Issues In Bioinformatics Research Articles

Fuzzy Prediction of Transmembrane Protein Topology

The prediction of the topology of transmembrane proteins is one of the open issues in bioinformatics. There are many methods proposed to predict transmembrane protein topology. However, these methods have some shortcomings to correctly predict on the boundary of the transmembrane region. In this paper, a new transmembrane prediction based on data fusion technology is proposed. The results of different prediction methods, represented as discrepant interval data, can be combined with induced ordered weighted averaging operator. The appropriate fuzzy interval can be determined. The transmembrane regions can be predicted by choosing the threshold. The real application in transmembrane prediction is used to show the efficiency of the proposed method.

RRSM with a data-dependent threshold for miRNA target prediction

Predicting miRNA target genes is one of the important issues in bioinformatics. The correlation analysis is a widely used method for exploring miRNA targets through microarray data. However, the experimental results show that correlation analysis leads to large false positive or negative results. In addition, the correlation analysis is not appropriate when multiple miRNAs simultaneously regulate a gene. Recently, the relative R squared method (RRSM) has been proposed for miRNA target prediction, which is shown to be superior to some existing methods. To adopt the RRSM, we need first to set thresholds to select a proportion of potential targets. In the previous studies, the threshold is set to be fixed, which does not depend on the characteristic of a gene. Due to the diversity of the functions of genes, a data-dependent threshold may be more feasible in real data applications than a data-independent threshold. In this study, we propose a threshold selection method which is based on the distribution of the relative R squared statistic. The proposed method is shown to significantly improve the previous prediction results by selecting more experimentally validated targets.

Mass spectrometry strategies for clinical metabolomics and lipidomics in psychiatry, neurology, and neuro-oncology.

Metabolomics research has the potential to provide biomarkers for the detection of disease, for subtyping complex disease populations, for monitoring disease progression and therapy, and for defining new molecular targets for therapeutic intervention. These potentials are far from being realized because of a number of technical, conceptual, financial, and bioinformatics issues. Mass spectrometry provides analytical platforms that address the technical barriers to success in metabolomics research; however, the limited commercial availability of analytical and stable isotope standards has created a bottleneck for the absolute quantitation of a number of metabolites. Conceptual and financial factors contribute to the generation of statistically under-powered clinical studies, whereas bioinformatics issues result in the publication of a large number of unidentified metabolites. The path forward in this field involves targeted metabolomics analyses of large control and patient populations to define both the normal range of a defined metabolite and the potential heterogeneity (eg, bimodal) in complex patient populations. This approach requires that metabolomics research groups, in addition to developing a number of analytical platforms, build sufficient chemistry resources to supply the analytical standards required for absolute metabolite quantitation. Examples of metabolomics evaluations of sulfur amino-acid metabolism in psychiatry, neurology, and neuro-oncology and of lipidomics in neurology will be reviewed.

Fighting against uncertainty: an essential issue in bioinformatics

Many bioinformatics problems, such as sequence alignment, gene prediction, phylogenetic tree estimation and RNA secondary structure prediction, are often affected by the 'uncertainty' of a solution, that is, the probability of the solution is extremely small. This situation arises for estimation problems on high-dimensional discrete spaces in which the number of possible discrete solutions is immense. In the analysis of biological data or the development of prediction algorithms, this uncertainty should be handled carefully and appropriately. In this review, I will explain several methods to combat this uncertainty, presenting a number of examples in bioinformatics. The methods include (i) avoiding point estimation, (ii) maximum expected accuracy (MEA) estimations and (iii) several strategies to design a pipeline involving several prediction methods. I believe that the basic concepts and ideas described in this review will be generally useful for estimation problems in various areas of bioinformatics.

A Punctual Algorithm for Small Gene Prediction in DNA Sequences Using a Time-Frequency Approach based on the Z-Curve

Identification of protein-coding regions in Deoxyribonucleic Acid (DNA) sequences because of their 3-base periodicity has been a challenging issue in bioinformatics. Many DSP (Digital Signal Processing) techniques have been applied for identification task and concentrated on assigning numerical values to the symbolic DNA sequence and then applying spectral analysis tools such as the short-time discrete Fourier transform (ST-DFT) to locate periodicity components. In this paper, we investigate the location of exons in DNA strand using Variable Length Window approach based on z-curve. Z-curve is a unique 3-D curve to illustrate DNA's sequence which presents a complete description of DNA's sequence biological behavior. The proposed algorithm has a high accuracy and resolution due to applying Gaussian window with an adjustable length to identify and estimate exonic areas and non-coding regions are totally eliminated. In order to extract period-3 component we used a narrow-band band-pass filter with a central frequency of . The proposed algorithm was applied on some gene sequences existed in GenBank dataset and its results were compared by other existing methods at the nucleotide level. Simulation results show that our algorithm increases the accuracy of exon detection relative to other methods for exon prediction.

