Hybrid optimization method with general switching strategy for parameter estimation

This article is available from: http://www.biomedcentral.com/1752-0509/2/26[Background] Modeling and simulation of cellular signaling and metabolic pathways as networks of biochemical reactions yields sets of non-linear ordinary differential equations. These models usually depend on several parameters and initial conditions. If these parameters are unknown, results from simulation studies can be misleading. Such a scenario can be avoided by fitting the model to experimental data before analyzing the system. This involves parameter estimation which is usually performed by minimizing a cost function which quantifies the difference between model predictions and measurements. Mathematically, this is formulated as a non-linear optimization problem which often results to be multi-modal (non-convex), rendering local optimization methods detrimental.[Results] In this work we propose a new hybrid global method, based on the combination of an evolutionary search strategy with a local multiple-shooting approach, which offers a reliable and efficient alternative for the solution of large scale parameter estimation problems.[Conclusion] The presented new hybrid strategy offers two main advantages over previous approaches: First, it is equipped with a switching strategy which allows the systematic determination of the transition from the local to global search. This avoids computationally expensive tests in advance. Second, using multiple-shooting as the local search procedure reduces the multi-modality of the non-linear optimization problem significantly. Because multiple-shooting avoids possible spurious solutions in the vicinity of the global optimum it often outperforms the frequently used initial value approach (single-shooting). Thereby, the use of multiple-shooting yields an enhanced robustness of the hybrid approach.This work was supported by the European Community as part of the FP6 COSBICS Project (STREP FP6-512060), the German Federal Ministry of Education and Research, BMBF-project FRISYS (grant 0313921) and Xunta de Galicia (PGIDIT05PXIC40201PM).Peer reviewe

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women

A Metaheuristic Framework for Bi-level Programming Problems with Multi-disciplinary Applications

Bi-level programming problems arise in situations when the decision maker has to take into account the responses of the users to his decisions. Several problems arising in engineering and economics can be cast within the bi-level programming framework. The bi-level programming model is also known as a Stackleberg or leader-follower game in which the leader chooses his variables so as to optimise his objective function, taking into account the response of the follower(s) who separately optimise their own objectives, treating the leader’s decisions as exogenous. In this chapter, we present a unified framework fully consistent with the Stackleberg paradigm of bi-level programming that allows for the integration of meta-heuristic algorithms with traditional gradient based optimisation algorithms for the solution of bi-level programming problems. In particular we employ Differential Evolution as the main meta-heuristic in our proposal.We subsequently apply the proposed method (DEBLP) to a range of problems from many fields such as transportation systems management, parameter estimation and game theory. It is demonstrated that DEBLP is a robust and powerful search heuristic for this class of problems characterised by non smoothness and non convexity

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Abstract: Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation