Citation: Siddhartha Mishra. A machine learning framework for data driven acceleration of computations of differential equations[J]. Mathematics in Engineering, 2019, 1(1): 118-146. doi: 10.3934/Mine.2018.1.118
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Differential dynamic systems with time delays play an important role in the modeling of real-life phenomena in various fields of applications. There exists an extensive literature on delay differential models in biology and biomedicine; see e.g., [6,7,16,18,24,26,27]. Though there is a vast literature on optimal control problems with time delays in control and state variables, so far only a few papers have applied the framework of optimal control with delays to biomedicine; cf. the recent papers [15,21,23]. The aim of this paper is to present two case studies in biomedicine which illustrate the application of delayed optimal control problems and demonstrate that there exist efficient numerical techniques to solve such problems.
In Section 2, we consider optimal control problems with multiple time delays in control and state variables The control process can be subject to mixed control-state constraints. We review the necessary optimality conditions that were derived in [10] in the form of a Pontryagin type Minimum Principle. It is assumed that the so-called commensurability assumption holds which requires that the time delays and the terminal time are integer multiples of a joint stepsize. This assumption also underlies the discretization and nonlinear programming techniques that are briefly reviewed in Section 3. In Section 4, we study the delay differential model for tumour-immune-response with chemo-immunotherapy in Rihan et al. [21]. Aside from the state delay in this model we introduce a time delay in the control variable representing the immune therapy. The delay accounts for the fact that the human immune system needs some time to respond to the immune therapy. In contrast to the
Section 5 considers the delay differential model in [7] describing the spread of Hepatitis B virus (HBV). The dynamical model exhibits a delay in the state variables. We introduce a control variable into this model and formulate an optimal control problem using
Let
0=:τ0<τ1<…<τd. |
Thus
J(x,u)=g(x(tf)) | (1) |
subject to the delayed (retarded) differential equation, boundary conditions and mixed control-state inequality constraints
˙x(t)=f(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd)),a.e. t∈[0,tf], | (2) |
x(t)=x0(t), t∈[−τd,0], | (3) |
u(t)=u0(t), t∈[−τd,0), | (4) |
ψ(x(T))=0, | (5) |
C(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd))≤0,a.e. t∈[0,tf]. | (6) |
The functions
Without lack of generality we have assumed that the cost functional is given in Mayer form (1). It is well known that an objective in Bolza form,
J(x,u)=g(x(tf))+tf∫0L(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd))dt, |
can be reduced to Mayer form by introducing an additional state variable
˙xn+1(t)=L(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd)), xn+1(0)=0. |
Then we have to minimize the functional
In the following, we shall use the placeholder variables
yδ(t)=x(t−τδ), vδ(t)=u(t−τδ) (δ=0,1,…,d). | (7) |
Note that we do not necessarily assume an equal number of state and control delays. The case of an unequal number of delays in state and control variables is included in this formulation as we admit that
∂h∂yδ=0 or ∂h∂vδ=0, h∈{f,C,L}, for some δ∈{0,…,d}. |
A Pontryagin-type minimum principle for problem (MDOCP) has been derived in [9,10]. The main result requires that all positive time delays
Assumption 2.1 (Commensurability Condition). Assume that there exist a constant
τδ=kδh(δ=1,…,d) and tf=Nh. | (8) |
In view of
H(t,y0,…,yd,v0,…,vd,λ)=λf(t,y0,…,yd,v0,…,vd), λ∈Rn, | (9) |
where the adjoint variable
H(t,y0,…,yd,v0,…,vd,λ,μ)=H(t,y0,…,yd,v0,…,vd,λ)+μC(t,y0,…,yd,v0,…,vd). | (10) |
For ease of notation we refrain from denoting an optimal pair
(x,u)∈W1,∞([0,tf],Rn)×L∞([0,tf],Rm) |
by a hat or a similar symbol. We require the following regularity condition for the active control-state constraints.
Assumption 2.2 (Regularity Condition). Let
J0(t):={j∈{1,…,p}|Cj(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd))=0} |
denote the set of active indices for the inequality constraints (6). Assume that the gradients
∂Cj(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd))∂(v0,…,vd), j∈J0(t), | (11) |
are linearly independent.
