Skip to main content
Log in

Identifiability Results for Several Classes of Linear Compartment Models

  • Original Article
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Identifiability concerns finding which unknown parameters of a model can be estimated, uniquely or otherwise, from given input–output data. If some subset of the parameters of a model cannot be determined given input–output data, then we say the model is unidentifiable. In this work, we study linear compartment models, which are a class of biological models commonly used in pharmacokinetics, physiology, and ecology. In past work, we used commutative algebra and graph theory to identify a class of linear compartment models that we call identifiable cycle models, which are unidentifiable but have the simplest possible identifiable functions (so-called monomial cycles). Here we show how to modify identifiable cycle models by adding inputs, adding outputs, or removing leaks, in such a way that we obtain an identifiable model. We also prove a constructive result on how to combine identifiable models, each corresponding to strongly connected graphs, into a larger identifiable model. We apply these theoretical results to several real-world biological models from physiology, cell biology, and ecology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Audoly S, Bellu G, D’Angio L, Saccomani MP, Cobelli C (2001) Global identifiability of nonlinear models of biological systems. IEEE Trans Biomed Eng 48:55–65

    Article  MATH  Google Scholar 

  • Anguelova M, Karlsson J, Jirstrand M (2012) Minimal output sets for identifiability. Math Biosci 239:139–153

    Article  MATH  MathSciNet  Google Scholar 

  • Baiijens J (2014) On the existence of identifiable reparametrizations for linear compartment models. Masters thesis, Technische Universiteit Eindhoven

  • Bache RA, Gray WM, Murray-Smith DJ (1981) Time-domain system identification applied to noninvasive estimation of cardiopulmonary quantities. Control Theory Appl IEEE Proc D 128:56–64

    Article  MathSciNet  Google Scholar 

  • Bearup DJ, Evans ND, Chappell MJ (2013) The input–output relationship approach to structural identifiability analysis. Comput Methods Progr Biomed 109:171–181

    Article  Google Scholar 

  • Bellman R, Astrom K (1970) On structural identifiability. Math Biosci 7:329–339

    Article  Google Scholar 

  • Bellu G, Saccomani MP, Audoly S, D’Angio L (2007) DAISY: a new software tool to test global identifiability of biological and physiological systems. Comput Methods Progr Biomed 88:52–61

    Article  Google Scholar 

  • Berman M, Schoenfeld R (1956) Invariants in experimental data on linear kinetics and the formulation of models. J Appl Phys 27:1361–1370

    Article  Google Scholar 

  • Berman M, Shahn E, Weiss MF (1962) Some formal approaches to the analysis of kinetic data in terms of linear compartmental systems. Biophys J 2:289–316

    Article  Google Scholar 

  • Birge SJ, Peck WA, Berman M, Whedon GD (1969) Study of calcium absorption in man: a kinetic analysis and physiologic model. J Clin Invest 48:1705–1713

    Article  Google Scholar 

  • Bressloff PC, Taylor JG (1993) Compartmental-model response function for dendritic trees. Biol Cybern 70:199–207

    Article  MATH  Google Scholar 

  • Cheung ASY, Yates JWT, Aarons L (2013) The design and analysis of parallel experiments to produce structurally identifiable models. J Pharmacokinet Pharmacodyn 40:93–100

    Article  Google Scholar 

  • D’Argenio DZ, Schumitzky A, Wolf W (1988) Simulation of linear compartment models with application to nuclear medicine kinetic modeling. Comput Methods Progr Biomed 27:47–54

    Article  Google Scholar 

  • Davidescu FP, Madsen H, Jorgensen SB (2007) Systematic qualitative experimental design based upon identifiability analysis. Comput Aided Chem Eng 24:57–62

    Article  Google Scholar 

  • DiStefano JJ III (2014) Dynamic systems biology modeling and simulation. Elsevier, London

    Google Scholar 

  • DiStefano JJ III, Feng D (1988) Comparative aspects of the distribution, metabolism, and excretion of six iodothyronines in the rat. Endocrinology 123:2514–2525

