Doubly stochastic continuous-time hidden Markov approach for analyzing genome tiling arrays

Microarrays have been developed that tile the entire nonrepetitive genomes of many different organisms, allowing for the unbiased mapping of active transcription regions or protein binding sites across the entire genome. These tiling array experiments produce massive correlated data sets that have many experimental artifacts, presenting many challenges to researchers that require innovative analysis methods and efficient computational algorithms. This paper presents a doubly stochastic latent variable analysis method for transcript discovery and protein binding region localization using tiling array data. This model is unique in that it considers actual genomic distance between probes. Additionally, the model is designed to be robust to cross-hybridized and nonresponsive probes, which can often lead to false-positive results in microarray experiments. We apply our model to a transcript finding data set to illustrate the consistency of our method. Additionally, we apply our method to a spike-in experiment that can be used as a benchmark data set for researchers interested in developing and comparing future tiling array methods. The results indicate that our method is very powerful, accurate and can be used on a single sample and without control experiments, thus defraying some of the overhead cost of conducting experiments on tiling arrays.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS248 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Bayesian nonparametric tests via sliced inverse modeling

We study the problem of independence and conditional independence tests between categorical covariates and a continuous response variable, which has an immediate application in genetics. Instead of estimating the conditional distribution of the response given values of covariates, we model the conditional distribution of covariates given the discretized response (aka "slices"). By assigning a prior probability to each possible discretization scheme, we can compute efficiently a Bayes factor (BF)-statistic for the independence (or conditional independence) test using a dynamic programming algorithm. Asymptotic and finite-sample properties such as power and null distribution of the BF statistic are studied, and a stepwise variable selection method based on the BF statistic is further developed. We compare the BF statistic with some existing classical methods and demonstrate its statistical power through extensive simulation studies. We apply the proposed method to a mouse genetics data set aiming to detect quantitative trait loci (QTLs) and obtain promising results.Comment: 32 pages, 7 figure

Bayesian meta-analysis for identifying periodically expressed genes in fission yeast cell cycle

The effort to identify genes with periodic expression during the cell cycle from genome-wide microarray time series data has been ongoing for a decade. However, the lack of rigorous modeling of periodic expression as well as the lack of a comprehensive model for integrating information across genes and experiments has impaired the effort for the accurate identification of periodically expressed genes. To address the problem, we introduce a Bayesian model to integrate multiple independent microarray data sets from three recent genome-wide cell cycle studies on fission yeast. A hierarchical model was used for data integration. In order to facilitate an efficient Monte Carlo sampling from the joint posterior distribution, we develop a novel Metropolis--Hastings group move. A surprising finding from our integrated analysis is that more than 40% of the genes in fission yeast are significantly periodically expressed, greatly enhancing the reported 10--15% of the genes in the current literature. It calls for a reconsideration of the periodically expressed gene detection problem.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS300 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org