The following theorem summarizes the first-order necessary conditions for optimality for the control problem (MDOCP) [10].
Theorem 2.3. (Minimum Principle for Optimal Control Problems with Multiple Time-Delays [10]): Let
1. Advanced Adjoint Differential Equation:
˙λ(t)=−d∑δ=0χ[0,tf−τδ](t)Hyδ(t+τδ), | (12) |
where
2. Transversality Condition:
λ(tf)=λ0gx(x(tf))+νψx(x(tf)). | (13) |
3. Minimum Condition for the Hamiltonian:
d∑δ=0χ[0,tf−τδ](t)H[t+τδ]≤H(t,…,u,u(t−τ1),…,u(t−τd),λ(t)) +d−1∑δ=1χ[0,tf−τδ](t)H(t+τδ,…,u(t+τδ−τδ−1),u,u(t+τδ−τδ+1),…) +χ[0,tf−τd](t)H(t+τd,…,u(t+τd−τ1),…,u(t+τd−τd−1),u,λ(t)) | (14) |
for all
C(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τδ−1),u,u(t−τδ+1),…,u(t−τd))≤0 for δ=0,…,d, |
where
4. Local Minimum Condition for the Augmented Hamiltonian Function:
d∑δ=0χ[0,tf−τδ](t)Hvδ[t+τδ]=0. | (15) |
5. Non-negativity of Multiplier and Complementarity Condition: for
μ(t)≥0,μ(t)C(t,x(t−τ0),…,x(t−τd,u(t−τ0),…,u(t−τd))=0. | (16) |
Similar to the case of non-delayed differential equations, we can employ integration methods of Runge-Kutta type or multistep methods, e.g., the Euler method and trapezoidal rule, to discretize the delay differential equation
˙x(t)=f(t,x(t−τ0),…,x(t−τd),u(t−τ0),…,u(t−τd)). |
Any integration method based on an equidistant discretization scheme utilizes a uniform step size
τδ=kδh (δ=0,…,d), tf=Nh, |
with integers
Let
fi=f(ti,xi,xi−k1,…,xi−kδ,ui,ui−k1,…,ui−kδ). |
The initial value profiles
x−i=x0(−ih) (i=0,..,kd), u−i=u0(−ih) (i=1,..,kd). | (17) |
Since the focus in this paper is not on discussing various numerical methods, we present only two integration methods that can be easily implemented. The simplest method is the first order method of Euler which is defined by the recursion
xi+1=xi+hfi, i=0,1,…,N−1. | (18) |
The trapezoidal rule is an implicit method of second order:
xi+1=xi+12h(fi+fi+1), i=0,1,…,N−1. | (19) |
Then for the Euler method and the optimization variable
z:=(u0,x1,u1,x2,...,uN−1,xN)∈RN(m+n) |
we obtain the following nonlinear programming problem (NLP) with equality and inequality constraints:
Minimize J(z)=g(xN) | (20) |
subject to
xi+1=xi+hf(ti,xi−k0,…,xi−kd,ui−k0,…,ui−kd), i=0,…,N−1, | (21) |
C(ti,xi−k0,…,xi−kd,ui−k0,…,ui−kd)≤0, i=0,…,N−1, | (22) |
ψ(xN)=0, | (23) |
and initial values (17). Using the trapezoidal method (19) we simply replace the equations (21) by the equations defined in (19).
Let
λ(ti)≈λi∈Rn, μ(ti)≈μi/h∈Rp (i=0,...,N−1), νN≈ν. | (24) |
This follows from the fact that the Lagrange multipliers
To solve the optimization problem (NLP) in (20)-(22) numerically, we employ the Applied Modeling Programming Language (AMPL) developed by Fourer, Gay and Kernighan [8] which can be linked to the interior-point optimization solver IPOPT developed by Wächter et al. [28] or to the SQP solver WORHP by Büskens and Gerdts [4]. Every solver provides the Lagrange multipliers and therefore gives access to approximations of adjoint variables and multiplier functions for the control problem (MDOCP) according to (24). Thus we can test whether the numerical solution is an extremal solution which satisfies the necessary optimality conditions in Theorem 2.3.