Detection of Protein Complexes Using Hierarchical Link Clustering and Core-Attachment Structure§

Identifying protein complexes from protein-protein interact ion (PPI) networks is an important issue in proteomics and bioinformatics. And various computational methods have been developed to solve it. In this paper, an approach called Hierarchical Link Clustering and Core-Attachment (HLC-CA) was proposed to detect protein complexes by integrating an HLC algorithm and the immanent core-attachment structure in protein complexes. Compared with other methods, HLC-CA has a low time complexity and few parameters to tune. HLC-CA includes four steps. Firstly, an HLC algorithm was used to obtain candidate clusters. Secondly, a density threshold was employed to filter the clusters in ord e r to identify complex cores. Thirdly, each core was recruited attachments by introducing the closeness. Finally, the cores chosen in the second step and their corresponding attachments were used to compose protein complexes. Evaluation results show that the proposed HLC-CA method outperforms most of the state-of-the-art methods. Keywords: Complex networks, core-attachment structure, hierarchical link clustering, overlapping communities, protein complexes, protein-protein interactions.

A Novel Fast Algorithm for Exon Prediction in Eukaryotic Genes using Linear Predictive Coding Model and Goertzel Algorithm based on the Z-Curve

identification of protein-coding regions in Deoxyribonucleic Acid (DNA) sequences because of their 3- base periodicity has been a challenging issue in bioinformatics. Many DSP (Digital Signal Processing) techniques have been applied for identification task and concentrated on assigning numerical values to the symbolic DNA sequence and then applying spectral analysis tools such as the short-time discrete Fourier transform (ST-DFT) to locate periodicity components. In this paper, first, the symbolic DNA sequences are converted to digital signal using the Z-curve method, which is a unique 3-D plot to illustrate DNA sequence and presents the biological behavior of DNA sequence. Then a novel fast algorithm is proposed to investigate the location of exons in DNA strand based on the combination of Linear Predictive Coding Model (LPCM) and Goertzel algorithm. The proposed algorithm leads to increase the speed of process and therefor reduce the computational complexity. Detection of small size exons in DNA sequences, exactly, is another advantage of our algorithm. The proposed algorithm ability in exon prediction is compared with several existing methods at the nucleotide level using: (i) specificity - sensitivity values; (ii) Receiver Operating Curves (ROC); and (iii) area under ROC curve. Simulation results show that our algorithm increases the accuracy of exon detection relative to other methods for exon prediction. In this paper, we have also developed a useful user friendly package to analyze DNA sequences. Keywordssequence; Protein coding regions; Signal processing; Exon; Linear predictive coding model; Goertzel algorithm.

WRF-TMH: predicting transmembrane helix by fusing composition index and physicochemical properties of amino acids

Membrane protein is the prime constituent of a cell, which performs a role of mediator between intra and extracellular processes. The prediction of transmembrane (TM) helix and its topology provides essential information regarding the function and structure of membrane proteins. However, prediction of TM helix and its topology is a challenging issue in bioinformatics and computational biology due to experimental complexities and lack of its established structures. Therefore, the location and orientation of TM helix segments are predicted from topogenic sequences. In this regard, we propose WRF-TMH model for effectively predicting TM helix segments. In this model, information is extracted from membrane protein sequences using compositional index and physicochemical properties. The redundant and irrelevant features are eliminated through singular value decomposition. The selected features provided by these feature extraction strategies are then fused to develop a hybrid model. Weighted random forest is adopted as a classification approach. We have used two benchmark datasets including low and high-resolution datasets. tenfold cross validation is employed to assess the performance of WRF-TMH model at different levels including per protein, per segment, and per residue. The success rates of WRF-TMH model are quite promising and are the best reported so far on the same datasets. It is observed that WRF-TMH model might play a substantial role, and will provide essential information for further structural and functional studies on membrane proteins. The accompanied web predictor is accessible at http://111.68.99.218/WRF-TMH/ .

