Mouse obesity network reconstruction with a variational Bayes algorithm to employ aggressive false positive control

<p>Abstract</p> <p>Background</p> <p>We propose a novel variational Bayes network reconstruction algorithm to extract the most relevant disease factors from high-throughput genomic data-sets. Our algorithm is the only scalable method for regularized network recovery that employs Bayesian model averaging and that can internally estimate an appropriate level of sparsity to ensure few false positives enter the model without the need for cross-validation or a model selection criterion. We use our algorithm to characterize the effect of genetic markers and liver gene expression traits on mouse obesity related phenotypes, including weight, cholesterol, glucose, and free fatty acid levels, in an experiment previously used for discovery and validation of network connections: an F2 intercross between the C57BL/6 J and C3H/HeJ mouse strains, where apolipoprotein E is null on the background.</p> <p>Results</p> <p>We identified eleven genes, Gch1, Zfp69, Dlgap1, Gna14, Yy1, Gabarapl1, Folr2, Fdft1, Cnr2, Slc24a3, and Ccl19, and a quantitative trait locus directly connected to weight, glucose, cholesterol, or free fatty acid levels in our network. None of these genes were identified by other network analyses of this mouse intercross data-set, but all have been previously associated with obesity or related pathologies in independent studies. In addition, through both simulations and data analysis we demonstrate that our algorithm achieves superior performance in terms of power and type I error control than other network recovery algorithms that use the lasso and have bounds on type I error control.</p> <p>Conclusions</p> <p>Our final network contains 118 previously associated and novel genes affecting weight, cholesterol, glucose, and free fatty acid levels that are excellent obesity risk candidates.</p

Bayesian Methods for Discovering Structure in Neural Spike Trains

Neuroscience is entering an exciting new age. Modern recording technologies enable simultaneous measurements of thousands of neurons in organisms performing complex behaviors. Such recordings offer an unprecedented opportunity to glean insight into the mechanistic underpinnings of intelligence, but they also present an extraordinary statistical and computational challenge: how do we make sense of these large scale recordings? This thesis develops a suite of tools that instantiate hypotheses about neural computation in the form of probabilistic models and a corresponding set of Bayesian inference algorithms that efficiently fit these models to neural spike trains. From the posterior distribution of model parameters and variables, we seek to advance our understanding of how the brain works. Concretely, the challenge is to hypothesize latent structure in neural populations, encode that structure in a probabilistic model, and efficiently fit the model to neural spike trains. To surmount this challenge, we introduce a collection of structural motifs, the design patterns from which we construct interpretable models. In particular, we focus on random network models, which provide an intuitive bridge between latent types and features of neurons and the temporal dynamics of neural populations. In order to reconcile these models with the discrete nature of spike trains, we build on the Hawkes process — a multivariate generalization of the Poisson process — and its discrete time analogue, the linear autoregressive Poisson model. By leveraging the linear nature of these models and the Poisson superposition principle, we derive elegant auxiliary variable formulations and efficient inference algorithms. We then generalize these to nonlinear and nonstationary models of neural spike trains and take advantage of the Pólya-gamma augmentation to develop novel Markov chain Monte Carlo (MCMC) inference algorithms. In a variety of real neural recordings, we show how our methods reveal interpretable structure underlying neural spike trains. In the latter chapters, we shift our focus from autoregressive models to latent state space models of neural activity. We perform an empirical study of Bayesian nonparametric methods for hidden Markov models of neural spike trains. Then, we develop an MCMC algorithm for switching linear dynamical systems with discrete observations and a novel algorithm for sampling Pólya-gamma random variables that enables efficient annealed importance sampling for model comparison. Finally, we consider the “Bayesian brain” hypothesis — the hypothesis that neural circuits are themselves performing Bayesian inference. We show how one particular implementation of this hypothesis implies autoregressive dynamics of the form studied in earlier chapters, thereby providing a theoretical interpretation of our probabilistic models. This closes the loop, connecting top-down theory with bottom-up inferences, and suggests a path toward translating large scale recording capabilities into new insights about neural computation.Engineering and Applied Sciences - Computer Scienc

Sparse Model Building From Genome-Wide Variation With Graphical Models

High throughput sequencing and expression characterization have lead to an explosion of phenotypic and genotypic molecular data underlying both experimental studies and outbred populations. We develop a novel class of algorithms to reconstruct sparse models among these molecular phenotypes (e.g. expression products) and genotypes (e.g. single nucleotide polymorphisms), via both a Bayesian hierarchical model, when the sample size is much smaller than the model dimension (i.e. p n) and the well characterized adaptive lasso algo- rithm. Specifically, we propose novel approaches to the problems of increasing power to detect additional loci in genome-wide association studies using our variational algorithm, efficiently learning directed cyclic graphs from expression and genotype data using the adaptive lasso, and constructing genomewide undirected graphs among genotype, expression and downstream phenotype data using an extension of the variational feature selection algorithm. The Bayesian hierarchical model is derived for a parametric multiple regression model with a mixture prior of a point mass and normal distribution for each regression coefficient, and appropriate priors for the set of hyperparameters. When combined with a probabilistic consistency bound on the model dimension, this approach leads to very sparse solutions without the need for cross validation. We use a variational Bayes approximate inference approach in our algorithm, where we impose a complete factorization across all parameters for the approximate posterior distribution, and then minimize the KullbackLeibler divergence between the approximate and true posterior distributions. Since the prior distribution is non-convex, we restart the algorithm many times to find multiple posterior modes, and combine information across all discovered modes in an approximate Bayesian model averaging framework, to reduce the variance of the posterior probability estimates. We perform analysis of three major publicly available data-sets: the HapMap 2 genotype and expression data collected on immortalized lymphoblastoid cell lines, the genome-wide gene expression and genetic marker data collected for a yeast intercross, and genomewide gene expression, genetic marker, and downstream phenotypes related to weight in a mouse F2 intercross. Based on both simulations and data analysis we show that our algorithms can outperform other state of the art model selection procedures when including thousands to hundreds of thousands of genotypes and expression traits, in terms of aggressively controlling false discovery rate, and generating rich simultaneous statistical models

