arXiv subjects

Mustafa Khammash

Publications and source records attributed to Mustafa Khammash.

At least 37 records · Page 2Linked to original sources

arXiv2019

A hidden integral structure endows Absolute Concentration Robust systems with resilience to dynamical concentration disturbances

Biochemical systems that express certain chemical species of interest at the same level at any positive equilibrium are called "absolute concentration robust" (ACR). These species behave in a stable, predictable way, in the sense that their expression is robust with respect to sudden changes in the species concentration, regardless the new positive equilibrium reached by the system. Such a property has been proven to be fundamentally important in certain gene regulatory networks and signaling systems. In the present paper, we mathematically prove that a well-known class of ACR systems studied by Shinar and Feinberg in 2010 hides an internal integral structure. This structure confers these systems with a higher degree of robustness that what was previously unknown. In particular, disturbances much more general than sudden changes in the species concentrations can be rejected, and robust perfect adaptation is achieved. Significantly, we show that these properties are maintained when the system is interconnected with other chemical reaction networks. This key feature enables design of insulator devices that are able to buffer the loading effect from downstream systems - a crucial requirement for modular circuit design in synthetic biology.

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arXiv2018

A finite state projection method for steady-state sensitivity analysis of stochastic reaction networks

Consider the standard stochastic reaction network model where the dynamics is given by a continuous-time Markov chain over a discrete lattice. For such models, estimation of parameter sensitivities is an important problem, but the existing computational approaches to solve this problem usually require time-consuming Monte Carlo simulations of the reaction dynamics. Therefore these simulation-based approaches can only be expected to work over finite time-intervals, while it is often of interest in applications to examine the sensitivity values at the steady-state after the Markov chain has relaxed to its stationary distribution. The aim of this paper is to present a computational method for the estimation of steady-state parameter sensitivities, which instead of using simulations, relies on the recently developed stationary Finite State Projection (sFSP) algorithm [J. Chem. Phys. 147, 154101 (2017)] that provides an accurate estimate of the stationary distribution at a fixed set of parameters. We show that sensitivity values at these parameters can be estimated from the solution of a Poisson equation associated with the infinitesimal generator of the Markov chain. We develop an approach to numerically solve the Poisson equation and this yields an efficient estimator for steady-state parameter sensitivities. We illustrate this method using several examples.

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arXiv2018

Robust and structural ergodicity analysis of stochastic biomolecular networks involving synthetic antithetic integral controllers

Ergodicity and output controllability have been shown to be fundamental concepts for the analysis and synthetic design of closed-loop stochastic reaction networks, as exemplified by the use of antithetic integral feedback controllers. In [Gupta, Briat & Khammash, PLoS Comput. Biol., 2014], some ergodicity and output controllability conditions for unimolecular and certain classes of bimolecular reaction networks were obtained and formulated through linear programs. To account for context dependence, these conditions were later extended in [Briat & Khammash, CDC, 2016] to reaction networks with uncertain rate parameters using simple and tractable, yet potentially conservative, methods. Here we develop some exact theoretical methods for verifying, in a robust setting, the original ergodicity and output controllability conditions based on algebraic and polynomial techniques. Some examples are given for illustration.

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arXiv2018

Robust ergodicity and tracking in antithetic integral control of stochastic biochemical reaction networks

Controlling stochastic reactions networks is a challenging problem with important implications in various fields such as systems and synthetic biology. Various regulation motifs have been discovered or posited over the recent years, the most recent one being the so-called Antithetic Integral Control (AIC) motif in Briat et al. (Cell Systems, 2016). Several favorable properties for the AIC motif have been demonstrated for classes of reaction networks that satisfy certain irreducibility, ergodicity and output controllability conditions. Here we address the problem of verifying these conditions for large sets of reaction networks with fixed topology using two different approaches. The first one is quantitative and relies on the notion of interval matrices while the second one is qualitative and is based on sign properties of matrices. The obtained results lie in the same spirit as those obtained in Briat et al. (Cell Systems, 2016) where properties of reaction networks are independently characterized in terms of control theoretic concepts, linear programming conditions and graph theoretic conditions.

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arXiv2018

Sensitivity analysis for multiscale stochastic reaction networks using hybrid approximations

We consider the problem of estimating parameter sensitivities for stochastic models of multiscale reaction networks. These sensitivity values are important for model analysis, and, the methods that currently exist for sensitivity estimation mostly rely on simulations of the stochastic dynamics. This is problematic because these simulations become computationally infeasible for multiscale networks due to reactions firing at several different timescales. However it is often possible to exploit the multiscale property to derive a "model reduction" and approximate the dynamics as a Piecewise Deterministic Markov process (PDMP), which is a hybrid process consisting of both discrete and continuous components. The aim of this paper is to show that such PDMP approximations can be used to accurately and efficiently estimate the parameter sensitivity for the original multiscale stochastic model. We prove the convergence of the original sensitivity to the corresponding PDMP sensitivity, in the limit where the PDMP approximation becomes exact. Moreover we establish a representation of the PDMP parameter sensitivity that separates the contributions of discrete and continuous components in the dynamics, and allows one to efficiently estimate both contributions.

