A Bilevel Integer Programming Approach for the Synchronous Attractor Control Problem

Abstract

Boolean networks are dynamical models of disease development in which the activation levels of genes are represented by binary variables. Given a Boolean network, controls represent mutations or medical treatments that fix the activation levels of selected genes so that all states in every attractor (i.e., long-term recurrent states) satisfy a desired phenotype. Our goal is to enumerate all minimal controls, identifying critical gene subsets in disease development and therapy. This problem has an inherent bilevel integer programming structure and is computationally challenging. We propose an infeasibility-based Benders decomposition, a logic-based Benders framework for bilevel integer programs with multiple subproblems. In our application, each subproblem finds a forbidden attractor of a given length and yields a problem-specific feasibility cut. We also propose an auxiliary IP called subspace separation that finds a Boolean subspace that includes multiple forbidden attractors and thereby strengthens the cut. Numerical experiments show that the resulting algorithms are much more scalable than state-of-the-art methods and that subspace separation substantially improves performance.