ODE/PDE Analysis of Multiple Myeloma-Programming

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 ODE/PDE Analysis
of Multiple Myeloma
 ODE/PDE Analysis
of Multiple Myeloma
Programming in R

William E. Schiesser
First edition published 2020
by CRC Press
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Library of Congress Cataloging. in. Publication Data

Names: Schiesser, W. E., author.

Title: ODE/PDE analysis of multiple myeloma : programming in R / William E. Schiesser.
Description: First edition. | Boca Raton, FL : CRC Press, 2020. | Includes bibliographical
references and index. | Summary: “The intent of this book is to present a methodology
for the formulation and computer implementation of mathematical models for multiple
myeloma, a form of bone cancer. The models are stated as systems of ordinary and partial
differential equations (ODE/PDEs). The ODE/PDE methodology is presented through
a series of examples, starting with a basic ODE model in chapter 1, and concluding
with a detailed ODE/PDE model in chapter 4 that gives the spatiotemporal distribution
of four components in the bone marrow and peripheral blood. The computer-based
implementation of the example models is presented through routines coded (programmed)
in R, a quality, open-source scientific computing system that is readily available from
the Internet. Formal mathematics is minimized, e.g., no theorems and proofs. Rather,
the presentation is through detailed examples that the reader/researcher/analyst can
execute on modest computers. The PDE analysis is based on the method of lines (MOL),
an established general algorithm for PDEs, implemented with finite differences. The
routines are available from a download link so that the example models can be executed
without having to first study numerical methods and computer coding. The routines can
then be applied to variations and extensions of the multiple myeloma models,
such as changes in the ODE/PDE parameters (constants) and form of the model
equations.”-- Provided by publisher.
Identifiers: LCCN 2020000933 | ISBN 9780367471354 (hardback) | ISBN
9780367473549 (ebook)
Subjects: LCSH: Multiple myeloma--Mathematical models. | Numerical
analysis--Computer programs. | R (Computer program language)
Classification: LCC RC280.B6 S34 2020 | DDC 616.99/418--dc23
LC record available at https://lccn.loc.gov/2020000933

ISBN: 978-0-367-47135-4 (hbk)

ISBN: 978-0-367-49551-0 (pbk)
ISBN: 978-0-367-47354-9 (ebk)

Typeset in Times
by Lumina Datamatics Limited

Visit the companion website: https://www.lehigh.edu/~wes1/dpde_download/

Visit the e-Resources: https://routledge.com/9780367471354
 To Anne Drennan and Gary Kohler,
with deep appreciation for your support.
Contents

Preface ......................................................................................................ix

Author.......................................................................................................xi

Chapter 1 Introductory ODE Model.............................................1

(1) Introduction................................................................1
(1.1) ODE model .....................................................2
(1.1.1) Main program for the ODE model ...4
(1.1.2) ODE routine ...................................11
(1.1.3) Numerical, graphical output...........14
(1.2) Summary and conclusions .............................15
References .........................................................................17

Chapter 2 Basic PDE Model ........................................................19

(2) Introduction..............................................................19
(2.1) PDE model....................................................19
(2.1.1) Main program.................................21
(2.1.2) ODE/MOL routine.........................31
(2.1.3) Numerical, graphical output...........37
(2.2) Summary and conclusions .............................47
References .........................................................................47

Chapter 3 PDE Model with External Transfer ......................... 49

(3) Introduction..............................................................49
(3.1) ODE/PDE model ..........................................49
(3.1.1) Main program.................................50
(3.1.2) ODE/MOL routine.........................52
(3.1.3) Numerical, graphical output...........60
(3.2) Summary and conclusions .............................70
References .........................................................................70

Chapter 4 ODE/PDE Model Parameter Analysis .................... 71

(4) Introduction..............................................................71
(4.1) ODE/PDE model with variable diffusivity ...71
(4.1.1) Main program.................................74
(4.1.2) ODE/PDE routine .........................75
(4.1.3) Subordinate routines ......................83
(4.1.4) Numerical, graphical output...........84
(4.2) Summary and conclusions .............................90

vii
viii Contents

Chapter 5 Detailed Analysis of PDEs in ODE/PDE Model... 93

(5) Introduction..............................................................93
(5.1) PDE LHS analysis.........................................93
(5.1.1) Main program for PDE LHS
analysis ...........................................93
(5.1.2) ODE/MOL routine....................... 104
(5.1.3) Numerical, graphical output......... 108
(5.2) PDE RHS analysis ...................................... 113
(5.2.1) Main program for N (r,t)
PDE RHS analysis........................ 113
(5.2.2) Graphical output .......................... 118
(5.3) Summary and conclusion............................. 125

dss044.......................................... 127
Appendix A1: Functions dss004, dss044

