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Networks and epidemic models.

Networks and the epidemiology of directly transmitted infectious diseases are fundamentally linked. The foundations of epidemiology and early epidemiological models were based on population wide random-mixing, but in practice each individual has a finite set of contacts to whom they can pass infection; the ensemble of all such contacts forms a 'mixing network'. Knowledge of the structure of the network allows models to compute the epidemic dynamics at the population scale from the individual-level behaviour of infections. Therefore, characteristics of mixing networks-and how these deviate from the random-mixing norm-have become important applied concerns that may enhance the understanding and prediction of epidemic patterns and intervention measures. Here, we review the basis of epidemiological theory (based on random-mixing models) and network theory (based on work from the social sciences and graph theory). We then describe a variety of methods that allow the mixing network, or an approximation to the network, to be ascertained. It is often the case that time and resources limit our ability to accurately find all connections within a network, and hence a generic understanding of the relationship between network structure and disease dynamics is needed. Therefore, we review some of the variety of idealized network types and approximation techniques that have been utilized to elucidate this link. Finally, we look to the future to suggest how the two fields of network theory and epidemiological modelling can deliver an improved understanding of disease dynamics and better public health through effective disease control.

Animals↗

Geometry of river networks. I. Scaling, fluctuations, and deviations.

This paper is the first in a series of three papers investigating the detailed geometry of river networks. Branching networks are a universal structure employed in the distribution and collection of material. Large-scale river networks mark an important class of two-dimensional branching networks, being not only of intrinsic interest but also a pervasive natural phenomenon. In the description of river network structure, scaling laws are uniformly observed. Reported values of scaling exponents vary, suggesting that no unique set of scaling exponents exists. To improve this current understanding of scaling in river networks and to provide a fuller description of branching network structure, here we report a theoretical and empirical study of fluctuations about and deviations from scaling. We examine data for continent-scale river networks such as the Mississippi and the Amazon and draw inspiration from a simple model of directed, random networks. We center our investigations on the scaling of the length of a subbasin's dominant stream with its area, a characterization of basin shape known as Hack's law. We generalize this relationship to a joint probability density, and provide observations and explanations of deviations from scaling. We show that fluctuations about scaling are substantial, and grow with system size. We find strong deviations from scaling at small scales which can be explained by the existence of a linear network structure. At intermediate scales, we find slow drifts in exponent values, indicating that scaling is only approximately obeyed and that universality remains indeterminate. At large scales, we observe a breakdown in scaling due to decreasing sample space and correlations with overall basin shape. The extent of approximate scaling is significantly restricted by these deviations, and will not be improved by increases in network resolution.

Ecosystem↗

Size of quantum networks.

The metric structure of bosonic scale-free networks and fermionic Cayley-tree networks is analyzed, focusing on the directed distance of nodes from the origin. The topology of the networks strongly depends on the dynamical parameter T, called the temperature. At T= infinity we show analytically that the two networks have a similar behavior: the distance of a generic node from the origin of the network scales as the logarithm of the number of nodes in the network. At T=0 the two networks have an opposite behavior: the bosonic network remains very clusterized (the distance from the origin remains constant as the network increases the number of nodes), while the fermionic network grows following a single branch of the tree, and the distance from the origin varies as a power law of the number of nodes in the network.

Journal Article↗

Topological generalizations of network motifs.

Biological and technological networks contain patterns, termed network motifs, which occur far more often than in randomized networks. Network motifs were suggested to be elementary building blocks that carry out key functions in the network. It is of interest to understand how network motifs combine to form larger structures. To address this, we present a systematic approach to define "motif generalizations": families of motifs of different sizes that share a common architectural theme. To define motif generalizations, we first define "roles" in a subgraph according to structural equivalence. For example, the feedforward loop triad--a motif in transcription, neuronal, and some electronic networks--has three roles: an input node, an output node, and an internal node. The roles are used to define possible generalizations of the motif. The feedforward loop can have three simple generalizations, based on replicating each of the three roles and their connections. We present algorithms for efficiently detecting motif generalizations. We find that the transcription networks of bacteria and yeast display only one of the three generalizations, the multi-output feedforward generalization. In contrast, the neuronal network of C. elegans mainly displays the multi-input generalization. Forward-logic electronic circuits display a multi-input, multi-output hybrid. Thus, networks which share a common motif can have very different generalizations of that motif. Using mathematical modeling, we describe the information processing functions of the different motif generalizations in transcription, neuronal, and electronic networks.

