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David Roche, Debora Gil, & Jesus Giraldo. (2011). An inference model for analyzing termination conditions of Evolutionary Algorithms. In 14th Congrès Català en Intel·ligencia Artificial (pp. 216–225).
Abstract: In real-world problems, it is mandatory to design a termination condition for Evolutionary Algorithms (EAs) ensuring stabilization close to the unknown optimum. Distribution-based quantities are good candidates as far as suitable parameters are used. A main limitation for application to real-world problems is that such parameters strongly depend on the topology of the objective function, as well as, the EA paradigm used.
We claim that the termination problem would be fully solved if we had a model measuring to what extent a distribution-based quantity asymptotically behaves like the solution accuracy. We present a regression-prediction model that relates any two given quantities and reports if they can be statistically swapped as termination conditions. Our framework is applied to two issues. First, exploring if the parameters involved in the computation of distribution-based quantities influence their asymptotic behavior. Second, to what extent existing distribution-based quantities can be asymptotically exchanged for the accuracy of the EA solution.
Keywords: Evolutionary Computation Convergence, Termination Conditions, Statistical Inference
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David Roche, Debora Gil, & Jesus Giraldo. (2012). Assessing agonist efficacy in an uncertain Em world. In A. Christopoulus and M. Bouvier (Ed.), 40th Keystone Symposia on mollecular and celular biology (79). Keystone Symposia.
Abstract: The operational model of agonism has been widely used for the analysis of agonist action since its formulation in 1983. The model includes the Em parameter, which is defined as the maximum response of the system. The methods for Em estimation provide Em values not significantly higher than the maximum responses achieved by full agonists. However, it has been found that that some classes of compounds as, for instance, superagonists and positive allosteric modulators can increase the full agonist maximum response, implying upper limits for Em and thereby posing doubts on the validity of Em estimates. Because of the correlation between Em and operational efficacy, τ, wrong Em estimates will yield wrong τ estimates.
In this presentation, the operational model of agonism and various methods for the simulation of allosteric modulation will be analyzed. Alternatives for curve fitting will be presented and discussed.
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David Roche, Debora Gil, & Jesus Giraldo. (2013). Detecting loss of diversity for an efficient termination of EAs. In 15th International Symposium on Symbolic and Numeric Algorithms for Scientific Computing (pp. 561–566).
Abstract: Termination of Evolutionary Algorithms (EA) at its steady state so that useless iterations are not performed is a main point for its efficient application to black-box problems. Many EA algorithms evolve while there is still diversity in their population and, thus, they could be terminated by analyzing the behavior some measures of EA population diversity. This paper presents a numeric approximation to steady states that can be used to detect the moment EA population has lost its diversity for EA termination. Our condition has been applied to 3 EA paradigms based on diversity and a selection of functions
covering the properties most relevant for EA convergence.
Experiments show that our condition works regardless of the search space dimension and function landscape.
Keywords: EA termination; EA population diversity; EA steady state
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David Roche, Debora Gil, & Jesus Giraldo. (2013). Multiple active receptor conformation, agonist efficacy and maximum effect of the system: the conformation-based operational model of agonism,. DDT - Drug Discovery Today, 18(7-8), 365–371.
Abstract: The operational model of agonism assumes that the maximum effect a particular receptor system can achieve (the Em parameter) is fixed. Em estimates are above but close to the asymptotic maximum effects of endogenous agonists. The concept of Em is contradicted by superagonists and those positive allosteric modulators that significantly increase the maximum effect of endogenous agonists. An extension of the operational model is proposed that assumes that the Em parameter does not necessarily have a single value for a receptor system but has multiple values associated to multiple active receptor conformations. The model provides a mechanistic link between active receptor conformation and agonist efficacy, which can be useful for the analysis of agonist response under different receptor scenarios.
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David Roche, Debora Gil, & Jesus Giraldo. (2013). Mechanistic analysis of the function of agonists and allosteric modulators: Reconciling two-state and operational models. BJP - British Journal of Pharmacology, 169(6), 1189–202.
Abstract: Two-state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor-dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two-state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one-by-one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism.
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David Roche, Debora Gil, & Jesus Giraldo. (2014). Mathematical modeling of G protein-coupled receptor function: What can we learn from empirical and mechanistic models? In G Protein-Coupled Receptors – Modeling and Simulation Advances in Experimental Medicine and Biology (Vol. 796, pp. 159–181). Springer Netherlands.
Abstract: Empirical and mechanistic models differ in their approaches to the analysis of pharmacological effect. Whereas the parameters of the former are not physical constants those of the latter embody the nature, often complex, of biology. Empirical models are exclusively used for curve fitting, merely to characterize the shape of the E/[A] curves. Mechanistic models, on the contrary, enable the examination of mechanistic hypotheses by parameter simulation. Regretfully, the many parameters that mechanistic models may include can represent a great difficulty for curve fitting, representing, thus, a challenge for computational method development. In the present study some empirical and mechanistic models are shown and the connections, which may appear in a number of cases between them, are analyzed from the curves they yield. It may be concluded that systematic and careful curve shape analysis can be extremely useful for the understanding of receptor function, ligand classification and drug discovery, thus providing a common language for the communication between pharmacologists and medicinal chemists.
Keywords: β-arrestin; biased agonism; curve fitting; empirical modeling; evolutionary algorithm; functional selectivity; G protein; GPCR; Hill coefficient; intrinsic efficacy; inverse agonism; mathematical modeling; mechanistic modeling; operational model; parameter optimization; receptor dimer; receptor oligomerization; receptor constitutive activity; signal transduction; two-state model
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