Generalizations of the ‘Linear Chain Trick’: incorporating more flexible dwell time distributions into mean field ODE models

In this paper we generalize the Linear Chain Trick (LCT; aka the Gamma Chain Trick) to help provide modelers more flexibility to incorporate appropriate dwell time assumptions into mean field ODEs, and help clarify connections between individual-level stochastic model assumptions and the structure of corresponding mean field ODEs. The LCT is a technique used to construct mean field ODE models from continuous-time stochastic state transition models where the time an individual spends in a given state (i.e., the dwell time) is Erlang distributed (i.e., gamma distributed with integer shape parameter). Despite the LCT’s widespread use, we lack general theory to facilitate the easy application of this technique, especially for complex models. Modelers must therefore choose between constructing ODE models using heuristics with oversimplified dwell time assumptions, using time consuming derivations from first principles, or to instead use non-ODE models (like integro-differential or delay differential equations) which can be cumbersome to derive and analyze. Here, we provide analytical results that enable modelers to more efficiently construct ODE models using the LCT or related extensions. Specifically, we provide (1) novel LCT extensions for various scenarios found in applications, including conditional dwell time distributions; (2) formulations of these LCT extensions that bypass the need to derive ODEs from integral equations; and (3) a novel Generalized Linear Chain Trick (GLCT) framework that extends the LCT to a much broader set of possible dwell time distribution assumptions, including the flexible phase-type distributions which can approximate distributions on \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathbb {R}}^+$$\end{document}R+ and can be fit to data.

[1]  S Cabras,et al.  Assessing the variability in transmission of bovine tuberculosis within Spanish cattle herds. , 2018, Epidemics.

[2]  O. Diekmann,et al.  The Dynamics of Physiologically Structured Populations , 1986 .

[3]  Philipp Reinecke,et al.  Cluster-based fitting of phase-type distributions to empirical data , 2012, Comput. Math. Appl..

[4]  Tadashi Dohi,et al.  mapfit: An R-Based Tool for PH/MAP Parameter Estimation , 2015, QEST.

[5]  Gábor Horváth,et al.  BuTools 2: a Rich Toolbox for Markovian Performance Evaluation , 2016, VALUETOOLS.

[6]  TheW-transform links delay and ordinary differential equations , 2004 .

[7]  Marcel Abendroth,et al.  Biological delay systems: Linear stability theory , 1990 .

[8]  Gábor Horváth,et al.  Efficient Generation of PH-Distributed Random Variates , 2012, ASMTA.

[9]  F. G. Boese The stability chart for the linearized Cushing equation with a discrete delay and with gamma-distributed delays , 1989 .

[10]  Mor Harchol-Balter,et al.  Closed form solutions for mapping general distributions to quasi-minimal PH distributions , 2006, Perform. Evaluation.

[11]  Miklós Telek,et al.  Phase Type and Matrix Exponential Distributions in Stochastic Modeling , 2016 .

[12]  Pejman Rohani,et al.  Appropriate Models for the Management of Infectious Diseases , 2005, PLoS medicine.

[13]  H. Hethcote,et al.  Integral equation models for endemic infectious diseases , 1980, Journal of mathematical biology.

[14]  A. Hill,et al.  Mathematical models of Ebola-Consequences of underlying assumptions. , 2016, Mathematical biosciences.

[15]  Jim M Cushing,et al.  The dynamics of hierarchical age-structured populations , 1994 .

[16]  Mats Gyllenberg,et al.  Mathematical aspects of physiologically structured populations: the contributions of J. A. J. Metz , 2007, Journal of biological dynamics.

[17]  O. Diekmann,et al.  Exact finite dimensional representations of models for physiologically structured populations , 1989 .

[18]  Peter Buchholz,et al.  A Novel Approach for Phase-Type Fitting with the EM Algorithm , 2006, IEEE Transactions on Dependable and Secure Computing.

[19]  Marek Bodnar,et al.  Influence of distributed delays on the dynamics of a generalized immune system cancerous cells interactions model , 2018, Commun. Nonlinear Sci. Numer. Simul..

