Prediction of transcriptional regulatory interactions in bacteria : a comparative genomics approach

Exponential growth of genomic data in the last two decades has made manual analyses impractical for all but trial studies. As genomic analyses have become more sophisticated, and move toward comparisons across large datasets, computational approaches have become essential. One of the most important biological questions is to understand the mechanisms underlying gene regulation. Genetic regulation is commonly investigated and modelled through the use of transcriptional regulatory network (TRN) structures. These model the regulatory interactions between two key components: transcription factors (TFs) and the target genes (TGs) they regulate. Transcriptional regulatory networks have proven to be invaluable scientific tools in Bioinformatics. When used in conjunction with comparative genomics, they have provided substantial insights into the evolution of regulatory interactions. Current approaches to regulatory network inference, however, omit two additional key entities: promoters and transcription factor binding sites (TFBSs). In this study, we attempted to explore the relationships among these regulatory components in bacteria. Our primary goal was to identify relationships that can assist in reducing the high false positive rates associated with transcription factor binding site predictions and thereupon enhance the reliability of the inferred transcription regulatory networks. In our preliminary exploration of relationships between the key regulatory components in Escherichia coli transcription, we discovered a number of potentially useful features. The combination of location score and sequence dissimilarity scores increased de novo binding site prediction accuracy by 13.6%. Another important observation made was with regards to the relationship between transcription factors grouped by their regulatory role and corresponding promoter strength. Our study of E.coli ��70 promoters, found support at the 0.1 significance level for our hypothesis | that weak promoters are preferentially associated with activator binding sites to enhance gene expression, whilst strong promoters have more repressor binding sites to repress or inhibit gene transcription. Although the observations were specific to �70, they nevertheless strongly encourage additional investigations when more experimentally confirmed data are available. In our preliminary exploration of relationships between the key regulatory components in E.coli transcription, we discovered a number of potentially useful features { some of which proved successful in reducing the number of false positives when applied to re-evaluate binding site predictions. Of chief interest was the relationship observed between promoter strength and TFs with respect to their regulatory role. Based on the common assumption, where promoter homology positively correlates with transcription rate, we hypothesised that weak promoters would have more transcription factors that enhance gene expression, whilst strong promoters would have more repressor binding sites. The t-tests assessed for E.coli �70 promoters returned a p-value of 0.072, which at 0.1 significance level suggested support for our (alternative) hypothesis; albeit this trend may only be present for promoters where corresponding TFBSs are either all repressors or all activators. Nevertheless, such suggestive results strongly encourage additional investigations when more experimentally confirmed data will become available. Much of the remainder of the thesis concerns a machine learning study of binding site prediction, using the SVM and kernel methods, principally the spectrum kernel. Spectrum kernels have been successfully applied in previous studies of protein classification [91, 92], as well as the related problem of promoter predictions [59], and we have here successfully applied the technique to refining TFBS predictions. The advantages provided by the SVM classifier were best seen in `moderately'-conserved transcription factor binding sites as represented by our E.coli CRP case study. Inclusion of additional position feature attributes further increased accuracy by 9.1% but more notable was the considerable decrease in false positive rate from 0.8 to 0.5 while retaining 0.9 sensitivity. Improved prediction of transcription factor binding sites is in turn extremely valuable in improving inference of regulatory relationships, a problem notoriously prone to false positive predictions. Here, the number of false regulatory interactions inferred using the conventional two-component model was substantially reduced when we integrated de novo transcription factor binding site predictions as an additional criterion for acceptance in a case study of inference in the Fur regulon. This initial work was extended to a comparative study of the iron regulatory system across 20 Yersinia strains. This work revealed interesting, strain-specific difierences, especially between pathogenic and non-pathogenic strains. Such difierences were made clear through interactive visualisations using the TRNDifi software developed as part of this work, and would have remained undetected using conventional methods. This approach led to the nomination of the Yfe iron-uptake system as a candidate for further wet-lab experimentation due to its potential active functionality in non-pathogens and its known participation in full virulence of the bubonic plague strain. Building on this work, we introduced novel structures we have labelled as `regulatory trees', inspired by the phylogenetic tree concept. Instead of using gene or protein sequence similarity, the regulatory trees were constructed based on the number of similar regulatory interactions. While the common phylogentic trees convey information regarding changes in gene repertoire, which we might regard being analogous to `hardware', the regulatory tree informs us of the changes in regulatory circuitry, in some respects analogous to `software'. In this context, we explored the `pan-regulatory network' for the Fur system, the entire set of regulatory interactions found for the Fur transcription factor across a group of genomes. In the pan-regulatory network, emphasis is placed on how the regulatory network for each target genome is inferred from multiple sources instead of a single source, as is the common approach. The benefit of using multiple reference networks, is a more comprehensive survey of the relationships, and increased confidence in the regulatory interactions predicted. In the present study, we distinguish between relationships found across the full set of genomes as the `core-regulatory-set', and interactions found only in a subset of genomes explored as the `sub-regulatory-set'. We found nine Fur target gene clusters present across the four genomes studied, this core set potentially identifying basic regulatory processes essential for survival. Species level difierences are seen at the sub-regulatory-set level; for example the known virulence factors, YbtA and PchR were found in Y.pestis and P.aerguinosa respectively, but were not present in both E.coli and B.subtilis. Such factors and the iron-uptake systems they regulate, are ideal candidates for wet-lab investigation to determine whether or not they are pathogenic specific. In this study, we employed a broad range of approaches to address our goals and assessed these methods using the Fur regulon as our initial case study. We identified a set of promising feature attributes; demonstrated their success in increasing transcription factor binding site prediction specificity while retaining sensitivity, and showed the importance of binding site predictions in enhancing the reliability of regulatory interaction inferences. Most importantly, these outcomes led to the introduction of a range of visualisations and techniques, which are applicable across the entire bacterial spectrum and can be utilised in studies beyond the understanding of transcriptional regulatory networks.

