Machine Learning for Exploring State Space Structure in Genetic Regulatory Networks

摘要

Genetic regulatory networks (GRN) offer a useful model for clinical biology. Specifically, such networks capture interactions among genes, proteins, and other metabolic factors. Unfortunately, it is difficult to understand and predict the behavior of networks that are of realistic size and complexity. In this dissertation, behavior refers to the trajectory of a state, through a series of state transitions over time, to an attractor in the network. This project assumes asynchronous Boolean networks, implying that a state may transition to more than one attractor. The goal of this project is to efficiently identify a network's set of attractors and to predict the likelihood with which an arbitrary state leads to each of the network's attractors. These probabilities will be represented using a fuzzy membership vector.;Predicting fuzzy membership vectors using machine learning techniques may address the intractability posed by networks of realistic size and complexity. Modeling and simulation can be used to provide the necessary training sets for machine learning methods to predict fuzzy membership vectors. The experiments comprise several GRNs, each represented by a set of output classes. These classes consist of thresholds tau and ¬tau, where tau = [tau low, tauhigh]; state s belongs to class tau if the probability of its transitioning to attractor A belongs to the range [taulow, tau high]; otherwise it belongs to class ¬tau. Finally, each machine learning classifier was trained with the training sets that was previously collected. The objective is to explore methods to discover patterns for meaningful classification of states in realistically complex regulatory networks.;The research design took a GRN and a machine learning method as input and produced output class and its negation ¬. For each GRN, attractors were identified, data was collected by sampling each state to create fuzzy membership vectors, and machine learning methods were trained to predict whether a state is in a healthy attractor or not. For T-LGL, SVMs had the highest accuracy in predictions (between 93.6% and 96.9%) and precision (between 94.59% and 97.87%). However, naive Bayesian classifiers had the highest recall (between 94.71% and 97.78%). This study showed that all experiments have extreme significance with p value < 0.0001. The contribution this research offers helps clinical biologist to submit genetic states to get an initial result on their outcomes. For future work, this implementation could use other machine learning classifiers such as xgboost or deep learning methods. Other suggestions offered are developing methods that improves the performance of state transition that allow for larger training sets to be sampled.