Orchestrating high-throughput genomic analysis with Bioconductor.

Bioconductor is an open-source, open-development software project for the analysis and comprehension of high-throughput data in genomics and molecular biology. The project aims to enable interdisciplinary research, collaboration and rapid development of scientific software. Based on the statistical programming language R, Bioconductor comprises 934 interoperable packages contributed by a large, diverse community of scientists. Packages cover a range of bioinformatic and statistical applications. They undergo formal initial review and continuous automated testing. We present an overview for prospective users and contributors.

VariantAnnotation: a Bioconductor package for exploration and annotation of genetic variants.

UNLABELLED: VariantAnnotation is an R / Bioconductor package for the exploration and annotation of genetic variants. Capabilities exist for reading, writing and filtering variant call format (VCF) files. VariantAnnotation allows ready access to additional R / Bioconductor facilities for advanced statistical analysis, data transformation, visualization and integration with diverse genomic resources. AVAILABILITY AND IMPLEMENTATION: This package is implemented in R and available for download at the Bioconductor Web site (http://bioconductor.org/packages/2.13/bioc/html/VariantAnnotation.html). The package contains extensive help pages for individual functions and a 'vignette' outlining typical work flows; it is made available under the open source 'Artistic-2.0' license. Version 1.9.38 was used in this article.

A hybrid EM and Monte Carlo EM algorithm and its application to analysis of transmission of infectious diseases.

In epidemics of infectious diseases such as influenza, an individual may have one of four possible final states: prior immune, escaped from infection, infected with symptoms, and infected asymptomatically. The exact state is often not observed. In addition, the unobserved transmission times of asymptomatic infections further complicate analysis. Under the assumption of missing at random, data-augmentation techniques can be used to integrate out such uncertainties. We adapt an importance-sampling-based Monte Carlo Expectation-Maximization (MCEM) algorithm to the setting of an infectious disease transmitted in close contact groups. Assuming the independence between close contact groups, we propose a hybrid EM-MCEM algorithm that applies the MCEM or the traditional EM algorithms to each close contact group depending on the dimension of missing data in that group, and discuss the variance estimation for this practice. In addition, we propose a bootstrap approach to assess the total Monte Carlo error and factor that error into the variance estimation. The proposed methods are evaluated using simulation studies. We use the hybrid EM-MCEM algorithm to analyze two influenza epidemics in the late 1970s to assess the effects of age and preseason antibody levels on the transmissibility and pathogenicity of the viruses.

Risk prediction using genome-wide association studies.

Over the last few years, many new genetic associations have been identified by genome-wide association studies (GWAS). There are potentially many uses of these identified variants: a better understanding of disease etiology, personalized medicine, new leads for studying underlying biology, and risk prediction. Recently, there has been some skepticism regarding the prospects of risk prediction using GWAS, primarily motivated by the fact that individual effect sizes of variants associated with the phenotype are mostly small. However, there have also been arguments that many disease-associated variants have not yet been identified; hence, prospects for risk prediction may improve if more variants are included. From a risk prediction perspective, it is reasonable to average a larger number of predictors, of which some may have (limited) predictive power, and some actually may be noise. The idea being that when added together, the combined small signals results in a signal that is stronger than the noise from the unrelated predictors. We examine various aspects of the construction of models for the estimation of disease probability. We compare different methods to construct such models, to examine how implementation of cross-validation may influence results, and to examine which single nucleotide polymorphisms (SNPs) are most useful for prediction. We carry out our investigation on GWAS of the Welcome Trust Case Control Consortium. For Crohn's disease, we confirm our results on another GWAS. Our results suggest that utilizing a larger number of SNPs than those which reach genome-wide significance, for example using the lasso, improves the construction of risk prediction models.

FluTE, a publicly available stochastic influenza epidemic simulation model.

Mathematical and computer models of epidemics have contributed to our understanding of the spread of infectious disease and the measures needed to contain or mitigate them. To help prepare for future influenza seasonal epidemics or pandemics, we developed a new stochastic model of the spread of influenza across a large population. Individuals in this model have realistic social contact networks, and transmission and infections are based on the current state of knowledge of the natural history of influenza. The model has been calibrated so that outcomes are consistent with the 1957/1958 Asian A(H2N2) and 2009 pandemic A(H1N1) influenza viruses. We present examples of how this model can be used to study the dynamics of influenza epidemics in the United States and simulate how to mitigate or delay them using pharmaceutical interventions and social distancing measures. Computer simulation models play an essential role in informing public policy and evaluating pandemic preparedness plans. We have made the source code of this model publicly available to encourage its use and further development.

Genomic Annotation Resources in R/Bioconductor.

Annotation resources make up a significant proportion of the Bioconductor project (Huber et al., Nat Methods 12:115-121, 2015). And there are also a diverse set of online resources available which are accessed using specific packages. Here we describe the most popular of these resources and give some high level examples on how to use them.