Microbial communities are constantly challenged by environmental stochasticity, rendering time-series data obtained from these communities inherently noisy. Traditional mathematical models, such as the first-order multivariate autoregressive (MAR) model and the deterministic generalized Lotka–Volterra model, are no longer suitable for predicting the stability of a microbiome from its time-series data, as they fail to capture volatility in the environment. To accurately measure microbiome stability, it is imperative to incorporate stochasticity into the existing mathematical models in microbiome research. In this paper, we introduce a stochastic generalized Lotka–Volterra (SgLV) system that characterizes the temporal dynamics of a microbial community. To study this system, we developed a comprehensive theoretical framework for calculating four resilience measures based on the SgLV model. These resilience metrics effectively capture the short- and long-term behaviors of the resilience of the microbiome. To illustrate the practical application of our approach, we demonstrate the procedure for calculating the four resilience measures using simulated microbial abundance datasets. The procedural simplicity enhances its utility as a valuable tool for application in various microbial and ecological communities.
Citation: Tuan A. Phan, Benjamin J. Ridenhour, Christopher H. Remien. Resilience of a stochastic generalized Lotka–Volterra model for microbiome studies[J]. Mathematical Biosciences and Engineering, 2025, 22(6): 1517-1550. doi: 10.3934/mbe.2025056
[1] | Suqi Ma . Low viral persistence of an immunological model. Mathematical Biosciences and Engineering, 2012, 9(4): 809-817. doi: 10.3934/mbe.2012.9.809 |
[2] | Cristina Anton, Alan Yong . Stochastic dynamics and survival analysis of a cell population model with random perturbations. Mathematical Biosciences and Engineering, 2018, 15(5): 1077-1098. doi: 10.3934/mbe.2018048 |
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[5] | Yongxin Gao, Shuyuan Yao . Persistence and extinction of a modified Leslie-Gower Holling-type Ⅱ predator-prey stochastic model in polluted environments with impulsive toxicant input. Mathematical Biosciences and Engineering, 2021, 18(4): 4894-4918. doi: 10.3934/mbe.2021249 |
[6] | Hsiu-Chuan Wei . Mathematical modeling of tumor growth: the MCF-7 breast cancer cell line. Mathematical Biosciences and Engineering, 2019, 16(6): 6512-6535. doi: 10.3934/mbe.2019325 |
[7] | Ann Nwankwo, Daniel Okuonghae . Mathematical assessment of the impact of different microclimate conditions on malaria transmission dynamics. Mathematical Biosciences and Engineering, 2019, 16(3): 1414-1444. doi: 10.3934/mbe.2019069 |
[8] | Thomas G. Hallam, Qingping Deng . Simulation of structured populations in chemically stressed environments. Mathematical Biosciences and Engineering, 2006, 3(1): 51-65. doi: 10.3934/mbe.2006.3.51 |
[9] | M. Hadjiandreou, Raul Conejeros, Vassilis S. Vassiliadis . Towards a long-term model construction for the dynamic simulation of HIV infection. Mathematical Biosciences and Engineering, 2007, 4(3): 489-504. doi: 10.3934/mbe.2007.4.489 |
[10] | Kimberlyn Roosa, Ruiyan Luo, Gerardo Chowell . Comparative assessment of parameter estimation methods in the presence of overdispersion: a simulation study. Mathematical Biosciences and Engineering, 2019, 16(5): 4299-4313. doi: 10.3934/mbe.2019214 |
Microbial communities are constantly challenged by environmental stochasticity, rendering time-series data obtained from these communities inherently noisy. Traditional mathematical models, such as the first-order multivariate autoregressive (MAR) model and the deterministic generalized Lotka–Volterra model, are no longer suitable for predicting the stability of a microbiome from its time-series data, as they fail to capture volatility in the environment. To accurately measure microbiome stability, it is imperative to incorporate stochasticity into the existing mathematical models in microbiome research. In this paper, we introduce a stochastic generalized Lotka–Volterra (SgLV) system that characterizes the temporal dynamics of a microbial community. To study this system, we developed a comprehensive theoretical framework for calculating four resilience measures based on the SgLV model. These resilience metrics effectively capture the short- and long-term behaviors of the resilience of the microbiome. To illustrate the practical application of our approach, we demonstrate the procedure for calculating the four resilience measures using simulated microbial abundance datasets. The procedural simplicity enhances its utility as a valuable tool for application in various microbial and ecological communities.
