Motivation: Histone modifications are among the most important factors that control gene regulation. Computational methods that predict gene expression from histone modification signals are highly desirable for understanding their combinatorial effects in gene regulation. This knowledge can help in developing 'epigenetic drugs' for diseases like cancer. Previous studies for quantifying the relationship between histone modifications and gene expression levels either failed to capture combinatorial effects or relied on multiple methods that separate predictions and combinatorial analysis. This paper develops a unified discriminative framework using a deep convolutional neural network to classify gene expression using histone modification data as input. Our system, called DeepChrome, allows automatic extraction of complex interactions among important features. To simultaneously visualize the combinatorial interactions among histone modifications, we propose a novel optimization-based technique that generates feature pattern maps from the learnt deep model. This provides an intuitive description of underlying epigenetic mechanisms that regulate genes. Results: We show that DeepChrome outperforms state-of-the-art models like Support Vector Machines and Random Forests for gene expression classification task on 56 different cell-types from REMC database. The output of our visualization technique not only validates the previous observations but also allows novel insights about combinatorial interactions among histone modification marks, some of which have recently been observed by experimental studies.
@cite_18 leveraged the correlated nature of epigenetic signals in the REMC database, including histone modifications. Their tool, ChromImpute, imputed signals for a particular new sample using an ensemble of regression trees on all the other signals and samples. EFilter ( @cite_28 ), a linear estimation algorithm, predicted gene expression in a new sample by using imputed expression levels from similar samples. Unlike the studies discussed above, these works focus on imputing or predicting signals for new samples.
@cite_28 @cite_18
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We present a new Markov Chain Monte Carlo (MCMC) sampling algorithm for probabilistic programs. Our approach and tool, called R2, has the unique feature of employing program analysis in order to improve the efficiency of MCMC sampling. Given an input program P, R2 propagates observations in P backwards to obtain a semantically equivalent program P′ in which every probabilistic assignment is immediately followed by an observe statement. Inference is performed by a suitably modified version of the Metropolis-Hastings algorithm that exploits the structure of the program P′. This has the overall effect of preventing rejections due to program executions that fail to satisfy observations in P. We formalize the semantics of probabilistic programs and rigorously prove the correctness of R2. We also empirically demonstrate the effectiveness of R2--in particular, we show that R2 is able to produce results of similar quality as the CHURCH and STAN probabilistic programming tools with much shorter execution time. A major challenge in molecular biology is reverse-engineering the cis-regulatory logic that plays a major role in the control of gene expression. This program includes searching through DNA sequences to identify “motifs” that serve as the binding sites for transcription factors or, more generally, are predictive of gene expression across cellular conditions. Several approaches have been proposed for de novo motif discovery–searching sequences without prior knowledge of binding sites or nucleotide patterns. However, unbiased validation is not straightforward. We consider two approaches to unbiased validation of discovered motifs: testing the statistical significance of a motif using a DNA “background” sequence model to represent the null hypothesis and measuring performance in predicting membership in gene clusters. We demonstrate that the background models typically used are “too null,” resulting in overly optimistic assessments of significance, and argue that performance in predicting TF binding or expression patterns from DNA motifs should be assessed by held-out data, as in predictive learning. Applying this criterion to common motif discovery methods resulted in universally poor performance, although there is a marked improvement when motifs are statistically significant against real background sequences. Moreover, on synthetic data where “ground truth” is known, discriminative performance of all algorithms is far below the theoretical upper bound, with pronounced “over-fitting” in training. A key conclusion from this work is that the failure of de novo discovery approaches to accurately identify motifs is basically due to statistical intractability resulting from the fixed size of co-regulated gene clusters, and thus such failures do not necessarily provide evidence that unfound motifs are not active biologically. Consequently, the use of prior knowledge to enhance motif discovery is not just advantageous but necessary. An implementation of the LR and ALR algorithms is available at http: code.google.com p likelihood-ratio-motifs . Motivation: High-throughput data is providing a comprehensive view of the molecular changes in cancer tissues. New technologies allow for the simultaneous genome-wide assay of the state of genome copy number variation, gene expression, DNA methylation and epigenetics of tumor samples and cancer cell lines. Analyses of current data sets find that genetic alterations between patients can differ but often involve common pathways. It is therefore critical to identify relevant pathways involved in cancer progression and detect how they are altered in different patients. Results: We present a novel method for inferring patient-specific genetic activities incorporating curated pathway interactions among genes. A gene is modeled by a factor graph as a set of interconnected variables encoding the expression and known activity of a gene and its products, allowing the incorporation of many types of omic data as evidence. The method predicts the degree to which a pathway's activities (e.g. internal gene states, interactions or high-level ‘outputs’) are altered in the patient using probabilistic inference. Compared with a competing pathway activity inference approach called SPIA, our method identifies altered activities in cancer-related pathways with fewer false-positives in both a glioblastoma multiform (GBM) and a breast cancer dataset. PARADIGM identified consistent pathway-level activities for subsets of the GBM patients that are overlooked when genes are considered in isolation. Further, grouping GBM patients based on their significant pathway perturbations divides them into clinically-relevant subgroups having significantly different survival outcomes. These findings suggest that therapeutics might be chosen that target genes at critical points in the commonly perturbed pathway(s) of a group of patients. Availability:Source code available at http: sbenz.github.com Paradigm Contact: jstuart@soe.ucsc.edu Supplementary information:Supplementary data are available at Bioinformatics online. Abstract We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person's complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) e4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer's disease (AD)) in cognitively normal, late-middle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70 of the subjects (27 e4 homozygotes, 36 e4 heterozygotes and 67 e4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-e4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30 of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-e4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-e4 gene dose and PET-MRI scores that were strongly correlated with APOE-e4 gene dose (p