An English-translated parallel corpus for the CJK Wikipedia collections

In this paper, we describe a machine-translated parallel English corpus for the NTCIR Chinese, Japanese and Korean (CJK) Wikipedia collections. This document collection is named CJK2E Wikipedia XML corpus. The corpus could be used by the information retrieval research community and knowledge sharing in Wikipedia in many ways; for example, this corpus could be used for experimentations in cross-lingual information retrieval, cross-lingual link discovery, or omni-lingual information retrieval research. Furthermore, the translated CJK articles could be used to further expand the current coverage of the English Wikipedia.

How activation, entanglement, and searching a semantic network contribute to event memory

Free association norms indicate that words are organized into semantic/associative neighborhoods within a larger network of words and links that bind the net together. We present evidence indicating that memory for a recent word event can depend on implicitly and simultaneously activating related words in its neighborhood. Processing a word during encoding primes its network representation as a function of the density of the links in its neighborhood. Such priming increases recall and recognition and can have long lasting effects when the word is processed in working memory. Evidence for this phenomenon is reviewed in extralist cuing, primed free association, intralist cuing, and single-item recognition tasks. The findings also show that when a related word is presented to cue the recall of a studied word, the cue activates it in an array of related words that distract and reduce the probability of its selection. The activation of the semantic network produces priming benefits during encoding and search costs during retrieval. In extralist cuing recall is a negative function of cue-to-distracter strength and a positive function of neighborhood density, cue-to-target strength, and target-to cue strength. We show how four measures derived from the network can be combined and used to predict memory performance. These measures play different roles in different tasks indicating that the contribution of the semantic network varies with the context provided by the task. We evaluate spreading activation and quantum-like entanglement explanations for the priming effect produced by neighborhood density.

Context-aware device self-configuration using self-organizing maps

Modern mobile computing devices are versatile, but bring the burden of constant settings adjustment according to the current conditions of the environment. While until today, this task has to be accomplished by the human user, the variety of sensors usually deployed in such a handset provides enough data for autonomous self-configuration by a learning, adaptive system. However, this data is not fully available at certain points in time, or can contain false values. Handling potentially incomplete sensor data to detect context changes without a semantic layer represents a scientific challenge which we address with our approach. A novel machine learning technique is presented - the Missing-Values-SOM - which solves this problem by predicting setting adjustments based on context information. Our method is centered around a self-organizing map, extending it to provide a means of handling missing values. We demonstrate the performance of our approach on mobile context snapshots, as well as on classical machine learning datasets.