Industrial chemicals might be environmental or health hazards, thus there is an increasing need for developing efficient methodologies for toxicity assessment. The traditional method of conducting in vivo assays is very efficient for understanding the mode of action of various toxicants, but it is expensive, time consuming, and there are moral issues regarding the use of animals. Cell-based in vitro assays [28] are attractive alternatives for the assessment of toxicity. We propose a mathematical model to study the effect of toxicants on human cells.
Our work is part of the cytotoxicity profiling project carried by Alberta Centre for Toxicology in which initially 63 chemicals [27] were investigated using the xCELLigence Real-Time Cell Analysis High Troughput (RTCA HT) Assay [19]. The xCELLigence RTCA HT system is developed by the ACEA Biosciences Inc. (San Diego, USA), utilizing 384 well electronic microtiter plates (E-Plates 384). Impedance is generated by cells attached to electrodes, impeding the electric current between electrodes. Therefore, the impedance signal is label free and non-invasive, enabling direct measurement of cellular status in real time. The impedance value is converted by a software to Cell Index, which closely reflects not only cell number, but also cell morphology and adhesion.
The cells were seeded into the wells of E-Plates 384 [19], and the test substances were added about 24 hours later to allow cells to attach to the bottom of the wells and adapt to growth. The 11 concentrations of the test substances were selected based on a literature study, and each of them was tested in at least quadruplicates [27]. Time-dependent concentration response curves (TCRCs) for each test substance in each cell line were generated [27].
Series of physiological events, such as changes in cell population, cell morphology, and cellular functions, that characterize an adverse biological response are referred to as mode of action (MOA) [27]. According to the MOA, the tested substances were divided in 10 groups [27]. For example, the TCRCs for two chemicals from the same group, PF431396 and monastrol, are displayed in Fig. 1.
The main objectives of our work are to develop a mathematical model capable of reproducing the TCRCs and, based on this model, to investigate the effects of toxicants on the survival/death of the cells' population. We consider a three dimensional model for a cells' population subjected to an acute dose of toxicant. The state variables are the cell index, as a proxy for the number of cells, the concentration of toxicant in the cell, and the concentration of toxicant in the environment, and they are coupled by a linear dose-response function. This model is a special case of the class of models proposed in [4], and it is related to the models considered in [5,10,15]. However, since we consider an acute dose of toxicant instead of a chronic one, the analysis of the survival/death of the cells' population is different from the one done in the previously mentioned papers. We analyze the stability of this system of ordinary differential equations analytically using an approach similar with the one in [7], and we find sufficient conditions for the survival or death of the cells' population.
An important contribution of this paper is the efficient statistical methodology used to validate the proposed mathematical model. For parameter estimation and prediction we propose an approach based on the Expectation Maximization (EM) algorithm [3] and the Unscented Filter [12]. This method can also be used to predict the concentration of toxicant outside the cells. These predictions are important in any system for toxicity monitoring. For example, a similar cytotoxicity mathematical dynamic model [8] is applied for early detection and quantification of the presence of toxicants in the water supply system. The estimation of the model parameters and prediction of the concentrations of the toxic agent presented in water supply are done using the moving horizon estimator (MHE) and extended Kalman filer (EKF). Although the model considered in [8] is less complicated than the model presented in this paper, for parameter estimation the MHE and the EKF require extensive tunning, so the EM algorithm is a much more efficient alternative.
Since the parameters of the proposed model are estimated not measured directly, there is uncertainty regarding their precise values. We use Monte Carlo simulations and parameter sensitivity analysis for uncertainty quantification. Sensitivity analysis [13] refers to a broad group of methods that provide valuable insight regarding the dependence of the model output on its parameters. We apply a global sensitivity analysis (GSA) method [23] to test the robustness of the results of our model in the presence of uncertainty, and to increase the understanding of the relationships between input and output variables in the model.
In addition to proposing an efficient statistical method for parameter estimation and prediction of the concentration of toxicant outside the cells, an important application of the mathematical model is to generate numerically the TCRCs. Based on these numerical simulations and a mathematical analysis of the model, we can determine the threshold value for the initial concentration of a chemical after which the death of the cells' population happens (i.e. the chemical considered becomes toxic for the cells).
From the information included in the TCRCs, various parameters, such as LC
The paper is organized as follows. We start by presenting the mathematical model in section 2 followed by the study of stability in section 3. Section 4 includes the methods used for parameter estimation and prediction. Next, in section 5, we validate the proposed model by comparing the experimental TCRCs with the predicted values for the cell index. The GSA and Monte Carlo Simulations are presented in section 6. The last section of the paper includes a summary and discussion of the main results and intended future work.
The data set used in this study is from the cytotoxicity test on human hepatocellular carcinoma cell line HepG2 [19].