We consider the delay differential model in Rihan et al. [21] that proposes a chemo-immuno-therapy of cancer. The authors introduce a time delay only in the state variable and present a stability analysis of drug free steady states. We shall extend the model by including also a control delay in the control
Denoting the state delay by
˙E(t)=σ+(ρη+T(t−τ1)−μe)E(t−τ1)T(t−τ1)−(δ+a1(1−e−U(t)))E(t)+u2(t−τ2)s1,˙T(t)=(r2(1−βT(t))−nTE(t)−c1N(t)−a2(1−e−U(t)))T(t),˙N(t)=(r3(1−β2N(t))−c2T(t)−a3(1−e−U(t)))N(t),˙U(t)=u1(t)−d1U(t). | (25) |
The initial values and initial functions for the delayed state and control variables are as follows:
E(0)=E0=0.3,E(t)=E0∀−τ1≤t≤0,T(0)=T0=300,T(t)=T0∀−τ1≤t≤0,N(0)=N0=0.9,u2(t)=0∀−τ2≤t<0.U(0)=U0=0.0. | (26) |
We shall consider the control constraints
0≤uk(t)≤uk,max ∀t∈[0,tf] (k=1,2). | (27) |
Let us denote the state and control variables by
x=(E,T,N,U)∈R4, u=(u1,u2)∈R2. |
For notational convenience, we simplify the notations (7) for the delayed state and control variables. In the context of the dynamical system (25) it is more convenient to consider the delayed state variables
y1(t)=x1(t−τ1)=E(t−τ1),y2(t)=x2(t−τ1)=T(t−τ1),v2(t)=u2(t−τ2). | (28) |
With these notations the dynamical system (25) can be written as
˙x(t)=f(x(t),y1(t),y2(t),u(t),v2(t)). | (29) |
Then the optimal control problem is as follows: determine a control function
Jp(x,u)=∫tf0(T(t)−E(t)+B1(u1(t))p+B2(u2(t))p)dt (p=1,2) | (30) |
subject to the dynamic constraints (25), initial conditions (26) and control constraints (27). The objective functional (30) represents a trade-off between minimizing the tumour cells and the total doses of the cytotoxic and immunologic agents on one hand and maximizing the plasma cells on the other hand. The constants
Parameter | Description | Value |
final time | ||
|
state delay | |
|
control delay | |
|
control bounds | |
|
cell kill rate response | |
|
reciprocal carrying capacities of tumour and host cells | |
|
scaling parameters | |
|
drug decay rate | |
|
immune cell death rate | |
|
steepness of immune response | |
|
uninfected effector cell decrease rate | |
|
immune cell influx and decay rate resp. | |
|
cell growth rates | |
|
immune effector cell decrease rate | |
|
weights |
Rihan et al. [21] consider only the
Now we apply the necessary optimality conditions in the form of a Minimum Principle as stated in Theorem 2.3. Denoting the adjoint variable by the row vector
H(x,y1,y2,u,v2,λ)=T−E+B1u1+B2u2+λf(x,y1,y2,u,v2). | (31) |
According to Theorem 2.3 (1), the advanced adjoint equations are given by
˙λE(t)=−HE[t]−χ[0,tf−τ1](t)Hy1[t+τ1],˙λT(t)=−HT[t]−χ[0,tf−τ1](t)Hy2[t+τ1],˙λN(t)=−HN[t],˙λU(t)=−HU[t]. | (32) |
We do not write out the adjoint variables explicitly, since the adjoint variables can be computed as Lagrange multipliers of the discretized control problem as explained in the preceding section. Due to the free terminal state, the transversality condition (13) is
λ(tf)=(0,0,0,0). | (33) |
The optimal control
ϕ1(t)=Hu1[t]=B1+λU(t),ϕ2(t)=Hu2(t)+χ[0,tf−τ2](t)Hv2[t+τ2]=B2+χ[0,tf−τ2](t)λE(t+τ2)s1, | (34) |
according to the control law
uk(t)={0,ifϕk(t)>0uk,max,ifϕk(t)<0singular,ifϕk(t)=0∀t∈Is⊂[0,tf]}, k=1,2. | (35) |
Singular controls will not be discussed further, since our computations only yield bang-bang controls. Due to the transversality condition
First, we present the solution for the non-delayed control problem with
uk(t)={1for0≤t<tk0fortk≤t≤tf} (k=1,2), 0<t1<t2<tf. | (36) |
To obtain a refinement of the solution, we solve the Induced Optimization Problem (IOP) with the switching times
J1(x,u)=1399.02,t1=3.93031,t2=9.76562,E(tf)=0.640303,T(tf)=0.180726,N(tf)=0.904968,U(tf)=2.96962. |
The initial values of the adjoint variables are
λE(0)=−770.13,λT(0)=2.9980,λN(0)=−0.027548,λU(0)=−281.11. |
The non-delayed solution is shown in Figure 1. A common strategy in medical practise is the administration of a pulse therapy or a blockwise application of drugs. Such a strategy is promoted by the controls in Figure 1.
