Differentially expressed heterogeneous overdispersion genes testing for count data.

The mRNA-seq data analysis is a powerful technology for inferring information from biological systems of interest. Specifically, the sequenced RNA fragments are aligned with genomic reference sequences, and we count the number of sequence fragments corresponding to each gene for each condition. A gene is identified as differentially expressed (DE) if the difference in its count numbers between conditions is statistically significant. Several statistical analysis methods have been developed to detect DE genes based on RNA-seq data. However, the existing methods could suffer decreasing power to identify DE genes arising from overdispersion and limited sample size, where overdispersion refers to the empirical phenomenon that the variance of read counts is larger than the mean of read counts. We propose a new differential expression analysis procedure: heterogeneous overdispersion genes testing (DEHOGT) based on heterogeneous overdispersion modeling and a post-hoc inference procedure. DEHOGT integrates sample information from all conditions and provides a more flexible and adaptive overdispersion modeling for the RNA-seq read count. DEHOGT adopts a gene-wise estimation scheme to enhance the detection power of differentially expressed genes when the number of replicates is limited as long as the number of conditions is large. DEHOGT is tested on the synthetic RNA-seq read count data and outperforms two popular existing methods, DESeq2 and EdgeR, in detecting DE genes. We apply the proposed method to a test dataset using RNAseq data from microglial cells. DEHOGT tends to detect more differently expressed genes potentially related to microglial cells under different stress hormones treatments.

False Discovery Rate Control in Cancer Biomarker Selection Using Knockoffs.

The discovery of biomarkers that are informative for cancer risk assessment, diagnosis, prognosis and treatment predictions is crucial. Recent advances in high-throughput genomics make it plausible to select biomarkers from the vast number of human genes in an unbiased manner. Yet, control of false discoveries is challenging given the large number of genes versus the relatively small number of patients in a typical cancer study. To ensure that most of the discoveries are true, we employ a knockoff procedure to control false discoveries. Our method is general and flexible, accommodating arbitrary covariate distributions, linear and nonlinear associations, and survival models. In simulations, our method compares favorably to the alternatives; its utility of identifying important genes in real clinical applications is demonstrated by the identification of seven genes associated with Breslow thickness in skin cutaneous melanoma patients.