    Article  Google Scholar 

  • DiStefano JJ III, Landaw EM (1984) Multiexponential, multicompartmental, and noncompartmental modeling. I. Methodological limitations and physiological interpretations. Am J Physiol Regul Integr Comp Physiol 246:R651–R664

    Google Scholar 

  • DiStefano JJ III, Mak PH (1979) On model and data requirements for determining the bioavailability of oral therapeutic agents: application to gut absorption of thyroid hormones. Am J Physiol Regul Integr Comp Physiol 236:R137–R141

    Google Scholar 

  • DiStefano JJ III, Mori F (1977) Parameter identifiability and experiment design: thyroid hormone metabolism parameters. Am J Physiol Regul Integr Comp Physiol 233:R134–R144

    Google Scholar 

  • Douglas PK, Cohen MS, DiStefano JJ III (2010) Chronic exposure to Mn inhalation may have lasting effects: a physiologically-based toxicokinetic model in rats. Toxicol Environ Chem 92:279–299

    Article  Google Scholar 

  • Douglas PK (2010) Physiologically based toxicokinetic modeling of manganese in rat and monkey and machine learning classification of belief vs. disbelief fMRI signals. Dissertation, University of California, Los Angeles

  • Eisenberg M, Samuels M, DiStefano JJ III (2006) L-T4 bioequivalence and hormone replacement studies via feedback control simulations. Thyroid 16:1279–1292

    Article  Google Scholar 

  • Eisenberg M, Samuels M, DiStefano JJ III (2008) Extensions, validation, and clinical applications of a feedback control system simulator of the hypothalamo-pituitary–thyroid axis. Thyroid 18:1071–1085

    Article  Google Scholar 

  • Evans ND, Moyse H, Lowe D, Briggs D, Higgins R, Mitchell D, Zehnder D, Chappell MJ (2012) Structural identifiability of surface binding reactions involving heterogenous analyte: application to surface plasmon resonance experiments. Automatica 49:48–57

    Article  MathSciNet  MATH  Google Scholar 

  • Evans ND, Chappell MJ (2000) Extensions to a procedure for generating locally identifiable reparameterisations of unidentifiable systems. Math Biosci 168:137–159

    Article  MATH  MathSciNet  Google Scholar 

  • Feng D, DiStefano JJ III (1991) Cut set analysis of compartmental models with applications to experiment design. Am J Physiol Endocrinol Metab 261:E269–E284

    Google Scholar 

  • Feng D, DiStefano JJ III (1992) Decomposition-based qualitative experiment design algorithms for a class of compartmental models. Math Biosci 110:27–43

    Article  MATH  Google Scholar 

  • Godfrey KR, Jones RP, Brown RF, Norton JP (1982) Factors affecting the identifiability of compartmental models. Automatica 18:285–293

    Article  MATH  MathSciNet  Google Scholar 

  • Glad ST (1990) Differential algebraic modelling of nonlinear systems. Realiz Model Syst Theory Prog Syst Control Theory 3:97–105

    MathSciNet  MATH  Google Scholar 

  • Greger JL, Davis CD, Suttie JW, Lyle BJ (1990) Intake, serum concentrations, and urinary excretion of manganese by adult males. Am J Clin Nutr 51:457–461

    Google Scholar 

  • Hays MT (2007) Parenteral thyroxine administration. Thyroid 17:127–129

    Article  Google Scholar 

  • Hori SS, Kurland IJ, DiStefano JJ III (2006) Role of endosomal trafficking dynamics on the regulation of hepatic insulin receptor activity: models for Fao cells. Ann Biomed Eng 34:879–892

    Article  Google Scholar 

  • Liu YY, Slotine JJ, Barabasia AL (2013) Observability of complex systems. PNAS 110:2460–2465

    Article  MATH  MathSciNet  Google Scholar 

  • Ljung L, Glad T (1994) On global identifiability for arbitrary model parameterization. Automatica 30:265–276

    Article  MATH  MathSciNet  Google Scholar 

  • Lutz RJ, Dedrick RL, Matthews HB, Eling TE, Anderson MW (1977) A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. Drug Metab Dispos 5:386–396