Without exposure to the test substances, a typical cell growth curve exhibits four phases: the lag, the log, the plateau and the decline phases. The lag phase is the phase when the cells do not divide and adapt to the culture conditions. In the log phase the cells actively proliferate and have an exponential increase in the cell density. In the plateau phase, the cellular proliferation reaches a steady-state level. Finally, in the decline phase, the cell death predominates and the number of viable cells declines due to the natural path of the cell cycle and depletion of the nutrient supplements.
We focus on the modeling of the log phase. After seeding the cells in E-Plates for 24 hours, eleven concentrations of each substance were applied. Negative controls were presented in each E-Plate 384, as the cells in these wells were treated with only assay buffer for substance dilution, but no testing substances. The cells were monitored totally for 89 hours. The TCRCs are truncated such that only the data from the log phase are kept.
To model the negative control curves, we start with the well-known logistic model describing cell growth in non-toxic environment [24]:
dn(t)dt=βn(t)(1−n(t)K), | (1) |
where
We consider the following model for cells growth/death in a toxic environment [4]. Let
dn(t)dt=βn(t)(1−n(t)K)−αC0(t)n(t). | (2) |
We suppose that the only source of toxicant is the environment. Linear kinetics is known to be relevant for certain toxicants, but there is evidence that higher order formulations are also important [4]. In [6] the mechanisms of in vitro cytotoxicity are analyzed, and in the proposed models the toxicant's uptake rate is considered to be a combination of a linear diffusive component and a saturable, carrier-mediated component (Michaelis-Menten like kinetics). The rapid on-line estimation of toxicant concentration in water supply proposed in [8] is also based on these models. However, after estimating the parameters, for some toxicants it appears that the Michaelis-Menten uptake is not significant [6], so we ignore carrier-mediated transportation and we use linear kinetics [4,24]:
dC0(t)dt=λ21CE(t)−η21C0(t), | (3) |
where
As in [4] we assume that the cells absorb part of the toxicant, and we express the rate of change of the total amount of toxicant in the environment as the sum of the rates of input to and losses from the environment. Supposing that the inputs to the environment are proportional with
dCE(t)dt=λ22C0(t)n(t)−η22CE(t)n(t) | (4) |
where
dn(t)dt=βn(t)(1−n(t)K)−αC0(t)n(t)dC0(t)dt=λ21CE(t)−η21C0(t)dCE(t)dt=λ22C0(t)n(t)−η22CE(t)n(t). | (5) |
The variables and parameters in this model are listed in Table 1.
Symbol | Definition |
cell index ≈ cell population | |
toxicant concentration inside the cell | |
toxicant concentration outside the cell | |
cell growth rate in the absence of toxicant | |
capacity volume | |
effect coefficient of toxicant on the cell's growth | |
the uptake rate of the toxicant from environment | |
the toxicant uptake rate from cells | |
the toxicant input rate to the environment | |
the losses rate of toxicant absorbed by cells |
Without loss of generality we suppose that the initial time is
As we have mentioned before, the model (5) is a particular case of the class of models introduce in [4]. More recently, similar models were studied in [5,10,15]. However, in these papers sufficient conditions for persistence or extinction of the population are expressed in terms of the toxicant input rate
We assume that all parameters of model (5) have positive values.
Equilibria are very important in the study of the asymptotic behavior of a dynamical system [7]. To determine the equilibria, we set the vector field in (5) equal to
J=[β−2βn/K−αC0−αn00−η21λ21λ22C0−η22CEλ22n−η22n]. |
We have the following equilibria.
• The extinction equilibria:
ξ1=β−αCE∗η21λ21,ξ2=−η21,ξ3=0 |
To determine the stability and the qualitative behavior in a neighborhood of these non-hyperbolic equilibria, we study the behavior on the local center manifold [21] (see appendix A for details regarding the center manifold). The analytical center manifold is given by the line
• The maximum capacity equilibrium:
ξ1=−β<0ξ2,3=−12(η21+η22K±√(η21+η22K)2+4(λ21λ22−η21η22)K) |
Notice that if
• The interior equilibrium: If
ξ1=0,ξ2=−β(1−αλ21CEβη21)<0,ξ3=−η21−η22K(1−αλ21CEβη21)<0, |
so these equilibria are non-hyperbolic fixed points.
Following [5,4] we define persistence and extinction as follows.
• The cell population is said to be uniformly persistent if there exist the constants
• The cell population is said to go to local extinction if
Intuitively, uniform persistence corresponds to the long term cells survival, and the cells death corresponds in the previous definition to local extinction.
