SAMHD1 is mutated recurrently in chronic lymphocytic leukemia and is involved in response to DNA damage.

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase and a nuclease that restricts HIV-1 in noncycling cells. Germ-line mutations in SAMHD1 have been described in patients with Aicardi-Goutières syndrome (AGS), a congenital autoimmune disease. In a previous longitudinal whole genome sequencing study of chronic lymphocytic leukemia (CLL), we revealed a SAMHD1 mutation as a potential founding event. Here, we describe an AGS patient carrying a pathogenic germ-line SAMHD1 mutation who developed CLL at 24 years of age. Using clinical trial samples, we show that acquired SAMHD1 mutations are associated with high variant allele frequency and reduced SAMHD1 expression and occur in 11% of relapsed/refractory CLL patients. We provide evidence that SAMHD1 regulates cell proliferation and survival and engages in specific protein interactions in response to DNA damage. We propose that SAMHD1 may have a function in DNA repair and that the presence of SAMHD1 mutations in CLL promotes leukemia development.

The Hamming Ball Sampler.

We introduce the Hamming ball sampler, a novel Markov chain Monte Carlo algorithm, for efficient inference in statistical models involving high-dimensional discrete state spaces. The sampling scheme uses an auxiliary variable construction that adaptively truncates the model space allowing iterative exploration of the full model space. The approach generalizes conventional Gibbs sampling schemes for discrete spaces and provides an intuitive means for user-controlled balance between statistical efficiency and computational tractability. We illustrate the generic utility of our sampling algorithm through application to a range of statistical models. Supplementary materials for this article are available online.

Bayesian feature and model selection for Gaussian mixture models.

We present a Bayesian method for mixture model training that simultaneously treats the feature selection and the model selection problem. The method is based on the integration of a mixture model formulation that takes into account the saliency of the features and a Bayesian approach to mixture learning that can be used to estimate the number of mixture components. The proposed learning algorithm follows the variational framework and can simultaneously optimize over the number of components, the saliency of the features, and the parameters of the mixture model. Experimental results using high-dimensional artificial and real data illustrate the effectiveness of the method.

Statistical Inference in Hidden Markov Models Using k-Segment Constraints.

Hidden Markov models (HMMs) are one of the most widely used statistical methods for analyzing sequence data. However, the reporting of output from HMMs has largely been restricted to the presentation of the most-probable (MAP) hidden state sequence, found via the Viterbi algorithm, or the sequence of most probable marginals using the forward-backward algorithm. In this article, we expand the amount of information we could obtain from the posterior distribution of an HMM by introducing linear-time dynamic programming recursions that, conditional on a user-specified constraint in the number of segments, allow us to (i) find MAP sequences, (ii) compute posterior probabilities, and (iii) simulate sample paths. We collectively call these recursions k-segment algorithms and illustrate their utility using simulated and real examples. We also highlight the prospective and retrospective use of k-segment constraints for fitting HMMs or exploring existing model fits. Supplementary materials for this article are available online.

Identifying targets of multiple co-regulating transcription factors from expression time-series by Bayesian model comparison.

BACKGROUND: Complete transcriptional regulatory network inference is a huge challenge because of the complexity of the network and sparsity of available data. One approach to make it more manageable is to focus on the inference of context-specific networks involving a few interacting transcription factors (TFs) and all of their target genes. RESULTS: We present a computational framework for Bayesian statistical inference of target genes of multiple interacting TFs from high-throughput gene expression time-series data. We use ordinary differential equation models that describe transcription of target genes taking into account combinatorial regulation. The method consists of a training and a prediction phase. During the training phase we infer the unobserved TF protein concentrations on a subnetwork of approximately known regulatory structure. During the prediction phase we apply Bayesian model selection on a genome-wide scale and score all alternative regulatory structures for each target gene. We use our methodology to identify targets of five TFs regulating Drosophila melanogaster mesoderm development. We find that confident predicted links between TFs and targets are significantly enriched for supporting ChIP-chip binding events and annotated TF-gene interations. Our method statistically significantly outperforms existing alternatives. CONCLUSIONS: Our results show that it is possible to infer regulatory links between multiple interacting TFs and their target genes even from a single relatively short time series and in presence of unmodelled confounders and unreliable prior knowledge on training network connectivity. Introducing data from several different experimental perturbations significantly increases the accuracy.

Mixture of experts classification using a hierarchical mixture model.

A three-level hierarchical mixture model for classification is presented that models the following data generation process: (1) the data are generated by a finite number of sources (clusters), and (2) the generation mechanism of each source assumes the existence of individual internal class-labeled sources (subclusters of the external cluster). The model estimates the posterior probability of class membership similar to a mixture of experts classifier. In order to learn the parameters of the model, we have developed a general training approach based on maximum likelihood that results in two efficient training algorithms. Compared to other classification mixture models, the proposed hierarchical model exhibits several advantages and provides improved classification performance as indicated by the experimental results.

Greedy learning of multiple objects in images using robust statistics and factorial learning.

We consider data that are images containing views of multiple objects. Our task is to learn about each of the objects present in the images. This task can be approached as a factorial learning problem, where each image must be explained by instantiating a model for each of the objects present with the correct instantiation parameters. A major problem with learning a factorial model is that as the number of objects increases, there is a combinatorial explosion of the number of configurations that need to be considered. We develop a method to extract object models sequentially from the data by making use of a robust statistical method, thus avoiding the combinatorial explosion, and present results showing successful extraction of objects from real images.