The identification of model effective dimensions using global sensitivity analysis

In pharmacometrics, understanding a covariate effect on an interested outcome is essential for assessing the importance of the covariate. Variance-based global sensitivity analysis (GSA) can simultaneously quantify contribution of each covariate effect to the variability for the interested outcome considering with random effects. The aim of this study was to apply GSA to pharmacometric models to assess covariate effects. Simulations were conducted with pharmacokinetic models to characterize the GSA for assessment of covariate effects and with an example of quantitative systems pharmacology (QSP) models to apply the GSA to a complex model. In the simulations, covariate and random variables were generated to simulate the outcomes using the models. Ratios of variance explained by each factor (each covariate and random effect) over the overall variance of the outcome were used as sensitivity indices. The sensitivity indices were consistent with the effect size of covariate. The sensitivity indices identified the importance of creatinine clearance on the pharmacokinetic exposure for a renally-excreted drug. These sensitivity indices could be applied to plasma concentrations over time (repeated measurable outcomes over time) as interested outcomes. Using the GSA, each contribution of all of the covariate effects could be efficiently identified even in the complex QSP model. Variance-based GSA can provide insight when considering the importance of covariate effects by simultaneously and quantitatively assessing all covariate and random effects on interested outcomes in pharmacometrics.

Event Abstract Back to Event Statistical uncertainty and sensitivity analysis of intracellular signaling models - through approximate Bayesian computation and variance based global sensitivity analysis Olivia Eriksson1, 2*, Alexandra Jauhiainen1, 3, Sara Maad Sasane4, Anu G Nair5, Carolina Sartorius4 and Jeanette Hellgren Kotaleski2, 5, 6 1 Contributed equally to this work, Sweden 2 Stockholm University, Department of Numerical Analysis and Computer Science, Sweden 3 AstraZeneca AB R&D, Early Clinical Biometrics, Sweden 4 Lund University, Centre for Mathematical Sciences, Sweden 5 KTH Royal Institute of Technology, School of Computer Science and Communication, Sweden 6 Karolinska Institute, Department of Neuroscience, Sweden Computational dynamical models describing intracellular signaling pathways of nerve cells are increasing in size and complexity as more information is obtained from experiments. Models describing protein interactions within neurons can contain over hundred protein reactions [1, 2]. These models are built from knowledge about the interaction topology, inferred from e.g. gene knock-out experiments, as well as from experimental quantitative data describing the input-output relationship of the observed system. The quantitative data are often sparse as compared to the size of the system, and translating the experimental information into dynamical models often results in large uncertainties in the parameter (e.g reaction rates) values. This uncertainty is partly due to the sparseness in experimental time series data (practical unidentifiability), but it is also an intrinsic feature of the modeled system (structural unidentifiability) and could reflect the possibility for biological variation [3]; in many biological systems the same function can be achieved in partly different ways due to degeneracy and redundancy. Here we investigate the extent of this parameter uncertainty, in a model describing calcium (Ca)-dependent activation of Calmodulin (CaM), Protein phosphatase 2B (PP2B) and Ca/CaM-dependent protein kinase II (CamKII) [4], which is an intracellular pathway of importance to synaptic plasticity. We presume that the structure of the model is correct and then characterize the uncertainty in the parameters based on data. This is done by sampling the subspace of parameter values which has an equally good fit to data (corresponding to the “viable space” in [5]), through a statistical approach known as Approximate Bayesian Computation (ABC) with Markov Chain Monte Carlo (MCMC) [6]. ABC has been proposed for parameter estimation in system biology models previously, albeit in slightly different settings, e.g. [7, 8], and can be applied to a wide range of problems. In order to characterize the viable space efficiently with several experimental datasets, we employ multivariate probability distributions called copulas as a part of the ABC sampling. The result is a multivariate posterior distribution for the parameters, which represents how much they are constrained by the data (i.e. the uncertainty) as illustrated in Figure 1 (pairwise plots of viable space for four parameters indicating constraints and dependencies before and after calibration to data). The next step is to look into how the parameter uncertainty is translated to uncertainty of the predictions made from the model. We also investigate the role and importance of different parameters, with respect to different model outputs including the predictions, by means of global sensitivity analysis [9]. Figure 2 illustrates the sensitivity of one of the outputs calculated by a method based on the decomposition of the variance [10, 11, 12], showing different types of sensitivity measures. Finally, we explore how the sensitivity of different