Sung-Gon Yi

Statistical tests for identifying differentially expressed genes in time-course microarray experiments

MOTIVATION Microarray technology allows the monitoring of expression levels for thousands of genes simultaneously. In time-course experiments in which gene expression is monitored over time, we are interested in testing gene expression profiles for different experimental groups. However, no sophisticated analytic methods have yet been proposed to handle time-course experiment data. RESULTS We propose a statistical test procedure based on the ANOVA model to identify genes that have different gene expression profiles among experimental groups in time-course experiments. Especially, we propose a permutation test which does not require the normality assumption. For this test, we use residuals from the ANOVA model only with time-effects. Using this test, we detect genes that have different gene expression profiles among experimental groups. The proposed model is illustrated using cDNA microarrays of 3840 genes obtained in an experiment to search for changes in gene expression profiles during neuronal differentiation of cortical stem cells.

New evaluation measures for multifactor dimensionality reduction classifiers in gene–gene interaction analysis

MOTIVATION Gene-gene interactions are important contributors to complex biological traits. Multifactor dimensionality reduction (MDR) is a method to analyze gene-gene interactions and has been applied to many genetics studies of complex diseases. In order to identify the best interaction model associated with disease susceptibility, MDR classifiers corresponding to interaction models has been constructed and evaluated as a predictor of disease status via a certain measure such as balanced accuracy (BA). It has been shown that the performance of MDR tends to depend on the choice of the evaluation measures. RESULTS In this article, we introduce two types of new evaluation measures. First, we develop weighted BA (wBA) that utilizes the quantitative information on the effect size of each multi-locus genotype on a trait. Second, we employ ordinal association measures to assess the performance of MDR classifiers. Simulation studies were conducted to compare the proposed measures with BA, a current measure. Our results showed that the wBA and tau(b) improved the power of MDR in detecting gene-gene interactions. Noticeably, the power increment was higher when data contains the greater number of genetic markers. Finally, we applied the proposed evaluation measures to real data.

Growth hormone-releasing hormone (GHRH) polymorphisms associated with carcass traits of meat in Korean cattle

BackgroundCold carcass weight (CW) and longissimus muscle area (EMA) are the major quantitative traits in beef cattle. In this study, we found several polymorphisms of growth hormone-releasing hormone (GHRH) gene and examined the association of polymorphisms with carcass traits (CW and EMA) in Korean native cattle (Hanwoo).ResultsBy direct DNA sequencing in 24 unrelated Korean cattle, we identified 12 single nucleotide polymorphisms within the 9 kb full gene region, including the 1.5 kb promoter region. Among them, six polymorphic sites were selected for genotyping in our beef cattle (n = 428) and five marker haplotypes (frequency > 0.1) were identified. Statistical analysis revealed that -4241A>T showed significant associations with CW and EMA.ConclusionOur findings suggest that polymorphisms in GHRH might be one of the important genetic factors that influence carcass yield in beef cattle. Sequence variation/haplotype information identified in this study would provide valuable information for the production of a commercial line of beef cattle.

Significant association of CHRNB3 variants with nicotine dependence in multiple ethnic populations

Significant association of CHRNB3 variants with nicotine dependence in multiple ethnic populations

Two-stage normalization using background intensities in cDNA microarray data

BackgroundIn the microarray experiment, many undesirable systematic variations are commonly observed. Normalization is the process of removing such variation that affects the measured gene expression levels. Normalization plays an important role in the earlier stage of microarray data analysis. The subsequent analysis results are highly dependent on normalization. One major source of variation is the background intensities. Recently, some methods have been employed for correcting the background intensities. However, all these methods focus on defining signal intensities appropriately from foreground and background intensities in the image analysis. Although a number of normalization methods have been proposed, no systematic methods have been proposed using the background intensities in the normalization process.ResultsIn this paper, we propose a two-stage method adjusting for the effect of background intensities in the normalization process. The first stage fits a regression model to adjust for the effect of background intensities and the second stage applies the usual normalization method such as a nonlinear LOWESS method to the background-adjusted intensities. In order to carry out the two-stage normalization method, we consider nine different background measures and investigate their performances in normalization. The performance of two-stage normalization is compared to those of global median normalization as well as intensity dependent nonlinear LOWESS normalization. We use the variability among the replicated slides to compare performance of normalization methods.ConclusionsFor the selected background measures, the proposed two-stage normalization method performs better than global or intensity dependent nonlinear LOWESS normalization method. Especially, when there is a strong relationship between the background intensity and the signal intensity, the proposed method performs much better. Regardless of background correction methods used in the image analysis, the proposed two-stage normalization method can be applicable as long as both signal intensity and background intensity are available.