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arXiv2018

Computational identification of irreducible state-spaces for stochastic reaction networks

Stochastic models of reaction networks are becoming increasingly important in Systems Biology. In these models, the dynamics is generally represented by a continuous-time Markov chain whose states denote the copy-numbers of the constituent species. The state-space on which this process resides is a subset of non-negative integer lattice and for many examples of interest, this state-space is countably infinite. This causes numerous problems in analyzing the Markov chain and understanding its long-term behavior. These problems are further confounded by the presence of conservation relations among species which constrain the dynamics in complicated ways. In this paper we provide a linear-algebraic procedure to disentangle these conservation relations and represent the state-space in a special decomposed form, based on the copy-number ranges of various species and dependencies among them. This decomposed form is advantageous for analyzing the stochastic model and for a large class of networks we demonstrate how this form can be used for finding all the closed communication classes for the Markov chain within the infinite state-space. Such communication classes are irreducible state-spaces for the dynamics and they support all the extremal stationary distributions for the Markov chain. Hence our results provide important insights into the long-term behavior and stability properties of stochastic models of reaction networks. We discuss how the knowledge of these irreducible state-spaces can be used in many ways such as speeding-up stochastic simulations of multiscale networks or in identifying the stationary distributions of complex-balanced networks. We illustrate our results with several examples of gene-expression networks from Systems Biology.

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arXiv2018

Estimation of parameter sensitivities for stochastic reaction networks using tau-leap simulations

We consider the important problem of estimating parameter sensitivities for stochastic models of reaction networks that describe the dynamics as a continuous-time Markov process over a discrete lattice. These sensitivity values are useful for understanding network properties, validating their design and identifying the pivotal model parameters. Many methods for sensitivity estimation have been developed, but their computational feasibility suffers from the critical bottleneck of requiring time-consuming Monte Carlo simulations of the exact reaction dynamics. To circumvent this problem one needs to devise methods that speed up the computations while suffering acceptable and quantifiable loss of accuracy. We develop such a method by first deriving a novel integral representation of parameter sensitivity and then demonstrating that this integral may be approximated by any convergent tau-leap method. Our method is easy to implement, works with any tau-leap simulation scheme and its accuracy is proved to be similar to that of the underlying tau-leap scheme. We demonstrate the efficiency of our methods through numerical examples. We also compare our method with the tau-leap versions of certain finite-difference schemes that are commonly used for sensitivity estimations.

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arXiv2017

Variance reduction for antithetic integral control of stochastic reaction networks

The antithetic integral feedback motif recently introduced in Briat, Gupta & Khammash (Cell Systems, 2017) is known to ensure robust perfect adaptation for the mean dynamics of a given molecular species involved in a complex stochastic biomolecular reaction network. However, it was observed that it also leads to a higher variance in the controlled network than that obtained when using a constitutive (i.e. open-loop) control strategy. This was interpreted as the cost of the adaptation property and may be viewed as a performance deterioration for the overall controlled network. To decrease this variance and improve the performance, we propose to combine the antithetic integral feedback motif with a negative feedback strategy. Both theoretical and numerical results are obtained. The theoretical ones are based on a tailored moment closure method allowing one to obtain approximate expressions for the stationary variance for the controlled network and predict that the variance can indeed be decreased by increasing the strength of the negative feedback. Numerical results verify the accuracy of this approximation and show that the controlled species variance can indeed be decreased, sometimes below its constitutive level. Three molecular networks are considered in order to verify the wide applicability of two types of negative feedback strategies. The main conclusion is that there is a trade-off between the speed of the settling-time of the mean trajectories and the stationary variance of the controlled species; i.e. smaller variance is associated with larger settling-time.

