Input variable selection in time-critical knowledge integration applications: A review, analysis, and recommendation paper

This is the post-print version of the final paper published in Advanced Engineering Informatics. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2013 Elsevier B.V.The purpose of this research is twofold: first, to undertake a thorough appraisal of existing Input Variable Selection (IVS) methods within the context of time-critical and computation resource-limited dimensionality reduction problems; second, to demonstrate improvements to, and the application of, a recently proposed time-critical sensitivity analysis method called EventTracker to an environment science industrial use-case, i.e., sub-surface drilling. Producing time-critical accurate knowledge about the state of a system (effect) under computational and data acquisition (cause) constraints is a major challenge, especially if the knowledge required is critical to the system operation where the safety of operators or integrity of costly equipment is at stake. Understanding and interpreting, a chain of interrelated events, predicted or unpredicted, that may or may not result in a specific state of the system, is the core challenge of this research. The main objective is then to identify which set of input data signals has a significant impact on the set of system state information (i.e. output). Through a cause-effect analysis technique, the proposed technique supports the filtering of unsolicited data that can otherwise clog up the communication and computational capabilities of a standard supervisory control and data acquisition system. The paper analyzes the performance of input variable selection techniques from a series of perspectives. It then expands the categorization and assessment of sensitivity analysis methods in a structured framework that takes into account the relationship between inputs and outputs, the nature of their time series, and the computational effort required. The outcome of this analysis is that established methods have a limited suitability for use by time-critical variable selection applications. By way of a geological drilling monitoring scenario, the suitability of the proposed EventTracker Sensitivity Analysis method for use in high volume and time critical input variable selection problems is demonstrated.E

Genome-wide inference of regulatory networks in Streptomyces coelicolor

Background: The onset of antibiotics production in Streptomyces species is co-ordinated with differentiation events. An understanding of the genetic circuits that regulate these coupled biological phenomena is essential to discover and engineer the pharmacologically important natural products made by these species. The availability of genomic tools and access to a large warehouse of transcriptome data for the model organism, Streptomyces coelicolor, provides incentive to decipher the intricacies of the regulatory cascades and develop biologically meaningful hypotheses. Results: In this study, more than 500 samples of genome-wide temporal transcriptome data, comprising wild-type and more than 25 regulatory gene mutants of Streptomyces coelicolor probed across multiple stress and medium conditions, were investigated. Information based on transcript and functional similarity was used to update a previously-predicted whole-genome operon map and further applied to predict transcriptional networks constituting modules enriched in diverse functions such as secondary metabolism, and sigma factor. The predicted network displays a scale-free architecture with a small-world property observed in many biological networks. The networks were further investigated to identify functionally-relevant modules that exhibit functional coherence and a consensus motif in the promoter elements indicative of DNA-binding elements. Conclusions: Despite the enormous experimental as well as computational challenges, a systems approach for integrating diverse genome-scale datasets to elucidate complex regulatory networks is beginning to emerge. We present an integrated analysis of transcriptome data and genomic features to refine a whole-genome operon map and to construct regulatory networks at the cistron level in Streptomyces coelicolor. The functionally-relevant modules identified in this study pose as potential targets for further studies and verification.

Extracting regulator activity profiles by integration of de novo motifs and expression data: characterizing key regulators of nutrient depletion responses in Streptomyces coelicolor

Determining transcriptional regulator activities is a major focus of systems biology, providing key insight into regulatory mechanisms and co-regulators. For organisms such as Escherichia coli, transcriptional regulator binding site data can be integrated with expression data to infer transcriptional regulator activities. However, for most organisms there is only sparse data on their transcriptional regulators, while their associated binding motifs are largely unknown. Here, we address the challenge of inferring activities of unknown regulators by generating de novo (binding) motifs and integrating with expression data. We identify a number of key regulators active in the metabolic switch, including PhoP with its associated directed repeat PHO box, candidate motifs for two SARPs, a CRP family regulator, an iron response regulator and that for LexA. Experimental validation for some of our predictions was obtained using gel-shift assays. Our analysis is applicable to any organism for which there is a reasonable amount of complementary expression data and for which motifs (either over represented or evolutionary conserved) can be identified in the genome

