Identifiability of linear compartmental models: The singular locus

This work addresses the problem of identifiability, that is, the question of whether parameters can be recovered from data, for linear compartment models. Using standard differential algebra techniques, the question of whether a given model is generically locally identifiable is equivalent to asking whether the Jacobian matrix of a certain coefficient map, arising from input-output equations, is generically full rank. We give a formula for these coefficient maps in terms of acyclic subgraphs of the model's underlying directed graph. As an application, we prove that two families of linear compartment models, cycle and mammillary (star) models with input and output in a single compartment, are identifiable, by determining the defining equation for the locus of non-identifiable parameter values. We also state a conjecture for the corresponding equation for a third family: catenary (path) models. These singular-locus equations, we show, give information on which submodels are identifiable. Finally, we introduce the identifiability degree, which is the number of parameter values that match generic input-output data. This degree was previously computed for mammillary and catenary models, and here we determine this degree for cycle models. Our work helps shed light on the question of which linear compartment models are identifiable.

[1]  Seth Sullivant,et al.  Identifiable reparametrizations of linear compartment models , 2013, J. Symb. Comput..

[2]  J. Wagner,et al.  History of pharmacokinetics. , 1981, Pharmacology & therapeutics.

[3]  Claudio Cobelli,et al.  Identifiability results on some constrained compartmental systems , 1979 .

[4]  M. Berman,et al.  Some formal approaches to the analysis of kinetic data in terms of linear compartmental systems. , 1962, Biophysical journal.

[5]  Joseph J. DiStefano,et al.  Dynamic Systems Biology Modeling and Simulation , 2015 .

[6]  R. Schoenfeld,et al.  Invariants in Experimental Data on Linear Kinetics and the Formulation of Models , 1956 .

[7]  T. Tozer Concepts basic to pharmacokinetics. , 1981, Pharmacology & therapeutics.

[8]  Gleb Pogudin,et al.  Input-output equations and identifiability of linear ODE models , 2022, IEEE Transactions on Automatic Control.

[9]  France,et al.  Symbolic lumping of some catenary, mamillary and circular compartmental systems , 2008, 0802.2806.

[10]  S. Audoly,et al.  On the identifiability of linear compartmental systems: a revisited transfer function approach based on topological properties , 1983 .

[11]  S. Vajda,et al.  Analysis of unique structural identifiability via submodels , 1984 .

[12]  Anne Shiu,et al.  Identifiability of Linear Compartmental Models: The Impact of Removing Leaks and Edges , 2021 .

[13]  R. Mulholland,et al.  Analysis of linear compartment models for ecosystems. , 1974, Journal of theoretical biology.

[14]  P Vicini,et al.  Identifiability and interval identifiability of mammillary and catenary compartmental models with some known rate constants. , 2000, Mathematical biosciences.

[15]  On Coefficients of the Characteristic Polynomial of the Laplace Matrix of a Weighted Digraph and the All Minors Theorem , 2016 .

[16]  S. Chaiken A Combinatorial Proof of the All Minors Matrix Tree Theorem , 1982 .

[17]  S. Vajda,et al.  Structural equivalence and exhaustive compartmental modeling , 1984 .

[18]  Keith Godfrey,et al.  Compartmental Models and Their Application , 1983 .

[19]  J J Distefano,et al.  Parameter space boundaries for unidentifiable compartmental models. , 1989, Mathematical biosciences.

[20]  Anne Shiu,et al.  Identifiability of linear compartmental models: the effect of moving inputs, outputs, and leaks , 2019 .

[21]  Heather A. Harrington,et al.  Linear Compartmental Models: Input-Output Equations and Operations That Preserve Identifiability , 2018, SIAM J. Appl. Math..

[22]  Seth Sullivant,et al.  Identifiability Results for Several Classes of Linear Compartment Models , 2014, Bulletin of Mathematical Biology.