PUTRACER: A NOVEL METHOD FOR IDENTIFICATION OF CONTINUOUS-DOMAINS IN MULTI-DOMAIN PROTEINS

Computer assisted assignment of protein domains is considered as an important issue in structural bioinformatics. The exponential increase in the number of known three dimensional protein structures and the significant role of proteins in biology, medicine and pharmacology illustrate the necessity of a reliable method to automatically detect structural domains as protein units. For this aim, we have developed a program based on the accessible surface area (ASA) and the hydrogen bonds energy in protein backbone (HBE). PUTracer (Protein Unit Tracer) is built on the features of a fast top-down approach to cut a chain into its domains (contiguous domains) with minimal change in ASA as well as HBE. Performance of the program was assessed by a comprehensive benchmark dataset of 124 protein chains, which is based on agreement among experts (e.g. CATH, SCOP) and was expanded to include structures with different types of domain combinations. Equal number of domains and at least 90% agreement in critical boundary accuracy were considered as correct assignment conditions. PUTracer assigned domains correctly in 81.45% of protein chains. Although low critical boundary accuracy in 18.55% of protein chains leads to the incorrect assignments, adjusting the scales causes to improve the performance up to 89.5%. We discuss here the success or failure of adjusting the scales with provided evidences. PUTracer is available at http://bioinf.modares.ac.ir/software/PUTracer/

A New Greedy Randomized Adaptive Search Procedure for Multiobjective RNA Structural Alignment

RNA secondary structures prediction is one of the main issues in bioinformatics. It seeks to elucidate structural conserved regions within a set of RNA sequences. Unfortunately, finding an accurate conserved structure is a very hard task to do. Within the present study, the prediction problem is considered as a multiobjective optimization process in which the structural conservation and the sensitivity of the multiple alignment are optimized. The proposed method called GRASPMORSA is based on an aggregate function and GRASP procedure. The initial solutions are obtained by using a random progressive local/ global algorithm, and then they are refined by an iterative realignment. Experiments within a large scale of data have shown the efficacy and effectiveness of the proposed method and its capacity to reach good quality solutions.

Automatic peak selection by a Benjamini-Hochberg-based algorithm.

A common issue in bioinformatics is that computational methods often generate a large number of predictions sorted according to certain confidence scores. A key problem is then determining how many predictions must be selected to include most of the true predictions while maintaining reasonably high precision. In nuclear magnetic resonance (NMR)-based protein structure determination, for instance, computational peak picking methods are becoming more and more common, although expert-knowledge remains the method of choice to determine how many peaks among thousands of candidate peaks should be taken into consideration to capture the true peaks. Here, we propose a Benjamini-Hochberg (B-H)-based approach that automatically selects the number of peaks. We formulate the peak selection problem as a multiple testing problem. Given a candidate peak list sorted by either volumes or intensities, we first convert the peaks into -values and then apply the B-H-based algorithm to automatically select the number of peaks. The proposed approach is tested on the state-of-the-art peak picking methods, including WaVPeak [1] and PICKY [2]. Compared with the traditional fixed number-based approach, our approach returns significantly more true peaks. For instance, by combining WaVPeak or PICKY with the proposed method, the missing peak rates are on average reduced by 20% and 26%, respectively, in a benchmark set of 32 spectra extracted from eight proteins. The consensus of the B-H-selected peaks from both WaVPeak and PICKY achieves 88% recall and 83% precision, which significantly outperforms each individual method and the consensus method without using the B-H algorithm. The proposed method can be used as a standard procedure for any peak picking method and straightforwardly applied to some other prediction selection problems in bioinformatics. The source code, documentation and example data of the proposed method is available at http://sfb.kaust.edu.sa/pages/software.aspx.

The battle for user-friendly bioinformatics

The battle for user-friendly bioinformatics

An ontological-based knowledge organization for bioinformatics workflow management system

Motivation and Objectives In the field of Computer Science, ontologies represent formal structures to define and organize knowledge of a specific application domain (Chandrasekaran et al., 1999). An ontology is composed of entities, called classes, and relationships among them. Classes are characterized by features, called attributes, and they can be arranged into a hierarchical organization. Ontologies are a fundamental instrument in Artificial Intelligence for the development of Knowledge-Based Systems (KBS). With its formal and well defined structure, in fact, an ontology provides a machine-understandable language that allows automatic reasoning for problems resolution. Typical KBS are Expert Systems (ES) and Decision Support Systems (DSS). ESs gather and formalize the knowledge of a human expert of a domain in order to produce inferences and recommendations given an initial query. DSSs are more interactive KBS, in the sense they offer support, rather than replacement, for the decision making process during the execution of a task, suggesting one possible strategy or tool given a set of initial conditions. DSSs are mainly adopted in the clinical field, where they are called Clinical DSS (CDSS). Ontology specification, structure and organization are then of fundamental importance for the development of a KBS. In this paper we present an improvement of our ontological approach for knowledge organization in DSS design. In our previous publication (Fiannaca et al., 2012) we defined a paradigm for ontology specification named Data Problem Solver (DPS) and we showed how our approach can be applied to bioinformatics domain, modeling the Protein-Protein Interaction Network extraction scenario. In the proposed approach, we aim at integrating into our ontology the concept of Workflow as a set of processes. Our main objective is to provide a general schema in order to add the functionalities and capability of a DSS to the more recent Workflow Management Systems, that especially in bioinformatics, with the Taverna workbench (Hull et al., 2006), represent a powerful instrument for researchers. We called our extended ontological approach Data Problem Solver Workflow (DPSW).