Algorithms↗

Exactly solvable scale-free network model.

We study a deterministic scale-free network recently proposed by Barabási, Ravasz, and Vicsek. We find that there are two types of nodes: the hub and rim nodes, which form a bipartite structure of the network. We first derive the exact numbers P (k) of nodes with degree k for the hub and rim nodes in each generation of the network, respectively. Using this, we obtain the exact exponents of the distribution function P (k) of nodes with k degree in the asymptotic limit of k-->infinity . We show that the degree distribution for the hub nodes exhibits the scale-free nature, P (k) proportional to k(-gamma) with gamma=ln 3/ln 2=1.584 962 , while the degree distribution for the rim nodes is given by P(k) proportional to e(-gamma'k) with gamma' =ln (3/2) =0.405 465 . Second, we analytically calculate the second-order average degree of nodes, d(-) . Third, we numerically as well as analytically calculate the spectra of the adjacency matrix A for representing topology of the network. We also analytically obtain the exact number of degeneracies at each eigenvalue in the network. The density of states (i.e., the distribution function of eigenvalues) exhibits the fractal nature with respect to the degeneracy. Fourth, we study the mathematical structure of the determinant of the eigenequation for the adjacency matrix. Fifth, we study hidden symmetry, zero modes, and its index theorem in the deterministic scale-free network. Finally, we study the nature of the maximum eigenvalue in the spectrum of the deterministic scale-free network. We will prove several theorems for it, using some mathematical theorems. Thus, we show that most of all important quantities in the network theory can be analytically obtained in the deterministic scale-free network model of Barabási, Ravasz, and Vicsek. Therefore, we may call this network model the exactly solvable scale-free network.

Journal Article↗

Optimization of the robustness of multimodal networks.

We investigate the robustness against both random and targeted node removal of networks in which P(k), the distribution of nodes with degree k, is a multimodal distribution, [formula--see text] with k(i) proportional to b -(i-1) and Dirac's delta function delta (x). We refer to this type of network as a scale-free multimodal network. For m=2, the network is a bimodal network; in the limit m approaches infinity, the network models a scale-free network. We calculate and optimize the robustness for given values of the number of modes m, the total number of nodes N, and the average degree , using analytical formulas for the random and targeted node removal thresholds for network collapse. We find, when N>>1, that (i) the robustness against random and targeted node removal for this multimodal network is controlled by a single combination of variables, N(1/m-1), (ii) the robustness of the multimodal network against targeted node removal decreases rapidly when the number of modes becomes larger than a critical value that is of the order of 1n N, and (iii) the values of exponent lambda(opt) that characterizes the scale-free degree distribution of the multimodal network that maximize the robustness against both random and targeted node removal fall between 2.5 and 3.

Journal Article↗

A "geographic information systems" based technique for the study of microvascular networks.

An automated system (ANET) has been developed to construct interactive maps of microvascular networks, calculate blood flow parameters, and simulate microvascular network blood flow using the geographic information systems (GIS) technology. ANET enables us to automatically collect and display topological, structural, and functional parameters and simulate blood flow in microvascular networks. The user-definable programming interface was used for the manipulation of drawings and data. Visual enhancement techniques such as color can be used to display useful information within a network. In ANET the network map becomes a graphical interface through which network information is stored and retrieved and simulations of microvascular network blood flow are carried out. We have used ANET to study the effects of ionizing radiation on normal tissue microvascular networks. Our results indicate that while vessel diameters significantly increased with age in control animals they decreased in irradiated animals. The tortuosity of irradiated vessels (16.3+/-1.1 mean+/-standard error of the mean) was significantly different from control vessels (10.0+/-1.3) only at 7 days postirradiation. Average red blood cell transit time was significantly different between control (1.6+/-0.6s) and irradiated (10.7+/-5.7s) microvascular networks at 30 days postirradiation. ANET provides an effective tool for handling the large volume of complex data that is usually obtained in microvascular network studies and for simulating blood flow in microvascular networks.

