Evaluating genome architecture of a complex region via generalized bipartite matching

With the remarkable development in inexpensive sequencing technologies and supporting computational tools, we have the promise of medicine being personalized by knowledge of the individual genome. Current technologies provide high throughput, but short reads. Reconstruction of the donor genome is based either on de novo assembly of the (short) reads, or on mapping donor reads to a standard reference. While such techniques demonstrate high success rates for inferring 'simple' genomic segments, they are confounded by segments with complex duplication patterns, including regions of direct medical relevance, like the HLA and the KIR regions. In this work, we address this problem with a method for assessing the quality of a predicted genome sequence for complex regions of the genome. This method combines two natural types of evidence: sequence similarity of the mapped reads to the predicted donor genome, and distribution of reads across the predicted genome. We define a new scoring function for read-to-genome matchings, which penalizes for sequence dissimilarities and deviations from expected read location distribution, and present an efficient algorithm for finding matchings that minimize the penalty. The algorithm is based on a formal problem, first defined in this paper, called Coverage Sensitive many-to-many min-cost bipartite Matching (CSM). This new problem variant generalizes the standard (one-to-one) weighted bipartite matching problem, and can be solved using network flows. The resulting Java-based tool, called SAGE (Scoring function for Assembled GEnomes), is freely available upon request. We demonstrate over simulated data that SAGE can be used to infer correct haplotypes of the highly repetitive KIR region on the Human chromosome 19.ope

Decoding heterogeneous big data in an integrative way

Biotechnologies in post-genomic era, especially those that generate data in high-throughput, bring opportunities and challenges that are never faced before. And one of them is how to decode big heterogeneous data for clues that are useful for biological questions. With the exponential growth of a variety of data, comes with more and more applications of systematic approaches that investigate biological questions in an integrative way. Systematic approaches inherently require integration of heterogeneous information, which is urgently calling for a lot more efforts. In this thesis, the effort is mainly devoted to the development of methods and tools that help to integrate big heterogeneous information. In Chapter 2, we employed a heuristic strategy to summarize/integrate genes that are essential for the determination of mouse retinal cells in the format of network. These networks with experimental evidence could be rediscovered in the analysis of high-throughput data set and thus would be useful in the leverage of high-throughput data. In Chapter 3, we described EnRICH, a tool that we developed to help qualitatively integrate heterogeneous intro-organism information. We also introduced how EnRICH could be applied to the construction of a composite network from different sources, and demonstrated how we used EnRICH to successfully prioritize retinal disease genes. Following the work of Chapter 3 (intro-organism information integration), in Chapter 4 we stepped to the development of method and tool that can help deal with inter-organism information integration. The method we proposed is able to match genes in a one-to-one fashion between any two genomes. In summary, this thesis contributes to integrative analysis of big heterogeneous data by its work on the integration of intro- and inter-organism information

Video OWL-ViT: Temporally-consistent open-world localization in video

We present an architecture and a training recipe that adapts pre-trained open-world image models to localization in videos. Understanding the open visual world (without being constrained by fixed label spaces) is crucial for many real-world vision tasks. Contrastive pre-training on large image-text datasets has recently led to significant improvements for image-level tasks. For more structured tasks involving object localization applying pre-trained models is more challenging. This is particularly true for video tasks, where task-specific data is limited. We show successful transfer of open-world models by building on the OWL-ViT open-vocabulary detection model and adapting it to video by adding a transformer decoder. The decoder propagates object representations recurrently through time by using the output tokens for one frame as the object queries for the next. Our model is end-to-end trainable on video data and enjoys improved temporal consistency compared to tracking-by-detection baselines, while retaining the open-world capabilities of the backbone detector. We evaluate our model on the challenging TAO-OW benchmark and demonstrate that open-world capabilities, learned from large-scale image-text pre-training, can be transferred successfully to open-world localization across diverse videos.Comment: ICCV 202