Similarly with [5] we can prove the following lemma (see appendix B for a detailed proof).
Lemma 3.1. If
We have noticed that for the chemicals considered in this paper, the estimated values of the parameters
Theorem 3.2. If
1. If
limt→∞n(t)=K,limt→∞C0(t)=limt→∞CE(t)=0. |
2. If
limt→∞n(t)=0,limt→∞C0(t)=CE∗λ21η21,limt→∞CE(t)=CE∗>βη21αλ21, |
Moreover, the population component is in
Notice that if
Corollary 1. If
This is illustrated numerically by the trajectories displayed in Fig. 2(a) for monastrol. These trajectories correspond to several sets of initial values
This means that if the initial concentration is sufficiently low, the presence of the chemical does not affect the convergence of the cell index towards the maximum capacity
If
However, if
For monastrol, the separation between persistence and extinction according to the initial values
In the next section we design an efficient method to estimate the parameters based on the TCRCs. With the proposed method, for a given chemical and a cell line, the parameters can be determined after only two experiments, namely the negative control and an experiment with a relatively high initial concentration of the testing substance. Thus, after two experiments we can determine the threshold
The non-linear system of ordinary differential equations (5) cannot be solved analytically, so to estimate the parameters we rewrite it in a state-space form. Notice that from the experimental data recorded in the TCRCs we get observations, possibly affected by measurement errors, only for the cell index
xk+1=xk+h[βxk[1](1−xk[1]K)−αxk[2]xk[1]λ21xk[3]−η21xk[2]λ22xk[2]xk[1]−η22xk[3]xk[1]]+vk+1 | (6) |
yk+1=Cxk+1+wk+1 | (7) |
Here
The parameters
The system (5) cannot be solved analytically, so to estimate the remaining parameters
The EM algorithm is especially useful when it is easier to calculate the likelihood of the model using not only the observed data
The state equation (6) is non-linear, so an approximation is needed during the E-step. The likelihood and the conditional likelihood are approximated based on a linearization, and the UF is used for filtering and smoothing. The next two sub-sections briefly present the implementation of the UF and the EM algorithm for the state-space model (6)-(7).
The UF was introduced by Julier and Uhlmann [12] as an alternative to the extended Kalman filter (EKF) for non-linear state-space models. This filter does not require the calculation of the Jacobians, and it is computationally at most as expensive as the EKF.
Both the EKF and the UF approximate the state distribution with a Gaussian one. However, instead of using the EKF linearization approach, the UF employs a deterministic sampling. The sample points completely capture the true mean and the true covariance. In contrast to the first-order accuracy of the EKF, the UF is capable to accurately capture the true posterior mean and the covariance up to the third order for a nonlinear system.
For the state-space model (6)-(7), let us denote
Let denote
f(x)=x+h[βx[1](1−x[1]K)−αx[2]x[1]λ21x[3]−η21x[2]λ22x[2]x[1]−η22x[3]x[1]],x∈R3 | (8) |
and consider the linearised system
xk+1=f(ˉxk)+∂f∂x(ˉxk)(xk−ˉxk)+vk+1, | (9) |
yk=Cxk+wk,. | (10) |
Notice that for the linearized system we have
ˉPxkxk+1=E[(xk−ˉxk)(xk+1−ˆxk+1)t|x1,…,xk]=ˉPk∂f∂xt(ˉxk), | (11) |
and with
Jk=ˉPxkxk+1ˆP−1k+1, | (12) |
we have the following backward recursions
xk−1|N=ˉxk−1+Jk−1(xk|N−ˆxk), | (13) |
Pk−1|N=ˉPk−1+Jk−1(Pk|N−ˆPk)Jtk−1. | (14) |
The UF filtering algorithm [11] can be used to compute
The algorithm starts with an initial guess
θn+1=argmaxθQ(θ|θn). |
We briefly explain the implementation of the proposed EM-algorithm for estimating the parameters
log(L)=logP(x1,…,xN,y1,…,yN)=logP(yN|yN−1,…,y1,xN,…,x1)+…+logP(y1|xN,…,x1)+logP(xN|xN−1,…,x1)+…+logP(x1). |
Using the linearized equations (9) and (10), we obtain:
log(L)=−5Nln(2π)−12N∑i=1ln(|R|)−12N∑i=1(yi−Cxi)tR−1(yi−Cxi)−12N∑i=2ln(|Q|)−12N∑i=2(xi−Fi−1xi−1−bi−1)tQ−1(xi−Fi−1xi−1−bi−1)−12ln(|Σ|)−12(x1−μ)tΣ−1(x1−μ), |
where
Fi=[1+h(β−2βˉxi[1]/K−αˉxi[2])−hαˉxi[1]001−η21hλ21hhλ22ˉxi[2]−hη22ˉxi[3]hλ22ˉxi[1]1−hη22ˉxi[1]] |
and
bi=[h(βˉxi[1]2/K+αˉxi[2]ˉxi[1])0h(−λ22ˉxi[2]ˉxi[1]+η22ˉxi[3]ˉxi[1])]. |
The EM algorithm iteratively maximizes