Now we show that the second-order sufficient conditions in [19], Chapter 7, are satisfied for the bang-bang control (36). For that purpose, we have to check two further conditions. First, notice that the objective
D2J1(t1,t2)=(19.16711.12011.12010.887). |
Furthermore, as can be seen in Figure 2, the following strict bang-bang property with respect to the Minimum Principle holds for
ϕk(t)<0 ∀0≤t<tk, ˙ϕk(tk)>0, ϕk(t)>0 ∀tk<t≤tf. | (37) |
Hence, the solution shown in Figure 1 provides a strict strong minimum.
We briefly compare the solutions for the functionals
E(tf)=0.615728,T(tf)=0.108124,N(tf)=0.903899,U(tf)=3.20922. |
We choose the state delay
uk(t)={1for0≤t<tk0fortk≤t≤tf} (k=1,2), 0<t1<t2<tf. | (38) |
We obtain the numerical results
J1(x,u)=2126.69,t1=4.692,t2=10.42,E(tf)=0.661258,T(tf)=0.136262,N(tf)=0.902747,U(tf)=3.55546. |
The initial values of the adjoint variables are
λE(0)=−485.41,λT(0)=2.2403,λN(0)=−0.022090,λU(0)=−248.50. |
Using the Euler method (18) with the same number
Finally, as in the non-delayed case we briefly compare the solutions for the functionals
We add the following mixed control-state constraint to the delayed optimal control problem:
U(t)+u2(t)≤3 ∀t∈[0,tf]. | (39) |
This constraint means that sum of the cytotoxic agent and the immune dose is bounded from above. Here we consider the augmented Hamiltonian
H(x,y1,y2,u,v2,λ,μ)=H(x,y1,y2,u,v2,λ)+μ(U+u2), | (40) |
where the mixed constraint is adjoined to the Hamiltonian (31) by a multiplier
0=Hu2[t]+χ[0,tf−τ2](t)Hv2[t+τ2]=ϕ2(t)+μ(t), | (41) |
where
μ(t)=−ϕ2(t)=−B2−χ[0,tf−τ2](t)λE(t+τ2)s1 ∀t∈[t1,t2]. | (42) |
Computations show that the control
0=˙U(t)=u1(t)−d1U(t)=u1(t)−d1(3−u2(t)). |
Since we have
u1(t)=d1(3−u2(t))=0.02 (d1=0.01). |
Using the trapezoidal method (19) with
u1(t)={1for0≤t<t10.02fort1≤t<t20fort2≤t≤tf}, u2(t)={1for0≤t<t30fort3≤t≤tf} | (43) |
with
J1(x,u)=2236.06,t1=2.045,t2=9.95,t3=10.98,E(tf)=0.725265,T(tf)=0.100546,N(tf)=0.919108,U(tf)=1.63720. |
Eikenberry et al. [7] report that currently about two billion people - roughly
x: number of healthy cells,p: number of exposed cells,y: number of infected cells,v: free virion load. |
The model (4.1)-(4.4) in [7] does not yet involve a control variable. We choose the control variable
˙x(t)=rx(t)(1−T(t)K)−dx(t)−βv(t)x(t)T(t),˙p(t)=−dp(t)+βv(t)x(t)T(t)−βe−dτv(t−τ)x(t−τ)T(t−τ),˙y(t)=βe−dτv(t−τ)x(t−τ)T(t−τ)−ay(t),˙v(t)=k(1−u(t))y(t)−μy(t). | (44) |
The variable
T=x+p+y. |
The delay
x(t)=x0,p(t)=p0,y(t)=y0 for −τ≤t≤0, v(0)=v0. | (45) |
We impose the control constraint
0≤u(t)≤1 ∀t∈[0,tf]. | (46) |
Denoting the state vector by
˙X=f(X,Y,u) | (47) |
with initial functions and conditions given in (45).
