Inferring context-sensitive probablistic boolean networks from gene expression data under multi-biological conditions

In recent years biological microarrays have emerged as a high-throughput data acquisition technology in bioinformatics. In conjunction with this, there is an increasing need to develop frameworks for the formal analysis of biological pathways. A modeling approach defined as Probabilistic Boolean Networks (PBNs) was proposed for inferring genetic regulatory networks [1]. This technology, an extension of Boolean Networks [2], is able to capture the time-varying dependencies with deterministic probabilities for a series of sets of predictor functions

Representation of probabilistic scientific knowledge

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Soldatova et al; licensee BioMed Central Ltd.The theory of probability is widely used in biomedical research for data analysis and modelling. In previous work the probabilities of the research hypotheses have been recorded as experimental metadata. The ontology HELO is designed to support probabilistic reasoning, and provides semantic descriptors for reporting on research that involves operations with probabilities. HELO explicitly links research statements such as hypotheses, models, laws, conclusions, etc. to the associated probabilities of these statements being true. HELO enables the explicit semantic representation and accurate recording of probabilities in hypotheses, as well as the inference methods used to generate and update those hypotheses. We demonstrate the utility of HELO on three worked examples: changes in the probability of the hypothesis that sirtuins regulate human life span; changes in the probability of hypotheses about gene functions in the S. cerevisiae aromatic amino acid pathway; and the use of active learning in drug design (quantitative structure activity relation learning), where a strategy for the selection of compounds with the highest probability of improving on the best known compound was used. HELO is open source and available at https://github.com/larisa-soldatova/HELO.This work was partially supported by grant BB/F008228/1 from the UK Biotechnology & Biological Sciences Research Council, from the European Commission under the FP7 Collaborative Programme, UNICELLSYS, KU Leuven GOA/08/008 and ERC Starting Grant 240186

Measuring reproducibility of high-throughput experiments

Reproducibility is essential to reliable scientific discovery in high-throughput experiments. In this work we propose a unified approach to measure the reproducibility of findings identified from replicate experiments and identify putative discoveries using reproducibility. Unlike the usual scalar measures of reproducibility, our approach creates a curve, which quantitatively assesses when the findings are no longer consistent across replicates. Our curve is fitted by a copula mixture model, from which we derive a quantitative reproducibility score, which we call the "irreproducible discovery rate" (IDR) analogous to the FDR. This score can be computed at each set of paired replicate ranks and permits the principled setting of thresholds both for assessing reproducibility and combining replicates. Since our approach permits an arbitrary scale for each replicate, it provides useful descriptive measures in a wide variety of situations to be explored. We study the performance of the algorithm using simulations and give a heuristic analysis of its theoretical properties. We demonstrate the effectiveness of our method in a ChIP-seq experiment.Comment: Published in at http://dx.doi.org/10.1214/11-AOAS466 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Probabilistic estimation of microarray data reliability and underlying gene expression

Background: The availability of high throughput methods for measurement of mRNA concentrations makes the reliability of conclusions drawn from the data and global quality control of samples and hybridization important issues. We address these issues by an information theoretic approach, applied to discretized expression values in replicated gene expression data. Results: Our approach yields a quantitative measure of two important parameter classes: First, the probability $P(\sigma | S)$ that a gene is in the biological state $\sigma$ in a certain variety, given its observed expression $S$ in the samples of that variety. Second, sample specific error probabilities which serve as consistency indicators of the measured samples of each variety. The method and its limitations are tested on gene expression data for developing murine B-cells and a $t$-test is used as reference. On a set of known genes it performs better than the $t$-test despite the crude discretization into only two expression levels. The consistency indicators, i.e. the error probabilities, correlate well with variations in the biological material and thus prove efficient. Conclusions: The proposed method is effective in determining differential gene expression and sample reliability in replicated microarray data. Already at two discrete expression levels in each sample, it gives a good explanation of the data and is comparable to standard techniques.Comment: 11 pages, 4 figure

Deep generative modeling for single-cell transcriptomics.

Single-cell transcriptome measurements can reveal unexplored biological diversity, but they suffer from technical noise and bias that must be modeled to account for the resulting uncertainty in downstream analyses. Here we introduce single-cell variational inference (scVI), a ready-to-use scalable framework for the probabilistic representation and analysis of gene expression in single cells ( https://github.com/YosefLab/scVI ). scVI uses stochastic optimization and deep neural networks to aggregate information across similar cells and genes and to approximate the distributions that underlie observed expression values, while accounting for batch effects and limited sensitivity. We used scVI for a range of fundamental analysis tasks including batch correction, visualization, clustering, and differential expression, and achieved high accuracy for each task