M-BISON: Microarray-based integration of data sources using networks

BACKGROUND: The accurate detection of differentially expressed (DE) genes has become a central task in microarray analysis. Unfortunately, the noise level and experimental variability of microarrays can be limiting. While a number of existing methods partially overcome these limitations by incorporating biological knowledge in the form of gene groups, these methods sacrifice gene-level resolution. This loss of precision can be inappropriate, especially if the desired output is a ranked list of individual genes. To address this shortcoming, we developed M-BISON (Microarray-Based Integration of data SOurces using Networks), a formal probabilistic model that integrates background biological knowledge with microarray data to predict individual DE genes. RESULTS: M-BISON improves signal detection on a range of simulated data, particularly when using very noisy microarray data. We also applied the method to the task of predicting heat shock-related differentially expressed genes in S. cerevisiae, using an hsf1 mutant microarray dataset and conserved yeast DNA sequence motifs. Our results demonstrate that M-BISON improves the analysis quality and makes predictions that are easy to interpret in concert with incorporated knowledge. Specifically, M-BISON increases the AUC of DE gene prediction from .541 to .623 when compared to a method using only microarray data, and M-BISON outperforms a related method, GeneRank. Furthermore, by analyzing M-BISON predictions in the context of the background knowledge, we identified YHR124W as a potentially novel player in the yeast heat shock response. CONCLUSION: This work provides a solid foundation for the principled integration of imperfect biological knowledge with gene expression data and other high-throughput data sources

Site fidelity and range size of wintering Barnacle Geese Branta leucopsis

Barnacle Geese restrict their movements to relatively few key sites and exhibit considerable variation in ranging behaviour. To examine individual and seasonal variation in site fidelity, habitat use, range size and foraging strategies of Barnacle Geese Branta leucopsis, the movements of 18 male Barnacle Geese tagged in two discrete areas were tracked for 3–6 months from late autumn until departure on the spring migration. Tagged geese concentrated their feeding in a relatively small proportion of apparently suitable habitat. Geese moved increasingly further afield in midwinter, and there was a clear predeparture shift to the largest area of relatively undisturbed, and possibly more nitrogen-rich, saltmarsh on the Solway. Birds from one of the two capture sites tended to be more sedentary and have smaller home ranges

Core module biomarker identification with network exploration for breast cancer metastasis

<p>Abstract</p> <p>Background</p> <p>In a complex disease, the expression of many genes can be significantly altered, leading to the appearance of a differentially expressed "disease module". Some of these genes directly correspond to the disease phenotype, (i.e. "driver" genes), while others represent closely-related first-degree neighbours in gene interaction space. The remaining genes consist of further removed "passenger" genes, which are often not directly related to the original cause of the disease. For prognostic and diagnostic purposes, it is crucial to be able to separate the group of "driver" genes and their first-degree neighbours, (i.e. "core module") from the general "disease module".</p> <p>Results</p> <p>We have developed COMBINER: COre Module Biomarker Identification with Network ExploRation. COMBINER is a novel pathway-based approach for selecting highly reproducible discriminative biomarkers. We applied COMBINER to three benchmark breast cancer datasets for identifying prognostic biomarkers. COMBINER-derived biomarkers exhibited 10-fold higher reproducibility than other methods, with up to 30-fold greater enrichment for known cancer-related genes, and 4-fold enrichment for known breast cancer susceptible genes. More than 50% and 40% of the resulting biomarkers were cancer and breast cancer specific, respectively. The identified modules were overlaid onto a map of intracellular pathways that comprehensively highlighted the hallmarks of cancer. Furthermore, we constructed a global regulatory network intertwining several functional clusters and uncovered 13 confident "driver" genes of breast cancer metastasis.</p> <p>Conclusions</p> <p>COMBINER can efficiently and robustly identify disease core module genes and construct their associated regulatory network. In the same way, it is potentially applicable in the characterization of any disease that can be probed with microarrays.</p

Using Pre-existing Microarray Datasets to Increase Experimental Power: Application to Insulin Resistance

Although they have become a widely used experimental technique for identifying differentially expressed (DE) genes, DNA microarrays are notorious for generating noisy data. A common strategy for mitigating the effects of noise is to perform many experimental replicates. This approach is often costly and sometimes impossible given limited resources; thus, analytical methods are needed which increase accuracy at no additional cost. One inexpensive source of microarray replicates comes from prior work: to date, data from hundreds of thousands of microarray experiments are in the public domain. Although these data assay a wide range of conditions, they cannot be used directly to inform any particular experiment and are thus ignored by most DE gene methods. We present the SVD Augmented Gene expression Analysis Tool (SAGAT), a mathematically principled, data-driven approach for identifying DE genes. SAGAT increases the power of a microarray experiment by using observed coexpression relationships from publicly available microarray datasets to reduce uncertainty in individual genes' expression measurements. We tested the method on three well-replicated human microarray datasets and demonstrate that use of SAGAT increased effective sample sizes by as many as 2.72 arrays. We applied SAGAT to unpublished data from a microarray study investigating transcriptional responses to insulin resistance, resulting in a 50% increase in the number of significant genes detected. We evaluated 11 (58%) of these genes experimentally using qPCR, confirming the directions of expression change for all 11 and statistical significance for three. Use of SAGAT revealed coherent biological changes in three pathways: inflammation, differentiation, and fatty acid synthesis, furthering our molecular understanding of a type 2 diabetes risk factor. We envision SAGAT as a means to maximize the potential for biological discovery from subtle transcriptional responses, and we provide it as a freely available software package that is immediately applicable to any human microarray study

Prognostic analysis of histopathological images using pre-trained convolutional neural networks: Application to hepatocellular carcinoma