Semantic labelling for document feature patterns using ontological subjects

Finding and labelling semantic features patterns of documents in a large, spatial corpus is a challenging problem. Text documents have characteristics that make semantic labelling difficult; the rapidly increasing volume of online documents makes a bottleneck in finding meaningful textual patterns. Aiming to deal with these issues, we propose an unsupervised documnent labelling approach based on semantic content and feature patterns. A world ontology with extensive topic coverage is exploited to supply controlled, structured subjects for labelling. An algorithm is also introduced to reduce dimensionality based on the study of ontological structure. The proposed approach was promisingly evaluated by compared with typical machine learning methods including SVMs, Rocchio, and kNN.

A pattern based two-stage text classifier

In a classification problem typically we face two challenging issues, the diverse characteristic of negative documents and sometimes a lot of negative documents that are closed to positive documents. Therefore, it is hard for a single classifier to clearly classify incoming documents into classes. This paper proposes a novel gradual problem solving to create a two-stage classifier. The first stage identifies reliable negatives (negative documents with weak positive characteristics). It concentrates on minimizing the number of false negative documents (recall-oriented). We use Rocchio, an existing recall based classifier, for this stage. The second stage is a precision-oriented “fine tuning”, concentrates on minimizing the number of false positive documents by applying pattern (a statistical phrase) mining techniques. In this stage a pattern-based scoring is followed by threshold setting (thresholding). Experiment shows that our statistical phrase based two-stage classifier is promising.

Timed Probabilistic Automaton : a bridge between Raven and Song Scope for automatic species recognition

Raven and Song Scope are two automated sound anal-ysis tools based on machine learning technique for en-vironmental monitoring. Many research works have been conducted upon them, however, no or rare explo-ration mentions about the performance and comparison between them. This paper investigates the comparisons from six aspects: theory, software interface, ease of use, detection targets, detection accuracy, and potential application. Through deep exploration one critical gap is identified that there is a lack of approach to detect both syllables and call structures, since Raven only aims to detect syllables while Song Scope targets call structures. Therefore, a Timed Probabilistic Automata (TPA) system is proposed which separates syllables first and clusters them into complex structures after.

Pattern-based topic models for information filtering

Topic modelling, such as Latent Dirichlet Allocation (LDA), was proposed to generate statistical models to represent multiple topics in a collection of documents, which has been widely utilized in the fields of machine learning and information retrieval, etc. But its effectiveness in information filtering is rarely known. Patterns are always thought to be more representative than single terms for representing documents. In this paper, a novel information filtering model, Pattern-based Topic Model(PBTM) , is proposed to represent the text documents not only using the topic distributions at general level but also using semantic pattern representations at detailed specific level, both of which contribute to the accurate document representation and document relevance ranking. Extensive experiments are conducted to evaluate the effectiveness of PBTM by using the TREC data collection Reuters Corpus Volume 1. The results show that the proposed model achieves outstanding performance.

Predicting fault-prone software modules with rank sum classification

The detection and correction of defects remains among the most time consuming and expensive aspects of software development. Extensive automated testing and code inspections may mitigate their effect, but some code fragments are necessarily more likely to be faulty than others, and automated identification of fault prone modules helps to focus testing and inspections, thus limiting wasted effort and potentially improving detection rates. However, software metrics data is often extremely noisy, with enormous imbalances in the size of the positive and negative classes. In this work, we present a new approach to predictive modelling of fault proneness in software modules, introducing a new feature representation to overcome some of these issues. This rank sum representation offers improved or at worst comparable performance to earlier approaches for standard data sets, and readily allows the user to choose an appropriate trade-off between precision and recall to optimise inspection effort to suit different testing environments. The method is evaluated using the NASA Metrics Data Program (MDP) data sets, and performance is compared with existing studies based on the Support Vector Machine (SVM) and Naïve Bayes (NB) Classifiers, and with our own comprehensive evaluation of these methods.

A topic based document relevance ranking model

Topic modelling has been widely used in the fields of information retrieval, text mining, machine learning, etc. In this paper, we propose a novel model, Pattern Enhanced Topic Model (PETM), which makes improvements to topic modelling by semantically representing topics with discriminative patterns, and also makes innovative contributions to information filtering by utilising the proposed PETM to determine document relevance based on topics distribution and maximum matched patterns proposed in this paper. Extensive experiments are conducted to evaluate the effectiveness of PETM by using the TREC data collection Reuters Corpus Volume 1. The results show that the proposed model significantly outperforms both state-of-the-art term-based models and pattern-based models.