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arXiv2017

A finite state projection algorithm for the stationary solution of the chemical master equation

The chemical master equation (CME) is frequently used in systems biology to quantify the effects of stochastic fluctuations that arise due to biomolecular species with low copy numbers. The CME is a system of ordinary differential equations that describes the evolution of probability density for each population vector in the state-space of the stochastic reaction dynamics. For many examples of interest, this state-space is infinite, making it difficult to obtain exact solutions of the CME. To deal with this problem, the Finite State Projection (FSP) algorithm was developed by Munsky and Khammash (Jour. Chem. Phys. 2006), to provide approximate solutions to the CME by truncating the state-space. The FSP works well for finite time-periods but it cannot be used for estimating the stationary solutions of CMEs, which are often of interest in systems biology. The aim of this paper is to develop a version of FSP which we refer to as the stationary FSP (sFSP) that allows one to obtain accurate approximations of the stationary solutions of a CME by solving a finite linear-algebraic system that yields the stationary distribution of a continuous-time Markov chain over the truncated state-space. We derive bounds for the approximation error incurred by sFSP and we establish that under certain stability conditions, these errors can be made arbitrarily small by appropriately expanding the truncated state-space. We provide several examples to illustrate our sFSP method and demonstrate its efficiency in estimating the stationary distributions. In particular, we show that using a quantised tensor train (QTT) implementation of our sFSP method, problems admitting more than 100 million states can be efficiently solved.

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arXiv2017

Dynamic disorder in simple enzymatic reactions induces stochastic amplification of substrate

A growing amount of evidence points to the fact that many enzymes exhibit fluctuations in their catalytic activity, which are associated with conformational changes on a broad range of timescales. The experimental study of this phenomenon, termed dynamic disorder, has become possible due to advances in single-molecule enzymology measurement techniques, through which the catalytic activity of individual enzyme molecules can be tracked in time. The biological role and importance of these fluctuations in a system with a small number of enzymes such as a living cell have only recently started being explored. In this work, we examine a simple stochastic reaction system consisting of an inflowing substrate and an enzyme with a randomly fluctuating catalytic reaction rate that converts the substrate into an outflowing product. To describe analytically the effect of rate fluctuations on the average substrate abundance at steady-state, we derive an explicit formula that connects the relative speed of enzymatic fluctuations with the mean substrate level. We demonstrate that the relative speed of rate fluctuations can have a dramatic effect on the mean substrate, and lead to large positive deviations from predictions based on the assumption of deterministic enzyme activity. Our results also establish an interesting connection between the amplification effect and the mixing properties of the Markov process describing the enzymatic activity fluctuations, which can be used to easily predict the fluctuation speed above which such deviations become negligible. As the techniques of single-molecule enzymology continuously evolve, it may soon be possible to study the stochastic phenomena due to enzymatic activity fluctuations within living cells. Our work can be used to formulate experimentally testable hypotheses regarding the magnitude of these fluctuations, as well as their phenotypic consequences.

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arXiv2017

Fundamental Limits and Tradeoffs in Autocatalytic Pathways

This paper develops some basic principles to study autocatalytic networks and exploit their structural properties in order to characterize their inherent fundamental limits and tradeoffs. In a dynamical system with autocatalytic structure, the system's output is necessary to catalyze its own production. We consider a simplified model of Glycolysis pathway as our motivating application. First, the properties of these class of pathways are investigated through a simplified two-state model, which is obtained by lumping all the intermediate reactions into a single intermediate reaction. Then, we generalize our results to autocatalytic pathways that are composed of a chain of enzymatically catalyzed intermediate reactions. We explicitly derive a hard limit on the minimum achievable $\mathcal L_2$-gain disturbance attenuation and a hard limit on its minimum required output energy. Finally, we show how these resulting hard limits lead to some fundamental tradeoffs between transient and steady-state behavior of the network and its net production.

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arXiv2017

Simple interval observers for linear impulsive systems with applications to sampled-data and switched systems

Sufficient conditions for the design of a simple class of interval observers for linear impulsive systems subject to minimum and range dwell-time constraints are obtained and formulated in terms of infinite-dimensional linear programs. The proposed approach is fully constructive in the sense that suitable observer gains can be extracted from the solution of the optimization problems and is flexible enough to be extended to include performance constraints and parametric uncertainties. In order to be solvable, the infinite-dimensional linear programs are relaxed using a method based on sum of squares which is known to be asymptotically exact in the present case. Three examples are given for illustration: the first one pertains on the interval observation of an impulsive system under a minimum dwell-time constraint, the second one is about the interval observation of an aperiodic sampled-data system and the last one is about the interval observation of a linear switched system.

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arXiv2017

Stability analysis of LPV systems with piecewise differentiable parameters

Linear Parameter-Varying (LPV) systems with piecewise differentiable parameters is a class of LPV systems for which no proper analysis conditions have been obtained so far. To fill this gap, we propose an approach based on the theory of hybrid systems. The underlying idea is to reformulate the considered LPV system as an equivalent hybrid system that will incorporate, through a suitable state augmentation, information on both the dynamics of the state of the system and the considered class of parameter trajectories. Then, using a result pertaining on the stability of hybrid systems, two stability conditions are established and shown to naturally generalize and unify the well-known quadratic and robust stability criteria together. The obtained conditions being infinite-dimensional, a relaxation approach based on sum of squares programming is used in order to obtain tractable finite-dimensional conditions. The approach is finally illustrated on two examples from the literature.

