Cambridge Bioinformatics
 

Publications

  • Silvia Chiappa, John Winn, Ana Viñuela, Hannah Tipney, and Timothy D. Spector, A probabilistic model of biological ageing of the lungs for analysing the effects of smoking, asthma and COPD, in Respiratory Research, vol. 14:60, 30 May 2013
  • Oliver Stegle, Leopold Parts, Matias Piipari, John Winn, and Richard Durbin, Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses, in Nature Protocols, vol. 7, pp. 500-507, Nature Publishing Group, February 2012

    We present PEER (probabilistic estimation of expression residuals), a software package implementing statistical models that improve the sensitivity and interpretability of genetic associations in population-scale expression data. This approach builds on factor analysis methods that infer broad variance components in the measurements. PEER takes as input transcript profiles and covariates from a set of individuals, and then outputs hidden factors that explain much of the expression variability. Optionally, these factors can be interpreted as pathway or transcription factor activations by providing prior information about which genes are involved in the pathway or targeted by the factor. The inferred factors are used in genetic association analyses. First, they are treated as additional covariates, and are included in the model to increase detection power for mapping expression traits. Second, they are analyzed as phenotypes themselves to understand the causes of global expression variability. PEER extends previous related surrogate variable models and can be implemented within hours on a desktop computer.

  • Leopold Parts, Oliver Stegle, John Winn, and Richard Durbin, Joint Genetic Analysis of Gene Expression Data with Inferred Cellular Phenotypes, in PLoS Genetics, PLoS, January 2011

    Even within a defined cell type, the expression level of a gene differs in individual samples. The effects of genotype, measured factors such as environmental conditions, and their interactions have been explored in recent studies. Methods have also been developed to identify unmeasured intermediate factors that coherently influence transcript levels of multiple genes. Here, we show how to bring these two approaches together and analyse genetic effects in the context of inferred determinants of gene expression. We use a sparse factor analysis model to infer hidden factors, which we treat as intermediate cellular phenotypes that in turn affect gene expression in a yeast dataset. We find that the inferred phenotypes are associated with locus genotypes and environmental conditions and can explain genetic associations to genes in trans. For the first time, we consider and find interactions between genotype and intermediate phenotypes inferred from gene expression levels, complementing and extending established results.

  • Oliver Stegle, Leopold Parts, Richard Durbin, and John Winn, A Bayesian Framework to Account for Complex Non-Genetic Factors in Gene Expression Levels Greatly Increases Power in eQTL Studies, in PLoS Computational Biology, PLoS Computational Biology (Public Library of Science Computational Biology), , 6 May 2010

    Gene expression measurements are influenced by a wide range of factors, such as the state of the cell, experimental conditions and variants in the sequence of regulatory regions. To understand the effect of a variable of interest, such as the genotype of a locus, it is important to account for variation that is due to confounding causes. Here, we present VBQTL, a probabilistic approach for mapping expression quantitative trait loci (eQTLs) that jointly models contributions from genotype as well as known and hidden confounding factors. VBQTL is implemented within an efficient and flexible inference framework, making it fast and tractable on large-scale problems. We compare the performance of VBQTL with alternative methods for dealing with confounding variability on eQTL mapping datasets from simulations, yeast, mouse, and human. Employing Bayesian complexity control and joint modelling is shown to result in more precise estimates of the contribution of different confounding factors resulting in additional associations to measured transcript levels compared to alternative approaches. We present a threefold larger collection of cis eQTLs than previously found in a whole-genome eQTL scan of an outbred human population. Altogether, 27% of the tested probes show a significant genetic association in cis, and we validate that the additional eQTLs are likely to be real by replicating them in different sets of individuals. Our method is the next step in the analysis of high-dimensional phenotype data, and its application has revealed insights into genetic regulation of gene expression by demonstrating more abundant cis-acting eQTLs in human than previously shown. Our software is freely available online at http://www.sanger.ac.uk/resources/softwa​re/peer/ .

  • Magnus Rattray, Oliver Stegle, Kevin Sharp, and John Winn, Inference algorithms and learning theory for Bayesian sparse factor analysis, in International Workshop on Statistical-Mechanical Informatics 2009, Journal of Physics: Conference Series, 2009

    Bayesian sparse factor analysis has many applications; for example, it has been applied to the problem of inferring a sparse regulatory network from gene expression data. We describe a number of inference algorithms for Bayesian sparse factor analysis using a slab and spike mixture prior. These include well-established Markov chain Monte Carlo (MCMC) and variational Bayes (VB) algorithms as well as a novel hybrid of VB and Expectation Propagation (EP). For the case of a single latent factor we derive a theory for learning performance using the replica method. We compare the MCMC and VB/EP algorithm results with simulated data to the theoretical prediction. The results for MCMC agree closely with the theory as expected. Results for VB/EP are slightly sub-optimal but show that the new algorithm is effective for sparse inference. In large-scale problems MCMC is infeasible due to computational limitations and the VB/EP algorithm then provides a very useful computationally efficient alternative.

  • Oliver Stegle, Anitha Kannan, Richard Durbin, and John M. Winn, Accounting for Non-genetic Factors Improves the Power of eQTL Studies, in International Conference on Research in Computational Molecular Biology, 2008

    The recent availability of large scale data sets profiling single nucleotide polymorphisms (SNPs) and gene expression across different human populations, has directed much attention towards discovering patterns of genetic variation and their association with gene regulation. The influence of environmental, developmental and other factors on gene expression can obscure such associations. We present a model that explicitly accounts for non-genetic factors so as to improve significantly the power of an expression Quantitative Trait Loci (eQTL) study. Our method also exploits the inherent block structure of haplotype data to further enhance its sensitivity. On data from the HapMap project, we find more than three times as many significant associations than a standard eQTL method.

  • Jim C. Huang, Anitha Kannan, and John M. Winn, Bayesian association of haplotypes and non-genetic factors to regulatory and phenotypic variation in human populations, in International Conference on Intelligent Systems for Molecular Biology, 2007
Overview