Genes and Gene Networks Related to Age-associated Learning Impairments

The incidence of cognitive impairments, including age-associated spatial learning impairment (ASLI), has risen dramatically in past decades due to increasing human longevity. To better understand the genes and gene networks involved in ASLI, data from a number of past gene expression microarray studies in rats are integrated and used to perform a meta- and network analysis. Results from the data selection and preprocessing steps show that for effective downstream analysis to take place both batch effects and outlier samples must be properly removed. The meta-analysis undertaken in this research has identified significant differentially expressed genes across both age and ASLI in rats. Knowledge based gene network analysis shows that these genes affect many key functions and pathways in aged compared to young rats. The resulting changes might manifest as various neurodegenerative diseases/disorders or syndromic memory impairments at old age. Other changes might result in altered synaptic plasticity, thereby leading to normal, non-syndromic learning impairments such as ASLI. Next, I employ the weighted gene co-expression network analysis (WGCNA) on the datasets. I identify several reproducible network modules each highly significant with genes functioning in specific biological functional categories. It identifies a “learning and memory” specific module containing many potential key ASLI hub genes. Functions of these ASLI hub genes link a different set of mechanisms to learning and memory formation, which meta-analysis was unable to detect. This study generates some new hypotheses related to the new candidate genes and networks in ASLI, which could be investigated through future research

DETECTING CANCER-RELATED GENES AND GENE-GENE INTERACTIONS BY MACHINE LEARNING METHODS

To understand the underlying molecular mechanisms of cancer and therefore to improve pathogenesis, prevention, diagnosis and treatment of cancer, it is necessary to explore the activities of cancer-related genes and the interactions among these genes. In this dissertation, I use machine learning and computational methods to identify differential gene relations and detect gene-gene interactions. To identify gene pairs that have different relationships in normal versus cancer tissues, I develop an integrative method based on the bootstrapping K-S test to evaluate a large number of microarray datasets. The experimental results demonstrate that my method can find meaningful alterations in gene relations. For gene-gene interaction detection, I propose to use two Bayesian Network based methods: DASSO-MB (Detection of ASSOciations using Markov Blanket) and EpiBN (Epistatic interaction detection using Bayesian Network model) to address the two critical challenges: searching and scoring. DASSO-MB is based on the concept of Markov Blanket in Bayesian Networks. In EpiBN, I develop a new scoring function, which can reflect higher-order gene-gene interactions and detect the true number of disease markers, and apply a fast Branch-and-Bound (B&B) algorithm to learn the structure of Bayesian Network. Both DASSO-MB and EpiBN outperform some other commonly-used methods and are scalable to genome-wide data

Predicting the carbon source for Bacillus subtilis by integrating gene expression profiles into a constraintbased metabolic model

Elucidating cellular metabolism led to many breakthroughs in biotechnology, synthetic biology, and health sciences. To date, deriving metabolic fluxes by 13C tracer experiments is the most prominent approach for studying metabolic fluxes quantitatively with high accuracy and precision. However, the technique has a high demand for experimental resources. Alternatively, flux balance analysis (FBA) has been employed to estimate metabolic fluxes without labeling experiments. It is less informative but can benefit from the low costs and low experimental efforts; especially, in experimentally difficult conditions. Methods to integrate experimental data have emerged to improve FBA flux estimations. Transcriptomic data is often used since it is easy to generate at the genome scale, typically embedded by a binarization of expression of genes coding for the respective enzymes. However, employing defined thresholds can result in disregarding the fine-grained regulation of metabolism. Besides this, thermodynamically infeasible loops (TIL) are a well-known complication in constraint-based modeling, leading to unrealistic flux distributions. Linear Programming based Gene Expression Model (LPM-GEM) was established to improve a context-specific model extraction method. LPM-GEM linearly embeds gene expression into FBA constraints, and three strategies were implemented to reduce TILs. A model of Bacillus subtilis (B. subtilis) grown in eight different carbon sources was built as a case study. The method obtained good flux predictions based on the respective transcription profiles when validating with 13C-tracer based metabolic flux data of the same conditions. LPM-GEM could well predict the specific carbon sources. Good prediction performance was also observed when testing the model on another unseen dataset. LPM-GEM supports gene expression-based FBA models and can be applied as an alternative to estimate metabolic fluxes when tracer experiments are inappropriate

Model-based deep autoencoders for clustering single-cell RNA sequencing data with side information

