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/

Genomic Regulatory Networks, Reduction Mappings and Control

All high-level living organisms are made of small cell units, containing DNA, RNA, genes, proteins etc. Genes are important components of the cells and it is necessary to understand the inter-gene relations, in order to comprehend, predict and ultimately intervene in the cells’ dynamics. Genetic regulatory networks (GRN) represent the gene interactions that dictate the cell behavior. Translational genomics aims to mathematically model GRNs and one of the main goals is to alter the networks’ behavior away from undesirable phenotypes such as cancer. The mathematical framework that has been often used for modeling GRNs is the probabilistic Boolean network (PBN), which is a collection of constituent Boolean networks with perturbation, BNp. This dissertation uses BNps, to model gene regulatory networks with an intent of designing stationary control policies (CP) for the networks to shift their dynamics toward more desirable states. Markov Chains (MC) are used to represent the PBNs and stochastic control has been employed to find stationary control policies to affect steady-state distribution of the MC. However, as the number of genes increases, it becomes computationally burdensome, or even infeasible, to derive optimal or greedy intervention policies. This dissertation considers the problem of modeling and intervening in large GRNs. To overcome the computational challenges associated with large networks, two approaches are proposed: first, a reduction mapping that deletes genes from the network; and second, a greedy control policy that can be directly designed on large networks. Simulation results show that these methods achieve the goal of controlling large networks by shifting the steady-state distribution of the networks toward more desirable states. Furthermore, a new inference method is used to derive a large 17-gene Boolean network from microarray experiments on gastrointestinal cancer samples. The new algorithm has similarities to a previously developed well-known inference method, which uses seed genes to grow subnetworks, out of a large network; however, it has major differences with that algorithm. Most importantly, the objective of the new algorithm is to infer a network from a seed gene with an intention to derive the Gene Activity Profile toward more desirable phenotypes. The newly introduced reduction mappings approach is used to delete genes from the 17-gene GRN and when the network is small enough, an intervention policy is designed for the reduced network and induced back to the original network. In another experiment, the greedy control policy approach is used to directly design an intervention policy on the large 17-gene network to beneficially change the long-run behavior of the network. Finally, a novel algorithm is developed for selecting only non-isomorphic BNs, while generating synthetic networks, using a method that generates synthetic BNs, with a prescribed set of attractors. The goal of the new method described in this dissertation is to discard isomorphic networks

Analysis and Optimization of Classifier Error Estimator Performance within a Bayesian Modeling Framework

With the advent of high-throughput genomic and proteomic technologies, in conjunction with the difficulty in obtaining even moderately sized samples, small-sample classifier design has become a major issue in the biological and medical communities. Training-data error estimation becomes mandatory, yet none of the popular error estimation techniques have been rigorously designed via statistical inference or optimization. In this investigation, we place classifier error estimation in a framework of minimum mean-square error (MMSE) signal estimation in the presence of uncertainty, where uncertainty is relative to a prior over a family of distributions. This results in a Bayesian approach to error estimation that is optimal and unbiased relative to the model. The prior addresses a trade-off between estimator robustness (modeling assumptions) and accuracy. Closed-form representations for Bayesian error estimators are provided for two important models: discrete classification with Dirichlet priors (the discrete model) and linear classification of Gaussian distributions with fixed, scaled identity or arbitrary covariances and conjugate priors (the Gaussian model). We examine robustness to false modeling assumptions and demonstrate that Bayesian error estimators perform especially well for moderate true errors. The Bayesian modeling framework facilitates both optimization and analysis. It naturally gives rise to a practical expected measure of performance for arbitrary error estimators: the sample-conditioned mean-square error (MSE). Closed-form expressions are provided for both Bayesian models. We examine the consistency of Bayesian error estimation and illustrate a salient application in censored sampling, where sample points are collected one at a time until the conditional MSE reaches a stopping criterion. We address practical considerations for gene-expression microarray data, including the suitability of the Gaussian model, a methodology for calibrating normal-inverse-Wishart priors from unused data, and an approximation method for non-linear classification. We observe superior performance on synthetic high-dimensional data and real data, especially for moderate to high expected true errors and small feature sizes. Finally, arbitrary error estimators may be optimally calibrated assuming a fixed Bayesian model, sample size, classification rule, and error estimation rule. Using a calibration function mapping error estimates to their optimally calibrated values off-line, error estimates may be calibrated on the fly whenever the assumptions apply