to identification of fragile sites for a real data set for Chinese patients with colorectal carcinoma for illustration of the proposed method.

Testing the nonrandomness of chromosomal breakpoints using highest observed breakages.

To determine whether a chromosomal band is a fragile site rather than a spontaneous breakpoint, an essential step is to test the nonrandomness of breakage at the region. In this paper, the nonapplicability of the testing procedure introduced by Bohm et al. is discussed, and a new detection procedure is proposed. This new procedure considers the relations of one site with the others, and can be applied to tests of the nonrandomness of breakpoints under either the proportional probability model, or the equiprobability model. A data set for Chinese patients with colorectal carcinoma is analyzed as an illustration of the proposed method.

A confirmation analysis method for identification of chromosomal fragile sites.

Fragile sites are chromosome bands that do not manifest a presumed breakage pattern. Identification of fragile sites is a way to investigate the mechanism of carcinogenesis because the fragility at a specific chromosome position may be the causation of an associated cancer. A problem in the identification of fragile sites is the high false positive rate arising from simultaneously carrying out a large number of significance tests. To control it, we propose to find a reference study to confirm the identification result of an objective study. We utilize the Bayesian concept for linking two studies. Basically, our method demonstrates a conservative way to take account of the prior information of a binomial parameter. The derived estimate of breakage probability can be interpreted as a resampling weighted sample-pooling method. It is applied to confirm the identification of fragile sites for a data set of neuroblastoma patients.

A method for testing the nonrandomness of chromosomal breakpoints.

Testing the nonrandomness of breakage at a chromosome band is an essential step fo identifying a fragile site. In this paper, we propose a method derived by using the relationship between the binomial and F distributions for testing nonrandomness. The method is simple in calculation. It was applied to the detection of fragile sites for Chinese patients with colorectal carcinoma.