Uncovering Genes with Divergent mRNA-Protein Dynamics in Streptomyces coelicolor

Many biological processes are intrinsically dynamic, incurring profound changes at both molecular and physiological levels. Systems analyses of such processes incorporating large-scale transcriptome or proteome profiling can be quite revealing. Although consistency between mRNA and proteins is often implicitly assumed in many studies, examples of divergent trends are frequently observed. Here, we present a comparative transcriptome and proteome analysis of growth and stationary phase adaptation in Streptomyces coelicolor, taking the time-dynamics of process into consideration. These processes are of immense interest in microbiology as they pertain to the physiological transformations eliciting biosynthesis of many naturally occurring therapeutic agents. A shotgun proteomics approach based on mass spectrometric analysis of isobaric stable isotope labeled peptides (iTRAQ™) enabled identification and rapid quantification of approximately 14% of the theoretical proteome of S. coelicolor. Independent principal component analyses of this and DNA microarray-derived transcriptome data revealed that the prominent patterns in both protein and mRNA domains are surprisingly well correlated. Despite this overall correlation, by employing a systematic concordance analysis, we estimated that over 30% of the analyzed genes likely exhibited significantly divergent patterns, of which nearly one-third displayed even opposing trends. Integrating this data with biological information, we discovered that certain groups of functionally related genes exhibit mRNA-protein discordance in a similar fashion. Our observations suggest that differences between mRNA and protein synthesis/degradation mechanisms are prominent in microbes while reaffirming the plausibility of such mechanisms acting in a concerted fashion at a protein complex or sub-pathway level

A framework to analyze multiple time series data: A case study with Streptomyces coelicolor

Transcriptional regulation in differentiating microorganisms is highly dynamic involving multiple and interwinding circuits consisted of many regulatory genes. Elucidation of these networks may provide the key to harness the full capacity of many organisms that produce natural products. A powerful tool evolved in the past decade is global transcriptional study of mutants in which one or more key regulatory genes of interest have been deleted. To study regulatory mutants of Streptomyces coelicolor , we developed a framework of systematic analysis of gene expression dynamics. Instead of pair-wise comparison of samples in different combinations, genomic DNA was used as a common reference for all samples in microarray assays, thus, enabling direct comparison of gene transcription dynamics across different isogenic mutants. As growth and various differentiation events may unfold at different rates in different mutants, the global transcription profiles of each mutant were first aligned computationally to those of the wild type, with respect to the corresponding growth and differentiation stages, prior to identification of kinetically differentially expressed genes. The genome scale transcriptome data from wild type and a Δ absA1 mutant of Streptomyces coelicolor were analyzed within this framework, and the regulatory elements affected by the gene knockout were identified. This methodology should find general applications in the analysis of other mutants in our repertoire and in other biological systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47950/1/10295_2005_Article_34.pd

Correcting for link loss in causal network inference caused by regulator interference

Motivation: There are a number of algorithms to infer causal regulatory networks from time-series (gene expression) data. Here we analyse the phenomena of regulator interference, where regulators with similar dynamics mutually suppress both the probability of regulating a target and the associated link strength; for instance interference between two identical strong regulators reduces link probabilities by about 50%. Results: We construct a robust method to define an interference corrected causal network based on an analysis of the conditional link probabilities that recovers links lost through interference. On a large real network (Streptomyces coelicolor, phosphate depletion) we demonstrate that significant interference can occur between regulators with a correlation as low as 0.865, losing an estimated 34% of links by interference. However, levels of interference cannot be predicted from the correlation between regulators alone and are data specific. Validating against known networks we show that high numbers of functional links are lost by regulator interference. Performance against other methods on DREAM4 data is excellent. Availability: The method is implemented in R and is publically available as the NIACS package at: http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software