Pattern-based topics for document modelling in information filtering

Many mature term-based or pattern-based approaches have been used in the field of information filtering to generate users’ information needs from a collection of documents. A fundamental assumption for these approaches is that the documents in the collection are all about one topic. However, in reality users’ interests can be diverse and the documents in the collection often involve multiple topics. Topic modelling, such as Latent Dirichlet Allocation (LDA), was proposed to generate statistical models to represent multiple topics in a collection of documents, and this has been widely utilized in the fields of machine learning and information retrieval, etc. But its effectiveness in information filtering has not been so well explored. Patterns are always thought to be more discriminative than single terms for describing documents. However, the enormous amount of discovered patterns hinder them from being effectively and efficiently used in real applications, therefore, selection of the most discriminative and representative patterns from the huge amount of discovered patterns becomes crucial. To deal with the above mentioned limitations and problems, in this paper, a novel information filtering model, Maximum matched Pattern-based Topic Model (MPBTM), is proposed. The main distinctive features of the proposed model include: (1) user information needs are generated in terms of multiple topics; (2) each topic is represented by patterns; (3) patterns are generated from topic models and are organized in terms of their statistical and taxonomic features, and; (4) the most discriminative and representative patterns, called Maximum Matched Patterns, are proposed to estimate the document relevance to the user’s information needs in order to filter out irrelevant documents. Extensive experiments are conducted to evaluate the effectiveness of the proposed model by using the TREC data collection Reuters Corpus Volume 1. The results show that the proposed model significantly outperforms both state-of-the-art term-based models and pattern-based models

Supplementary information : weighted tree kernels for sequence analysis

Genomic sequences are fundamentally text documents, admitting various representations according to need and tokenization. Gene expression depends crucially on binding of enzymes to the DNA sequence at small, poorly conserved binding sites, limiting the utility of standard pattern search. However, one may exploit the regular syntactic structure of the enzyme's component proteins and the corresponding binding sites, framing the problem as one of detecting grammatically correct genomic phrases. In this paper we propose new kernels based on weighted tree structures, traversing the paths within them to capture the features which underpin the task. Experimentally, we and that these kernels provide performance comparable with state of the art approaches for this problem, while offering significant computational advantages over earlier methods. The methods proposed may be applied to a broad range of sequence or tree-structured data in molecular biology and other domains.

Automatic de-identification of electronic health records : an Australian perspective

We present an approach to automatically de-identify health records. In our approach, personal health information is identified using a Conditional Random Fields machine learning classifier, a large set of linguistic and lexical features, and pattern matching techniques. Identified personal information is then removed from the reports. The de-identification of personal health information is fundamental for the sharing and secondary use of electronic health records, for example for data mining and disease monitoring. The effectiveness of our approach is first evaluated on the 2007 i2b2 Shared Task dataset, a widely adopted dataset for evaluating de-identification techniques. Subsequently, we investigate the robustness of the approach to limited training data; we study its effectiveness on different type and quality of data by evaluating the approach on scanned pathology reports from an Australian institution. This data contains optical character recognition errors, as well as linguistic conventions that differ from those contained in the i2b2 dataset, for example different date formats. The findings suggest that our approach compares to the best approach from the 2007 i2b2 Shared Task; in addition, the approach is found to be robust to variations of training size, data type and quality in presence of sufficient training data.

Using performance-based evaluation to close the loop between biological and robotic navigation

In this paper we describe the benefits of a performance-based approach to modeling biological systems for use in robotics. Specifically, we describe the RatSLAM system, a computational model of the navigation processes thought to drive navigation in a part of the rodent brain called the hippocampus. Unlike typical computational modeling approaches, which focus on biological fidelity, RatSLAM’s development cycle has been driven primarily by performance evaluation on robots navigating in a wide variety of challenging, real world environments. We briefly describe three seminal results, two in robotics and one in biology. In addition, we present current research on brain-inspired learning algorithms with the aim of enabling a robot to autonomously learn how best to use its sensor suite to navigate, without requiring any specific knowledge of the robot, sensor types or environment characteristics. Our aim is to drive discussion on the merits of practical, performance-focused implementations of biological models in robotics.