subsets of parameters change as different parts of the viable space are investigated, which is shown in Figure 3, where sensitivity profiles are clustered into groups with different sensitivity characteristics. Figure 1 Figure 2 Figure 3 Acknowledgements This research was supported by funding from the Swedish e-Science Research Centre and the Human Brain Project References [1] Gutierrez-Arenas O, Eriksson O, Hellgren Kotaleski J (2014) Segregation and Crosstalk of D1 Receptor-Mediated Activation of ERK in Striatal Medium Spiny Neurons upon Acute Administration of Psychostimulants. PLoS Comput Biol 10, e1003445. [2] Nair AG, Gutierrez-Arenas O, Eriksson O, Vincent P, and Hellgren Kotaleski J (2015) Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons. J. Neuroscience 35, 14017-14030. [3] Marder E, Goeritz ML, Otopalik AG (2015) Robust circuit rhythms in small circuits arise from variable circuit components and mechanisms. Curr Opin Neurobiol 31, 156-163. [4] Nair AG, Gutierrez-Arenas O, Eriksson O, Jauhiainen A, Blackwell KT and Kotaleski, JH (2014). Modeling intracellular signaling underlying striatal function in health and disease. Progress in molecular biology and translational science, 123, 277 [5] Zamora-Sillero E, Hafner M, Ibig A, Stelling J, and Wagner, A. (2011). Efficient characterization of high-dimensional parameter spaces for systems biology. BMC systems biology 5, 142. [6] Marjoram P, Molitor J, Plagnol V, and Tavare S (2003) Markov chain Monte Carlo without likelihoods. Proc. Natl. Acad. Sci. U.S.A. 100, 15324–15328. [7] Toni T, Welch D, Strelkowa N, Ipsen A, and Stumpf MP. Approximate Bayesian computation scheme for parameter inference and model selection in dynamical systems. J R Soc Interface, 6, 187–202. [8] Liepe J, Kirk P, Filippi S, Toni T, Barnes CP, and Stumpf MP. A framework for parameter estimation and model selection from experimental data in systems biology using approximate Bayesian computation. Nat Protoc, 9, 439–456. [9] Saltelli A, Ratto M, Andres T, Campolongo F, Cariboni J, Gatelli D, Saisana M, Tarantola S Global sensitivity analysis: the primer. In Wiley 2008 New York, NY:Wiley. [10] Sobol IM (2001) Global sensitivity indices for nonlinear mathematical models and their Monte Carlo estimates, Math. Comput. Simul. 55, 271–280. [11] Saltelli A (2002) Making best use of model evaluations to compute sensitivity indices. Comp Phys Comm 145, 280 – 297. [12] Halnes G, Ulfhielm E Ljunggren EE, Kotaleski JH and Rospars JP (2009) Modelling and sensitivity analysis of the reactions involving receptor, G-protein and effector in vertebrate olfactory receptor neurons. Journal of computational neuroscience 27, 471-491. Keywords: sensitivity analysis, Approximate Bayesian Computation, copulas, intracellular signalling, Dynamical Modeling, global sensitivity analysis, Markov chain Monte Carlo, variance decomposition Conference: Neuroinformatics 2016, Reading, United Kingdom, 3 Sep - 4 Sep, 2016. Presentation Type: Investigator presentations Topic: Computational neuroscience Citation: Eriksson O, Jauhiainen A, Maad Sasane S, Nair A, Sartorius C and Hellgren Kotaleski J (2016). Statistical uncertainty and sensitivity analysis of intracellular signaling models - through approximate Bayesian computation and variance based global sensitivity analysis. Front. Neuroinform. Conference Abstract: Neuroinformatics 2016. doi: 10.3389/conf.fninf.2016.20.00014 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 31 May 2016; Published Online: 18 Jul 2016. * Correspondence: PhD. Olivia Eriksson, Contributed equally to this work, Stockholm, Sweden, olivia@kth.se Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Olivia Eriksson Alexandra Jauhiainen Sara Maad Sasane Anu G Nair Carolina Sartorius Jeanette Hellgren Kotaleski Google Olivia Eriksson Alexandra Jauhiainen Sara Maad Sasane Anu G Nair Carolina Sartorius Jeanette Hellgren Kotaleski Google Scholar Olivia Eriksson Alexandra Jauhiainen Sara Maad Sasane Anu G Nair Carolina Sartorius Jeanette Hellgren Kotaleski PubMed Olivia Eriksson Alexandra Jauhiainen Sara Maad Sasane Anu G Nair Carolina Sartorius Jeanette Hellgren Kotaleski Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Global sensitivity analysis (GSA) measures the variation of a model output as a function of the variations of the model inputs given their ranges. In this paper we consider variance-based GSA methods that do not rely on certain assumptions about the model structure such as linearity or monotonicity. These variance-based methods decompose the output variance into terms of increasing dimensionality called 'sensitivity indices', first introduced by Sobol' [25]. Sobol' developed a method of estimating these sensitivity indices using Monte Carlo simulations. McKay [13] proposed an efficient method using replicated Latin hypercube sampling to compute the 'correlation ratios' or 'main effects', which have been shown to be equivalent to Sobol's first-order sensitivity indices. Practical issues with using these variance estimators are how to choose adequate sample sizes and how to assess the accuracy of the results. This paper proposes a modified McKay main effect method featuring an adaptive procedure for accuracy assessment and improvement. We also extend our adaptive technique to the computation of second-order sensitivity indices. Details of the proposed adaptive procedure as wells as numerical results are included in this paper.

