Physiological functioning of an organ system such as healthy brain functioning is enabled by orchestrated information flow between molecular entities within cells, between cells, and across tissues and its understanding requires a systems approach. In complex disease such as Alzheimer's disease, there are numerous subtle, moderate, and strong perturbations across biological networks which result in disease onset and progression. High-throughput multi-omics profiling of genetic variants, the epigenome, transcriptome, proteome, metabolome, and microbiome is a first step in probing the complexity of biological systems and disease etiologies. There remains the problems of multi-omics integration, modeling and interpretation, and accessibility of computational analyses. To address these issues, in the methods development section of my dissertation research, I developed the complete overhaul of the web server for Mergeomics, a method for pathway- and network-level understanding of complex disease using multi-omics integration, which significantly improved the usability and functionality of the tool. To facilitate omics-driven drug discovery, I implemented the PharmOmics web server and the direct pipeline from Mergeomics, allowing users to gain immediate therapeutic insight from disease-associated pathways, key drivers, and key driver subnetworks. The second focus of my dissertation was the application of systems biology analytical tools to understand metabolic contributions to Alzheimer's disease. I determined hippocampal and hypothalamic cell type specific alterations in response to amyloid-beta accumulation in the 5XFAD mouse model and investigated the effect of metabolically challenging 5XFAD mice with fructose overconsumption and supplementation with docosahexaenoic acid and nicotinamide riboside. I identified cell type- and tissue-resolved pathway and network mechanisms of disease exacerbation by metabolic challenge and disease alleviation by docosahexaenoic acid and nicotinamide. My efforts in developing the web server implementations of Mergeomics and PharmOmics have promoted greater accessibility of deriving mechanistic insight from big biological data for the broader scientific community, and use of these tools have allowed unbiased examination into the connection between metabolic syndrome and Alzheimer's disease and uncovered potential therapeutic targets and strategies via dietary modulation.
As the cost of high-throughput sequencing goes down, huge volumes of biological and medical data have been produced from various sequencing platforms at multiple molecular levels including genome, transcriptome, proteome, epigenome, metabolome, and so on. For a long time, data analysis on single molecular levels has paved the way to answer many important research questions. However, many Aging-Related Neuronal Diseases (ARNDs) and Central Nervous System (CNS) aging involve interactions of molecules from multiple molecular levels, in which conclusions based on single molecular levels are usually incomplete and sometimes misleading. In these scenarios, multi-omics data analysis has unprecedentedly helped capture much more useful information for the diagnosis, treatment, prognosis, and drug discovery of ARNDs. The first step towards a multi-omics analysis is to establish reliable and robust multi-omics datasets. In the past years, a few important ARNDs-associated multi-omics databases like Allen Brain have been constructed, which raised immediate needs like data curation, normalization, interpretation, and visualization for integrative multi-omics explorations. Though there have been several well-established multi-omics databases for ARNDs like Alzheimer’s disease, similar databases for other ARNDs are still in urgent need. After the databases establish, many computational tools and experiential strategies should be developed specifically for them. First, the multi-omics data are usually extremely noisy, complex, heterogeneous and in high dimension, which presents the need for appropriate denoising and dimension reduction methods. Second, since the multi-omics and non-omics data like pathological and clinical data are usually in different data spaces, a useful algorithm to mapping them into the same data space and integrate them is nontrivial. In the multi-omics era, there are numerous data-centric tools for the integration of multi-omics datasets, which could be generally divided into three categories: unsupervised, supervised, and semi-supervised methods. Commonly used algorithms include but not limited to Bayesian-based methods, Network-based methods, multi-step analysis methods, and multiple kernel learning methods. Third, methods are needed in studying and verifying the association between two or more levels of multi-omics data and non-omics data. For example, expression quantitative trait loci (eQTL) analysis is widely used to infer the association between a single nucleotide polymorphism (SNP) and the expression of a gene. Recently, the association between omics data and more complex data like pathological and clinical imaging data has been a hot research topic. The outcomes may reveal the underlying molecular mechanism and promote de novo drug design as well as drug repurposing for ARNDs. Here, we welcome investigators to share their Original Research, Review, Mini Review, Hypothesis and Theory, Perspective, Conceptual Analysis, Data Report, Brief Research Report, Code related to multi-omics studies of ARNDs, which can be applied for better diagnosis, treatment, prognosis and drug discovery of human diseases in the future era of precision medicine. Potential contents include but are not limited to the following: ▪ Methods for integrating, interpreting, or visualizing two or more omics data. ▪ Methods for identifying interactions between different data modalities. ▪ Methods for disease subtyping, biomarker prediction. ▪ Machine learning or deep learning methods on dimensional reduction and feature selection for big noisy data. ▪ Methods for studying the association among different omics data or between omics and non-omics data like clinical, pathological, and imaging data. ▪ Review of multi-omics resource about ARNDs and/or CNS aging. ▪ Experimental validation of biomarkers identified from multi-omics data analysis. ▪ Disease diagnosis and prognosis prediction from imaging and non-imaging data analysis, or both. ▪ Clinical applications or validations of findings from multi-omics data analysis.
