A survey on methods for modeling and analyzing integrated biological networks

Understanding how cellular systems build up integrated responses to their dynamically changing environment is one of the open questions in Systems Biology. Despite their intertwinement, signaling networks, gene regulation and metabolism have been frequently modeled independently in the context of well-defined subsystems. For this purpose, several mathematical formalisms have been developed according to the features of each particular network under study. Nonetheless, a deeper understanding of cellular behavior requires the integration of these various systems into a model capable of capturing how they operate as an ensemble. With the recent advances in the "omics" technologies, more data is becoming available and, thus, recent efforts have been driven toward this integrated modeling approach. We herein review and discuss methodological frameworks currently available for modeling and analyzing integrated biological networks, in particular metabolic, gene regulatory and signaling networks. These include network-based methods and Chemical Organization Theory, Flux-Balance Analysis and its extensions, logical discrete modeling, Petri Nets, traditional kinetic modeling, Hybrid Systems and stochastic models. Comparisons are also established regarding data requirements, scalability with network size and computational burden. The methods are illustrated with successful case studies in large-scale genome models and in particular subsystems of various organisms.     

Constructing biological networks through combined literature mining and microarray analysis: a LMMA approach

MOTIVATION: Network reconstruction of biological entities is very important for understanding biological processes and the organizational principles of biological systems. This work focuses on integrating both the literatures and microarray gene-expression data, and a combined literature mining and microarray analysis (LMMA) approach is developed to construct gene networks of a specific biological system. RESULTS: In the LMMA approach, a global network is first constructed using the literature-based co-occurrence method. It is then refined using microarray data through a multivariate selection procedure. An application of LMMA to the angiogenesis is presented. Our result shows that the LMMA-based network is more reliable than the co-occurrence-based network in dealing with multiple levels of KEGG gene, KEGG Orthology and pathway. AVAILABILITY: The LMMA program is available upon request.     

BicNET: Flexible module discovery in large-scale biological networks using biclustering

Background

Despite the recognized importance of module discovery in biological networks to enhance our understanding of complex biological systems, existing methods generally suffer from two major drawbacks. First, there is a focus on modules where biological entities are strongly connected, leading to the discovery of trivial/well-known modules and to the inaccurate exclusion of biological entities with subtler yet relevant roles. Second, there is a generalized intolerance towards different forms of noise, including uncertainty associated with less-studied biological entities (in the context of literature-driven networks) and experimental noise (in the context of data-driven networks). Although state-of-the-art biclustering algorithms are able to discover modules with varying coherency and robustness to noise, their application for the discovery of non-dense modules in biological networks has been poorly explored and it is further challenged by efficiency bottlenecks.

Methods

This work proposes Biclustering NETworks (BicNET), a biclustering algorithm to discover non-trivial yet coherent modules in weighted biological networks with heightened efficiency. Three major contributions are provided. First, we motivate the relevance of discovering network modules given by constant, symmetric, plaid and order-preserving biclustering models. Second, we propose an algorithm to discover these modules and to robustly handle noisy and missing interactions. Finally, we provide new searches to tackle time and memory bottlenecks by effectively exploring the inherent structural sparsity of network data.

Results

Results in synthetic network data confirm the soundness, efficiency and superiority of BicNET. The application of BicNET on protein interaction and gene interaction networks from yeast, E. coli and Human reveals new modules with heightened biological significance.

Conclusions

BicNET is, to our knowledge, the first method enabling the efficient unsupervised analysis of large-scale network data for the discovery of coherent modules with parameterizable homogeneity.

     

PConPy--a Python module for generating 2D protein maps

PConPy is an open-source Python module for generating protein contact maps, distance maps and hydrogen bond plots. These maps can be generated in a number of publication-quality vector and raster image formats. Contact maps can be annotated with secondary structure and hydrogen bond assignments. PConPy offers a more flexible choice of contact definition parameters than existing toolkits, most notably a greater choice of inter-residue distance metrics. PConPy can be used as a stand-alone application or imported into existing source code. A web-interface to PConPy is also available for use. AVAILABILITY: The PConPy web-interface and source code can be accessed from its website at http://www.csse.unimelb.edu.au/~hohkhkh1/pconpy/. CONTACT: hohkhkh1@csse.unimelb.edu.au     

A novel framework for the comparative analysis of biological networks

Genome sequencing projects provide nearly complete lists of the individual components present in an organism, but reveal little about how they work together. Follow-up initiatives have deciphered thousands of dynamic and context-dependent interrelationships between gene products that need to be analyzed with novel bioinformatics approaches able to capture their complex emerging properties. Here, we present a novel framework for the alignment and comparative analysis of biological networks of arbitrary topology. Our strategy includes the prediction of likely conserved interactions, based on evolutionary distances, to counter the high number of missing interactions in the current interactome networks, and a fast assessment of the statistical significance of individual alignment solutions, which vastly increases its performance with respect to existing tools. Finally, we illustrate the biological significance of the results through the identification of novel complex components and potential cases of cross-talk between pathways and alternative signaling routes.     

