Systems approaches and algorithms for discovery of combinatorial therapies

Effective therapy of complex diseases requires control of highly non-linear complex networks that remain incompletely characterized. In particular, drug intervention can be seen as control of signaling in cellular networks. Identification of control parameters presents an extreme challenge due to the combinatorial explosion of control possibilities in combination therapy and to the incomplete knowledge of the systems biology of cells. In this review paper we describe the main current and proposed approaches to the design of combinatorial therapies, including the empirical methods used now by clinicians and alternative approaches suggested recently by several authors. New approaches for designing combinations arising from systems biology are described. We discuss in special detail the design of algorithms that identify optimal control parameters in cellular networks based on a quantitative characterization of control landscapes, maximizing utilization of incomplete knowledge of the state and structure of intracellular networks. The use of new technology for high-throughput measurements is key to these new approaches to combination therapy and essential for the characterization of control landscapes and implementation of the algorithms. Combinatorial optimization in medical therapy is also compared with the combinatorial optimization of engineering and materials science and similarities and differences are delineated.Comment: 25 page

Developments in linear and integer programming

In this review we describe recent developments in linear and integer (linear) programming. For over 50 years Operational Research practitioners have made use of linear optimisation models to aid decision making and over this period the size of problems that can be solved has increased dramatically, the time required to solve problems has decreased substantially and the flexibility of modelling and solving systems has increased steadily. Large models are no longer confined to large computers, and the flexibility of optimisation systems embedded in other decision support tools has made on-line decision making using linear programming a reality (and using integer programming a possibility). The review focuses on recent developments in algorithms, software and applications and investigates some connections between linear optimisation and other technologies

The edge-disjoint path problem on random graphs by message-passing

We present a message-passing algorithm to solve the edge disjoint path problem (EDP) on graphs incorporating under a unique framework both traffic optimization and path length minimization. The min-sum equations for this problem present an exponential computational cost in the number of paths. To overcome this obstacle we propose an efficient implementation by mapping the equations onto a weighted combinatorial matching problem over an auxiliary graph. We perform extensive numerical simulations on random graphs of various types to test the performance both in terms of path length minimization and maximization of the number of accommodated paths. In addition, we test the performance on benchmark instances on various graphs by comparison with state-of-the-art algorithms and results found in the literature. Our message-passing algorithm always outperforms the others in terms of the number of accommodated paths when considering non trivial instances (otherwise it gives the same trivial results). Remarkably, the largest improvement in performance with respect to the other methods employed is found in the case of benchmarks with meshes, where the validity hypothesis behind message-passing is expected to worsen. In these cases, even though the exact message-passing equations do not converge, by introducing a reinforcement parameter to force convergence towards a sub optimal solution, we were able to always outperform the other algorithms with a peak of 27% performance improvement in terms of accommodated paths. On random graphs, we numerically observe two separated regimes: one in which all paths can be accommodated and one in which this is not possible. We also investigate the behaviour of both the number of paths to be accommodated and their minimum total length.Comment: 14 pages, 8 figure

Optimal Vaccine Allocation to Control Epidemic Outbreaks in Arbitrary Networks

We consider the problem of controlling the propagation of an epidemic outbreak in an arbitrary contact network by distributing vaccination resources throughout the network. We analyze a networked version of the Susceptible-Infected-Susceptible (SIS) epidemic model when individuals in the network present different levels of susceptibility to the epidemic. In this context, controlling the spread of an epidemic outbreak can be written as a spectral condition involving the eigenvalues of a matrix that depends on the network structure and the parameters of the model. We study the problem of finding the optimal distribution of vaccines throughout the network to control the spread of an epidemic outbreak. We propose a convex framework to find cost-optimal distribution of vaccination resources when different levels of vaccination are allowed. We also propose a greedy approach with quality guarantees for the case of all-or-nothing vaccination. We illustrate our approaches with numerical simulations in a real social network