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1186/2190-5983-1-9 RESEARCH Open Access

**Generalized models for high-throughput analysis of uncertain nonlinear systems
**

Thilo Gross · Stefan Siegmund

Accepted: 12 December 2011 / Published online: 12 December 2011 © 2011 Gross, Siegmund; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Purpose: Describe a high-throughput method for the analysis of uncertain models, e.g. in biological research. Methods: Generalized modeling for conceptual analysis of large classes of models. Results: Local dynamics of uncertain networks are revealed as a function of intuitive parameters. Conclusions: Generalized modeling easily scales to very large networks. Keywords Generalized modeling · high-throughput method · uncertain models · biological research 1 Background The ongoing revolution in systems biology is revealing the structure of important systems. For understanding the functioning and failure of these systems, mathematical modeling is instrumental, cp. Table 1. However, application of the traditional modeling paradigm, based on systems of speciﬁc equations, faces some principal difﬁculties in these systems. Insights from modeling are most desirable during the early stages of exploration of a system, so that insights from modeling can feed into experimental set ups.

T Gross Max-Planck Institute for the Physics of Complex Systems, Nöthnitzer Str. 38, 01187 Dresden, Germany e-mail: thilo.gross@physics.org T Gross · S Siegmund ( ) Department of Mathematics, Center for Dynamics, Technical University Dresden, 01062 Dresden, Germany e-mail: siegmund@tu-dresden.de T Gross e-mail: gross@pks.mpg.de

i. Although such models cannot be studied by simulation. The idea of this approach is to consider not a single model but the whole class of models which are plausible given the available information. Siegmund Diagrammatic representation Generalized model Conventional model However. Modeling can start from a diagrammatic sketch. generalized models reveal the dynamics close to every possible steady state in the whole class of systems depending on a number of parameters that are identiﬁed in the modeling process. other tools can be applied more easily and efﬁciently than in conventional models. 3 Results In the past it has been shown that generalized modeling enables high-throughput analysis of complex nonlinear systems in various applications [1. In particular. 2].Page 2 of 4 Table 1 Three different levels of modeling.e. For determining the stability of X ∗ one can use dynamical systems theory and evaluate the Jacobian of Equation 1 at X ∗ J∗ = ∂G ∂X X =X ∗ − ∂L ∂X . X =X ∗ . We consider all positive steady states in the whole class of systems described by Equation 1 and ask which of those states are stable equilibria. whereas simulation does not allow efﬁcient exploration of large parameter spaces. ˙ = G(X) − L(X) X ˙ = aX − mX p X k +X Gross. For this purpose denote an arbitrary positive steady state of the system by X ∗ . 4 Discussion For illustration consider a population X subject to a gains G and losses L. the number of variables in the current models prohibits analytical investigation. d X = G(X) − L(X). Further. X ∗ is a placeholder for every positive steady state that exists in the class of systems. (1) dt where G(X) and L(X) are unspeciﬁed functions. 2 Method Here we present the approach of generalized modeling. which is translated into a generalized model containing unspeciﬁed functions. In particular it was shown that generalized models can be used to obtain statistically highly-signiﬁcant results on systems with thousands of unknown parameters [3]. at this stage the knowledge of the system is often insufﬁcient to restrict the processes to speciﬁc functional forms.

e. e. a term ∗) L(X ∗ ) prefactors G(X X ∗ and X ∗ denote per-capita gain X := To interpret gX and X note that for any power law L(X) = mX p the elasticity is X = p . For more complex functions G and L the elasticG(X) = X ities can depend on the location of the steady state X ∗ . Here. Constant functions have an elasticity 0. which holds for positive X and F (X ). the generalized model analysis showed that the area of parameter space most likely realized in vivo is close to Hopf and saddle-node bifurcations. 5 Conclusion The simple example already shows that generalized modeling • reveals boundaries of stability. quadratic functions an elasticity 2. By Equation 1 gain and loss rates balance in the steady state X ∗ such that we can deﬁne G(X ∗ ) L(X ∗ ) = . So far we succeeded in expressing the Jacobian of the model as a function of three easily interpretable parameters. A change of stability occurs if gX = X as Equation 1 undergoes a saddle-node bifurcation. the Holling type-II functional response G(X) = kaX +X is linear for low density X (gX ≈ 1) and saturates for high density X (gX ≈ 0). In the present model this implies that a given steady state is stable whenever the elasticity of the loss exceeds the elasticity of the gain gX < X . m has elasticity gX = −1. X∗ X∗ where gX := ∂ log G ∗ ∂ log X |X =X and mainly used in economics.g. However. α := X∗ X∗ which can be interpreted as a characteristic turnover rate of X . ∂ log L ∗ ∂ log X |X =X are so-called elasticities. A steady state X ∗ in a dynamical system is stable if and only if the real parts of all eigenvalues of the Jacobian are negative. respectively. We write G(X ∗ ) L(X ∗ ) g − J∗ = X X. Both approaches are illustrated in a recent paper on bone remodeling [4]. even in this case the interpretation of the elasticity is intuitive. We can thus write the Jacobian at X ∗ as J∗ = α(gX − X ). valid for a class of models and robust against uncertainties in speciﬁc models • avoids expensive numerical approximation of steady states and can be scaled to high-dimensional models Also in larger models it is generally straight forward to derive an analytical expression that states the Jacobian of the generalized model as a function of simple parameters. which enhances . all linear functions an elasticity 1. This Jacobian can then analyzed analytically or numerically by a random sampling procedure.g. The and loss rates. This also extends to decreasing functions.Journal of Mathematics in Industry (2011) 1:9 Page 3 of 4 For expressing the Jacobian as a function of easily interpretable parameters we use (X ∗ ) ∂ log F ∂F ∗ ∗ |X=X∗ = F X the identity ∂X ∗ ∂ log X |X =X ∗ .

In particular. T. B.bone.. PNAS 103. Gross... Phys. U. Dieckmann.. Bone (2011)..: Generalized models as a universal approach to the analysis of nonlinear dynamical systems. 747 (2009) 4. but decreases stability against perturbations. T. Rudolf. Stiefs. D. Rev. T. 11868 (2006) 3. Feudel. Gross. Science 320. E 73. Authors’ contributions The authors have developed this note jointly. it is apparent that a bifurcation happening in vivo would lead to pathological dynamics. Zumsande. A system operating in this parameter regime may therefore be destabilized by small variations in certain parameters.Page 4 of 4 Gross.: General analysis of mathematical models for bone remodeling.: Generalized models reveal stabilizing factors in food webs.. Siegmund.. U.. doi:10. This result illustrates the ability of generalized models to reveal insights into systems on which only limited information is available.010 . J. 016205 (2006) 2. S. Levin. S. Steuer. Gross..2010. a Hopf bifurcation could lead to oscillatory rates of remodeling that are observed in Paget’s disease of bone.12.1016/j. The method of generalized modeling was invented by the ﬁrst author. Competing interests The authors declare that they have no competing interests. L. References 1. Blasius. M.A. T. Siegmund responsiveness. Gross..: Structural kinetic modeling of metabolic networks. Although theoretical analysis alone cannot prove that such transitions are the cause of pathologies in patients. R. Selbig.

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