The applicability of recurrent neural networks for biological sequence analysis

Selection of machine learning techniques requires a certain sensitivity to the requirements of the problem. In particular, the problem can be made more tractable by deliberately using algorithms that are biased toward solutions of the requisite kind. In this paper, we argue that recurrent neural networks have a natural bias toward a problem domain of which biological sequence analysis tasks are a subset. We use experiments with synthetic data to illustrate this bias. We then demonstrate that this bias can be exploitable using a data set of protein sequences containing several classes of subcellular localization targeting peptides. The results show that, compared with feed forward, recurrent neural networks will generally perform better on sequence analysis tasks. Furthermore, as the patterns within the sequence become more ambiguous, the choice of specific recurrent architecture becomes more critical.     

Gene module level analysis: identification to networks and dynamics

Nature exhibits modular design in biological systems. Gene module level analysis is based on this module concept, aiming to understand biological network design and systems behavior in disease and development by emphasizing on modules of genes rather than individual genes. Module level analysis has been extensively applied in genome wide level analysis, exploring the organization of biological systems from identifying modules to reconstructing module networks and analyzing module dynamics. Such module level perspective provides a high level representation of the regulatory scenario and design of biological systems, promising to revolutionize our view of systems biology, genetic engineering as well as disease mechanisms and molecular medicine.     

GLay: community structure analysis of biological networks

SUMMARY: GLay provides Cytoscape users an assorted collection of versatile community structure algorithms and graph layout functions for network clustering and structured visualization. High performance is achieved by dynamically linking highly optimized C functions to the Cytoscape JAVA program, which makes GLay especially suitable for decomposition, display and exploratory analysis of large biological networks. AVAILABILITY: http://brainarray.mbni.med.umich.edu/glay/.     

Constructing benchmark test sets for biological sequence analysis using independent set algorithms

Biological sequence families contain many sequences that are very similar to each other because they are related by evolution, so the strategy for splitting data into separate training and test sets is a nontrivial choice in benchmarking sequence analysis methods. A random split is insufficient because it will yield test sequences that are closely related or even identical to training sequences. Adapting ideas from independent set graph algorithms, we describe two new methods for splitting sequence data into dissimilar training and test sets. These algorithms input a sequence family and produce a split in which each test sequence is less than p% identical to any individual training sequence. These algorithms successfully split more families than a previous approach, enabling construction of more diverse benchmark datasets.     

An integrated approach for the analysis of biological pathways using mixed models

Gene class, ontology, or pathway testing analysis has become increasingly popular in microarray data analysis. Such approaches allow the integration of gene annotation databases, such as Gene Ontology and KEGG Pathway, to formally test for subtle but coordinated changes at a system level. Higher power in gene class testing is gained by combining weak signals from a number of individual genes in each pathway. We propose an alternative approach for gene-class testing based on mixed models, a class of statistical models that: a) provides the ability to model and borrow strength across genes that are both up and down in a pathway, b) operates within a well-established statistical framework amenable to direct control of false positive or false discovery rates, c) exhibits improved power over widely used methods under normal location-based alternative hypotheses, and d) handles complex experimental designs for which permutation resampling is difficult. We compare the properties of this mixed models approach with nonparametric method GSEA and parametric method PAGE using a simulation study, and illustrate its application with a diabetes data set and a dose-response data set.     

Task scheduling for MapReduce in heterogeneous networks

In this paper, the task scheduling in MapReduce is considered for geo-distributed data centers on heterogeneous networks. Adaptive heartbeats, job deadlines and data locality are concerned. Job deadlines are divided according to the maximum data volume of tasks. With the considered constraints, the task scheduling is formulated as an assignment problem in each heartbeat, in which adaptive heartbeats are calculated by the processing times of tasks, jobs are sequencing in terms of the divided deadlines and tasks are scheduled by the Hungarian algorithm. Taking into account both the data transfer and processing times, the most suitable data center for all mapped jobs are determined in the reduce phase. Experimental results show that the proposed algorithms outperform the current existing ones. The proposals with sorted task-sequences have better performance than those with random task-sequences.     

BIOZON: a system for unification, management and analysis of heterogeneous biological data

Background  

Integration of heterogeneous data types is a challenging problem, especially in biology, where the number of databases and data types increase rapidly. Amongst the problems that one has to face are integrity, consistency, redundancy, connectivity, expressiveness and updatability.