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arXiv2017

A Molecular Implementation of the Least Mean Squares Estimator

In order to function reliably, synthetic molecular circuits require mechanisms that allow them to adapt to environmental disturbances. Least mean squares (LMS) schemes, such as commonly encountered in signal processing and control, provide a powerful means to accomplish that goal. In this paper we show how the traditional LMS algorithm can be implemented at the molecular level using only a few elementary biomolecular reactions. We demonstrate our approach using several simulation studies and discuss its relevance to synthetic biology.

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arXiv2016

Interval peak-to-peak observers for continuous- and discrete-time systems with persistent inputs and delays

While the design of optimal peak-to-peak controllers/observers for linear systems is known to be a difficult problem, this problem becomes interestingly much easier in the context of interval observers because of the positive nature of the error dynamics. Indeed, by exploiting several recent results on positive systems, we propose a novel and non-conservative approach formulated in terms of tractable finite-dimensional linear programs for designing a class of interval observers achieving minimum peak-to-peak gain. The optimal observer is notably shown to be uniform over the set of all possible mappings between observation errors and their weighted versions, which parallels a recent result on the stabilization of linear positive systems. Results pertaining on the interval observation of time-delay and discrete-time systems are then obtained as a direct application of the proposed method, emphasizing then its versatility. Several examples on the interval observation of linear and nonlinear systems are finally given for illustration.

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arXiv2016

Parameter inference method for stochastic single-cell dynamics from tree-structured data

With the advance of experimental techniques such as time-lapse fluorescence microscopy, the availability of single-cell trajectory data has vastly increased, and so has the demand for computational methods suitable for parameter inference with this type of data. However, most of the currently available methods treat single-cell trajectories independently, ignoring the mother-daughter relationships and the information provided by population structure. This information is however essential if a process of interest happens at cell division, or if it evolves slowly compared to the duration of the cell cycle. In this work, we highlight the importance of tracking cell lineage trees and propose a Bayesian framework for parameter inference on tree-structured data. Our method relies on a combination of Sequential Monte Carlo for likelihood approximation and Markov Chain Monte Carlo for parameter sampling. We demonstrate the capabilities of our inference framework on two simple examples in which the lineage tree information is necessary: one in which the cell phenotype can only switch at cell division and another where the cell type fluctuates randomly over timescales that extend well beyond the lifetime of a single cell.

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arXiv2016

A parallelizable sampling method for parameter inference of large biochemical reaction models

The development of mechanistic models of biological systems is a central part of Systems Biology. One major task in developing these models is the inference of the correct model parameters. Due to the size of most realistic models and their possibly complex dynamical behaviour one must usually rely on sample based methods. In this paper we present a novel algorithm that reliably estimates model parameters for deterministic as well as stochastic models from trajectory data. Our algorithm samples iteratively independent particles from the level sets of the likelihood and recovers the posterior from these level sets. The presented approach is easily parallelizable and, by utilizing density estimation through Dirichlet Process Gaussian Mixture Models, can deal with high dimensional parameter spaces. We illustrate that our algorithm is applicable to large, realistic deterministic and stochastic models and succeeds in inferring the correct posterior from a given number of observed trajectories. This algorithm presents a novel, computationally feasible approach to identify parameters of large biochemical reaction models based on sample path data.

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arXiv2016

Antithetic Integral Feedback ensures robust perfect adaptation in noisy biomolecular networks

Homeostasis is a running theme in biology. Often achieved through feedback regulation strategies, homeostasis allows living cells to control their internal environment as a means for surviving changing and unfavourable environments. While many endogenous homeostatic motifs have been studied in living cells, some other motifs may remain under-explored or even undiscovered. At the same time, known regulatory motifs have been mostly analyzed at the deterministic level, and the effect of noise on their regulatory function has received low attention. Here we lay the foundation for a regulation theory at the molecular level that explicitly takes into account the noisy nature of biochemical reactions and provides novel tools for the analysis and design of robust homeostatic circuits. Using these ideas, we propose a new regulation motif, which we refer to as {\em antithetic integral feedback, and demonstrate its effectiveness as a strategy for generically regulating a wide class of reaction networks. By combining tools from probability and control theory, we show that the proposed motif preserves the stability of the overall network, steers the population of any regulated species to a desired set point, and achieves robust perfect adaptation -- all with low prior knowledge of reaction rates. Moreover, our proposed regulatory motif can be implemented using a very small number of molecules and hence has a negligible metabolic load. Strikingly, the regulatory motif exploits stochastic noise, leading to enhanced regulation in scenarios where noise-free implementations result in dysregulation. Finally, we discuss the possible manifestation of the proposed antithetic integral feedback motif in endogenous biological circuits and its realization in synthetic circuits.

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