Animals↗

Relationship between structural and hemodynamic heterogeneity in microvascular networks.

The relationship between structural and hemodynamic heterogeneity of microvascular networks is examined by analyzing the effects of topological and geometric irregularities on network hemodynamics. Microscopic observations of a network in the rat mesentery provided data on length, diameter, and interconnection of all 913 segments. Two idealized network structures were derived from the observed network. In one, the topological structure was made symmetric; in another a further idealization was made by assigning equal lengths and diameters to all segments with topologically equivalent positions in the network. Blood flow through these three networks was simulated with a mathematical model based on experimental information on blood rheology. Overall network conductance and pressure distribution within the network were found to depend strongly on topological heterogeneity and less on geometric heterogeneity. In contrast, mean capillary hematocrit was sensitive to geometric heterogeneity but not to topological heterogeneity. Geometric and topological heterogeneity contributed equally to the dispersion of arteriovenous transit time. Hemodynamic characteristics of heterogeneous microvascular networks can only be adequately described if both topological and geometric variability in network structure are taken into account.

Animals↗

Synaptic integration in rat frontal cortex shaped by network activity.

Neocortical neurons in vivo are embedded in networks with intensive ongoing activity. How this network activity affects the neurons' integrative properties and what function this may imply at the network level remain largely unknown. Most of our knowledge regarding synaptic communication and integration is based on recordings in vitro, where network activity is strongly diminished or even absent. Here, we present results from two complementary series of experiments based on intracellular in vivo recordings in anesthetized rat frontal cortex. Specifically, we measured 1) the relationship between the excursions of a neuron's membrane potential and the spiking activity in the surrounding network and 2) how the summation of several inputs to a single neuron changes with the different levels of its membrane potential excursions and the associated states of network activity. The combination of these measurements enables us to assess how the level of network activity influences synaptic integration. We present direct evidence that integration of synaptic inputs in frontal cortex is linear, independent of the level of network activity. However, during periods of high network activity, the neurons' response to synaptic input is markedly reduced in both amplitude and duration. This results in a drastic shortening of its window for temporal integration, requiring more precise coordination of presynaptic spike discharges to reliably drive the neuron to spike under conditions of high network activity. We conclude that ongoing activity, as present in the active brain, emphasizes the need for neuronal cooperation at the network level, and cannot be ignored in the exploration of cortical function.

Action Potentials↗

Language processing modulated by literacy: a network analysis of verbal repetition in literate and illiterate subjects.

Previous behavioral and functional neuroimaging data indicate that certain aspects of phonological processing may not be acquired spontaneously, but are modulated by learning an alphabetic written language, that is, learning to read and write. It appears that learning an alphabetic written language modifies the auditory-verbal (spoken) language processing competence in a nontrivial way. We have previously suggested, based on behavioral and functional neuroimaging data, that auditory-verbal and written language interact not only during certain language tasks, but that learning and developing alphabetic written language capacities significantly modulates the spoken language system. Specifically, the acquisition of alphabetic orthographic knowledge has a modulatory influence on sublexical phonological processing and the awareness of sublexical phonological structure. We have suggested that developing an orthographic representation system for an alphabetic written language, and integrating a phoneme-grapheme correspondence with an existing infrastructure for auditory-verbal language processing, will result in a modified language network. Specifically, we suggest that the parallel interactive processing characteristics of the underlying language-processing brain network differ in literate and illiterate subjects. Therefore, the pattern of interactions between the regions of a suitably defined large-scale functional-anatomical network for language processing will differ between literate and illiterate subjects during certain language tasks. In order to investigate this hypothesis further, we analyzed the observed covariance structure in a PET data set from a simple auditory-verbal repetition paradigm in literate and illiterate subjects, with a network approach based on structural equation modeling (SEM). Based on a simple network model for language processing, the results of the present network analysis indicate that the network interactions during word and pseudoword repetition in the illiterate group differ, while there were no significant differences in the literate group. The differences between the two tasks in the illiterate group may reflect differences in attentional modulation of the language network, executive aspects of verbal working memory and the articulatory organization of verbal output. There were no significant differences between the literate and illiterate group during word repetition. In contrast, the network interactions differed between the literate and illiterate group during pseudoword repetition. In addition to differences similar to those observed in the illiterate group between word and pseudoword repetition, there were differences related to the interactions of the phonological loop between the groups. In particular, these differences related to the interaction between Broca's area and the inferior parietal cortex as well as the posterior-midinsula bridge between Wernicke's and Broca's area. In conclusion, the results of this network analysis are consistent with our previously presented results and support the hypothesis that learning to read and write during childhood influences the functional architecture of the adult human brain. In particular, the basic auditory-verbal language network in the human brain is modified as a consequence of acquiring orthographic language skills.