ˆE=−5Nln(2π)−N2log(|R|)−12N∑n=1tr[R−1(ynytn−ynxtn|NCt−Cxn|Nytn+CPn|NCt)]−12N∑n=2log(|Q|)−12N∑n=2tr[Q−1(Pn|N−Pn,n−1|NFtn−1−xn|Nbtn−1−Fn−1Ptn,n−1|N+Fn−1Pn−1|NFtn−1+Fn−1xn|Nbtn−1−bxtn|N+bn−1xtn|NFtn−1+bn−1btn−1)]−12log(|Σ|)−12tr[Σ−1(P1−μxt1|N−x1|Nμt+μμt)] |
The smoothed values
Initialize the model parameters |
Repeat until the log likelihood has converged |
The E step |
For k=1 to N |
Run the UF filter to compute |
For k=N to 1 |
Calculate the smoothed values |
The M step |
Update the values of the parameters |
The main advantage of using the EM-algorithm is the guaranteed convergence [26,18]. However, depending on the initial guess, the algorithm can only converge to a local maximum. Various strategies for choosing the initial guess are proposed in [1], and methods for accelerating the convergence are presented in [17].
We divide the experimental data into a training set (containing
We start with the validation of the logistic model on the negative control cell growth data, and we estimate the cell growth rate
Figure 4 shows the fitting of the negative control data of four replicates. The data predicted by the logistic model is in agreement with all the experimental data. Moreover the estimated parameters of all replicated experiments are consistent. Thus we conclude that the logistic equation (1) is a suitable model to represent the cell growth in non-responsive environment.
To test the responsive model (5), we present here the results obtained for PF431396, monastrol, ABT888, and HA1100 hydrochloride. These chemicals are selected from Cluster Ⅰ: DNA/RNA-nucleic acid targets, and Cluster Ⅹ: protein -motor targets. These two clusters are the top 2 most common clusters in the 63 compounds experiments, covering more than half of the cases.
We perform preprocessing of the experiment data before testing the toxicity model. Since the cell index is not measured uniformly on time, we apply a smoothing spline to approximate the experimental data. Figure 5 presents a good agreement between the experimental data and the fitting spline.
After interpolation with a smoothing spline, we sample uniformly from the approximating spline, and we use the first 70% experimental data (i.e. the training set) to estimate the parameters,
From Figs. 6-8, the predictions are in agreement with the experimental data. We have plotted only the TCRCs corresponding to the largest 8 out of 11 values of the initial concentration of the chemicals because the curves corresponding to the first 3 values are similar to the negative control. The observations from the initial time
In addition to the point estimates obtained with the EM algorithm, we analyze the effect of parameter uncertainty on predicting the cell index using Monte Carlo simulations and global sensitivity analysis (GSA). Sensitivity Analysis (SA) refers to a broad group of methods that ranks parameters by their effect on output variables. GSA is the most suitable group of sensitivity analysis methods for application in highly nonlinear dynamic models [13]. In GSA, variations of all input parameters simultaneously are considered. As a result, interactions among different inputs can be detected. There is a variety of GSA methods, and here we apply the Sobol's method [23].
To account for parameter uncertainty, we run simulations assuming that all parameters are random variables with triangle distributions on intervals centered around the estimated values of the parameters given in Table 1. Based on these simulations we determine the expected cell index and the extinction probability. We consider intervals corresponding to perturbations of 10%, we run the model for 1000 realizations and we simulate for t=60 hours (similarly with the experimental settings). In Figs. 10(a), 11(a) we display some TCRCs recorded after experiments for PF431396 and ABT888. We compare these curves with the simulations results obtained using the proposed mathematical model.
In Figs. 10(b), 11(b) we plot the expected cell index and the probability of extinction against the concentration of PF431396 and ABT888. Notice that the values of the expected cell index are in good agreement with the experimental data represented in the TCRCs. The probability of extinction increases very steeply from 0 to 1 when the concentrations increase and pass a certain threshold. This illustrates the conclusions of the stability analysis presented in section 3.
