Delay-dependent Stability of Genetic Regulatory Networks

Genetic regulatory networks are biochemical reaction systems, consisting of a network of interacting genes and associated proteins. The dynamics of genetic regulatory networks contain many complex facets that require careful consideration during the modeling process. The classical modeling approach involves studying systems of ordinary differential equations (ODEs) that model biochemical reactions in a deterministic, continuous, and instantaneous fashion. In reality, the dynamics of these systems are stochastic, discrete, and widely delayed. The first two complications are often successfully addressed by modeling regulatory networks using the Gillespie stochastic simulation algorithm (SSA), while the delayed behavior of biochemical events such as transcription and translation are often ignored due to their mathematically difficult nature. We develop techniques based on delay-differential equations (DDEs) and the delayed Gillespie SSA to study the effects of delays, in both continuous deterministic and discrete stochastic settings. Our analysis applies techniques from Floquet theory and advanced numerical analysis within the context of delay-differential equations, and we are able to derive stability sensitivities for biochemical switches and oscillators across the constituent pathways, showing which pathways in the regulatory networks improve or worsen the stability of the system attractors. These delay sensitivities can be far from trivial, and we offer a computational framework validated across multiple levels of modeling fidelity. This work suggests that delays may play an important and previously overlooked role in providing robust dynamical behavior for certain genetic regulatory networks, and perhaps more importantly, may offer an accessible tuning parameter for robust bioengineering

Graph cluster randomization: network exposure to multiple universes

A/B testing is a standard approach for evaluating the effect of online experiments; the goal is to estimate the `average treatment effect' of a new feature or condition by exposing a sample of the overall population to it. A drawback with A/B testing is that it is poorly suited for experiments involving social interference, when the treatment of individuals spills over to neighboring individuals along an underlying social network. In this work, we propose a novel methodology using graph clustering to analyze average treatment effects under social interference. To begin, we characterize graph-theoretic conditions under which individuals can be considered to be `network exposed' to an experiment. We then show how graph cluster randomization admits an efficient exact algorithm to compute the probabilities for each vertex being network exposed under several of these exposure conditions. Using these probabilities as inverse weights, a Horvitz-Thompson estimator can then provide an effect estimate that is unbiased, provided that the exposure model has been properly specified. Given an estimator that is unbiased, we focus on minimizing the variance. First, we develop simple sufficient conditions for the variance of the estimator to be asymptotically small in n, the size of the graph. However, for general randomization schemes, this variance can be lower bounded by an exponential function of the degrees of a graph. In contrast, we show that if a graph satisfies a restricted-growth condition on the growth rate of neighborhoods, then there exists a natural clustering algorithm, based on vertex neighborhoods, for which the variance of the estimator can be upper bounded by a linear function of the degrees. Thus we show that proper cluster randomization can lead to exponentially lower estimator variance when experimentally measuring average treatment effects under interference.Comment: 9 pages, 2 figure