Statistical Applications in Genetics and Molecular Biology最新文献

Batch effect Reduction of mIcroarray data with Dependent samples usinG Empirical Bayes (BRIDGE) is a recently developed statistical method to address the issue of batch effect correction in batch-confounded microarray studies with dependent samples. The key component of the BRIDGE methodology is the use of samples run as technical replicates in two or more batches, "bridging samples", to inform batch effect correction/attenuation. While previously published results indicate a relationship between the number of bridging samples, M, and the statistical power of downstream statistical testing on the batch-corrected data, there is of yet no formal statistical framework or user-friendly software, for estimating M to achieve a specific statistical power for hypothesis tests conducted on the batch-corrected data. To fill this gap, we developed pwrBRIDGE, a simulation-based approach to estimate the bridging sample size, M, in batch-confounded longitudinal microarray studies. To illustrate the use of pwrBRIDGE, we consider a hypothetical, longitudinal batch-confounded study whose goal is to identify Alzheimer's disease (AD) progression-associated genes from amnestic mild cognitive impairment (aMCI) to AD in human blood after a 5-year follow-up. pwrBRIDGE helps researchers design and plan batch-confounded microarray studies with dependent samples to avoid over- or under-powered studies.

Correlation analysis is widely used in biological studies to infer molecular relationships within biological networks. Recently, single-cell analysis has drawn tremendous interests, for its ability to obtain high-resolution molecular phenotypes. It turns out that there is little overlap of co-expressed genes identified in single-cell level investigations with that of population level investigations. However, the nature of the relationship of correlations between single-cell and population levels remains unclear. In this manuscript, we aimed to unveil the origin of the differences between the correlation coefficients at the single-cell level and that at the population level, and bridge the gap between them. Through developing formulations to link correlations at the single-cell and the population level, we illustrated that aggregated correlations could be stronger, weaker or equal to the corresponding individual correlations, depending on the variations and the correlations within the population. When the correlation within the population is weaker than the individual correlation, the aggregated correlation is stronger than the corresponding individual correlation. Besides, our data indicated that aggregated correlation is more likely to be stronger than the corresponding individual correlation, and it was rare to find gene-pairs exclusively strongly correlated at the single-cell level. Through a bottom-up approach to model interactions between molecules in a signaling cascade or a multi-regulator-controlled gene expression, we surprisingly found that the existence of interaction between two components could not be excluded simply based on their low correlation coefficients, suggesting a reconsideration of connectivity within biological networks which was derived solely from correlation analysis. We also investigated the impact of technical random measurement errors on the correlation coefficients for the single-cell level and the population level. The results indicate that the aggregated correlation is relatively robust and less affected. Because of the heterogeneity among single cells, correlation coefficients calculated based on data of the single-cell level might be different from that of the population level. Depending on the specific question we are asking, proper sampling and normalization procedure should be done before we draw any conclusions.

Gene selection is one of the key steps for gene expression data analysis. An SVM-based ensemble feature selection method is proposed in this paper. Firstly, the method builds many subsets by using Monte Carlo sampling. Secondly, ranking all the features on each of the subsets and integrating them to obtain a final ranking list. Finally, the optimum feature set is determined by a backward feature elimination strategy. This method is applied to the analysis of 4 public datasets: the Leukemia, Prostate, Colorectal, and SMK_CAN, resulting 7, 10, 13, and 32 features. The AUC obtained from independent test sets are 0.9867, 0.9796, 0.9571, and 0.9575, respectively. These results indicate that the features selected by the proposed method can improve sample classification accuracy, and thus be effective for gene selection from gene expression data.

Due to the advancement of genome sequencing techniques, a great stride has been made in exome sequencing such that the association study between disease and genetic variants has become feasible. Some powerful and well-known association tests have been proposed to test the association between a group of genes and the disease of interest. However, some challenges still remain, in particular, many factors can affect the performance of testing power, e.g., the sample size, the number of causal and non-causal variants, and direction of the effect of causal variants. Recently, a powerful test, called T_REM , is derived based on a random effects model. T_REM has the advantages of being less sensitive to the inclusion of non-causal rare variants or low effect common variants or the presence of missing genotypes. However, the testing power of T_REM can be low when a portion of causal variants has effects in opposite directions. To improve the drawback of T_REM , we propose a novel test, called T_ROB , which keeps the advantages of T_REM and is more robust than T_REM in terms of having adequate power in the case of variants with opposite directions of effect. Simulation results show that T_ROB has a stable type I error rate and outperforms T_REM when the proportion of risk variants decreases to a certain level and its advantage over T_REM increases as the proportion decreases. Furthermore, T_ROB outperforms several other competing tests in most scenarios. The proposed methodology is illustrated using the Shanghai Breast Cancer Study.

RNA-protein interactions have long being recognised as crucial regulators of gene expression. Recently, the development of scalable experimental techniques to measure these interactions has revolutionised the field, leading to the production of large-scale datasets which offer both opportunities and challenges for machine learning techniques. In this brief note, we will discuss some of the major stumbling blocks towards the use of machine learning in computational RNA biology, focusing specifically on the problem of predicting RNA-protein interactions from next-generation sequencing data.

The inference of genetic regulatory networks (GRNs) reveals how genes interact with each other. A few genes can regulate many genes as targets to control cell functions. We present new methods based on the order-1 vector autoregression (VAR1) for inferring GRNs from gene expression time series. The methods use the automatic relevance determination (ARD) to incorporate the regulatory hub structure into the estimation of VAR1 in a Bayesian framework. Several sparse approximation schemes are applied to the estimated regression weights or VAR1 model to generate the sparse weighted adjacency matrices representing the inferred GRNs. We apply the proposed and several widespread reference methods to infer GRNs with up to 100 genes using simulated, DREAM4 in silico and experimental E. coli gene expression time series. We show that the proposed methods are efficient on simulated hub GRNs and scale-free GRNs using short time series simulated by VAR1s and outperform reference methods on small-scale DREAM4 in silico GRNs and E. coli GRNs. They can utilize the known major regulatory hubs to improve the performance on larger DREAM4 in silico GRNs and E. coli GRNs. The impact of nonlinear time series data on the performance of proposed methods is discussed.

Batch-effects present challenges in the analysis of high-throughput molecular data and are particularly problematic in longitudinal studies when interest lies in identifying genes/features whose expression changes over time, but time is confounded with batch. While many methods to correct for batch-effects exist, most assume independence across samples; an assumption that is unlikely to hold in longitudinal microarray studies. We propose Batch effect Reduction of mIcroarray data with Dependent samples usinGEmpirical Bayes (BRIDGE), a three-step parametric empirical Bayes approach that leverages technical replicate samples profiled at multiple timepoints/batches, so-called "bridge samples", to inform batch-effect reduction/attenuation in longitudinal microarray studies. Extensive simulation studies and an analysis of a real biological data set were conducted to benchmark the performance of BRIDGE against both ComBat and longitudinalComBat. Our results demonstrate that while all methods perform well in facilitating accurate estimates of time effects, BRIDGE outperforms both ComBat and longitudinal ComBat in the removal of batch-effects in data sets with bridging samples, and perhaps as a result, was observed to have improved statistical power for detecting genes with a time effect. BRIDGE demonstrated competitive performance in batch effect reduction of confounded longitudinal microarray studies, both in simulated and a real data sets, and may serve as a useful preprocessing method for researchers conducting longitudinal microarray studies that include bridging samples.