Weakly Supervised Visual Semantic Parsing

Scene Graph Generation (SGG) aims to extract entities, predicates and their semantic structure from images, enabling deep understanding of visual content, with many applications such as visual reasoning and image retrieval. Nevertheless, existing SGG methods require millions of manually annotated bounding boxes for training, and are computationally inefficient, as they exhaustively process all pairs of object proposals to detect predicates. In this paper, we address those two limitations by first proposing a generalized formulation of SGG, namely Visual Semantic Parsing, which disentangles entity and predicate recognition, and enables sub-quadratic performance. Then we propose the Visual Semantic Parsing Network, VSPNet, based on a dynamic, attention-based, bipartite message passing framework that jointly infers graph nodes and edges through an iterative process. Additionally, we propose the first graph-based weakly supervised learning framework, based on a novel graph alignment algorithm, which enables training without bounding box annotations. Through extensive experiments, we show that VSPNet outperforms weakly supervised baselines significantly and approaches fully supervised performance, while being several times faster. We publicly release the source code of our method.Comment: To be presented at CVPR 2020 (oral paper

Statistical methods for gene selection and genetic association studies

This dissertation includes five Chapters. A brief description of each chapter is organized as follows. In Chapter One, we propose a signed bipartite genotype and phenotype network (GPN) by linking phenotypes and genotypes based on the statistical associations. It provides a new insight to investigate the genetic architecture among multiple correlated phenotypes and explore where phenotypes might be related at a higher level of cellular and organismal organization. We show that multiple phenotypes association studies by considering the proposed network are improved by incorporating the genetic information into the phenotype clustering. In Chapter Two, we first illustrate the proposed GPN to GWAS summary statistics. Then, we assess contributions to constructing a well-defined GPN with a clear representation of genetic associations by comparing the network properties with a random network, including connectivity, centrality, and community structure. The network topology annotations based on the sparse representations of GPN can be used to understand the disease heritability for the highly correlated phenotypes. In applications of phenome-wide association studies, the proposed GPN can identify more significant pairs of genetic variant and phenotype categories. In Chapter Three, a powerful and computationally efficient gene-based association test is proposed, aggregating information from different gene-based association tests and also incorporating expression quantitative trait locus information. We show that the proposed method controls the type I error rates very well and has higher power in the simulation studies and can identify more significant genes in the real data analyses. In Chapter Four, we develop six statistical selection methods based on the penalized regression for inferring target genes of a transcription factor (TF). In this study, the proposed selection methods combine statistics, machine learning , and convex optimization approach, which have great efficacy in identifying the true target genes. The methods will fill the gap of lacking the appropriate methods for predicting target genes of a TF, and are instrumental for validating experimental results yielding from ChIP-seq and DAP-seq, and conversely, selection and annotation of TFs based on their target genes. In Chapter Five, we propose a gene selection approach by capturing gene-level signals in network-based regression into case-control association studies with DNA sequence data or DNA methylation data, inspired by the popular gene-based association tests using a weighted combination of genetic variants to capture the combined effect of individual genetic variants within a gene. We show that the proposed gene selection approach have higher true positive rates than using traditional dimension reduction techniques in the simulation studies and select potentially rheumatoid arthritis related genes that are missed by existing methods

A Computational Framework for Learning from Complex Data: Formulations, Algorithms, and Applications

Many real-world processes are dynamically changing over time. As a consequence, the observed complex data generated by these processes also evolve smoothly. For example, in computational biology, the expression data matrices are evolving, since gene expression controls are deployed sequentially during development in many biological processes. Investigations into the spatial and temporal gene expression dynamics are essential for understanding the regulatory biology governing development. In this dissertation, I mainly focus on two types of complex data: genome-wide spatial gene expression patterns in the model organism fruit fly and Allen Brain Atlas mouse brain data. I provide a framework to explore spatiotemporal regulation of gene expression during development. I develop evolutionary co-clustering formulation to identify co-expressed domains and the associated genes simultaneously over different temporal stages using a mesh-generation pipeline. I also propose to employ the deep convolutional neural networks as a multi-layer feature extractor to generate generic representations for gene expression pattern in situ hybridization (ISH) images. Furthermore, I employ the multi-task learning method to fine-tune the pre-trained models with labeled ISH images. My proposed computational methods are evaluated using synthetic data sets and real biological data sets including the gene expression data from the fruit fly BDGP data sets and Allen Developing Mouse Brain Atlas in comparison with baseline existing methods. Experimental results indicate that the proposed representations, formulations, and methods are efficient and effective in annotating and analyzing the large-scale biological data sets

