Efficient experimental design for uncertainty reduction in gene regulatory networks

BACKGROUND: An accurate understanding of interactions among genes plays a major role in developing therapeutic intervention methods. Gene regulatory networks often contain a significant amount of uncertainty. The process of prioritizing biological experiments to reduce the uncertainty of gene regulatory networks is called experimental design. Under such a strategy, the experiments with high priority are suggested to be conducted first. RESULTS: The authors have already proposed an optimal experimental design method based upon the objective for modeling gene regulatory networks, such as deriving therapeutic interventions. The experimental design method utilizes the concept of mean objective cost of uncertainty (MOCU). MOCU quantifies the expected increase of cost resulting from uncertainty. The optimal experiment to be conducted first is the one which leads to the minimum expected remaining MOCU subsequent to the experiment. In the process, one must find the optimal intervention for every gene regulatory network compatible with the prior knowledge, which can be prohibitively expensive when the size of the network is large. In this paper, we propose a computationally efficient experimental design method. This method incorporates a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments. We then estimate the approximate expected remaining MOCU at a lower computational cost using the reduced networks. CONCLUSIONS: Simulation results based on synthetic and real gene regulatory networks show that the proposed approximate method has close performance to that of the optimal method but at lower computational cost. The proposed approximate method also outperforms the random selection policy significantly. A MATLAB software implementing the proposed experimental design method is available at http://gsp.tamu.edu/Publications/supplementary/roozbeh15a/

Advancing multiple model-based control of complex biological systems: Applications in T cell biology

Activated CD4+ T cells are important regulators of the adaptive immune response against invading pathogens and cancerous host cells. The process of activation is mediated by the T cell receptor and a vast network of intracellular signal transduction pathways, which recognize and interpret antigenic signals to determine the cell\u27s response. The critical role of these early signaling events in normal cell function and the pathogenesis of disease ultimately make them attractive therapeutic targets for numerous autoimmune diseases and cancers. Scientists increasingly rely on predictive mathematical models and control-theoretic tools to design effective strategies to manipulate cellular processes for the advancement of knowledge or therapeutic gain. However, the application of modern control theory to intracellular signal transduction is complicated by a unique set of intrinsic properties and technical limitations. These include complexities in the signaling network such as crosstalk, feedback and nonlinearity, and a dearth of rapid quantitative measurement techniques and specific and orthogonal modulators, the major consequences of which are uncertainty in the model representation and the prevention of real-time measurement feedback. Integrating such uncertainties and limitations into a control-theoretic approach under practical constraints represents an open challenge in controller design. The work presented in this dissertation addresses these challenges through the development of a computational methodology to aid in the design of experimental strategies to predictably manipulate intracellular signaling during the process of CD4+ T cell activation. This work achieves two main objectives: (1) the development of a generalized control-theoretic tool to effectively control uncertain nonlinear systems in the absence of real-time measurement feedback, and (2) the development and calibration of a predictive mathematical model (or collection of models) of CD4+ T cell activation to help derive experimental inputs to robustly force the system dynamics along prescribed trajectories. The crux of this strategy is the use of multiple data-supported models to inform the controller design. These models may represent alternative hypotheses for signaling mechanisms and give rise to distinct network topologies or kinetic rate scenarios and yet remain consistent with available data. Here, a novel adaptive weighting algorithm predicts variations in the models\u27 predictive accuracy over the admissible input space to produce a more reliable compromise solution from multiple competing objectives, a result corroborated by several experimental studies. This dissertation provides a practical means to effectively utilize the collective predictive capacity of multiple prediction models to predictably and robustly direct CD4 + T cells to exhibit regulatory, helper and anergic T cell-like signaling profiles through pharmacological manipulations in the absence of measurement feedback. The framework and procedures developed herein are expected to widely applicable to a more general class of continuous dynamical systems for which real-time feedback is not readily available. Furthermore, the ability to predictably and precisely control biological systems could greatly advance how we study and interrogate such systems and aid in the development of novel therapeutic designs for the treatment of disease

Optimal Experimental Design in the Context of Objective-Based Uncertainty Quantification

