We discuss implicit and explicit knowledge representation mechanisms for evolutionary algorithms (EAs). We also describe offline and online metaheuristics as examples of explicit methods to leverage this knowledge. We illustrate the benefits of this approach with four real-world applications. The first application is automated insurance underwriting-a discrete classification problem, which requires a careful tradeoff between the percentage of insurance applications handled by the classifier and its classification accuracy. The second application is flexible design and manufacturing-a combinatorial assignment problem, where we optimize design and manufacturing assignments with respect to time and cost of design and manufacturing for a given product. Both problems use metaheuristics as a way to encode domain knowledge. In the first application, the EA is used at the metalevel, while in the second application, the EA is the object-level problem solver. In both cases, the EAs use a single-valued fitness function that represents the required tradeoffs. The third application is a lamp spectrum optimization that is formulated as a multiobjective optimization problem. Using domain customized mutation operators, we obtain a well-sampled Pareto front showing all the nondominated solutions. The fourth application describes a scheduling problem for the maintenance tasks of a constellation of 25 low earth orbit satellites. The domain knowledge in this application is embedded in the design of a structured chromosome, a collection of time-value transformations to reflect static constraints, and a time-dependent penalty function to prevent schedule collisions.

MOTIVATION: To be valuable to biological or biomedical research, in silico methods must be scaled to complex pathways and large numbers of interacting molecular species. The correct method for performing such simulations, discrete event simulation by Monte Carlo generation, is computationally costly for large complex systems. Approximation of molecular behavior by continuous models fails to capture stochastic behavior that is essential to many biological phenomena. RESULTS: We present a novel approach to building hybrid simulations in which some processes are simulated discretely, while other processes are handled in a continuous simulation by differential equations. This approach preserves the stochastic behavior of cellular pathways, yet enables scaling to large populations of molecules. We present an algorithm for synchronizing data in a hybrid simulation and discuss the trade-offs in such simulation. We have implemented the hybrid simulation algorithm and have validated it by simulating the statistical behavior of the well-known lambda phage switch. Hybrid simulation provides a new method for exploring the sources and nature of stochastic behavior in cells.