Learning Structured Representations for Understanding Visual and Multimedia Data

Recent advances in Deep Learning (DL) have achieved impressive performance in a variety of Computer Vision (CV) tasks, leading to an exciting wave of academic and industrial efforts to develop Artificial Intelligence (AI) facilities for every aspect of human life. Nevertheless, there are inherent limitations in the understanding ability of DL models, which limit the potential of AI in real-world applications, especially in the face of complex, multimedia input. Despite tremendous progress in solving basic CV tasks, such as object detection and action recognition, state-of-the-art CV models can merely extract a partial summary of visual content, which lacks a comprehensive understanding of what happens in the scene. This is partly due to the oversimplified definition of CV tasks, which often ignore the compositional nature of semantics and scene structure. It is even less studied how to understand the content of multiple modalities, which requires processing visual and textual information in a holistic and coordinated manner, and extracting interconnected structures despite the semantic gap between the two modalities. In this thesis, we argue that a key to improve the understanding capacity of DL models in visual and multimedia domains is to use structured, graph-based representations, to extract and convey semantic information more comprehensively. To this end, we explore a variety of ideas to define more realistic DL tasks in both visual and multimedia domains, and propose novel methods to solve those tasks by addressing several fundamental challenges, such as weak supervision, discovery and incorporation of commonsense knowledge, and scaling up vocabulary. More specifically, inspired by the rich literature of semantic graphs in Natural Language Processing (NLP), we explore innovative scene understanding tasks and methods that describe images using semantic graphs, which reflect the scene structure and interactions between objects. In the first part of this thesis, we present progress towards such graph-based scene understanding solutions, which are more accurate, need less supervision, and have more human-like common sense compared to the state of the art. In the second part of this thesis, we extend our results on graph-based scene understanding to the multimedia domain, by incorporating the recent advances in NLP and CV, and developing a new task and method from the ground up, specialized for joint information extraction in the multimedia domain. We address the inherent semantic gap between visual content and text by creating high-level graph-based representations of images, and developing a multitask learning framework to establish a common, structured semantic space for representing both modalities. In the third part of this thesis, we explore another extension of our scene understanding methodology, to open-vocabulary settings, in order to make scene understanding methods more scalable and versatile. We develop visually grounded language models that use naturally supervised data to learn the meaning of all words, and transfer that knowledge to CV tasks such as object detection with little supervision. Collectively, the proposed solutions and empirical results set a new state of the art for the semantic comprehension of visual and multimedia content in a structured way, in terms of accuracy, efficiency, scalability, and robustness

Exploiting Latent Features of Text and Graphs

As the size and scope of online data continues to grow, new machine learning techniques become necessary to best capitalize on the wealth of available information. However, the models that help convert data into knowledge require nontrivial processes to make sense of large collections of text and massive online graphs. In both scenarios, modern machine learning pipelines produce embeddings --- semantically rich vectors of latent features --- to convert human constructs for machine understanding. In this dissertation we focus on information available within biomedical science, including human-written abstracts of scientific papers, as well as machine-generated graphs of biomedical entity relationships. We present the Moliere system, and our method for identifying new discoveries through the use of natural language processing and graph mining algorithms. We propose heuristically-based ranking criteria to augment Moliere, and leverage this ranking to identify a new gene-treatment target for HIV-associated Neurodegenerative Disorders. We additionally focus on the latent features of graphs, and propose a new bipartite graph embedding technique. Using our graph embedding, we advance the state-of-the-art in hypergraph partitioning quality. Having newfound intuition of graph embeddings, we present Agatha, a deep-learning approach to hypothesis generation. This system learns a data-driven ranking criteria derived from the embeddings of our large proposed biomedical semantic graph. To produce human-readable results, we additionally propose CBAG, a technique for conditional biomedical abstract generation