We present several techniques for knowledge engineering of large belief networks (BNs) based on the our experiences with a network derived from a large medical knowledge base. The noisy MAX, a generalization of the noisy-OR gate, is used to model causal independence in a BN with multi valued variables. We describe the use of leak probabilities to enforce the closed-world assumption in our model. We present Netview, a visualization tool based on causal independence and the use of leak probabilities. The Netview software allows knowledge engineers to dynamically view subnetworks for knowledge engineering, and it provides version control for editing a BN. Netview generates sub-networks in which leak probabilities are dynamically updated to reflect the missing portions of the network.

The quantitative analysis of biochemical reactions and metabolites is at frontier of biological sciences. The recent availability of high-throughput technology data sets in biology has paved the way for new modelling approaches at various levels of complexity including the metabolome of a cell or an organism. Understanding the metabolism of a single cell and multi-cell organism will provide the knowledge for the rational design of growth conditions to produce commercially valuable reagents in biotechnology. Here, we demonstrate how equations representing steady state mass conservation, energy conservation, the second law of thermodynamics, and reversible enzyme kinetics can be formulated as a single system of linear equalities and inequalities, in addition to linear equalities on exponential variables. Even though the feasible set is non-convex, the reformulation is exact and amenable to large-scale numerical analysis, a prerequisite for computationally feasible genome scale modelling. Integrating flux, concentration and kinetic variables in a unified constraint-based formulation is aimed at increasing the quantitative predictive capacity of flux balance analysis. Incorporation of experimental and theoretical bounds on thermodynamic and kinetic variables ensures that the predicted steady state fluxes are both thermodynamically and biochemically feasible. The resulting in silico predictions are tested against fluxomic data for central metabolism in E. coli and compare favourably with in silico prediction by flux balance analysis.

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Model-based diagnostic reasoning often leads to a large number of diagnostic hypotheses. The set of diagnoses can be reduced by taking into account extra observations (passive monitoring), measuring additional variables (probing) or executing additional tests (sequential diagnosis/test sequencing). In this paper we combine the above approaches with techniques from Automated Test Pattern Generation (ATPG) and Model-Based Diagnosis (MBD) into a framework called Fractal (FRamework for ACtive Testing ALgorithms). Apart from the inputs and outputs that connect a system to its environment, in active testing we consider additional input variables to which a sequence of test vectors can be supplied. We address the computationally hard problem of computing optimal control assignments (as defined in Fractal) in terms of a greedy approximation algorithm called Fractal G . We compare the decrease in the number of remaining minimal cardinality diagnoses of Fractal G to that of two more Fractal algorithms: Fractal ATPG and Fractal P . Fractal ATPG is based on ATPG and sequential diagnosis while Fractal P is based on probing and, although not an active testing algorithm, provides a baseline for comparing the lower bound on the number of reachable diagnoses for the Fractal algorithms. We empirically evaluate the trade-offs of the three Fractal algorithms by performing extensive experimentation on the ISCAS85/74XXX benchmark of combinational circuits.

The genetic code appears to be optimized in its robustness to missense errors and frameshift errors. In addition, the genetic code is near-optimal in terms of its ability to carry information in addition to the sequences of encoded proteins. As evolution has no foresight, optimality of the modern genetic code suggests that it evolved from less optimal code variants. The length of codons in the genetic code is also optimal, as three is the minimal nucleotide combination that can encode the twenty standard amino acids. The apparent impossibility of transitions between codon sizes in a discontinuous manner during evolution has resulted in an unbending view that the genetic code was always triplet. Yet, recent experimental evidence on quadruplet decoding, as well as the discovery of organisms with ambiguous and dual decoding, suggest that the possibility of the evolution of triplet decoding from living systems with non-triplet decoding merits reconsideration and further exploration. To explore this possibility we designed a mathematical model of the evolution of primitive digital coding systems which can decode nucleotide sequences into protein sequences. These coding systems can evolve their nucleotide sequences via genetic events of Darwinian evolution, such as point-mutations. The replication rates of such coding systems depend on the accuracy of the generated protein sequences. Computer simulations based on our model show that decoding systems with codons of length greater than three spontaneously evolve into predominantly triplet decoding systems. Our findings suggest a plausible scenario for the evolution of the triplet genetic code in a continuous manner. This scenario suggests an explanation of how protein synthesis could be accomplished by means of long RNA-RNA interactions prior to the emergence of the complex decoding machinery, such as the ribosome, that is required for stabilization and discrimination of otherwise weak triplet codon-anticodon interactions.