Global Sensitivity Analysis of Arrhythmic Risk Biomarkers in Cardiac Single Cell Models

A re-sampling statistics based imprecise moment independent global sensitivity analysis methodology with limited data of uncorrelated and correlated geotechnical properties

Global sensitivity analysis has been widely used to detect the relative contributions of input variables to the uncertainty of model output, and then more resources can be assigned to the important input variables to reduce the uncertainty of model output more efficiently. In this paper, a new kind of global sensitivity index based on Gini’s mean difference is proposed. The proposed sensitivity index is more robust than the variance-based first order sensitivity index for the cases with non-normal distributions. Through the decomposition of Gini’s mean difference, it shows that the proposed sensitivity index can be represented by the energy distance, which measures the difference between probability distributions. Therefore, the proposed sensitivity index also takes the probability distribution of model output into consideration. In order to estimate the proposed sensitivity index efficiently, an efficient Monte Carlo simulation method is also proposed, which avoids the nested sampling procedure. The test examples show that the proposed sensitivity index is more robust than the variance-based first order sensitivity index for the cases with non-normal distributions.

Unraveling the complex dynamics of temporal moments for multispecies contaminant transport in saturated porous media: A global sensitivity analysis approach

This article focuses on reliability-oriented global sensitivity analysis of the fatigue limit state of a steel member stressed by many times repeated loading. The fatigue limit state is associated with fatigue failure, which is caused by brittle fracture due to propagation of a fatigue crack from initial to critical size. The fatigue crack propagation is analysed using linear fracture mechanics. The fundamental question in terms of structural reliability is how significant is the effect of input random quantities on the probability of failure. A new type of global sensitivity analysis subordinated to a contrast identified the equivalent stress range and initial edge crack length as random quantities that most significantly influence the failure probability. The new findings obtained using the contrast-based global sensitivity analyses show interaction effects that are unusually strong in comparison with some results of Sobol’s sensitivity analysis aimed at the reliability of structures. The sensitivity indices are estimated using double-nested-loop simulation of the Latin Hypercube Sampling method.