Adult↗

Hierarchical structure and modules in the Escherichia coli transcriptional regulatory network revealed by a new top-down approach.

BACKGROUND: Cellular functions are coordinately carried out by groups of genes forming functional modules. Identifying such modules in the transcriptional regulatory network (TRN) of organisms is important for understanding the structure and function of these fundamental cellular networks and essential for the emerging modular biology. So far, the global connectivity structure of TRN has not been well studied and consequently not applied for the identification of functional modules. Moreover, network motifs such as feed forward loop are recently proposed to be basic building blocks of TRN. However, their relationship to functional modules is not clear. RESULTS: In this work we proposed a top-down approach to identify modules in the TRN of E. coli. By studying the global connectivity structure of the regulatory network, we first revealed a five-layer hierarchical structure in which all the regulatory relationships are downward. Based on this regulatory hierarchy, we developed a new method to decompose the regulatory network into functional modules and to identify global regulators governing multiple modules. As a result, 10 global regulators and 39 modules were identified and shown to have well defined functions. We then investigated the distribution and composition of the two basic network motifs (feed forward loop and bi-fan motif) in the hierarchical structure of TRN. We found that most of these network motifs include global regulators, indicating that these motifs are not basic building blocks of modules since modules should not contain global regulators. CONCLUSION: The transcriptional regulatory network of E. coli possesses a multi-layer hierarchical modular structure without feedback regulation at transcription level. This hierarchical structure builds the basis for a new and simple decomposition method which is suitable for the identification of functional modules and global regulators in the transcriptional regulatory network of E. coli. Analysis of the distribution of feed forward loops and bi-fan motifs in the hierarchical structure suggests that these network motifs are not elementary building blocks of functional modules in the transcriptional regulatory network of E. coli.

Amino Acid Motifs↗

Hierarchical modularity of nested bow-ties in metabolic networks.

BACKGROUND: The exploration of the structural topology and the organizing principles of genome-based large-scale metabolic networks is essential for studying possible relations between structure and functionality of metabolic networks. Topological analysis of graph models has often been applied to study the structural characteristics of complex metabolic networks. RESULTS: In this work, metabolic networks of 75 organisms were investigated from a topological point of view. Network decomposition of three microbes (Escherichia coli, Aeropyrum pernix and Saccharomyces cerevisiae) shows that almost all of the sub-networks exhibit a highly modularized bow-tie topological pattern similar to that of the global metabolic networks. Moreover, these small bow-ties are hierarchically nested into larger ones and collectively integrated into a large metabolic network, and important features of this modularity are not observed in the random shuffled network. In addition, such a bow-tie pattern appears to be present in certain chemically isolated functional modules and spatially separated modules including carbohydrate metabolism, cytosol and mitochondrion respectively. CONCLUSION: The highly modularized bow-tie pattern is present at different levels and scales, and in different chemical and spatial modules of metabolic networks, which is likely the result of the evolutionary process rather than a random accident. Identification and analysis of such a pattern is helpful for understanding the design principles and facilitate the modelling of metabolic networks.

Algorithms↗

On the attenuation and amplification of molecular noise in genetic regulatory networks.