Diagnostic plots for detecting outlying slides in a cDNA microarray experiment

Different sources of systematic and random error variations are often observed in cDNA microarray experiments. A simple scatter plot is commonly used to examine outlying slides that have unusual expression patterns or larger variability than other slides. These outlying slides tend to have large impacts on the subsequent analyses, such as identification of differentially expressed genes and clustering analysis. However, it is difficult to select outlying slides rigorously and consistently based on subjective human pattern recognition on their scatter plots. A graphical method and a rigorous diagnostic measure are proposed to detect outlying slides. The proposed graphical method is easy to implement and shown to be quite effective in detecting outlying slides in real microarray data sets. This diagnostic measure is also informative to compare variability among slides. Two cDNA microarray data sets are carefully examined to illustrate the proposed approach. A 3840-gene microarray experiment for neuronal differentiation of cortical stem cells and a 2076-gene microarray experiment for anticancer compound time-course expression of the NCI-60 cancer cell lines.

arrayQCplot: software for checking the quality of microarray data

UNLABELLED arrayQCplot is a software for the exploratory analysis of microarray data. This software focuses on quality control and generates newly developed plots for quality and reproducibility checks. It is developed using R and provides a user-friendly graphical interface for graphics and statistical analysis. Therefore, novice users will find arrayQCplot as an easy-to-use software for checking the quality of their data by a simple mouse click. AVAILABILITY arrayQCplot software is available from Bioconductor at http://www.bioconductor.org. A more detailed manual is available at http://bibs.snu.ac.kr/software/arrayQCplot CONTACT tspark@stats.snu.ac.kr.

GWAS-GMDR: A program package for genome-wide scan of gene-gene interactions with covariate adjustment based on multifactor dimensionality reduction

Multifactor dimensionality reduction (MDR) has been successfully applied to identification of gene-gene interactions for the complex traits. Generalized MDR (GMDR) was its extension that allows adjustment for covariates. The current GMDR software mainly focuses on candidate gene association studies with a relatively small number of genetic markers and has some limitations to be extended to genome-wide association studies (GWAS) with a large number of genetic markers. We develop GWAS-GMDR, an effective parallel computing program package with special features for GWAS with a large number of genetic markers by using distributed job scheduling method and/or CUDA-enabled high-performance graphic processing units (GPU). First, GWAS-GMDR implements an effective memory handling algorithm and efficient procedures for GMDR to make joint analysis of multiple genes feasible for GWAS. Second, a weighted version of cross-validation consistency based on ‘top-K selection’ (WCVCK) is proposed to report multiple candidates for causal gene-gene interactions. Third, various performance measures are implemented to evaluate MDR classifiers, including balanced accuracy, tau-b, likelihood ratio and normalized mutual information. Fourth, some popular methods for handling missing genotypes are implemented. Finally, our applications support both CPU-based and GPU-based parallel computing system. We applied our applications using a real genome wide data set from WTCCC Crohns disease dataset to identify two-way interaction models in genome-wide scale. The GWAS-GMDR package is a powerful tool for the gene-gene interaction analysis in a genome-wide scale. High-performance implementations are provided as native binaries for Linux, Mac OS X and Windows systems.

SPOT INTENSITY RATIO STATISTICS IN TWO-CHANNEL MICROARRAY EXPERIMENTS

In two-channel microarray experiments, the image analysis extracts red and green fluorescence intensities. The ratio of the two fluorescence intensities represents the relative abundance of the corresponding DNA sequence. The subsequent analysis is performed by taking a log-transformation of this ratio. Therefore, the statistical analyses depend on accuracy of the ratios calculated from the image analysis. However, not many studies have been proposed for developing more reliable ratio statistics. In this paper, we consider a new type of log-transformed ratio statistic. We compare the new ratio statistic with the conventional ratio statistic commonly used in two-channel microarray experiments. First, under the specific log-normal distributional assumption, we compare analytically the new statistics with the conventional ratio statistic. Second, we compare those ratio statistics using a two-channel microarray data obtained by hybridizing a mixture of mouse RNA and yeast in vitro transcript (IVT). Both comparisons show that the proposed ratio statistic performs better than the conventional one.