Unsupervised learning of transcriptional regulatory networks via latent tree graphical models

Gene expression is a readily-observed quantification of transcriptional activity and cellular state that enables the recovery of the relationships between regulators and their target genes. Reconstructing transcriptional regulatory networks from gene expression data is a problem that has attracted much attention, but previous work often makes the simplifying (but unrealistic) assumption that regulator activity is represented by mRNA levels. We use a latent tree graphical model to analyze gene expression without relying on transcription factor expression as a proxy for regulator activity. The latent tree model is a type of Markov random field that includes both observed gene variables and latent (hidden) variables, which factorize on a Markov tree. Through efficient unsupervised learning approaches, we determine which groups of genes are co-regulated by hidden regulators and the activity levels of those regulators. Post-processing annotates many of these discovered latent variables as specific transcription factors or groups of transcription factors. Other latent variables do not necessarily represent physical regulators but instead reveal hidden structure in the gene expression such as shared biological function. We apply the latent tree graphical model to a yeast stress response dataset. In addition to novel predictions, such as condition-specific binding of the transcription factor Msn4, our model recovers many known aspects of the yeast regulatory network. These include groups of co-regulated genes, condition-specific regulator activity, and combinatorial regulation among transcription factors. The latent tree graphical model is a general approach for analyzing gene expression data that requires no prior knowledge of which possible regulators exist, regulator activity, or where transcription factors physically bind

Unsupervised learning of transcriptional regulatory networks via latent tree graphical models

Gene expression is a readily-observed quantification of transcriptional activity and cellular state that enables the recovery of the relationships between regulators and their target genes. Reconstructing transcriptional regulatory networks from gene expression data is a problem that has attracted much attention, but previous work often makes the simplifying (but unrealistic) assumption that regulator activity is represented by mRNA levels. We use a latent tree graphical model to analyze gene expression without relying on transcription factor expression as a proxy for regulator activity. The latent tree model is a type of Markov random field that includes both observed gene variables and latent (hidden) variables, which factorize on a Markov tree. Through efficient unsupervised learning approaches, we determine which groups of genes are co-regulated by hidden regulators and the activity levels of those regulators. Post-processing annotates many of these discovered latent variables as specific transcription factors or groups of transcription factors. Other latent variables do not necessarily represent physical regulators but instead reveal hidden structure in the gene expression such as shared biological function. We apply the latent tree graphical model to a yeast stress response dataset. In addition to novel predictions, such as condition-specific binding of the transcription factor Msn4, our model recovers many known aspects of the yeast regulatory network. These include groups of co-regulated genes, condition-specific regulator activity, and combinatorial regulation among transcription factors. The latent tree graphical model is a general approach for analyzing gene expression data that requires no prior knowledge of which possible regulators exist, regulator activity, or where transcription factors physically bind

Machine Learning and Integrative Analysis of Biomedical Big Data.

Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues

Learning condition-specific networks

Condition-specific cellular networks are networks of genes and proteins that describe functional interactions among genes occurring under different environmental conditions. These networks provide a systems-level view of how the parts-list (genes and proteins) interact within the cell as it functions under changing environmental conditions and can provide insight into mechanisms of stress response, cellular differentiation and disease susceptibility. The principle challenge, however, is that cellular networks remain unknown for most conditions and must be inferred from activity levels of genes (mRNA levels) under different conditions. This dissertation aims to develop computational approaches for inferring, analyzing and validating cellular networks of genes from expression data. This dissertation first describes an unsupervised machine learning framework for inferring cellular networks using expression data from a single condition. Here cellular networks are represented as undirected probabilistic graphical models and are learned using a novel, data-driven algorithm. Then several approaches are described that can learn networks using data from multiple conditions. These approaches apply to cases where the condition may or may not be known and, therefore, must be inferred as part of the learning problem. For the latter, the condition variable is allowed to influence expression of genes at different levels of granularity: condition variable per gene to a single condition variable for all genes. Results on simulated data suggest that the algorithm performance depends greatly on the size and number of connected components of the union network of all conditions. These algorithms are also applied to microarray data from two yeast populations, quiescent and non-quiescent, isolated from glucose starved cultures. Our results suggest that by sharing information across multiple conditions, better networks can be learned for both conditions, with many more biologically meaningful dependencies, than if networks were learned for these conditions independently. In particular, processes that were shared among both cell populations were involved in response to glucose starvation, whereas the processes specific to individual populations captured characteristics unique to each population. These algorithms were also applied for learning networks across multiple species: yeast (S. cerevisiae) and fly (D. melanogaster). Preliminary analysis suggests that sharing patterns across species is much more complex than across different populations of the same species and basic metabolic processes are shared across the two species. Finally, this dissertation focuses on validation of cellular networks. This validation framework describes scores for measuring how well network learning algorithms capture higher-order dependencies. This framework also introduces a measure for evaluating the entire inferred network structure based on the extent to which similarly functioning genes are close together on the network

Artificial intelligence used in genome analysis studies

Next Generation Sequencing (NGS) or deep sequencing technology enables parallel reading of multiple individual DNA fragments, thereby enabling the identification of millions of base pairs in several hours. Recent research has clearly shown that machine learning technologies can efficiently analyse large sets of genomic data and help to identify novel gene functions and regulation regions. A deep artificial neural network consists of a group of artificial neurons that mimic the properties of living neurons. These mathematical models, termed Artificial Neural Networks (ANN), can be used to solve artificial intelligence engineering problems in several different technological fields (e.g., biology, genomics, proteomics, and metabolomics). In practical terms, neural networks are non-linear statistical structures that are organized as modelling tools and are used to simulate complex genomic relationships between inputs and outputs. To date, Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNN) have been demonstrated to be the best tools for improving performance in problem solving tasks within the genomic field