BACKGROUND: Noise has many important roles in cellular genetic regulatory functions at the nanomolar scale. At present, no good theory exists for identifying all possible mechanisms of genetic regulatory networks to attenuate the molecular noise to achieve regulatory ability or to amplify the molecular noise to randomize outcomes to the advantage of diversity. Therefore, the noise filtering of genetic regulatory network is an important topic for gene networks under intrinsic fluctuation and extrinsic noise. RESULTS: Based on stochastic dynamic regulation equation, the intrinsic fluctuation in reaction rates is modeled as a state-dependent stochastic process, which will influence the stability of gene regulatory network, especially, with low concentrations of reacting species. Then the mechanisms of genetic regulatory network to attenuate or amplify extrinsic fluctuation are revealed from the nonlinear stochastic filtering point of view. Furthermore, a simple measure of attenuation level or amplification level of extrinsic noise for genetic regulatory networks is also introduced by nonlinear robust filtering method. Based on the global linearization scheme, a convenient method is introduced to measure noise attenuation or amplification for each gene of the nonlinear stochastic regulatory network by solving a set of filtering problems, which correspond to a set of linearized stochastic regulatory networks. Finally, by the proposed methods, several simulation examples of genetic regulatory networks are given to measure their robust stability under intrinsic fluctuations, and to estimate the genes' attenuation and amplification levels under extrinsic noises. CONCLUSION: In this study, a stochastic nonlinear dynamic model is developed for genetic regulatory networks under intrinsic fluctuation and extrinsic noise. By the method we proposed, we could determine the robust stability under intrinsic fluctuations and identify the genes that are significantly affected by extrinsic noises, which we call the weak structure of the network. This method will be potential for robust gene circuit design in future, on which a drug design could be based.

Animals↗

Setting directions for capacity building in primary health care: a survey of a research network.

BACKGROUND: The South Australian Research Network 'SARNet' aims to build research capacity in primary health care, as part of a national government-funded strategy to integrate research into clinical practice. Internationally, research networks have been a fundamental part of research culture change, and a variety of network models exist. The 'SARNet' model uses a whole system, multidisciplinary approach to capacity building and supports individuals and groups. We undertook a descriptive baseline survey in order to understand the background and needs of SARNet members and to tailor network activities towards those needs. METHODS: A questionnaire survey, assessing members' professional background, research experience, and interest in research development and training, was sent to all members who joined the network in its first year. The visual 'research spider' tool was used to ascertain members' experience in ten core research skills, as well as their interest in developing these skills. Individuals were asked to classify themselves into one of four categories of researchers, based on previous research experience. These self-assessment categories ranged from non-participant to academic. RESULTS: Network membership was diverse. Of the 89 survey participants, 55% were general practitioners or allied health professionals. Overall, most survey respondents indicated little to moderate experience in 7 out of the 10 skills depicted in the 'research spider'. In comparison, respondents were generally highly interested in developing their research skills in all areas. Respondents' research skills correlated significantly with their self-assessed category of research participation (Spearman rank correlation, r = 0.82, p < 0.0005). Correlations between research category and publication record (Gamma association, gamma = 0.53, p < 0.0005) or funding record (Gamma association, gamma = 0.62, p < 0.0005) supported the internal validity of the survey instrument. CONCLUSION: Literature describing evaluation of the impact of networks is scarce. Our survey questionnaire could provide a useful instrument for evaluation of both networks and capacity building initiatives. The survey including the 'research spider' tool provided valuable information about members' needs and interest in strategies to develop their research skills. Initial needs analyses as well as on-going evaluation of network activities are important to include into the business plans of research networks, in order to ensure the network's effectiveness and support of its membership.

Adult↗

A method for the generation of standardized qualitative dynamical systems of regulatory networks.

BACKGROUND: Modeling of molecular networks is necessary to understand their dynamical properties. While a wealth of information on molecular connectivity is available, there are still relatively few data regarding the precise stoichiometry and kinetics of the biochemical reactions underlying most molecular networks. This imbalance has limited the development of dynamical models of biological networks to a small number of well-characterized systems. To overcome this problem, we wanted to develop a methodology that would systematically create dynamical models of regulatory networks where the flow of information is known but the biochemical reactions are not. There are already diverse methodologies for modeling regulatory networks, but we aimed to create a method that could be completely standardized, i.e. independent of the network under study, so as to use it systematically. RESULTS: We developed a set of equations that can be used to translate the graph of any regulatory network into a continuous dynamical system. Furthermore, it is also possible to locate its stable steady states. The method is based on the construction of two dynamical systems for a given network, one discrete and one continuous. The stable steady states of the discrete system can be found analytically, so they are used to locate the stable steady states of the continuous system numerically. To provide an example of the applicability of the method, we used it to model the regulatory network controlling T helper cell differentiation. CONCLUSION: The proposed equations have a form that permit any regulatory network to be translated into a continuous dynamical system, and also find its steady stable states. We showed that by applying the method to the T helper regulatory network it is possible to find its known states of activation, which correspond the molecular profiles observed in the precursor and effector cell types.