[20]  R. Watson,et al.  On the spread of a disease with gamma distributed latent and infectious periods , 1980 .

[21]  Horst R. Thieme,et al.  Endemic Models with Arbitrarily Distributed Periods of Infection I: Fundamental Properties of the Model , 2000, SIAM J. Appl. Math..

[22]  A. Lloyd Sensitivity of Model-Based Epidemiological Parameter Estimation to Model Assumptions , 2009, Mathematical and Statistical Estimation Approaches in Epidemiology.

[23]  Hal L. Smith,et al.  An introduction to delay differential equations with applications to the life sciences / Hal Smith , 2010 .

[24]  H. Banks,et al.  A Comparison of Stochastic Systems with Different Types of Delays , 2013 .

[25]  Philipp Reinecke,et al.  Phase-Type Distributions , 2012, Resilience Assessment and Evaluation of Computing Systems.

[26]  Doron Levy,et al.  A Review of Mathematical Models for Leukemia and Lymphoma. , 2015, Drug discovery today. Disease models.

[27]  Bard Ermentrout,et al.  Simulating, analyzing, and animating dynamical systems - a guide to XPPAUT for researchers and students , 2002, Software, environments, tools.

[28]  T. Ohtsuka,et al.  Intronic delay is essential for oscillatory expression in the segmentation clock , 2011, Proceedings of the National Academy of Sciences.

[29]  T. A. Burton,et al.  Volterra integral and differential equations , 1983 .

[30]  Christian A Yates,et al.  A Multi-stage Representation of Cell Proliferation as a Markov Process , 2017, Bulletin of Mathematical Biology.

[31]  D. Earn,et al.  Generality of the Final Size Formula for an Epidemic of a Newly Invading Infectious Disease , 2006, Bulletin of mathematical biology.

[32]  Michael Y. Li,et al.  A graph-theoretic approach to the method of global Lyapunov functions , 2008 .

[33]  J. Jacquez,et al.  Qualitative theory of compartmental systems with lags. , 2002, Mathematical biosciences.

[34]  Willy Govaerts,et al.  Numerical computation of bifurcations in large equilibrium systems in matlab , 2014, J. Comput. Appl. Math..

[35]  M. Roussel The Use of Delay Differential Equations in Chemical Kinetics , 1996 .

[36]  Michael Y. Li,et al.  Global-stability problem for coupled systems of differential equations on networks , 2010 .

[37]  Juan F. Pérez,et al.  jPhase: an object-oriented tool for modeling phase-type distributions , 2006, SMCtools '06.

[38]  A. Domoshnitsky,et al.  About reducing integro-differential equations with infinite limits of integration to systems of ordinary differential equations , 2013, Advances in Difference Equations.

[39]  HighWire Press Proceedings of the Royal Society of London. Series A, Containing papers of a mathematical and physical character , 1934 .

[40]  L. Allen,et al.  A primer on stochastic epidemic models: Formulation, numerical simulation, and analysis , 2017, Infectious Disease Modelling.

[41]  G. Wolkowicz,et al.  An Alternative Formulation for a Distributed Delayed Logistic Equation , 2018, Bulletin of mathematical biology.

[42]  Benny Van Houdt,et al.  Proceeding from the 2006 workshop on Tools for solving structured Markov chains , 2006 .

[43]  Yang Kuang,et al.  Mathematical models and software tools for the glucose-insulin regulatory system and diabetes: an overview , 2006 .

[44]  Jim Freeman Probability Metrics and the Stability of Stochastic Models , 1991 .

[45]  Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression , 2018, Journal of Pharmacokinetics and Pharmacodynamics.

[46]  L. Allen An introduction to stochastic processes with applications to biology , 2003 .

[47]  A L Lloyd,et al.  Destabilization of epidemic models with the inclusion of realistic distributions of infectious periods , 2001, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[48]  William Gurney,et al.  Stage Structure Models Applied in Evolutionary Ecology , 1989 .