Index ...................................................................................................... 133

Preface
Multiple myeloma is a cancer of the bone marrow plasma cells. Normal plasma
cells are an important part of the immune system.
Mathematical models for multiple myeloma based on ordinary and partial
differential equations (ODE/PDEs) are presented in this book, starting with
a basic ODE model in Chapter 1, and concluding with a detailed ODE/PDE
model in Chapters 4 and 5 that gives the spatiotemporal distribution of four
dependent variable components in the bone marrow and peripheral blood: (1)
protein produced by multiple myeloma cells, termed the M protein, (2) cyto-
toxic T lymphocytes (CTLs), (3) natural killer (NK ) cells, and (4) regulatory
T cells (Tregs ).
The computer-based implementation of the example models is presented
through routines coded (programmed) in R, a quality, open-source scientific
computing system that is readily available from the Internet. Formal math-
ematics is minimized, e.g., no theorems and proofs. Rather, the presentation
is through detailed examples that the reader/researcher/analyst can execute
on modest computers. The PDE analysis is based on the method of lines
(MOL), an established general algorithm for PDEs, implemented with finite
differences.
The routines are available from a download link (https://www.routledge.
com/9780367471354) so that the example models can be executed without
having to first study numerical methods and computer coding. The routines
can then be applied to variations and extensions of the multiple myeloma
models, such as changes in the ODE/PDE parameters (constants) and form
of the model equations.
The author would welcome comments/suggestions concerning this
approach to multiple myeloma analysis (directed to [email protected]).

William E. Schiesser
Bethlehem, PA

ix
Author
William E. Schiesser is the Emeritus McCann Professor in the chemical and
biomolecular engineering department at Lehigh University as well as a former
professor in the mathematics department. He recently authored several books
on computer-based solutions to model real-life phenomena, such as the devel-
opment of Parkinson’s disease. He holds a PhD from Princeton University and
an honorary ScD from the University of Mons, Belgium. He is the author or
co-author of a series of books in his field of research on numerical methods and
associated software for ordinary, differential-algebraic and partial differential
equations (ODE/DAE/PDEs) and the development of mathematical models
based on ODE/DAE/PDEs.

xi
 1 Introductory ODE Model
(1) Introduction

The following background statement from [1] defines the term multiple
myeloma:

Multiple myeloma is a cancer of plasma cells. Normal plasma cells

are found in the bone marrow and are an important part of the im-
mune system. The immune system is made up of several types of cells
that work together to fight infections and other diseases. Lymphocytes
(lymph cells) are one of the main types of white blood cells in the im-
mune system and include T cells and B cells. Lymphocytes are in many
areas of the body, such as lymph nodes, the bone marrow, the intestines,
and the bloodstream.
When B cells respond to an infection, they mature and change into
plasma cells. Plasma cells make the antibodies (also called immunoglob-
ulins) that help the body attack and kill germs. Plasma cells, are found
mainly in the bone marrow. Bone marrow is the soft tissue inside bones.
In addition to plasma cells, normal bone marrow is also the home for
other blood cells such as red cells, white cells, and platelets.
In general, when plasma cells become cancerous and grow out of
control, this is called multiple myeloma. The plasma cells make an ab-
normal protein (antibody) known by several different names, including
monoclonal immunoglobulin, monoclonal protein (M-protein), M-spike,
or paraprotein.

As further background, multiple myeloma (M M ) is a cancer of plasma

blood cells [1]. The M M model discussed initially in Chapter 1 [1,2] defines
as a function of time the concentrations in the blood stream of: (1) protein
produced by M M cells, termed the M protein, (2) cytotoxic T lymphocytes
(CT Ls), (3) natural killer (N K) cells, and (4) regulatory T cells (Tregs ).
CTLs, NK cells, and Tregs are the immune system’s response to the M M
cells.