From figures 6, 8, 9 we can notice that the TCRCs for PF431396, ABT888 and HA1100 hydrochloride cover both cases corresponding to persistence and to extinction. However, from figures 7 we can notice that the experiments for monastrol are done with too small initial concentrations because all TCRCs show persistence. The results of this type of simulations can be used to determine an appropriate range for the initial concentration of chemicals
Sobol's sensitivity measures [23] that utilize the analysis of variance (ANOVA) of the model output are among the most widely used GSA methods [13] [9]. In Sobol's method, the variance of the model output is decomposed into components that result from individual parameters as well as from parameter interactions.
Consider a mathematical model represented by the square integrable function
f(x)=f∅+∑kf[k](xk)+∑k1<k2f[k1,k2](xk1,xk2)+⋯+f[1,⋯,d](x1,…,xd) | (15) |
where
∫10f[k1,…,kr](xk1,⋯,xkr)dxki=0. |
Thus the summands in (15) are orthogonal to each other and we have
∫[0,1]df(x)dx=f∅. |
Let us define
D:=∫[0,1]df2(x)dx−f2∅ |
Dk1,…,kr:=∫[0,1]rf2[k1,…,kr](xk1,⋯,xkr)dxk1⋯dxkr. |
We have Var
Sk1,…,kr=Dk1,…,krD. |
Squaring (15), integrating over
d∑r=1∑k1<k2<⋯<krDk1,…,kr=D. |
The GSA indices of a model can be evaluated using Monte Carlo numerical integration. To demonstrate the process, we present the estimation of first order indices
Let
f∅≈1NN∑i=1f(ξi),D≈1NN∑i=1f2(ξi)−f2∅. |
Then we generate another group of samples
Dj≈1NN∑i=1f(ξi1,…,ξid)f(ˆξi1,…,ˆξij−1,ξij,ˆξij+1,…,ˆξid)−f2∅Dj1,j2≈1NN∑i=1f(ξi1,…,ξid)f(ˆξi1,…,ˆξij1−1,ξij1ˆξij1+1,…,ˆξij2−1,ξij2,ˆξij2+1,…,ˆξid)−f2∅ |
We present the GSA studies for our proposed model. The estimated values of the parameters for different chemicals are given in Table 3. We consider that all parameters are random variables with uniform distribution on intervals corresponding to perturbations of 10%. To calculate the Sobol's indices we use the Matlab toolbox named GSAT developed by Cannavó [2].
Toxicant | Cluster | β | K | |||||
PF431396 | Ⅹ | 0.077 | 21.912 | 0.273 | 0.058 | 0 | 0.008 | 0.238 |
monastrol | Ⅹ | 0.074 | 18.17 | 0.209 | 0.177 | 0.204 | 0.5 | 0.016 |
ABT888 | Ⅰ | 0.083 | 17.543 | 0.079 | 0.177 | 0.205 | 0.5 | 0.005 |
HA1100 hydrochloride | Ⅰ | 0.077 | 21.913 | 0.143 | 0.0098 | 0.0786 | 0.147 | 0.351 |
In Figs. (12), (13), we present the ranking for the GSA indices for PF431396 and ABT888 with various concentration, respectively. We can notice that when the chemicals' concentration is small the capacity
Figure (14) present the second order GSA indices for the same chemicals at the transition stage from persistence to extinction. The thickness of lines of any pair of parameters represents the rank of their co-sensitivity (the thicker the line, the greater the co-sensitivity). These pictures also show that the intakes and outtakes rates are the most sensitive parameters for the cells' population model. Similar results are obtained for monastrol and HA1100 hydrochloride.
The novelty of this paper is the application of a dual methodology, including an efficient statistical method for parameter estimation and prediction of the cell index and chemicals' concentration, followed by a numerical and analytical stability study for the dynamical system modeling the cells' growth/death.
We propose a mathematical model expressed by a three dimensional system of differential equations that can be expressed in a state-space form, and we design an EM algorithm based on the unscented filter for parameter estimation and prediction. Since it requires less tunning, the EM algorithm is a more efficient alternative for parameter estimation than the MHE or the EKF [8]. The results presented here for four chemicals with different MOAs illustrate the efficiency of the proposed algorithm and validate the mathematical model. Our approach is very efficient because the model parameters can be estimated based on TCRCs provided by only two experiments, namely the negative control and an experiment with a relatively large initial concentration of the chemical. Using the mathematical model, accurate TCRCs for other concentrations can be obtained numerically.