[49]  P. Kaye Infectious diseases of humans: Dynamics and control , 1993 .

[50]  S. A. Campbell,et al.  Approximating the Stability Region for a Differential Equation with a Distributed Delay , 2009 .

[51]  T. Altiok On the Phase-Type Approximations of General Distributions , 1985 .

[52]  N. Macdonald Time lags in biological models , 1978 .

[53]  Michael Y. Li,et al.  Impact of network connectivity on the synchronization and global dynamics of coupled systems of differential equations , 2014 .

[54]  Haiyun Zhao,et al.  Epidemiological Models with Non-Exponentially Distributed Disease Stages and Applications to Disease Control , 2007, Bulletin of mathematical biology.

[55]  J. Cushing,et al.  A matter of maturity: To delay or not to delay? Continuous‐time compartmental models of structured populations in the literature 2000–2016 , 2018 .

[56]  T. Kurtz Solutions of ordinary differential equations as limits of pure jump markov processes , 1970, Journal of Applied Probability.

[57]  Benjamin Armbruster,et al.  Elementary proof of convergence to the mean-field model for the SIR process , 2015, Journal of mathematical biology.

[58]  Gail S. K. Wolkowicz,et al.  Competition in the Chemostat: A Distributed Delay Model and Its Global Asymptotic Behavior , 1997, SIAM J. Appl. Math..

[59]  J. Watmough,et al.  Reproduction numbers and sub-threshold endemic equilibria for compartmental models of disease transmission. , 2002, Mathematical biosciences.

[60]  Zhi-Hong Guan,et al.  Dynamic Analysis of Genetic Regulatory Networks with Delays , 2018 .

[61]  Maoan Han,et al.  Slow-fast dynamics of Hopfield spruce-budworm model with memory effects , 2016, Advances in Difference Equations.

[62]  R M Nisbet,et al.  The dynamics of population models with distributed maturation periods. , 1984, Theoretical population biology.

[63]  W. O. Kermack,et al.  A contribution to the mathematical theory of epidemics , 1927 .

[64]  Odo Diekmann,et al.  Finite Dimensional State Representation of Linear and Nonlinear Delay Systems , 2017, Journal of Dynamics and Differential Equations.

[65]  D. A. Baxter,et al.  Modeling transcriptional control in gene networks—methods, recent results, and future directions , 2000, Bulletin of mathematical biology.

[66]  Catherine Bonnet,et al.  Stability analysis of systems with distributed delays and application to hematopoietic cell maturation dynamics , 2008, 2008 47th IEEE Conference on Decision and Control.

[67]  M. Bonsall,et al.  Pathogen responses to host immunity: the impact of time delays and memory on the evolution of virulence , 2006, Proceedings of the Royal Society B: Biological Sciences.

[68]  Willy Govaerts,et al.  MATCONT: A MATLAB package for numerical bifurcation analysis of ODEs , 2003, TOMS.

[69]  J. Dushoff,et al.  Equivalence of the Erlang Seir Epidemic Model and the Renewal Equation , 2018, bioRxiv.

[70]  Ren Asmussen,et al.  Fitting Phase-type Distributions via the EM Algorithm , 1996 .

[71]  D. Earn,et al.  Effects of the infectious period distribution on predicted transitions in childhood disease dynamics , 2013, Journal of The Royal Society Interface.

[72]  A L Lloyd,et al.  Realistic distributions of infectious periods in epidemic models: changing patterns of persistence and dynamics. , 2001, Theoretical population biology.

[73]  T. Kurtz Limit theorems for sequences of jump Markov processes approximating ordinary differential processes , 1971, Journal of Applied Probability.

[74]  A. R. Humphries,et al.  Transit and lifespan in neutrophil production: implications for drug intervention , 2017, Journal of Pharmacokinetics and Pharmacodynamics.

[75]  S. Strogatz Nonlinear Dynamics and Chaos: With Applications to Physics, Biology, Chemistry and Engineering , 1995 .