Sinan Erten

DADA: Degree-Aware Algorithms for Network- Based Disease Gene Prioritization

BackgroundHigh-throughput molecular interaction data have been used effectively to prioritize candidate genes that are linked to a disease, based on the observation that the products of genes associated with similar diseases are likely to interact with each other heavily in a network of protein-protein interactions (PPIs). An important challenge for these applications, however, is the incomplete and noisy nature of PPI data. Information flow based methods alleviate these problems to a certain extent, by considering indirect interactions and multiplicity of paths.ResultsWe demonstrate that existing methods are likely to favor highly connected genes, making prioritization sensitive to the skewed degree distribution of PPI networks, as well as ascertainment bias in available interaction and disease association data. Motivated by this observation, we propose several statistical adjustment methods to account for the degree distribution of known disease and candidate genes, using a PPI network with associated confidence scores for interactions. We show that the proposed methods can detect loosely connected disease genes that are missed by existing approaches, however, this improvement might come at the price of more false negatives for highly connected genes. Consequently, we develop a suite called DA DA, which includes different uniform prioritization methods that effectively integrate existing approaches with the proposed statistical adjustment strategies. Comprehensive experimental results on the Online Mendelian Inheritance in Man (OMIM) database show that DA DA outperforms existing methods in prioritizing candidate disease genes.ConclusionsThese results demonstrate the importance of employing accurate statistical models and associated adjustment methods in network-based disease gene prioritization, as well as other network-based functional inference applications. DA DA is implemented in Matlab and is freely available at http://compbio.case.edu/dada/.

Phylogenetic analysis of modularity in protein interaction networks

BackgroundIn systems biology, comparative analyses of molecular interactions across diverse species indicate that conservation and divergence of networks can be used to understand functional evolution from a systems perspective. A key characteristic of these networks is their modularity, which contributes significantly to their robustness, as well as adaptability. Consequently, analysis of modular network structures from a phylogenetic perspective may be useful in understanding the emergence, conservation, and diversification of functional modularity.ResultsIn this paper, we propose a phylogenetic framework for analyzing network modules, with applications that extend well beyond network-based phylogeny reconstruction. Our approach is based on identification of modular network components from each network separately, followed by projection of these modules onto the networks of other species to compare different networks. Subsequently, we use the conservation of various modules in each network to assess the similarity between different networks. Compared to traditional methods that rely on topological comparisons, our approach has key advantages in (i) avoiding intractable graph comparison problems in comparative network analysis, (ii) accounting for noise and missing data through flexible treatment of network conservation, and (iii) providing insights on the evolution of biological systems through investigation of the evolutionary trajectories of network modules. We test our method, MOPHY, on synthetic data generated by simulation of network evolution, as well as existing protein-protein interaction data for seven diverse species. Comprehensive experimental results show that MOPHY is promising in reconstructing evolutionary histories of extant networks based on conservation of modularity, it is highly robust to noise, and outperforms existing methods that quantify network similarity in terms of conservation of network topology.ConclusionThese results establish modularity and network proximity as useful features in comparative network analysis and motivate detailed studies of the evolutionary histories of network modules.

Role of centrality in network-based prioritization of disease genes

High-throughput molecular interaction data have been used effectively to prioritize candidate genes that are linked to a disease, based on the notion that the products of genes associated with similar diseases are likely to interact with each other heavily in a network of protein-protein interactions (PPIs). An important challenge for these applications, however, is the incomplete and noisy nature of PPI data. Random walk and network propagation based methods alleviate these problems to a certain extent, by considering indirect interactions and multiplicity of paths. However, as we demonstrate in this paper, such methods are likely to favor highly connected genes, making prioritization sensitive to the skewed degree distribution of PPI networks, as well as ascertainment bias in available interaction and disease association data. Here, we propose several statistical correction schemes that aim to account for the degree distribution of known disease and candidate genes. We show that, while the proposed schemes are very effective in detecting loosely connected disease genes that are missed by existing approaches, this improvement might come at the price of more false negatives for highly connected genes. Motivated by these results, we develop uniform prioritization methods that effectively integrate existing methods with the proposed statistical correction schemes. Comprehensive experimental results on the Online Mendelian Inheritance in Man (OMIM) database show that the resulting hybrid schemes outperform existing methods in prioritizing candidate disease genes.

