David V. Foster

Edge direction and the structure of networks.

Directed networks are ubiquitous and are necessary to represent complex systems with asymmetric interactions—from food webs to the World Wide Web. Despite the importance of edge direction for detecting local and community structure, it has been disregarded in studying a basic type of global diversity in networks: the tendency of nodes with similar numbers of edges to connect. This tendency, called assortativity, affects crucial structural and dynamic properties of real-world networks, such as error tolerance or epidemic spreading. Here we demonstrate that edge direction has profound effects on assortativity. We define a set of four directed assortativity measures and assign statistical significance by comparison to randomized networks. We apply these measures to three network classes—online/social networks, food webs, and word-adjacency networks. Our measures (i) reveal patterns common to each class, (ii) separate networks that have been previously classified together, and (iii) expose limitations of several existing theoretical models. We reject the standard classification of directed networks as purely assortative or disassortative. Many display a class-specific mixture, likely reflecting functional or historical constraints, contingencies, and forces guiding the system’s evolution.

Statistical mixture modeling for cell subtype identification in flow cytometry.

Statistical mixture modeling provides an opportunity for automated identification and resolution of cell subtypes in flow cytometric data. The configuration of cells as represented by multiple markers simultaneously can be modeled arbitrarily well as a mixture of Gaussian distributions in the dimension of the number of markers. Cellular subtypes may be related to one or multiple components of such mixtures, and fitted mixture models can be evaluated in the full set of markers as an alternative, or adjunct, to traditional subjective gating methods that rely on choosing one or two dimensions. Four color flow data from human blood cells labeled with FITC‐conjugated anti‐CD3, PE‐conjugated anti‐CD8, PE‐Cy5‐conjugated anti‐CD4, and APC‐conjugated anti‐CD19 Abs was acquired on a FACSCalibur. Cells from four murine cell lines, JAWS II, RAW 264.7, CTLL‐2, and A20, were also stained with FITC‐conjugated anti‐CD11c, PE‐conjugated anti‐CD11b, PE‐Cy5‐conjugated anti‐CD8a, and PE‐Cy7‐conjugated‐CD45R/B220 Abs, respectively, and single color flow data were collected on an LSRII. The data were fitted with a mixture of multivariate Gaussians using standard Bayesian statistical approaches and Markov chain Monte Carlo computations. Statistical mixture models were able to identify and purify major cell subsets in human peripheral blood, using an automated process that can be generalized to an arbitrary number of markers. Validation against both traditional expert gating and synthetic mixtures of murine cell lines with known mixing proportions was also performed. This article describes the studies of statistical mixture modeling of flow cytometric data, and demonstrates their utility in examples with four‐color flow data from human peripheral blood samples and synthetic mixtures of murine cell lines.

A model of sequential branching in hierarchical cell fate determination.

Multipotent stem or progenitor cells undergo a sequential series of binary fate decisions, which ultimately generate the diversity of differentiated cells. Efforts to understand cell fate control have focused on simple gene regulatory circuits that predict the presence of multiple stable states, bifurcations and switch-like transitions. However, existing gene network models do not explain more complex properties of cell fate dynamics such as the hierarchical branching of developmental paths. Here, we construct a generic minimal model of the genetic regulatory network controlling cell fate determination, which exhibits five elementary characteristics of cell differentiation: stability, directionality, branching, exclusivity, and promiscuous expression. We argue that a modular architecture comprising repeated network elements reproduces these features of differentiation by sequentially repressing selected modules and hence restricting the dynamics to lower dimensional subspaces of the high-dimensional state space. We implement our model both with ordinary differential equations (ODEs), to explore the role of bifurcations in producing the one-way character of differentiation, and with stochastic differential equations (SDEs), to demonstrate the effect of noise on the system. We further argue that binary cell fate decisions are prevalent in cell differentiation due to general features of the underlying dynamical system. This minimal model makes testable predictions about the structural basis for directional, discrete and diversifying cell phenotype development and thus can guide the evaluation of real gene regulatory networks that govern differentiation.

Clustering drives assortativity and community structure in ensembles of networks

Clustering, assortativity, and communities are key features of complex networks. We probe dependencies between these features and find that ensembles of networks with high clustering display both high assortativity by degree and prominent community structure, while ensembles with high assortativity show much less enhancement of the clustering or community structure. Further, clustering can amplify a small homophilic bias for trait assortativity in network ensembles. This marked asymmetry suggests that transitivity could play a larger role than homophily in determining the structure of many complex networks.

Lower Bounds on Mutual Information

We correct claims about lower bounds on mutual information (MI) between real-valued random variables made by Kraskov et al., Phys. Rev. E 69, 066138 (2004). We show that non-trivial lower bounds on MI in terms of linear correlations depend on the marginal (single variable) distributions. This is so in spite of the invariance of MI under reparametrizations, because linear correlations are not invariant under them. The simplest bounds are obtained for Gaussians, but the most interesting ones for practical purposes are obtained for uniform marginal distributions. The latter can be enforced in general by using the ranks of the individual variables instead of their actual values, in which case one obtains bounds on MI in terms of Spearman correlation coefficients. We show with gene expression data that these bounds are in general nontrivial, and the degree of their (non)saturation yields valuable insight.

Maximal Information Transfer and Behavior Diversity in Random Threshold Networks

Random Threshold Networks (RTNs) are an idealized model of diluted, non-symmetric spin glasses, neural networks or gene regulatory networks. RTNs also serve as an interesting general example of any coordinated causal system. Here we study the conditions for maximal information transfer and behavior diversity in RTNs. These conditions are likely to play a major role in physical and biological systems, perhaps serving as important selective traits in biological systems. We show that the pairwise mutual information is maximized in dynamically critical networks. Also, we show that the correlated behavior diversity is maximized for slightly chaotic networks, close to the critical region. Importantly, critical networks maximize coordinated, diverse dynamical behavior across the network and across time: the information transmission between source and receiver nodes and the diversity of dynamical behaviors, when measured with a time delay between the source and receiver, are maximized for critical networks.