The optimal control problem then consists in determining a control function
J(X,u)=∫tf0(−x(t)+Bu(t))dt (B>0), | (48) |
subject to the dynamics (44) with initial conditions (45) and the control constraint (46). The objective functional represents a trade-off between maximizing the number of healthy cells and minimizing the treatment cost.
We briefly discuss the necessary optimality conditions in Theorem 2.1. The Hamiltonian is given by
H(X,Y,u,λ)=−x+Bu+λf(X,Y,u), λ=(λx,λp,λy,λv)∈R4. | (49) |
We do not explicitly write out the advanced adjoint equation (12):
˙λ(t)=−HX[t]−χ[0,tf−τ](t)HY[t+τ]. | (50) |
The control variable
ϕ(t)=Hu[t]=B−λv(t)ky(t), | (51) |
the minimizing control is characterized by the control law
u(t)={0,ifϕ(t)>01,ifϕ(t)<0singular,ifϕ(t)=0∀t∈Is⊂[0,tf]}. | (52) |
Singular controls will not be discussed further, because we only found bang-bang controls. The following parameters from [7], page 294 below, will be used in our computations:
a=0.011,d=0.0039,β=4.8⋅10−5,k=200,K=2,r=1,μ=0.693. | (53) |
The state variable
x(t)=1.4, p(t)=0.3, y(t)=0.2 ∀−τ≤t≤0, v(0)=500. | (54) |
The time horizon is
We compare the solutions for the delays
u(t)={1for0≤t<t10fort1≤t≤tf}. | (55) |
In the non-delayed case, a refinement of the solution is obtained by solving the Induced Optimization Problem (IOP) with respect to the switching time [17,19]. We get the numerical results:
τ=0:J(X,u)=893.072,t1=261.70,τ=10:J(X,u)=913.388,t1=293.50,τ=15:J(X,u)=923.032,t1=304.10. |
A comparison of the controls and switching functions for the delays
ϕ(t)<0 for0≤t<t1, ˙ϕ(t1)>0, ϕ(t)>0 fort1<t≤tf=500. |
Note that the strict bang-bang property is also satisfied for the delayed control with delays
We presented two applications of delayed optimal control problems in biomedicine. In the first case study, we extended the delay differential model of tumour-immune-response in Rihan et al. [21] by including a time delay in the control variable
Therefore, we improved the results in this paper in two regards. First, we considered a more realistic
The second delay differential model, which describes the spread of Hepatitis B virus, was taken from Eikenberry at al. [7]. We introduced a control variable into the originally uncontrolled model and considered
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Parameter | Description | Value |
final time | ||
|
state delay | |
|
control delay | |
|
control bounds | |
|
cell kill rate response | |
|
reciprocal carrying capacities of tumour and host cells | |
|
scaling parameters | |
|
drug decay rate | |
|
immune cell death rate | |
|
steepness of immune response | |
|
uninfected effector cell decrease rate | |
|
immune cell influx and decay rate resp. | |
|
cell growth rates | |
|
immune effector cell decrease rate | |
|
weights |
Parameter | Description | Value |
final time | ||
|
state delay | |
|
control delay | |
|
control bounds | |
|
cell kill rate response | |
|
reciprocal carrying capacities of tumour and host cells | |
|
scaling parameters | |
|
drug decay rate | |
|
immune cell death rate | |
|
steepness of immune response | |
|
uninfected effector cell decrease rate | |
|
immune cell influx and decay rate resp. | |
|
cell growth rates | |
|
immune effector cell decrease rate | |
|
weights |