Applications of Approximate Learning and Inference for Probabilistic Models

We develop approximate inference and learning methods for facilitating the use of probabilistic modeling techniques motivated by applications in two different areas. First, we consider the ill-posed inverse problem of recovering an image from an underdetermined system of linear measurements corrupted by noise. Second, we consider the problem of inferring user preferences for items from counts, pairwise comparisons and user activity logs, instances of implicit feedback. Plausible models for images and the noise, incurred when recording them, render posterior inference intractable, while the scale of the inference problem makes sampling based approximations ineffective. Therefore, we develop deterministic approximate inference algorithms for two different augmentations of a typical sparse linear model: first, for the rectified-linear Poisson likelihood, and second, for tree-structured super-Gaussian mixture models. The rectified-linear Poisson likelihood is an alternative noise model, applicable in astronomical and biomedical imaging applications, that operate in intensity regimes in which quantum effects lead to observations that are best described by counts of particles arriving at a sensor, as well as in general Poisson regression problems arising in various fields. In this context we show, that the model-specific computations for Expectation Propagation can be robustly solved by a simple dynamic program. Next, we develop a scalable approximate inference algorithm for structured mixture models, that uses a discrete graphical model to represent dependencies between the latent mixture components of a collection of mixture models. Specifically, we use tree-structured mixtures of super-Gaussians to model the persistence across scales of large coefficients of the Wavelet transform of an image for improved reconstruction. In the second part on models of user preference, we consider two settings: the global static and the contextual dynamic setting. In the global static setting, we represent user-item preferences by a latent low-rank matrix. Instead of using numeric ratings we develop methods to infer this latent representation for two types of implicit feedback: aggregate counts of users interacting with a service and the binary outcomes of pairwise comparisons. We model count data using a latent Gaussian bilinear model with Poisson likelihoods. For this model, we show that the Variational Gaussian approximation can be further relaxed to be available in closed-form by adding additional constraints, leading to an efficient inference algorithm. In the second implicit feedback scenario, we infer the latent preference matrix from pairwise preference statements. We combine a low-rank bilinear model with non-parameteric item- feature regression and develop a novel approximate variational Expectation Maximization algorithm that mitigates the computational challenges due to latent couplings induced by the pairwise comparisons. Finally, in the contextual dynamic setting, we model sequences of user activity at the granularity of single interaction events instead of aggregate counts. Routinely gathered in the background at a large scale in many applications, such sequences can reveal temporal and contextual aspects of user behavior through recurrent patterns. To describe such data, we propose a generic collaborative sequence model based on recurrent neural networks, that combines ideas from collaborative filtering and language modeling

Structured data abstractions and interpretable latent representations for single-cell multimodal genomics

Single-cell multimodal genomics involves simultaneous measurement of multiple types of molecular data, such as gene expression, epigenetic marks and protein abundance, in individual cells. This allows for a comprehensive and nuanced understanding of the molecular basis of cellular identity and function. The large volume of data generated by single-cell multimodal genomics experiments requires specialised methods and tools for handling, storing, and analysing it. This work provides contributions on multiple levels. First, it introduces a single-cell multimodal data standard — MuData — designed to facilitate the handling, storage and exchange of multimodal data. MuData provides interfaces that enable transparent access to multimodal annotations as well as data from individual modalities. This data structure has formed the foundation for the multimodal integration framework, which enables complex and composable workflows that can be naturally integrated with existing omics-specific analysis approaches. Joint analysis of multimodal data can be performed using integration methods. In order to enable integration of single-cell data, an improved multi-omics factor analysis model (MOFA+) has been designed and implemented building on the canonical dimensionality reduction approach for multi-omics integration. Inferring later factors that explain variation across multiple modalities of the data, MOFA+ enables the modelling of latent factors with cell group-specific patterns of activity. MOFA+ model has been implemented as part of the respective multi-omics integration framework, and its utility has been extended by software solutions that facilitate interactive model exploration and interpretation. The newly improved model for multi-omics integration of single cells has been applied to the study of gene expression signatures upon targeted gene activation. In a dataset featuring targeted activation of candidate regulators of zygotic genome activation (ZGA) — a crucial transcriptional event in early embryonic development, — modelling expression of both coding and non-coding loci with MOFA+ allowed to rank genes by their potency to activate a ZGA-like transcriptional response. With identification of Patz1, Dppa2 and Smarca5 as potent inducers of ZGA-like transcription in mouse embryonic stem cells, these findings have contributed to the understanding of molecular mechanisms behind ZGA and laid the foundation for future research of ZGA in vivo. In summary, this work’s contributions include the development of data handling and integration methods as well as new biological insights that arose from applying these methods to studying gene expression regulation in early development. This highlights how single-cell multimodal genomics can aid to generate valuable insights into complex biological systems