Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.

Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder-specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders

Modeling Persistent Trends in Distributions

We present a nonparametric framework to model a short sequence of probability distributions that vary both due to underlying effects of sequential progression and confounding noise. To distinguish between these two types of variation and estimate the sequential-progression effects, our approach leverages an assumption that these effects follow a persistent trend. This work is motivated by the recent rise of single-cell RNA-sequencing experiments over a brief time course, which aim to identify genes relevant to the progression of a particular biological process across diverse cell populations. While classical statistical tools focus on scalar-response regression or order-agnostic differences between distributions, it is desirable in this setting to consider both the full distributions as well as the structure imposed by their ordering. We introduce a new regression model for ordinal covariates where responses are univariate distributions and the underlying relationship reflects consistent changes in the distributions over increasing levels of the covariate. This concept is formalized as a "trend" in distributions, which we define as an evolution that is linear under the Wasserstein metric. Implemented via a fast alternating projections algorithm, our method exhibits numerous strengths in simulations and analyses of single-cell gene expression data.Comment: To appear in: Journal of the American Statistical Associatio

Big data analytics in computational biology and bioinformatics

Big data analytics in computational biology and bioinformatics refers to an array of operations including biological pattern discovery, classification, prediction, inference, clustering as well as data mining in the cloud, among others. This dissertation addresses big data analytics by investigating two important operations, namely pattern discovery and network inference. The dissertation starts by focusing on biological pattern discovery at a genomic scale. Research reveals that the secondary structure in non-coding RNA (ncRNA) is more conserved during evolution than its primary nucleotide sequence. Using a covariance model approach, the stems and loops of an ncRNA secondary structure are represented as a statistical image against which an entire genome can be efficiently scanned for matching patterns. The covariance model approach is then further extended, in combination with a structural clustering algorithm and a random forests classifier, to perform genome-wide search for similarities in ncRNA tertiary structures. The dissertation then presents methods for gene network inference. Vast bodies of genomic data containing gene and protein expression patterns are now available for analysis. One challenge is to apply efficient methodologies to uncover more knowledge about the cellular functions. Very little is known concerning how genes regulate cellular activities. A gene regulatory network (GRN) can be represented by a directed graph in which each node is a gene and each edge or link is a regulatory effect that one gene has on another gene. By evaluating gene expression patterns, researchers perform in silico data analyses in systems biology, in particular GRN inference, where the “reverse engineering” is involved in predicting how a system works by looking at the system output alone. Many algorithmic and statistical approaches have been developed to computationally reverse engineer biological systems. However, there are no known bioin-formatics tools capable of performing perfect GRN inference. Here, extensive experiments are conducted to evaluate and compare recent bioinformatics tools for inferring GRNs from time-series gene expression data. Standard performance metrics for these tools based on both simulated and real data sets are generally low, suggesting that further efforts are needed to develop more reliable GRN inference tools. It is also observed that using multiple tools together can help identify true regulatory interactions between genes, a finding consistent with those reported in the literature. Finally, the dissertation discusses and presents a framework for parallelizing GRN inference methods using Apache Hadoop in a cloud environment

Mining High Utility Patterns Over Data Streams

Mining useful patterns from sequential data is a challenging topic in data mining. An important task for mining sequential data is sequential pattern mining, which discovers sequences of itemsets that frequently appear in a sequence database. In sequential pattern mining, the selection of sequences is generally based on the frequency/support framework. However, most of the patterns returned by sequential pattern mining may not be informative enough to business people and are not particularly related to a business objective. In view of this, high utility sequential pattern (HUSP) mining has emerged as a novel research topic in data mining recently. The main objective of HUSP mining is to extract valuable and useful sequential patterns from data by considering the utility of a pattern that captures a business objective (e.g., profit, users interest). In HUSP mining, the goal is to find sequences whose utility in the database is no less than a user-specified minimum utility threshold. Nowadays, many applications generate a huge volume of data in the form of data streams. A number of studies have been conducted on mining HUSPs, but they are mainly intended for non-streaming data and thus do not take data stream characteristics into consideration. Mining HUSP from such data poses many challenges. First, it is infeasible to keep all streaming data in the memory due to the high volume of data accumulated over time. Second, mining algorithms need to process the arriving data in real time with one scan of data. Third, depending on the minimum utility threshold value, the number of patterns returned by a HUSP mining algorithm can be large and overwhelms the user. In general, it is hard for the user to determine the value for the threshold. Thus, algorithms that can find the most valuable patterns (i.e., top-k high utility patterns) are more desirable. Mining the most valuable patterns is interesting in both static data and data streams. To address these research limitations and challenges, this dissertation proposes techniques and algorithms for mining high utility sequential patterns over data streams. We work on mining HUSPs over both a long portion of a data stream and a short period of time. We also work on how to efficiently identify the most significant high utility patterns (namely, the top-k high utility patterns) over data streams. In the first part, we explore a fundamental problem that is how the limited memory space can be well utilized to produce high quality HUSPs over the entire data stream. An approximation algorithm, called MAHUSP, is designed which employs memory adaptive mechanisms to use a bounded portion of memory, to efficiently discover HUSPs over the entire data streams. The second part of the dissertation presents a new sliding window-based algorithm to discover recent high utility sequential patterns over data streams. A novel data structure named HUSP-Tree is proposed to maintain the essential information for mining recenT HUSPs. An efficient and single-pass algorithm named HUSP-Stream is proposed to generate recent HUSPs from HUSP-Tree. The third part addresses the problem of top-k high utility pattern mining over data streams. Two novel methods, named T-HUDS and T-HUSP, for finding top-k high utility patterns over a data stream are proposed. T-HUDS discovers top-k high utility itemsets and T-HUSP discovers top-k high utility sequential patterns over a data stream. T-HUDS is based on a compressed tree structure, called HUDS-Tree, that can be used to efficiently find potential top-k high utility itemsets over data streams. T-HUSP incrementally maintains the content of top-k HUSPs in a data stream in a summary data structure, named TKList, and discovers top-k HUSPs efficiently. All of the algorithms are evaluated using both synthetic and real datasets. The performances, including the running time, memory consumption, precision, recall and Fmeasure, are compared. In order to show the effectiveness and efficiency of the proposed methods in reallife applications, the fourth part of this dissertation presents applications of one of the proposed methods (i.e., MAHUSP) to extract meaningful patterns from a real web clickstream dataset and a real biosequence dataset. The utility-based sequential patterns are compared with the patterns in the frequency/support framework. The results show that high utility sequential pattern mining provides meaningful patterns in real-life applications

Scalable Mining of High-Utility Sequential Patterns With Three-Tier MapReduce Model

High-utility sequential pattern mining (HUSPM) is a hot research topic in recent decades since it combines both sequential and utility properties to reveal more information and knowledge rather than the traditional frequent itemset mining or sequential pattern mining. Several works of HUSPM have been presented but most of them are based on main memory to speed up mining performance. However, this assumption is not realistic and not suitable in large-scale environments since in real industry, the size of the collected data is very huge and it is impossible to fit the data into the main memory of a single machine. In this article, we first develop a parallel and distributed three-stage MapReduce model for mining high-utility sequential patterns based on large-scale databases. Two properties are then developed to hold the correctness and completeness of the discovered patterns in the developed framework. In addition, two data structures called sidset and utility-linked list are utilized in the developed framework to accelerate the computation for mining the required patterns. From the results, we can observe that the designed model has good performance in large-scale datasets in terms of runtime, memory, efficiency of the number of distributed nodes, and scalability compared to the serial HUSP-Span approach.acceptedVersio