Volume 14, Issue 1

We present a multiple testing method for hypotheses that are ordered in space or time. Given such hypotheses, the elementary hypotheses as well as regions of consecutive hypotheses are of interest. These region hypotheses not only have intrinsic meaning but testing them also has the advantage that (potentially small) signals across a region are combined in one test. Because the expected number and length of potentially interesting regions are usually not available beforehand, we propose a method that tests all possible region hypotheses as well as all individual hypotheses in a single multiple testing procedure that controls the familywise error rate. We start at testing the global null-hypothesis and when this hypothesis can be rejected we continue with further specifying the exact location/locations of the effect present. The method is implemented in the R package cherry and is illustrated on a DNA copy number data set.

The analysis of polygenic, phenotypic characteristics such as quantitative traits or inheritable diseases requires reliable scoring of many genetic markers covering the entire genome. The advent of high-throughput sequencing technologies provides a new way to evaluate large numbers of single nucleotide polymorphisms as genetic markers. Combining the technologies with pooling of segregants, as performed in bulk segregant analysis, should, in principle, allow the simultaneous mapping of multiple genetic loci present throughout the genome. We propose a hidden Markov-model to analyze the marker data obtained by the bulk segregant next generation sequencing. The model includes several states, each associated with a different probability of observing the same/different nucleotide in an offspring as compared to the parent. The transitions between the molecular markers imply transitions between the states of the model. After estimating the transition probabilities and state-related probabilities of nucleotide (dis)similarity, the most probable state for each SNP is selected. The most probable states can then be used to indicate which genomic regions may be likely to contain trait-related genes. The application of the model is illustrated on the data from a study of ethanol tolerance in yeast. Software is written in R. R-functions, R-scripts and documentation are available on www.ibiostat.be/software/bioinformatics.

The binding behavior of molecules in nuclei of living cells can be studied through the analysis of images from fluorescence recovery after photobleaching experiments. However, there is still a lack of methodology for the statistical evaluation of FRAP data, especially for the joint analysis of multiple dynamic images. We propose a hierarchical Bayesian nonlinear model with mixed-effect priors based on local compartment models in order to obtain joint parameter estimates for all nuclei as well as to account for the heterogeneity of the nuclei population. We apply our method to a series of FRAP experiments of DNA methyltransferase 1 tagged to green fluorescent protein expressed in a somatic mouse cell line and compare the results to the application of three different fixed-effects models to the same series of FRAP experiments. With the proposed model, we get estimates of the off-rates of the interactions of the molecules under study together with credible intervals, and additionally gain information about the variability between nuclei. The proposed model is superior to and more robust than the tested fixed-effects models. Therefore, it can be used for the joint analysis of data from FRAP experiments on various similar nuclei.

Chromatin interactions mediated by a particular protein are of interest for studying gene regulation, especially the regulation of genes that are associated with, or known to be causative of, a disease. A recent molecular technique, Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET), that uses chromatin immunoprecipitation (ChIP) and high throughput paired-end sequencing, is able to detect such chromatin interactions genomewide. However, ChIA-PET may generate noise (i.e., pairings of DNA fragments by random chance) in addition to true signal (i.e., pairings of DNA fragments by interactions). In this paper, we propose MC_DIST based on a mixture modeling framework to identify true chromatin interactions from ChIA-PET count data (counts of DNA fragment pairs). The model is cast into a Bayesian framework to take into account the dependency among the data and the available information on protein binding sites and gene promoters to reduce false positives. A simulation study showed that MC_DIST outperforms the previously proposed hypergeometric model in terms of both power and type I error rate. A real data study showed that MC_DIST may identify potential chromatin interactions between protein binding sites and gene promoters that may be missed by the hypergeometric model. An R package implementing the MC_DIST model is available at http://www.stat.osu.edu/~statgen/SOFTWARE/MDM.

Experimental evolution is an important research method that allows for the study of evolutionary processes occurring in microorganisms. Here we present a novel approach to experimental evolution that is based on application of next generation sequencing. Under this approach population level sequencing is applied to an evolving population in which multiple first-step beneficial mutations occur concurrently. As a result, frequencies of multiple beneficial mutations are observed in each replicate of an experiment. For this new type of data we develop methods of statistical inference. In particular, we propose a method for imputing selection coefficients of first-step beneficial mutations. The imputed selection coefficient are then used for testing the distribution of first-step beneficial mutations and for estimation of mean selection coefficient. In the case when selection coefficients are uniformly distributed, collected data may also be used to estimate the total number of available first-step beneficial mutations.

Association rule mining is a knowledge discovery technique which informs researchers about relationships between variables in data. These relationships can be focused to a specific set of response variables. We propose an augmented version of this method to discover groups of genotypes which relate to specific outcomes. We derive the methodology to find these candidate groups of genotypes and illustrate how the method works on data regarding neuroinvasive complications of West Nile virus and through simulation.

An ordinal scale is commonly used to measure health status and disease related outcomes in hospital settings as well as in translational medical research. In addition, repeated measurements are common in clinical practice for tracking and monitoring the progression of complex diseases. Classical methodology based on statistical inference, in particular, ordinal modeling has contributed to the analysis of data in which the response categories are ordered and the number of covariates ( p ) remains smaller than the sample size ( n ). With the emergence of genomic technologies being increasingly applied for more accurate diagnosis and prognosis, high-dimensional data where the number of covariates ( p ) is much larger than the number of samples ( n ), are generated. To meet the emerging needs, we introduce our proposed model which is a two-stage algorithm: Extend the generalized monotone incremental forward stagewise (GMIFS) method to the cumulative logit ordinal model; and combine the GMIFS procedure with the classical mixed-effects model for classifying disease status in disease progression along with time. We demonstrate the efficiency and accuracy of the proposed models in classification using a time-course microarray dataset collected from the Inflammation and the Host Response to Injury study.