MOBAS: identification of disease-associated protein subnetworks using modularity-based scoring

Network-based analyses are commonly used as powerful tools to interpret the findings of genome-wide association studies (GWAS) in a functional context. In particular, identification of disease-associated functional modules, i.e., highly connected protein-protein interaction (PPI) subnetworks with high aggregate disease association, are shown to be promising in uncovering the functional relationships among genes and proteins associated with diseases. An important issue in this regard is the scoring of subnetworks by integrating two quantities: disease association of individual gene products and network connectivity among proteins. Current scoring schemes either disregard the level of connectivity and focus on the aggregate disease association of connected proteins or use a linear combination of these two quantities. However, such scoring schemes may produce arbitrarily large subnetworks which are often not statistically significant or require tuning of parameters that are used to weigh the contributions of network connectivity and disease association.Here, we propose a parameter-free scoring scheme that aims to score subnetworks by assessing the disease association of interactions between pairs of gene products. We also incorporate the statistical significance of network connectivity and disease association into the scoring function. We test the proposed scoring scheme on a GWAS dataset for two complex diseases type II diabetes (T2D) and psoriasis (PS). Our results suggest that subnetworks identified by commonly used methods may fail tests of statistical significance after correction for multiple hypothesis testing. In contrast, the proposed scoring scheme yields highly significant subnetworks, which contain biologically relevant proteins that cannot be identified by analysis of genome-wide association data alone. We also show that the proposed scoring scheme identifies subnetworks that are reproducible across different cohorts, and it can robustly recover relevant subnetworks at lower sampling rates.

Comparative Analysis of Modularity in Biological Systems

In systems biology, comparative analysis of molecular interactions across diverse species indicates that conservation and divergence of networks can be used to understand functional evolution from a systems perspective. A key characteristic of these networks is their modularity, which contributes significantly to their robustness, as well as adaptability. In this paper, we investigate the evolution of modularity in biological networks through phylogenetic analysis of network modules. Namely, we develop a computational framework, which identifies modules in networks of diverse species independently and projects these modules into the networks of other species, with aview to capturing the evolutionary trajectories of functional modules. These trajectories can then be used to reconstruct modular phylogenies and whole-network phylogenies, or to enhance identification of functional modules. In the context of phylogeny reconstruction, our experiments on a comprehensive collection of simulated and real networks show that comparison of networks based on module trajectories is more informative than other measures of network similarity. These results demonstrate the key role of modularity in the functional evolution of biological systems and motivate further investigation of the evolution of functional modules.

What Do We Learn from Network-Based Analysis of Genome-Wide Association Data?

Network based analyses are commonly used as powerful tools to interpret the findings of genome-wide association studies (GWAS) in a functional context. In particular, identification of disease-associated functional modules, i.e., highly connected protein-protein interaction (PPI) subnetworks with high aggregate disease association, are shown to be promising in uncovering the functional relationships among genes and proteins associated with diseases. An important issue in this regard is the scoring of subnetworks by integrating two quantities that are not readily compatible: disease association of individual gene products and network connectivity among proteins. Current scoring schemes either disregard the level of connectivity and focus on the aggregate disease association of connected proteins or use a linear combination of these two quantities. However, such scoring schemes may produce arbitrarily large subnetworks which are often not statistically significant, or require tuning of parameters that are used to weigh the contributions of network connectivity and disease association. Here, we propose a parameter-free scoring scheme that aims to score subnetworks by assessing the disease association of pairwise interactions and incorporating the statistical significance of network connectivity and disease association. We test the proposed scoring scheme on a GWAS dataset for type II diabetes (T2D). Our results suggest that subnetworks identified by commonly used methods may fail tests of statistical significance after correction for multiple hypothesis testing. In contrast, the proposed scoring scheme yields highly significant subnetworks, which contain biologically relevant proteins that cannot be identified by analysis of genome-wide association data alone.

Molecular Networks and Complex Diseases

Many human diseases are based on a set of complex interactions among multiple genetic and environmental factors. Recent developments in biotechnology have enabled interrogation of the cell at various levels leading to many types of “omic” data that provide valuable information on these factors and their interactions. These data include (1) genomic data, which reveals possible genetic factors involved in disease, (2) transcriptomic data, which reveals changes in regulation of gene expression, and (3) proteomic data, which reveals irregularities in the amount of functional proteins in affected tissues. While these data are very useful in understanding differences between disease phenotypes, they provide information at the level of a single molecular type. To integrate these disparate data types, molecular network analysis is invaluable in uncovering the relations between disparate molecular targets and understanding disease development and progression at the systems level. This chapter provides an overview of current findings on the systems biology of human diseases in the context of molecular networks and outlines current computational approaches in network biology of human diseases.

Identification of Modules in Protein-Protein Interaction Networks

In biological systems, most processes are carried out through orchestration of multiple interacting molecules. These interactions are often abstracted using network models. A key feature of cellular networks is their modularity, which contributes significantly to the robustness, as well as adaptability of biological systems. Therefore, modularization of cellular networks is likely to be useful in obtaining insights into the working principles of cellular systems, as well as building tractable models of cellular organization and dynamics. A common, high-throughput source of data on molecular interactions is in the form of physical interactions between proteins, which are organized into protein-protein interaction (PPI) networks. This chapter provides an overview on identification and analysis of functional modules in PPI networks, which has been an active area of research in the last decade.