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Based on ideas from Support Vector Machines (SVMs), Learning To Classify Text Using Support Vector Machines presents a new approach to generating text classifiers from examples. The approach combines high performance and efficiency with theoretical understanding and improved robustness. In particular, it is highly effective without greedy heuristic components. The SVM approach is computationally efficient in training and classification, and it comes with a learning theory that can guide real-world applications. Learning To Classify Text Using Support Vector Machines gives a complete and detailed description of the SVM approach to learning text classifiers, including training algorithms, transductive text classification, efficient performance estimation, and a statistical learning model of text classification. In addition, it includes an overview of the field of text classification, making it self-contained even for newcomers to the field. This book gives a concise introduction to SVMs for pattern recognition, and it includes a detailed description of how to formulate text-classification tasks for machine learning.
The fields of rare diseases research and orphan products development continue to expand with more products in research and development status. In recent years, the role of the patient advocacy groups has evolved into a research partner with the academic research community and the bio-pharmaceutical industry. Unique approaches to research and development require epidemiological data not previously available to assist in protocol study design and patient recruitment for clinical trials required by regulatory agencies prior to approval for access by patents and practicing physicians.
This comprehensively revised second edition of Computational Systems Biology discusses the experimental and theoretical foundations of the function of biological systems at the molecular, cellular or organismal level over temporal and spatial scales, as systems biology advances to provide clinical solutions to complex medical problems. In particular the work focuses on the engineering of biological systems and network modeling. Logical information flow aids understanding of basic building blocks of life through disease phenotypes Evolved principles gives insight into underlying organizational principles of biological organizations, and systems processes, governing functions such as adaptation or response patterns Coverage of technical tools and systems helps researchers to understand and resolve specific systems biology problems using advanced computation Multi-scale modeling on disparate scales aids researchers understanding of dependencies and constraints of spatio-temporal relationships fundamental to biological organization and function.
This book is written by leading researchers in the fields about the intersection of genetics and metabolomics which can lead to more comprehensive studies of inborn variation of metabolism.