Clustering analysis has been conducted extensively in single-cell RNA sequencing (scRNA-seq) studies. scRNA-seq can profile tens of thousands of genes\u27 activities within a single cell. Thousands or tens of thousands of cells can be captured simultaneously in a typical scRNA-seq experiment. Biologists would like to cluster these cells for exploring and elucidating cell types or subtypes. Numerous methods have been designed for clustering scRNA-seq data. Yet, single-cell technologies develop so fast in the past few years that those existing methods do not catch up with these rapid changes and fail to fully fulfil their potential. For instance, besides profiling transcription expression levels of genes, recent single-cell technologies can capture other auxiliary information at the single-cell level, such as protein expression (multi-omics scRNA-seq) and cells\u27 spatial location information (spatial-resolved scRNA-seq). Most existing clustering methods for scRNA-seq are performed in an unsupervised manner and fail to exploit available side information for optimizing clustering performance. This dissertation focuses on developing novel computational methods for clustering scRNA-seq data. The basic models are built on a deep autoencoder (AE) framework, which is coupled with a ZINB (zero-inflated negative binomial) loss to characterize the zero-inflated and over-dispersed scRNA-seq count data. To integrate multi-omics scRNA-seq data, a multimodal autoencoder (MAE) is employed. It applies one encoder for the multimodal inputs and two decoders for reconstructing each omics of data. This model is named scMDC (Single-Cell Multi-omics Deep Clustering). Besides, it is expected that cells in spatial proximity tend to be of the same cell types. To exploit cellular spatial information available for spatial-resolved scRNA-seq (sp-scRNA-seq) data, a novel model, DSSC (Deep Spatial-constrained Single-cell Clustering), is developed. DSSC integrates the spatial information of cells into the clustering process by two steps: 1) the spatial information is encoded by using a graphical neural network model; 2) cell-to-cell constraints are built based on the spatially expression pattern of the marker genes and added in the model to guide the clustering process. DSSC is the first model which can utilize the information from both the spatial coordinates and the marker genes to guide the cell/spot clustering. For both scMDC and DSSC, a clustering loss is optimized on the bottleneck layer of autoencoder along with the learning of feature representation. Extensive experiments on both simulated and real datasets demonstrate that scMDC and DSSC boost clustering performance significantly while costing no extra time and space during the training process. These models hold great promise as valuable tools for harnessing the full potential of state-of-the-art single-cell data

ARIANA: Adaptive Robust and Integrative Analysis for finding Novel Associations

The effective mining of biological literature can provide a range of services such as hypothesis-generation, semantic-sensitive information retrieval, and knowledge discovery, which can be important to understand the confluence of different diseases, genes, and risk factors. Furthermore, integration of different tools at specific levels could be valuable. The main focus of the dissertation is developing and integrating tools in finding network of semantically related entities. The key contribution is the design and implementation of an Adaptive Robust and Integrative Analysis for finding Novel Associations. ARIANA is a software architecture and a web-based system for efficient and scalable knowledge discovery. It integrates semantic-sensitive analysis of text-data through ontology-mapping with database search technology to ensure the required specificity. ARIANA was prototyped using the Medical Subject Headings ontology and PubMed database and has demonstrated great success as a dynamic-data-driven system. ARIANA has five main components: (i) Data Stratification, (ii) Ontology-Mapping, (iii) Parameter Optimized Latent Semantic Analysis, (iv) Relevance Model and (v) Interface and Visualization. The other contribution is integration of ARIANA with Online Mendelian Inheritance in Man database, and Medical Subject Headings ontology to provide gene-disease associations. Empirical studies produced some exciting knowledge discovery instances. Among them was the connection between the hexamethonium and pulmonary inflammation and fibrosis. In 2001, a research study at John Hopkins used the drug hexamethonium on a healthy volunteer that ended in a tragic death due to pulmonary inflammation and fibrosis. This accident might have been prevented if the researcher knew of published case report. Since the original case report in 1955, there has not been any publications regarding that association. ARIANA extracted this knowledge even though its database contains publications from 1960 to 2012. Out of 2,545 concepts, ARIANA ranked “Scleroderma, Systemic”, “Neoplasms, Fibrous Tissue”, “Pneumonia”, “Fibroma”, and “Pulmonary Fibrosis” as the 13th, 16th, 38th, 174th and 257th ranked concept respectively. The researcher had access to such knowledge this drug would likely not have been used on healthy subjects.In today\u27s world where data and knowledge are moving away from each other, semantic-sensitive tools such as ARIANA can bridge that gap and advance dissemination of knowledge

Complexity, Emergent Systems and Complex Biological Systems:\ud Complex Systems Theory and Biodynamics. [Edited book by I.C. Baianu, with listed contributors (2011)]

An overview is presented of System dynamics, the study of the behaviour of complex systems, Dynamical system in mathematics Dynamic programming in computer science and control theory, Complex systems biology, Neurodynamics and Psychodynamics.\u