1
2 ODE/PDE Analysis of Multiple Myeloma

The initial model consists of four ordinary differential equations (ODEs).

The solution to the ODEs is computed with a library routine for initial value
ODEs available in R1 . The R routines that implement the model are next
listed and discussed in detail.
The routines are also available through a download link so that the
reader/analyst/researcher can access them to confirm the reported solutions.
The routines can then be modified and extended for computer-based experi-
mentation with the model.
The ODE model is extended to a system of partial differential equations
(PDEs) in subsequent chapters to define the spatiotemporal distribution of
(1)–(4) in the bone marrow where the cancer originates, and in the peripheral
blood.

(1.1) ODE model

The 4 × 4 (four ODEs in four unknows) model is stated as eqs. (1.1).

 
dM M
= sM + rM 1− M
dt KM
  
aN M N aCM TC N TC
−δM 1 + + + aCN M · ·
bN M + N bCM + TC bN M + N bCM + TC
 
aM M M aRM TR
1− − ·M (1.1-1)
bM M + M bRM + TR

  
dTC TC aM C M aN C N
= rC 1− 1+ + T C − δC TC (1.1-2)
dt KC bM C + M bN C + N

  
dN N aCN TC
= sN + rN 1− 1+ N − δN N (1.1-3)
dt KN bCN + TC

  
dTR TR aM R M
= rR 1 − 1+ T R − δR TR (1.1-4)
dt KR bM R + M

1 R is a quality open source scientific computing system that is available from the
Internet [4].
Introductory ODE Model 3

The dependent variables of eqs. (1.1) are listed in Table 1.1.

Table 1.1: Dependent variables of eqs. (1.1)

M (t) protein produced by M M cells
TC (t) cytotoxic T lymphocytes (CT Ls)
N (t) natural killer (N K) cells
TR (t) regulatory T cells (Tregs )

A schematic diagram of eqs. (1.1) is given in [2], Figure 1.

Equations (1.1) are first order in t, so each requires one initial
condition (IC).

M (t = 0) = M 0 = 4 (1.2-1)

TC (t = 0) = TC0 = 464 (1.2-2)

N (t = 0) = N 0 = 227 (1.2-3)

TR (t = 0) = TR0 = 42 (1.2-4)

The initial values, 4, 464, 227, 42, are taken from [2], Table 2.
The parameters in eqs. (1.1) are taken from [2], base case of Table 2.

Table 1.2: Parameters of eqs. (1.1)

Eq. (1.1-1)
sM = 0.001 rM = 0.0175 KM = 10
δM = 0.002 aN M = 5 bN M = 150
aCM = 5 bCM = 375 aCN M = 8
aM M = 0.5 bM M = 3 aRM = 0.5
bRM = 25
Eq. (1.1-2)
rC = 0.013 KC = 800 aM C = 5
bM C = 3 aN C = 1 bN C = 150
δC = 0.02
Eq. (1.1-3)
sN = 0.03 rN = 0.04 KN = 450
aCN = 1 bCN = 375 δN = 0.025
Eq. (1.1-4)
rR = 0.0831 KR = 80 aM R = 2
bM R = 3 δR = 0.0757

The nonlinear interaction terms of eqs. (1.1) are explained briefly in

Table 1.3 as in [2], Table 1.
4 ODE/PDE Analysis of Multiple Myeloma

Table 1.3: Brief explanation of the interaction terms of eqs. (1.1)

Term Equation Interaction
 
aN M N
M (1.1-1) N cells kill myeloma cells and
bN M + N
decrease M
 
aCM TC
M (1.1-1) TC cells kill myeloma cells and
bCM + TC
decrease M
 
N TC
aCN M · M (1.1-1) TC increases activation/efficacy of N
bN M + N bCM + TC
 
aM M M
(1.1-1) Myeloma cells decrease efficacy of N
bM M + M
and TC
 
aRM TR
(1.1-1) TR decreases efficacy of N and TC
bRM + TR
 
aM C M
TC (1.1-2) Antigens shed from M stimulate TC
bM C + M
proliferation
 
aN C N
TC (1.1-2) N crosstalk with TC ; boosts TC
bN C + N
proliferation
 
aCN TC
N (1.1-3) TC crosstalk with N ; boosts N
bCN + TC
proliferation
 
aM R M
TR (1.1-4) Myeloma cells boost TR proliferation
bM R + M

The parameters (constants) in Table 1.3 have the numerical values in

Table 1.2.
Equations (1.1), (1.2) constitute the ODE model which are integrated
(solved) numerically with a library initial value ODE integrator, lsodes [4].
The R routines that implement the integration are considered next, starting
with a main program.