    Google Scholar 

  • McMullin TS, Brzezicki JM, Cranmer BK, Tessari JD, Andersen ME (2003) Pharmacokinetic modeling of disposition and time-course studies with \([C^{14}]\) atrazine. J Toxicol Environ Health A 66:941–964

    Article  Google Scholar 

  • Meshkat N, Anderson C, DiStefano JJ III (2012) Alternative to Ritt’s pseudodivision for finding the input–output equations of multi-output models. Math Biosci 239:117–123

    Article  MATH  MathSciNet  Google Scholar 

  • Meshkat N, Sullivant S (2014) Identifiable reparametrizations of linear compartment models. J Symb Comput 63:46–67

    Article  MATH  MathSciNet  Google Scholar 

  • Mulholland RJ, Keener MS (1974) Analysis of linear compartment models for ecosystems. J Theor Biol 44:105–116

    Article  Google Scholar 

  • Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R (1990) Thyroidal and peripheral projection of 3,5,\(3^{\prime }\)-triiodothyronine in humans by multi compartmental analysis. Am J Physiol 258:E715–E726

    Google Scholar 

  • Pohjanpalo H (1978) System identifiability based on the power series expansion of the solution. Math Biosci 41:21–33

    Article  MATH  MathSciNet  Google Scholar 

  • Roberts SM, Weimar WR, Vinson JRT, Munson JW, Bergeron RJ (2002) Measurement of arsenic bioavailability in soil using a primate model. Toxicol Sci 67:303–310

    Article  Google Scholar 

  • Ritt JF (1950) Differential algebra. American Mathematical Society, New York

    MATH  Google Scholar 

  • Saccomani MP, Audoly S, Bellu G, D’Angio L (2001) A new differential algebra algorithm to test identifiability of nonlinear systems with given initial conditions. In: Proceedings of the 40th IEEE conference on decision and control, Orlando, Florida, USA, pp 3108–3113

  • Saccomani MP, Audoly S, D’Angio L (2003) Parameter identifiability of nonlinear systems: the role of initial conditions. Automatica 39:619–632

    Article  MATH  MathSciNet  Google Scholar 

  • Scheuhammer AM, Cherian MG (1982) Influence of chronic MnCl2 and EDTA treatment on tissue levels and urinary excretion of trace metals in rats. Arch Environ Contam Toxicol 11:515–520

    Article  Google Scholar 

  • Stanley R (1999) Enumerative combinatorics, vol 2. Cambridge University Press, Cambridge

    Book  MATH  Google Scholar 

  • Tozer TN (1981) Concepts basic to pharmacokinetics. Pharmacol Ther 12:109–131

    Article  Google Scholar 

  • Vajda S (1984) Analysis of unique structural identifiability via submodels. Math Biosci 71:125–146

    Article  MATH  MathSciNet  Google Scholar 

  • Vicini P, Su H-T, DiStefano JJ III (2000) Identifiability and interval identifiability of mammillary and catenary compartmental models with some known rate constants. Math Biosci 167:145–161

    Article  MATH  Google Scholar 

  • Wagner JG (1981) History of pharmacokinetics. Pharmacol Ther 12:537–562

    Article  Google Scholar 

  • Walter E, Pronzato L (1990) Qualitative and quantitative experiment design for phenomenological models—a survey. Automatica 26:195–213

    Article  MATH  MathSciNet  Google Scholar 

  • Widmark E, Tandberg J (1924) Uber die bedingungen f’tirdie Akkumulation Indifferenter Narkoliken Theoretische Bereckerunger. Biochem Z 147:358–369

    Google Scholar 

Download references

Acknowledgments

Nicolette Meshkat was partially supported by the David and Lucille Packard Foundation. Seth Sullivant was partially supported by the David and Lucille Packard Foundation and the US National Science Foundation (DMS 0954865).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nicolette Meshkat.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meshkat, N., Sullivant, S. & Eisenberg, M. Identifiability Results for Several Classes of Linear Compartment Models. Bull Math Biol 77, 1620–1651 (2015). https://doi.org/10.1007/s11538-015-0098-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11538-015-0098-0

Keywords

Navigation