An ontological-based knowledge organization for bioinformatics workflow management system

An ontological-based knowledge organization for bioinformatics workflow management system

Protein Data Representation: A Survey

One of the critical issues in bioinformatics is the data structure used for representing the protein data; this representation is a base for the operations applied such as sequence alignment, structure alignment and motif finding. In this paper, a survey of different representations and wellknown data structures used for protein data is presented from a computer science perspective. This work presents a survey and summarizes the efforts done for protein data representation and approximation. Hence, it could be a basic reference for research that is aiming to develop applications in the field of bioinformatics.

MULTI-LEVEL CLUSTERING OF PHYLOGENETIC PROFILES

The prediction of gene function from genome sequences is one of the main issues in Bioinformatics. Most computational approaches are based on the similarity between sequences to infer gene function. However, the availability of several fully sequenced genomes has enabled alternative approaches, such as phylogenetic profiles. Phylogenetic profiles are vectors which indicate the presence or absence of a gene in other genomes. The main concept of phylogenetic profiles is that proteins participating in a common structural complex or metabolic pathway are likely to evolve in a correlated fashion. In this paper, a multi-level clustering algorithm of phylogenetic profiles is presented, which aims to detect inter- and intra-genome gene clusters.

Bioinformatics algorithm based on a parallel implementation of a machine learning approach using transducers

Finite automata, in which each transition is augmented with an output label in addition to the familiar input label, are considered finite-state transducers. Transducers have been used to analyze some fundamental issues in bioinformatics. Weighted finite-state transducers have been proposed to pairwise alignments of DNA and protein sequences; as well as to develop kernels for computational biology. Machine learning algorithms for conditional transducers have been implemented and used for DNA sequence analysis. Transducer learning algorithms are based on conditional probability computation. It is calculated by using techniques, such as pair-database creation, normalization (with Maximum-Likelihood normalization) and parameters optimization (with Expectation-Maximization - EM). These techniques are intrinsically costly for computation, even worse when are applied to bioinformatics, because the databases sizes are large. In this work, we describe a parallel implementation of an algorithm to learn conditional transducers using these techniques. The algorithm is oriented to bioinformatics applications, such as alignments, phylogenetic trees, and other genome evolution studies. Indeed, several experiences were developed using the parallel and sequential algorithm on Westgrid (specifically, on the Breeze cluster). As results, we obtain that our parallel algorithm is scalable, because execution times are reduced considerably when the data size parameter is increased. Another experience is developed by changing precision parameter. In this case, we obtain smaller execution times using the parallel algorithm. Finally, number of threads used to execute the parallel algorithm on the Breezy cluster is changed. In this last experience, we obtain as result that speedup is considerably increased when more threads are used; however there is a convergence for number of threads equal to or greater than 16.

SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants

Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.

Graph Constrained Discriminant Analysis: A New Method for the Integration of a Graph into a Classification Process

Integrating gene regulatory networks (GRNs) into the classification process of DNA microarrays is an important issue in bioinformatics, both because this information has a true biological interest and because it helps in the interpretation of the final classifier. We present a method called graph-constrained discriminant analysis (gCDA), which aims to integrate the information contained in one or several GRNs into a classification procedure. We show that when the integrated graph includes erroneous information, gCDA's performance is only slightly worse, thus showing robustness to misspecifications in the given GRNs. The gCDA framework also allows the classification process to take into account as many a priori graphs as there are classes in the dataset. The gCDA procedure was applied to simulated data and to three publicly available microarray datasets. gCDA shows very interesting performance when compared to state-of-the-art classification methods. The software package gcda, along with the real datasets that were used in this study, are available online: http://biodev.cea.fr/gcda/.

National Cancer Institute Prostate Cancer Genetics Workshop

Compelling evidence supports a genetic component to prostate cancer susceptibility and aggressiveness. Recent genome-wide association studies have identified more than 30 single-nucleotide polymorphisms associated with prostate cancer susceptibility. It remains unclear, however, whether such genetic variants are associated with disease aggressiveness--one of the most important questions in prostate cancer research today. To help clarify this and substantially expand research in the genetic determinants of prostate cancer aggressiveness, the first National Cancer Institute Prostate Cancer Genetics Workshop assembled researchers to develop plans for a large new research consortium and patient cohort. The workshop reviewed the prior work in this area and addressed the practical issues in planning future studies. With new DNA sequencing technology, the potential application of sequencing information to patient care is emerging. The workshop, therefore, included state-of-the-art presentations by experts on new genotyping technologies, including sequencing and associated bioinformatics issues, which are just beginning to be applied to cancer genetics.