Based on the TCRCs, clustering methods or machine learning algorithms can be applied to classify the chemicals. However, some chemicals were tested with either too low concentrations (so no significant effect on the cells growth/death is noticed) or too high concentrations (so the only effect that can be noticed is the rapid cells' death). Consequently, the TCRCs generated after this kind of experiments do not have the features necessary for statistical classification. The main practical motivation of this study was to find a way to determine the lowest concentration of toxin that can kill the cells (i.e. the value of chemical's initial concentration that separate the persistent cells' populations from those that go to extinction).
Once the parameters are estimated, the stability analysis and numerical simulations can provide a range of values for the chemical's initial concentration that give TCRCs with useful features. The asymptotic analysis of the proposed model shows that persistence occurs if the initial concentration of chemical is smaller than a certain threshold. For the persistent trajectories, the cell index tends toward the nominal carrying capacity of the population, and the internal and external chemical concentrations tend toward zero. Extinction depends on the initial concentration of toxicant and the entire past history of the population. The extinction behavior is more complex because when the cell index tends to zero, the internal and external toxicant concentrations can approach an infinite number of limiting values.
We illustrate this analytical and numerical analysis for monastrol, but the proposed model based on first order kinetics gives accurate predictions for the TCRCs corresponding to the 63 chemicals considered in this study. However, there might be limitations for different experimental settings or chemicals with different MOA.
We plan to further extend this study using uncertainty quantification methods. Although the proposed model was validated by experimental data, parameter uncertainty is inherent. To account for parameter uncertainty and calculate the probability of extinction, we have considered random perturbation of parameters' values, we have done Monte Carlo simulations, and we have calculated the Sobol's GSA indices to find out which parameters are important and sensitive to change. Based on the results of the GSA we plan to introduce a model with random parameters, for example to consider a system of stochastic differential equations similar with the ones in [15,16].
This work was supported by a Mathematics of Information Technology and Complex Systems (MITACS) Accelerate Clusters grant and by a grant from the Natural Sciences and Engineering Research Council of Canada.
Let
dn(t)dt=(β−αλ21CE∗η21)n(t)−βn(t)2K−αy1(t)n(t)dy1(t)dt=λ21z1(t)−η21y1(t)dz1(t)dt=CE∗(−η21η22+λ21λ22)n(t)η21+λ22y1(t)n(t)−η22z1(t)n(t). | (16) |
The diagonal form of this system is
dxdt=−(αCE∗λ21−βη21)η21x+F1(x,y,z)dydt=−η21y+F2(x,y,z)dzdt=F3(x,y,z) | (17) |
where the new variables are
x=CE∗(η21η22−λ21λ22)(αCE∗λ21−βη21)ny=(η21η22−λ21λ22)CE∗λ21(αCE∗λ21−η41−βη21)η21n+y1−λ21η21z1z=CE∗(η21η22−λ21λ22)(αCE∗λ21−βη21)n+z1, |
and the non-linear terms are of the form
x=h(z)=a1z2+a2z3+…y=g(z)=b1z2+b2z3+…. | (18) |
To determine the coefficients
F3(h(z),g(z),z)D[h(z)g(z)]−[−(αCE∗λ21−βη21)η21h(z)+F1(h(z),g(z),z)−η21g(z)+F2(h(z),g(z),z)]=0 | (19) |
Simple, but long calculations give
dxdt=−(αCE∗λ21−βη21)η21xdydt=−η21ydzdt=0. | (20) |
and, in terms of the initial variables, the local center manifold is the line
Before we give the proofs for the lemma and theorem included in section 3, we notice that the we have the following formulas for the solutions of system (5) (see also [4]). Since equations (3) and (4) are linear we have