(1.1.1) Main program for the ODE model

The main program for eqs. (1.1), (1.2) is in Listing 1.1.

Listing 1.1: Main program for eqs. (1.1), (1.2)

#
# Four ODE MM model
#
# Delete previous workspaces
rm(list=ls(all=TRUE))
(Continued)
Introductory ODE Model 5

Listing 1.1 (Continued): Main program for eqs. (1.1), (1.2)

#
# Access ODE integrator
library("deSolve");
#
# Access functions for numerical solution
setwd("f:/multipleMyeloma/chap1");
source("ode1a.R");
#
# Parameters
#
# Eq. (1.1-1)
sM = 0.001; rM = 0.0175; KM = 10;
delM = 0.002; aNM = 5; bNM = 150;
aCM = 5; bCM = 375; aCNM = 8;
aMM = 0.5; bMM = 3; aRM = 0.5;
bRM = 25;
#
# Eq. (1.1-2)
rC =0.013; KC = 800; aMC = 5;
bMC = 3; aNC = 1; bNC = 150;
delC = 0.02;
#
# Eq. (1.1-3)
sN = 0.03; rN = 0.04; KN = 450;
aCN = 1; bCN= 375; delN = 0.025;
#
# Eq. (1.1-4)
rR = 0.0831; KR = 80; aMR = 2;
bMR = 3; delR = 0.0757;
#
# Independent variable for ODE integration
t0=0;tf=1.0e+03;nout=41;
tout=seq(from=t0,to=tf,by=(tf-t0)/(nout-1));
#
# Initial conditions (t=0)
y0=rep(0,4);
y0[1]=4;
y0[2]=464;

(Continued)
6 ODE/PDE Analysis of Multiple Myeloma

Listing 1.1 (Continued): Main program for eqs. (1.1), (1.2)

y0[3]=227;
y0[4]=42;
ncall=0;
#
# ODE integration
out=lsodes(y=y0,times=tout,func=ode1a,
sparsetype ="sparseint",rtol=1e-6,
atol=1e-6,maxord=5);
nrow(out)
ncol(out)
#
# Arrays for plotting numerical solution
M=rep(0,nout);
TC=rep(0,nout);
N=rep(0,nout);
TR=rep(0,nout);
for(it in 1:nout){
M[it]=out[it,2];
TC[it]=out[it,3];
N[it]=out[it,4];
TR[it]=out[it,5];
}
#
# Display numerical solution
cat(sprintf("\n t M(t) TC(t)
N(t) TR(t)"));
iv=seq(from=1,to=nout,by=2);
for(it in iv){
cat(sprintf("%10.2f %10.3f %10.3f %10.3f %10.3f\n",
tout[it],M[it],TC[it],N[it],TR[it]));
}
#
# Calls to ODE routine
cat(sprintf("\n\n ncall = %5d\n\n",ncall));
#
# Plot ODE solutions
#
# M(t)
plot(tout,M,xlab="time (days)",ylab="M(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");
(Continued)
Introductory ODE Model 7

Listing 1.1 (Continued): Main program for eqs. (1.1), (1.2)

#
# TC(t)
plot(tout,TC,xlab="time (days)",ylab="TC(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");
#
# N(t)
plot(tout,N,xlab="time (days)",ylab="N(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");
#
# TR(t)
plot(tout,TR,xlab="time (days)",ylab="TR(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");

We can note the following details about the main program of Listing 1.1.

• Previous workspaces are deleted.

#
# Four ODE MM model
#
# Delete previous workspaces
rm(list=ls(all=TRUE))

• The R ODE integrator library deSolve is accessed. Then the di-

rectory with the files for the solution of eqs. (1.1), (1.2) is desig-
nated. Note that setwd (set working directory) uses / rather than
the usual \.