Cell Differentiation↗

Women's networks and the social world of fertility behavior.

CONTEXT: Demographic phenomena occur within social contexts and, therefore, should be studied as social processes. However, how to conceptualize and measure the social worlds that individuals inhabit has been the subject of debate. METHODS: Data from a study conducted in Mali in 1996-1997 are used to explore the social networks of Bamanan women and their impact on fertility decisions. Ordinary least-squares and logistic regression techniques are employed to examine the relationship between selected household and social network characteristics and two fertility measures: children ever born and ever-use of contraceptives. RESULTS: Household characteristics do not have a significant effect on either outcome, whereas network attributes do. The more prominently conjugal kin are represented in a network, the fewer children a woman has ever had; however, fertility increases if the husband or unrelated older women are part of the network. Ever-use of contraceptives is elevated if the woman participates in a credit scheme, and rises as the proportion of network members located outside the village increases; it declines sharply as the proportion of network members who are conjugal kin increases, and is significantly elevated if the woman's mother is present. Network effects on fertility are much more pronounced for women aged 30 or older than for younger women, and network effects on contraceptive use are markedly different for younger and older women. CONCLUSIONS: Programs should consider not only women's individual and household characteristics, but also their larger social networks. Additionally, programs should be designed for specific age-groups, given the different network effects on older and younger women.

Adolescent↗

Functional partitioning of yeast co-expression networks after genome duplication.

Several species of yeast, including the baker's yeast Saccharomyces cerevisiae, underwent a genome duplication roughly 100 million years ago. We analyze genetic networks whose members were involved in this duplication. Many networks show detectable redundancy and strong asymmetry in their interactions. For networks of co-expressed genes, we find evidence for network partitioning whereby the paralogs appear to have formed two relatively independent subnetworks from the ancestral network. We simulate the degeneration of networks after duplication and find that a model wherein the rate of interaction loss depends on the "neighborliness" of the interacting genes produces networks with parameters similar to those seen in the real partitioned networks. We propose that the rationalization of network structure through the loss of pair-wise gene interactions after genome duplication provides a mechanism for the creation of semi-independent daughter networks through the division of ancestral functions between these daughter networks.

Base Sequence↗

Evaluation of a social network HIV prevention intervention program for young men who have sex with men in Russia and Bulgaria.

HIV prevention, by intervening within social networks, is potentially important but highly understudied. Approaches that systematically identify, train, and enlist known social influence leaders to advise members of their own networks in risk reduction constitute ways to reach hidden population segments, persons who are distrustful of authorities but trust their peers, and those who cannot be reached through traditional professionally delivered counseling. This article illustrates and provides evaluation data on a program that recruited 14 intact social networks of young men who have sex with men (YMSM) in St. Petersburg, Russia, and Sofia, Bulgaria. Sociometric measures were used to identify the social leader of each network, and baseline risk assessment measures were administered to all members of each social network. The sociometrically determined leaders then attended a six-session group program that provided training and guidance in how to carry out theory-based and tailored HIV prevention conversations with members of their own social networks. Four months after leaders completed the program, all network members were readministered risk assessment measures. Pre- to postintervention data revealed that the program produced: (1) increases in the level and comfort with which network members talked about AIDS prevention topics in their daily conversations; (2) increased network-level AIDS risk reduction knowledge and improved risk reduction norm perceptions, attitudes, behavioral intentions, and self-efficacy; and (3) increased condom use levels among network members. Although not a controlled, randomized trial, these program evaluation findings strongly support the feasibility of social network-level HIV prevention approaches.

Adult↗