C0(t)=λ21e−η21t∫t0CE(s)eη21sdsCE(t)=CE(0)exp(−η22∫t0n(s)ds)+λ22exp(−η22∫t0n(s)ds) | (21) |
∫t0C0(s)n(s)exp(η22∫s0n(l)dl)ds,t≥0. | (22) |
Equation (2) is a Bernoulli equation, so we get
n(t)=n(0)exp(βt−α∫t0C0(s)ds)1+n(0)βK∫t0exp(βs−α∫s0C0(l)dl)ds,t≥0. | (23) |
Assume that there exists
From (21) we get for any
0≤C0(t)=λ21e−η22t∫t0CE(s)eη21sds≤λ21e−η22tCE(0)∫t0eη21sds=λ21CE(0)η21(1−e−η21t)≤λ21CE(0)η21 |
Thus, for any
0≤∫t0C0(s)ds≤λ21CE(0)tη21<∞ | (24) |
and from equation (23) we have
CE(t)≥CE(0)exp(−η22∫t0n(s)ds)>0, | (25) |
so
Moreover, if
dCEdt|t=T=λ22C0(T)n(T)−η22CE(T)n(T)≤CE(0)n(T)(λ21λ22η21−η22)<0 | (26) |
So there exists
Thus, we have proved that
Since from Lemma 3.1 we know that
If
∫t0C0(s)n(s)exp(η22∫s0n(l)dl)ds≤λ21CE(0)η21exp(η22|n|1)|n|1, | (27) |
so
limt→∞CE(t)=CE(0)exp(−η22|n|1)+λ22Mexp(−η22|n|1)<∞. | (28) |
Consequently, there exists
∫t0CE(s)eη21sds≥∫tT1CE(s)eη21sds≥CE(0)exp(−η22|n|1)/2∫tT1eη21sds. |
So we can apply L'Hospital rule in (21), and we get
limt→∞C0(t)=λ21η21limt→∞CE(t). | (29) |
Thus, if
Next we consider the case when
0≤λ22η22lim inft→∞C0(t)≤lim inft→∞CE(t)≤lim supt→∞CE(t)≤λ22η22lim supt→∞C0(t) | (30) |
Similarly, from (21) we either get that
0≤λ21η21lim inft→∞CE(t)≤lim inft→∞C0(t)≤lim supt→∞C0(t)≤λ21η21lim supt→∞CE(t), | (31) |
(if
limt→∞C0(t)=limt→∞CE(t)=0, | (32) |
because
In conclusion, we have shown that in both cases
To prove the first part of the theorem we first show that if
limt→∞exp(βt−α∫t0C0(s)ds)=∞,limt→∞∫t0exp(βs−α∫s0C0(l)dl)ds=∞ |
Hence, from L'Hospital rule in (23) we have
0≤limt→∞n(t)=K(β−αlimt→∞C0(t))β | (33) |
If
Next, if
limt→∞exp(βt−α∫t0C0(s)ds)=0. |
Thus
0<n(t)≤n(0)exp(βt−α∫t0C0(s)ds). |
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Symbol | Definition |
cell index ≈ cell population | |
toxicant concentration inside the cell | |
toxicant concentration outside the cell | |
cell growth rate in the absence of toxicant | |
capacity volume | |
effect coefficient of toxicant on the cell's growth | |
the uptake rate of the toxicant from environment | |
the toxicant uptake rate from cells | |
the toxicant input rate to the environment | |
the losses rate of toxicant absorbed by cells |
Initialize the model parameters |
Repeat until the log likelihood has converged |
The E step |
For k=1 to N |
Run the UF filter to compute |
For k=N to 1 |
Calculate the smoothed values |
The M step |
Update the values of the parameters |
Toxicant | Cluster | β | K | |||||
PF431396 | Ⅹ | 0.077 | 21.912 | 0.273 | 0.058 | 0 | 0.008 | 0.238 |
monastrol | Ⅹ | 0.074 | 18.17 | 0.209 | 0.177 | 0.204 | 0.5 | 0.016 |
ABT888 | Ⅰ | 0.083 | 17.543 | 0.079 | 0.177 | 0.205 | 0.5 | 0.005 |
HA1100 hydrochloride | Ⅰ | 0.077 | 21.913 | 0.143 | 0.0098 | 0.0786 | 0.147 | 0.351 |
Symbol | Definition |
cell index ≈ cell population | |
toxicant concentration inside the cell | |
toxicant concentration outside the cell | |
cell growth rate in the absence of toxicant | |
capacity volume | |
effect coefficient of toxicant on the cell's growth | |
the uptake rate of the toxicant from environment | |
the toxicant uptake rate from cells | |
the toxicant input rate to the environment | |
the losses rate of toxicant absorbed by cells |
Initialize the model parameters |
Repeat until the log likelihood has converged |
The E step |
For k=1 to N |
Run the UF filter to compute |
For k=N to 1 |
Calculate the smoothed values |
The M step |
Update the values of the parameters |
Toxicant | Cluster | β | K | |||||
PF431396 | Ⅹ | 0.077 | 21.912 | 0.273 | 0.058 | 0 | 0.008 | 0.238 |
monastrol | Ⅹ | 0.074 | 18.17 | 0.209 | 0.177 | 0.204 | 0.5 | 0.016 |
ABT888 | Ⅰ | 0.083 | 17.543 | 0.079 | 0.177 | 0.205 | 0.5 | 0.005 |
HA1100 hydrochloride | Ⅰ | 0.077 | 21.913 | 0.143 | 0.0098 | 0.0786 | 0.147 | 0.351 |