In many real-world engineering applications, model uncertainty is inherent. Largescale dynamical systems cannot be perfectly modeled due to systems complexity, lack of enough training data, perturbation, or noise. Hence, it is often of interest to acquire more data through additional experiments to enhance system model. On the other hand, high cost of experiments and limited operational resources make it necessary to devise a cost-effective plan to conduct experiments. In this dissertation, we are concerned with the problem of prioritizing experiments, called experimental design, aimed at uncertainty reduction in dynamical systems. We take an objective-based view where both uncertainty and modeling objective are taken into account for experimental design. To do so, we utilize the concept of mean objective cost of uncertainty to quantify uncertainty. The first part of this dissertation is devoted to the experimental design for gene regulatory networks. Owing to the complexity of these networks, accurate inference is practically challenging. Moreover, from a translational perspective it is crucial that gene regulatory network uncertainty be quantified and reduced in a manner that pertains to the additional cost of network intervention that it induces. We propose a criterion to rank potential experiments based on the concept of mean objective cost of uncertainty. To lower the computational cost of the experimental design, we also propose a network reduction scheme by introducing a novel cost function that takes into account the disruption in the ranking of potential experiments caused by gene deletion. We investigate the performance of both the optimal and the approximate experimental design methods on synthetic and real gene regulatory networks. In the second part, we turn our attention to canonical expansions. Canonical expansions are convenient representations that can facilitate the study of random processes. We discuss objective-based experimental design in the context of canonical expansions for three major applications: filtering, signal detection, and signal compression. We present the general experimental design framework for linear filtering and specifically solve it for Wiener filtering. Then we focus on Karhunen-Loève expansion to study experimental design for signal detection and signal compression applications when the noise variance and the signal covariance matrix are unknown, respectively. In particular, we find the closed-form solution for the intrinsically Bayesian robust Karhunen-Loève compression which is required for the experimental design in the case of signal compression

Towards a Multi-Subject Analysis of Neural Connectivity

Directed acyclic graphs (DAGs) and associated probability models are widely used to model neural connectivity and communication channels. In many experiments, data are collected from multiple subjects whose connectivities may differ but are likely to share many features. In such circumstances it is natural to leverage similarity between subjects to improve statistical efficiency. The first exact algorithm for estimation of multiple related DAGs was recently proposed by Oates et al. 2014; in this letter we present examples and discuss implications of the methodology as applied to the analysis of fMRI data from a multi-subject experiment. Elicitation of tuning parameters requires care and we illustrate how this may proceed retrospectively based on technical replicate data. In addition to joint learning of subject-specific connectivity, we allow for heterogeneous collections of subjects and simultaneously estimate relationships between the subjects themselves. This letter aims to highlight the potential for exact estimation in the multi-subject setting.Comment: to appear in Neural Computation 27:1-2

Random Neural Networks and Optimisation

In this thesis we introduce new models and learning algorithms for the Random Neural Network (RNN), and we develop RNN-based and other approaches for the solution of emergency management optimisation problems. With respect to RNN developments, two novel supervised learning algorithms are proposed. The first, is a gradient descent algorithm for an RNN extension model that we have introduced, the RNN with synchronised interactions (RNNSI), which was inspired from the synchronised firing activity observed in brain neural circuits. The second algorithm is based on modelling the signal-flow equations in RNN as a nonnegative least squares (NNLS) problem. NNLS is solved using a limited-memory quasi-Newton algorithm specifically designed for the RNN case. Regarding the investigation of emergency management optimisation problems, we examine combinatorial assignment problems that require fast, distributed and close to optimal solution, under information uncertainty. We consider three different problems with the above characteristics associated with the assignment of emergency units to incidents with injured civilians (AEUI), the assignment of assets to tasks under execution uncertainty (ATAU), and the deployment of a robotic network to establish communication with trapped civilians (DRNCTC). AEUI is solved by training an RNN tool with instances of the optimisation problem and then using the trained RNN for decision making; training is achieved using the developed learning algorithms. For the solution of ATAU problem, we introduce two different approaches. The first is based on mapping parameters of the optimisation problem to RNN parameters, and the second on solving a sequence of minimum cost flow problems on appropriately constructed networks with estimated arc costs. For the exact solution of DRNCTC problem, we develop a mixed-integer linear programming formulation, which is based on network flows. Finally, we design and implement distributed heuristic algorithms for the deployment of robots when the civilian locations are known or uncertain

In-Vivo Real-Time Control of Protein Expression from Endogenous and Synthetic Gene Networks

We describe an innovative experimental and computational approach to control the expression of a protein in a population of yeast cells. We designed a simple control algorithm to automatically regulate the administration of inducer molecules to the cells by comparing the actual protein expression level in the cell population with the desired expression level. We then built an automated platform based on a microfluidic device, a time-lapse microscopy apparatus, and a set of motorized syringes, all controlled by a computer. We tested the platform to force yeast cells to express a desired fixed, or time-varying, amount of a reporter protein over thousands of minutes. The computer automatically switched the type of sugar administered to the cells, its concentration and its duration, according to the control algorithm. Our approach can be used to control expression of any protein, fused to a fluorescent reporter, provided that an external molecule known to (indirectly) affect its promoter activity is available