#
# Access ODE integrator
library("deSolve");
#
# Access functions for numerical solution
setwd("f:/multipleMyeloma/chap1");
source("ode1a.R");

ode1a.R is the routine with the programming of eqs. (1.1), (1.2).

8 ODE/PDE Analysis of Multiple Myeloma

• The model parameters are specified numerically.

#
# Parameters
#
# Eq. (1.1-1)
sM = 0.001; rM = 0.0175; KM = 10;
delM = 0.002; aNM = 5; bNM = 150;
aCM = 5; bCM = 375; aCNM = 8;
aMM = 0.5; bMM = 3; aRM = 0.5;
bRM = 25;
#
# Eq. (1.1-2)
rC =0.013; KC = 800; aMC = 5;
bMC = 3; aNC = 1; bNC = 150;
delC = 0.02;
#
# Eq. (1.1-3)
sN = 0.03; rN = 0.04; KN = 450;
aCN = 1; bCN= 375; delN = 0.025;
#
# Eq. (1.1-4)
rR = 0.0831; KR = 80; aMR = 2;
bMR = 3; delR = 0.0757;

• An interval in t of 41 points is defined for 0 ≤ t ≤ 1000 so that

tout=0,1000/40,...,1000.

#
# Independent variable for ODE integration
t0=0;tf=1.0e+03;nout=41;
tout=seq(from=t0,to=tf,by=(tf-t0)/(nout-1));

• ICs (1.2) are defined (from [1]).

#
# Initial conditions (t=0)
y0=rep(0,4);
y0[1]=4;
y0[2]=464;
y0[3]=227;
y0[4]=42;
ncall=0;

Also, the counter for the calls to ode1a is initialized.

Introductory ODE Model 9

• The system of 4 ODEs is integrated by the library integrator lsodes

(available in deSolve, [4]). As expected, the inputs to lsodes are
the ODE function, ode1a, the IC vector y0, and the vector of output
values of t, tout. The length of y0 (4) informs lsodes how many
ODEs are to be integrated. func,y,times are reserved names.

#
# ODE integration
out=lsodes(y=y0,times=tout,func=ode1a,
sparsetype ="sparseint",rtol=1e-6,
atol=1e-6,maxord=5);
nrow(out)
ncol(out)

The numerical solution to the ODEs is returned in matrix out. In

this case, out has the dimensions nout × (4 + 1) = 41 × 5, which
are confirmed by the output from nrow(out),ncol(out) (included
in the numerical output considered subsequently). The offset +1 is
required since the first element of out is the value of t, and the 2 to
5 elements are the values of M (t), TC (t), N (t), TR (t).
• Vectors are defined for the computed ODE solution (in array out
returned by lsodes). The solution is then placed in these arrays.

#
# Arrays for plotting numerical solution
M=rep(0,nout);
TC=rep(0,nout);
N=rep(0,nout);
TR=rep(0,nout);
for(it in 1:nout){
M[it]=out[it,2];
TC[it]=out[it,3];
N[it]=out[it,4];
TR[it]=out[it,5];
}

Again, the offset +1 is required since the first element of each solution
vector (for a particular index it) is the value of t associated with
the solution.
• The four dependent variables M (t), TC (t), N (t), TR (t) are displayed
as a function of t with a for. Every second value of t appears from
by=2.

#
# Display numerical solution
10 ODE/PDE Analysis of Multiple Myeloma

cat(sprintf("\n t M(t) TC(t)

N(t) TR(t)"));
iv=seq(from=1,to=nout,by=2);
for(it in iv){
cat(sprintf("%10.2f %10.3f %10.3f %10.3f %10.3f\n",
tout[it],M[it],TC[it],N[it],TR[it]));
}

• The number of calls to ode1a is displayed at the end of the solution.

#
# Calls to ODE routine
cat(sprintf("\n\n ncall = %5d\n\n",ncall));

• The four dependent variable are plotted against t with the R utility
plot. The argument type="l" specfied a continuous line (rather
than discrete points).