Histopathological images contain rich phenotypic descriptions of the molecular processes underlying disease progression. Convolutional neural networks, state-of-the-art image analysis techniques in computer vision, automatically learn representative features from such images which can be useful for disease diagnosis, prognosis, and subtyping. Hepatocellular carcinoma (HCC) is the sixth most common type of primary liver malignancy. Despite the high mortality rate of HCC, little previous work has made use of CNN models to explore the use of histopathological images for prognosis and clinical survival prediction of HCC. We applied three pre-trained CNN models-VGG 16, Inception V3 and ResNet 50-to extract features from HCC histopathological images. Sample visualization and classification analyses based on these features showed a very clear separation between cancer and normal samples. In a univariate Cox regression analysis, 21.4% and 16% of image features on average were significantly associated with overall survival (OS) and disease-free survival (DFS), respectively. We also observed significant correlations between these features and integrated biological pathways derived from gene expression and copy number variation. Using an elastic net regularized Cox Proportional Hazards model of OS constructed from Inception image features, we obtained a concordance index (C-index) of 0.789 and a significant log-rank test (p = 7.6E-18). We also performed unsupervised classification to identify HCC subgroups from image features. The optimal two subgroups discovered using Inception model image features showed significant differences in both overall (C-index = 0.628 and p = 7.39E-07) and DFS (C-index = 0.558 and p = 0.012). Our work demonstrates the utility of extracting image features using pre-trained models by using them to build accurate prognostic models of HCC as well as highlight significant correlations between these features, clinical survival, and relevant biological pathways. Image features extracted from HCC histopathological images using the pre-trained CNN models VGG 16, Inception V3 and ResNet 50 can accurately distinguish normal and cancer samples. Furthermore, these image features are significantly correlated with survival and relevant biological pathways

SParSE++: Improved event-based stochastic parameter search

Background: Despite the increasing availability of high performance computing capabilities, analysis and characterization of stochastic biochemical systems remain a computational challenge. To address this challenge, the Stochastic Parameter Search for Events (SParSE) was developed to automatically identify reaction rates that yield a probabilistic user-specified event. SParSE consists of three main components: the multi-level cross-entropy method, which identifies biasing parameters to push the system toward the event of interest, the related inverse biasing method, and an optional interpolation of identified parameters. While effective for many examples, SParSE depends on the existence of a sufficient amount of intrinsic stochasticity in the system of interest. In the absence of this stochasticity, SParSE can either converge slowly or not at all. Results: We have developed SParSE++, a substantially improved algorithm for characterizing target events in terms of system parameters. SParSE++ makes use of a series of novel parameter leaping methods that accelerate the convergence rate to the target event, particularly in low stochasticity cases. In addition, the interpolation stage is modified to compute multiple interpolants and to choose the optimal one in a statistically rigorous manner. We demonstrate the performance of SParSE++ on four example systems: a birth-death process, a reversible isomerization model, SIRS disease dynamics, and a yeast polarization model. In all four cases, SParSE++ shows significantly improved computational efficiency over SParSE, with the largest improvements resulting from analyses with the strictest error tolerances. Conclusions: As researchers continue to model realistic biochemical systems, the need for efficient methods to characterize target events will grow. The algorithmic advancements provided by SParSE++ fulfill this need, enabling characterization of computationally intensive biochemical events that are currently resistant to analysis

Additional file 1 of SParSE++: improved event-based stochastic parameter search

Appendix. In this file, we present a list of variables and definitions used in the manuscript (Section A). Detailed pseudocode for the SParSE++ driver, multi-level CE method, and inverse biasing method are given in Section B. Section C contains two tables regarding the yeast polarization process. The first table (Table 4) lists thirty randomly generated initial reaction rates that were used to run the SParSE and SParSE++ algorithms. The second table (Table 5) contains an algorithmic breakdown for each of the initial reaction rates. (PDF 234 kb

GEOlimma: differential expression analysis and feature selection using pre-existing microarray data

Background: Differential expression and feature selection analyses are essential steps for the development of accurate diagnostic/prognostic classifiers of complicated human diseases using transcriptomics data. These steps are particularly challenging due to the curse of dimensionality and the presence of technical and biological noise. A promising strategy for overcoming these challenges is the incorporation of pre-existing transcriptomics data in the identification of differentially expressed (DE) genes. This approach has the potential to improve the quality of selected genes, increase classification performance, and enhance biological interpretability. While a number of methods have been developed that use pre-existing data for differential expression analysis, existing methods do not leverage the identities of experimental conditions to create a robust metric for identifying DE genes. Results: In this study, we propose a novel differential expression and feature selection method—GEOlimma—which combines pre-existing microarray data from the Gene Expression Omnibus (GEO) with the widely-applied Limma method for differential expression analysis. We first quantify differential gene expression across 2481 pairwise comparisons from 602 curated GEO Datasets, and we convert differential expression frequencies to DE prior probabilities. Genes with high DE prior probabilities show enrichment in cell growth and death, signal transduction, and cancer-related biological pathways, while genes with low prior probabilities were enriched in sensory system pathways. We then applied GEOlimma to four differential expression comparisons within two human disease datasets and performed differential expression, feature selection, and supervised classification analyses. Our results suggest that use of GEOlimma provides greater experimental power to detect DE genes compared to Limma, due to its increased effective sample size. Furthermore, in a supervised classification analysis using GEOlimma as a feature selection method, we observed similar or better classification performance than Limma given small, noisy subsets of an asthma dataset. Conclusions: Our results demonstrate that GEOlimma is a more effective method for differential gene expression and feature selection analyses compared to the standard Limma method. Due to its focus on gene-level differential expression, GEOlimma also has the potential to be applied to other high-throughput biological datasets