Single-cell omics is a progressing frontier that stems from the sequencing of the human genome and the development of omics technologies, particularly genomics, transcriptomics, epigenomics and proteomics, but the sensitivity is now improved to single-cell level. The new generation of methodologies, especially the next generation sequencing (NGS) technology, plays a leading role in genomics related fields; however, the conventional techniques of omics require number of cells to be large, usually on the order of millions of cells, which is hardly accessible in some cases. More importantly, harnessing the power of omics technologies and applying those at the single-cell level are crucial since every cell is specific and unique, and almost every cell population in every systems, derived in either vivo or in vitro, is heterogeneous. Deciphering the heterogeneity of the cell population hence becomes critical for recognizing the mechanism and significance of the system. However, without an extensive examination of individual cells, a massive analysis of cell population would only give an average output of the cells, but neglect the differences among cells. Single-cell omics seeks to study a number of individual cells in parallel for their different dimensions of molecular profile on genome-wide scale, providing unprecedented resolution for the interpretation of both the structure and function of an organ, tissue or other system, as well as the interaction (and communication) and dynamics of single cells or subpopulations of cells and their lineages. Importantly single-cell omics enables the identification of a minor subpopulation of cells that may play a critical role in biological process over a dominant subpolulation such as a cancer and a developing organ. It provides an ultra-sensitive tool for us to clarify specific molecular mechanisms and pathways and reveal the nature of cell heterogeneity. Besides, it also empowers the clinical investigation of patients when facing a very low quantity of cell available for analysis, such as noninvasive cancer screening with circulating tumor cells (CTC), noninvasive prenatal diagnostics (NIPD) and preimplantation genetic test (PGT) for in vitro fertilization. Single-cell omics greatly promotes the understanding of life at a more fundamental level, bring vast applications in medicine. Accordingly, single-cell omics is also called as single-cell analysis or single-cell biology. Within only a couple of years, single-cell omics, especially transcriptomic sequencing (scRNA-seq), whole genome and exome sequencing (scWGS, scWES), has become robust and broadly accessible. Besides the existing technologies, recently, multiplexing barcode design and combinatorial indexing technology, in combination with microfluidic platform exampled by Drop-seq, or even being independent of microfluidic platform but using a regular PCR-plate, enable us a greater capacity of single cell analysis, switching from one single cell to thousands of single cells in a single test. The unique molecular identifiers (UMIs) allow the amplification bias among the original molecules to be corrected faithfully, resulting in a reliable quantitative measurement of omics in single cells. Of late, a variety of single-cell epigenomics analyses are becoming sophisticated, particularly single cell chromatin accessibility (scATAC-seq) and CpG methylation profiling (scBS-seq, scRRBS-seq). High resolution single molecular Fluorescence in situ hybridization (smFISH) and its revolutionary versions (ex. seqFISH, MERFISH, and so on), in addition to the spatial transcriptome sequencing, make the native relationship of the individual cells of a tissue to be in 3D or 4D format visually and quantitatively clarified. On the other hand, CRISPR/cas9 editing-based In vivo lineage tracing methods enable dynamic profile of a whole developmental process to be accurately displayed. Multi-omics analysis facilitates the study of multi-dimensional regulation and relationship of different elements of the central dogma in a single cell, as well as permitting a clear dissection of the complicated omics heterogeneity of a system. Last but not the least, the technology, biological noise, sequence dropout, and batch effect bring a huge challenge to the bioinformatics of single cell omics. While significant progress in the data analysis has been made since then, revolutionary theory and algorithm logics for single cell omics are expected. Indeed, single-cell analysis exert considerable impacts on the fields of biological studies, particularly cancers, neuron and neural system, stem cells, embryo development and immune system; other than that, it also tremendously motivates pharmaceutic RD, clinical diagnosis and monitoring, as well as precision medicine. This book hereby summarizes the recent developments and general considerations of single-cell analysis, with a detailed presentation on selected technologies and applications. Starting with the experimental design on single-cell omics, the book then emphasizes the consideration on heterogeneity of cancer and other systems. It also gives an introduction of the basic methods and key facts for bioinformatics analysis. Secondary, this book provides a summary of two types of popular technologies, the fundamental tools on single-cell isolation, and the developments of single cell multi-omics, followed by descriptions of FISH technologies, though other popular technologies are not covered here due to the fact that they are intensively described here and there recently. Finally, the book illustrates an elastomer-based integrated fluidic circuit that allows a connection between single cell functional studies combining stimulation, response, imaging and measurement, and corresponding single cell sequencing. This is a model system for single cell functional genomics. In addition, it reports a pipeline for single-cell proteomics with an analysis of the early development of Xenopus embryo, a single-cell qRT-PCR application that defined the subpopulations related to cell cycling, and a new method for synergistic assembly of single cell genome with sequencing of amplification product by phi29 DNA polymerase. Due to the tremendous progresses of single-cell omics in recent years, the topics covered here are incomplete, but each individual topic is excellently addressed, significantly interesting and beneficial to scientists working in or affiliated with this field.
Big data, genomics, and quantitative approaches to network-based analysis are combining to advance the frontiers of medicine as never before. With contributions from leading experts, Network Medicine introduces this rapidly evolving field of research, which promises to revolutionize the diagnosis and treatment of human diseases.