#
# Plot ODE solutions
#
# M(t)
plot(tout,M,xlab="time (days)",ylab="M(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");
#
# TC(t)
plot(tout,TC,xlab="time (days)",ylab="TC(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");
#
# N(t)
plot(tout,N,xlab="time (days)",ylab="N(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");
#
# TR(t)
plot(tout,TR,xlab="time (days)",ylab="TR(t)",
xlim=c(t0,tf),main="",type="l",lwd=2,
col="black");

This completes the discussion of the main program of Listing 1.1. The
subordinate routine ode1a called by ODE integrator lsodes is considered
next.
Introductory ODE Model 11

(1.1.2) ODE routine

Listing 1.2: ODE routine ode1a for eqs. (1.1), (1.2)

ode1a=function(t,y,parms){
#
# Function ode1a computes the t derivatives
# of M(t),TC(t),N(t),TR(t)
#
# One vector to four scalars
M=y[1];
TC=y[2];
N=y[3];
TR=y[4];
#
# ODEs
Mt=sM+rM*(1-M/KM)*M-
delM*(1+(aNM*N/(bNM+N)+aCM*TC/(bCM+TC)+
aCNM*N/(bNM+N)*TC/(bCM+TC))*(1-aMM*M/(bMM+M)-
aRM*TR/(bRM+TR)))*M;
TCt=rC*(1-TC/KC)*(1+aMC*M/(bMC+M)+aNC*TR/(bRM+TR))*TC-
delC*TC;
Nt=sN+rN*(1-N/KN)*(1+aCN*TC/(bCN+TC))*N-delN*N;
TRt=rR*(1-TR/KR)*(1+aMR*M/(bMR+M))*TR-delR*TR;
#
# Four scalars to one vector
yt=rep(0,4);
yt[1]=Mt;
yt[2]=TCt;
yt[3]=Nt;
yt[4]=TRt;
#
# Increment calls to ode1a
ncall <<- ncall+1;
#
# Return derivative vector
return(list(c(yt)));
}
12 ODE/PDE Analysis of Multiple Myeloma

We can note the following details about the ODE programming of

Listing 1.2.

• The function is defined.

ode1a=function(t,y,parms){
#
# Function ode1a computes the t derivatives
# of M(t),TC(t),N(t),TR(t)

t is the current value of t in eqs. (1.1). y is the 4-vector of ODE

dependent variables. parms is an argument to pass parameters to
ode1a (unused, but required in the argument list). The arguments
must be listed in the order stated to properly interface with lsodes
called in the main program of Listing 1.1. The derivative vector
of the LHS of eqs. (1.1) is calculated and returned to lsodes as
explained subsequently.
• Vector y is placed in four scalars to facilitate the programming of
eqs. (1.1).

#
# One vector to four scalars
M=y[1];
TC=y[2];
N=y[3];
TR=y[4];
 
dM
• Equation (1.1-1) is programmed Mt = .
dt

#
# ODEs
Mt=sM+rM*(1-M/KM)*M-
delM*(1+(aNM*N/(bNM+N)+aCM*TC/(bCM+TC)+
aCNM*N/(bNM+N)*TC/(bCM+TC))*(1-aMM*M/(bMM+M)-
aRM*TR/(bRM+TR)))*M;

The parameters (constants) defined in the main program of

Listing 1.1 are available to ode1a without any special designation
(a feature of R). Also, lines can be continued onto second lines with-
out any special designation (a feature of R), but a character at the
end of the first line indicating a continuation is recommended (e.g.,
the first line ends in - indicating a continuation onto a second line).
This is a better procedure than placing the - at the beginning of
the second line.
Introductory ODE Model 13

 
dTC
• Equation (1.1-2) is programmed TCt = .
dt

TCt=rC*(1-TC/KC)*(1+aMC*M/(bMC+M)+aNC*TR/(bRM+TR))*TC-
delC*TC;
 
dN
• Equation (1.1-3) is programmed Nt = .
dt

Nt=sN+rN*(1-N/KN)*(1+aCN*TC/(bCN+TC))*N-delN*N;
 
dTR
• Equation (1.1-4) is programmed TRt = .
dt

TRt=rR*(1-TR/KR)*(1+aMR*M/(bMR+M))*TR-delR*TR;

• With the completion of the four LHS t derivatives of eqs. (1.1), the
derivatives are placed in a vector yt for return to lsodes.

