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Heterogeneous ensembles consist of predictors of different types, which are likely to have different biases. If these biases are complementary, the combination of their decisions is beneficial and could be superior to homogeneous ensembles. In this paper, a family of heterogeneous ensembles is built by pooling classifiers from M homogeneous ensembles of different types of size T. Depending on the fraction of base classifiers of each type, a particular heterogeneous combination in this family is represented by a point in a regular simplex in M dimensions. The M vertices of this simplex represent the different homogeneous ensembles. A displacement away from one of these vertices effects a smooth transformation of the corresponding homogeneous ensemble into a heterogeneous one. The optimal composition of such heterogeneous ensemble can be determined using cross-validation or, if bootstrap samples are used to build the individual classifiers, out-of-bag data. The proposed heterogeneous ensemble building strategy, composed of neural networks, SVMs, and random trees (i.e. from a standard random forest), is analyzed in a comprehensive empirical analysis and compared to a benchmark of other heterogeneous and homogeneous ensembles. The achieved results illustrate the gains that can be achieved by the proposed ensemble creation method with respect to both homogeneous ensembles and to the tested heterogeneous building strategy at a fraction of the training cost.

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Engineered microbial cells present a sustainable alternative to fossil-based synthesis of chemicals and fuels. Cellular synthesis routes are readily assembled and introduced into microbial strains using state-of-the-art synthetic biology tools. However, the optimization of the strains required to reach industrially feasible production levels is far less efficient. It typically relies on trial-and-error leading into high uncertainty in total duration and cost. New techniques that can cope with the complexity and limited mechanistic knowledge of the cellular regulation are called for guiding the strain optimization. In this paper, we put forward a multi-agent reinforcement learning (MARL) approach that learns from experiments to tune the metabolic enzyme levels so that the production is improved. Our method is model-free and does not assume prior knowledge of the microbe’s metabolic network or its regulation. The multi-agent approach is well-suited to make use of parallel experiments such as multi-well plates commonly used for screening microbial strains. We demonstrate the method’s capabilities using the genome-scale kinetic model of Escherichia coli, k-ecoli457, as a surrogate for an in vivo cell behaviour in cultivation experiments. We investigate the method’s performance relevant for practical applicability in strain engineering i.e. the speed of convergence towards the optimum response, noise tolerance, and the statistical stability of the solutions found. We further evaluate the proposed MARL approach in improving L-tryptophan production by yeast Saccharomyces cerevisiae, using publicly available experimental data on the performance of a combinatorial strain library. Overall, our results show that multi-agent reinforcement learning is a promising approach for guiding the strain optimization beyond mechanistic knowledge, with the goal of faster and more reliably obtaining industrially attractive production levels.

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