Global sensitivity analysis (GSA) is useful to recognize important inputs for assigning priority and unimportant inputs for simplifying models by exploring whole distribution ranges. Meanwhile, regional sensitivity analysis (RSA) is also studied for finding the contribution of the critical region of an input, which can be viewed as the complementary of GSA. However, there is a lack of GSA and RSA research in presence of fuzzy uncertainty. Thus, a new global sensitivity index (GSI) under the fuzzy uncertainty is devoted on the credibility distribution function (CrDF), a comprehensive distribution description under the fuzzy uncertainty. The CrDF-based GSI is defined by the fuzzy expectation of the difference between the CrDF and the conditional CrDF of the output on fixing the fuzzy input over its whole distribution range, which can quantify the contribution of the fuzzy input to the output CrDF. Then, a new fuzzy RSA technique, the contribution to this CrDF based index (shortened by CCI) plot, is also proposed, and it can assess the effect of given regions of important inputs on output CrDF. Besides, mathematical properties of the CrDF based GSI and the CCI plot are discussed, and their solution are established by use of the fuzzy simulation with the same set of samples. After the accuracy of established fuzzy simulation solution for the CrDF based GSI and the CCI plot are verified by an analytical example, other examples are used to demonstrate the reasonability and applicability of proposed CrDF based GSI and CCI plot under fuzzy uncertainty.

Load modeling plays an important role in accessing and enhancing the dynamic stability of power systems. Though the Synthesis Load Model Considering Voltage Regulation of Distribution Network ( $\pi $ model) has high accuracy, its parameters are too many. In order to improve the identification efficiency and reduce the difficulty of identification, a simplified model identification strategy based on parameter sensitivity analysis is proposed. Firstly, based on the global sensitivity analysis, the sensitivity analysis of the model parameters is carried out to obtain the First Order Sensitivity Indices ( FSI )and Total Sensitivity Indices ( TSI ). Secondly, the FSI and TSI of each parameter are analyzed, and the effect on the output of model of each parameter is determined by FSI . For less influential parameters, whether the parameter should be fixed as constant is determined by the value of TSI . The parameter whose TSI equal or approximately equal to zero should be fixed as a constant. Finally, the improved genetic algorithm is used to identify the parameter-simplified model, and the effectiveness of the simplified identification strategy is verified by comparing the fitting effects with the measured curve and the residual and the integrated parameter models.

The design space (DS) is defined as the combination of materials and process conditions that provides assurance of quality for a pharmaceutical product. A model-based approach to identify a probability-based DS requires costly simulations across the entire process parameter space (certain) and the uncertain model parameter space and material properties space. We demonstrate that application of global sensitivity analysis (GSA) can significantly reduce model complexity and reduce computational time for identifying and quantifying a probabilistic DS by screening out nonimportant uncertain parameters. The novelty of this approach is that the use of an indicator function, which takes only binary values as a model function, allows application of a straightforward GSA based on Sobol' sensitivity indices and avoids using more costly Monte Carlo filtering or GSA for constrained problems. We consider a chemical reaction example to illustrate how this formulation results in a model reduction and a significant decrease of model runs.

Global sensitivity analysis with variance-based measures suffers from several theoretical and practical limitations, since they focus only on the variance of the output and handle multivariate variables in a limited way. In this paper, we introduce a new class of sensitivity indices based on dependence measures which overcomes these insufficiencies. Our approach originates from the idea to compare the output distribution with its conditional counterpart when one of the input variables is fixed. We establish that this comparison yields previously proposed indices when it is performed with Csiszár f-divergences, as well as sensitivity indices which are well-known dependence measures between random variables. This leads us to investigate completely new sensitivity indices based on recent state-of-the-art dependence measures, such as distance correlation and the Hilbert–Schmidt independence criterion. We also emphasize the potential of feature selection techniques relying on such dependence measures as alternatives to screening in high dimension.