#
# Four scalars to one vector
yt=rep(0,4);
yt[1]=Mt;
yt[2]=TCt;
yt[3]=Nt;
yt[4]=TRt;

• The counter for the calls to ode1a is incremented and returned to

the main program of Listing 1.1 by <<-.

#
# Increment calls to ode1a
ncall <<- ncall+1;

• The vector yt is returned to lsodes for the next step along the
solution.

#
# Return derivative vector
return(list(c(yt)));
}

The vector yt is returned as a list as required by lsodes. c is the

R vector utility. The final } concludes ode1a.

This completes the discussion of ode1a. The output from the main program
of Listing 1.1 and ODE routine ode1a of Listing 1.2 is considered next.
14 ODE/PDE Analysis of Multiple Myeloma

(1.1.3) Numerical, graphical output

The numerical output is in Table 1.4.
We can note the following details about this output.

• 41 t output points as the first dimension of the solution matrix out

from lsodes as programmed in the main program of Listing 1.1
(with nout=41).
• The solution matrix out returned by lsodes has 5 elements as a
second dimension. The first element is the value of t. Elements 2
to 5 are M (t), TC (t), N (t), TR (t) from eqs. (1.1) (for each of the 41
output points).

Table 1.4: Abbreviated output from Listings 1.1, 1.2

[1] 41

[1] 5
t M(t) TC(t) N(t) TR(t)
0.00 4.000 464.000 227.000 42.000
50.00 4.334 520.253 264.319 46.477
100.00 4.570 533.274 272.048 46.922
150.00 4.747 537.642 273.483 47.210
200.00 4.879 540.026 273.815 47.413
250.00 4.976 541.615 273.940 47.557
300.00 5.047 542.722 274.011 47.659
350.00 5.098 543.499 274.058 47.730
400.00 5.135 544.044 274.091 47.781
450.00 5.160 544.427 274.114 47.816
500.00 5.179 544.695 274.130 47.841
550.00 5.192 544.883 274.141 47.859
600.00 5.201 545.015 274.149 47.871
650.00 5.207 545.107 274.155 47.879
700.00 5.211 545.172 274.159 47.885
750.00 5.215 545.217 274.161 47.890
800.00 5.217 545.248 274.163 47.892
850.00 5.218 545.270 274.165 47.895
900.00 5.219 545.286 274.165 47.896
950.00 5.220 545.297 274.166 47.897
1000.00 5.221 545.304 274.167 47.898

ncall = 131
Introductory ODE Model 15

• The solution is displayed for t = 0, 50, ..., 1000 as programmed in

Listing 1.1 (every second value of t displayed as explained previ-
ously).
• ICs (1.2) are confirmed (t = 0).
• M (t), TC (t), N (t), TR (t) approach an equilibrium (steady state) so-
lution as t → 1000.
• The computational effort as indicated by ncall = 131 is modest so
that lsodes computed the solution to eqs. (1.1) efficiently.

The graphical output is in Figures 1.1.

5.2
5.0
4.8
M(t)
4.64.4
4.2
4.0

0 200 400 600 800 1000

time (days)

Figure 1.1-1: Numerical solution M (t) from eq. (1.1-1).

Figures 1.1 confirm the solutions in Table 1.4. In particular, the ICs (1.2)
and the approach to an equilibrium solution are clear.

(1.2) Summary and conclusions

The R programming for eqs. (1.1), (1.2) is straightforward through the use of
the library initial value ODE integrator lsodes. The approach to the equilib-
rium solution could be confirmed further by displaying the t derivatives (from
ode1a), dMdt(t) , dTdt
C (t)
, dNdt(t) , dTdt
R (t)
which approach zero for large t. This is
left as an exercise.
Equations (1.1) are derived as mass balances on the peripheral blood [2].
The model is now extended in Chapter 2 to the bone marrow represented in
16 ODE/PDE Analysis of Multiple Myeloma

540
520
TC(t)
500 480

0 200 400 600 800 1000

time (days)

Figure 1.1-2: Numerical solution TC (t) from eq. (1.1-2).

270
260
N(t)
250
240
230

0 200 400 600 800 1000

time (days)

Figure 1.1-3: Numerical solution N (t) from eq. (1.1-3).

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