The ratemaking process is a key issue in insurance pricing. It consists in pooling together policyholders with similar risk profiles into rating classes and assigning the same premium for policyholders in the same class. In actuarial practice, rating systems are typically not based on all risk factors but rather only some of factors are selected to construct the rating classes. The objective of this study is to investigate the selection of risk factors in order to construct rating classes that exhibit maximum internal homogeneity. For this selection, we adopt the Shapley effects from global sensitivity analysis. While these sensitivity indices are used for model interpretability, we apply them to construct rating classes. We provide a new strategy to estimate them, and we connect them to the intra-class variability and heterogeneity of the rating classes. To verify the appropriateness of our procedure, we introduce a measure of heterogeneity specifically designed to compare rating systems with a different number of classes. Using a well-known car insurance dataset, we show that the rating system constructed with the Shapley effects is the one minimizing this heterogeneity measure.

In drug development decision-making is often supported through model-based methods, such as physiologically-based pharmacokinetics (PBPK). Global sensitivity analysis (GSA) is gaining use for quality assessment of model-informed inference. However, the inclusion and interpretation of correlated factors in GSA has proven an issue. Here we developed and evaluated a latent variable approach for dealing with correlated factors in GSA. An approach was developed that describes the correlation between two model inputs through the causal relationship of three independent factors: the latent variable and the unique variances of the two correlated parameters. The latent variable approach was applied to a set of algebraic models and a case from PBPK. Then, this method was compared to Sobol’s GSA assuming no correlations, Sobol’s GSA with groups and the Kucherenko approach. For the latent variable approach, GSA was performed with Sobol’s method. By using the latent variable approach, it is possible to devise a unique and easy interpretation of the sensitivity indices while maintaining the correlation between the factors. Compared methods either consider the parameters independent, group the dependent variables into one unique factor or present difficulties in the interpretation of the sensitivity indices. In situations where GSA is called upon to support model-informed decision-making, the latent variable approach offers a practical method, in terms of ease of implementation and interpretability, for applying GSA to models with correlated inputs that does not violate the independence assumption. Prerequisites and limitations of the approach are discussed.

The terrestrial biosphere currently acts as a carbon sink, mitigating atmospheric CO 2 increases caused by human activities. However, the sink's strength remains highly uncertain, with recent terrestrial biosphere model estimates ranging from 1.0 to 3.2 PgC yr − 1 during 2014–2023. Some of this broad inter-model difference is due to input parameter uncertainties. To better understand the effects of parameter uncertainties, we conducted a global sensitivity analysis (GSA) using the Canadian Land Surface Scheme Including Biogeochemical Cycles (CLASSIC). We assessed how input parameter uncertainties influence simulated historical carbon cycle variables over long timescales. Our two-step GSA was applied to seven grid cells, each located in a different biome, and for two statistical measures, the 30-year mean and 30-year trends. In the first step, we applied the Morris method, a qualitative, coarse-sample screening approach, to 124 input parameters and reduced the set to fewer than 20 influential parameters per biome. In the second step, we used the Sobol' method, a fine-sample quantitative technique, to estimate the absolute effects of these parameters. The analysis identified that the maximum carboxylation rate was consistently the most influential across five of the seven biomes for both statistical measures of net biome productivity. Despite six weeks of computation on 120 parallel cores, the confidence intervals for sensitivity indices remained broad, preventing definitive parameter rankings. Influential parameters were associated to ecosystem processes such as photosynthesis, phenology, rooting, respiration, mortality, and carbon allocation. Notably, the sensitivity indices for trends were less robust than those for means. Overall, our results indicate that only 13–15 parameters account for most of the uncertainty in output variables for different variables, statistical measures, and biome locations. Our study shows that GSA is a crucial step before model calibration, helping to prioritise parameters that most influence carbon cycle simulations.