Month: August 2016

Some quick math to calculate numerical convergence rates

I find myself needing to re-derive this often enough that it’s worth jotting down for current and future students. 🙂

Introduction

A very common task in our field is to assess the convergence rate of a numerical algorithm: if I shrink \(\Delta t\) (or \(\Delta x\)), how quickly does my error shrink? And in fact, does my error shrink? Assuming you have a method to compute the error for a simulation (say, a simple test case where you know the exact solution), you want a fit an expression like this:

\[ \mathrm{Error}(\Delta t) = C \Delta t^n ,\] where \( C\) is a constant, and \( n \) is the order of convergence. Usually, if \( n \) isn’t at least 1, it’s bad.

So, suppose you are testing an algorithm, and you have the error \( E_1 \) for \( \Delta t_1 \) and \( E_2 \) for \( \Delta t_2 \). Then one way to go about this calculation is to try to cancel out \( C\):

\begin{eqnarray} \frac{ E_1}{E_2} = \frac{C \Delta t_1^n }{C \Delta t_2^n } = \left( \frac{ \Delta t_1 }{\Delta t_2} \right)^n & \Longrightarrow & n = \frac{ \log\left( E_1 / E_2 \right) }{ \log\left( \Delta t_1 / \Delta t_2 \right) } \end{eqnarray}

Another way to look at this problem is to rewrite the error equation in log-log space:

\begin{eqnarray} E = C \Delta t^N & \Longrightarrow & \log{E} = \log{C} + n \log{ \Delta t} \end{eqnarray}
so \(n\) is the slope of the equation in log space. If you only have two points, then,
\[ n = \frac{ \log{E_1} – \log{E_2} }{ \log{\Delta t_1} – \log{\Delta t_1} } = \frac{ \log\left( E_1 / E_2 \right) }{ \log\left( \Delta t_1 / \Delta t_2 \right) }, \] and so we end up with the exact same convergence rate as before.

However, if you have calculated the error \( E_i \) for a whole bunch of values \( \Delta t_i \), then you can extend this idea to get a better sense of the overall convergence rate for all your values of \(  \Delta t \), rather than just two values. Just find the linear least squares fit to the points \( \left\{ ( \log\Delta t_i, \log E_i ) \right\} \). If there are just two points, it’s the same as above. If there are many, it’s a better representation of overall convergence.

Trying it out

Let’s demonstrate this on a simple test problem:

\[ \frac{du}{dt} = -10 u, \hspace{.5in} u(0) = 1.\]

We’ll simulate using (1st-order) forward Euler and (2nd-order) Adams-Bashforth:

dt_vals = [.2 .1 .05 .01 .001 .0001]; 

min_t = 0; 
max_t = 1; 

lambda = 10; 
initial = 1; 

errors_forward_euler = []; 
errors_adams_bashforth = []; 

for j=1:length( dt_vals )
    dt = dt_vals(j);
    T = min_t:dt:max_t; 
    
    % allocate memory 
    
    solution_forward_euler = zeros(1,length(T)); 
    solution_forward_euler(1) = initial; 
    solution_adams_bashforth = solution_forward_euler;
    
    % exact solution 
    
    solution_exact = initial * exp( -lambda * T ); 

    % forward euler 
    
    for i=2:length(T)
        solution_forward_euler(i) = solution_forward_euler(i-1)...
            - dt*lambda*solution_forward_euler(i-1); 
    end
    
    % adams-bashforth -- use high-res Euler to jump-start
    
    dt_fine = dt * 0.1; 
    t = min_t + dt_fine; 
    temp = initial ;
    for i=1:10
        temp = temp - dt_fine*lambda*temp;        
    end
    solution_adams_bashforth(2) = temp;
    
    for i=3:length(T)
        solution_adams_bashforth(i) = solution_adams_bashforth(i-1)...
            - 0.5*dt*lambda*( 3*solution_adams_bashforth(i-1)...
            - solution_adams_bashforth(i-2 ) );  
    end

%     Uncomments if you want to see plots. 
%     figure(1) 
%     clf; 
%     plot( T, solution_exact, 'r*' , T , solution_forward_euler,...
%         'b-o', T , solution_adams_bashforth , 'k-s'  ); 
%     pause ; 
    
    errors_forward_euler(j) = ...
        max(abs( solution_exact - solution_forward_euler ) );
    errors_adams_bashforth(j) = ...
        max(abs( solution_exact - solution_adams_bashforth ) );
    
end

Here is a plot of the errors:

figure(2)
loglog( dt_vals, errors_forward_euler, 'b-s' ,...
    dt_vals, errors_adams_bashforth, 'r-o' ,...
    'linewidth', 2 );
legend( 'Forward Euler', 'Adams-Bashforth' , 4 );
xlabel( '\Delta t (log scale)' , 'fontsize', 14 ); 
ylabel( 'Absolute errors (log scale)', 'fontsize', 14 ); 
title( 'Errors vs. \Delta t', 'fontsize' , 16 );
set( gca, 'fontsize' , 14 );

errors
Note that calculating the convergence rate based on the first two errors, and first and last errors, is not terribly
representative, compared with using all the errors:

% Convergence rate based on the first two errors
polyfit( log(dt_vals(1:2)) , log(errors_forward_euler(1:2)) , 1 )
polyfit( log(dt_vals(1:2)) , log(errors_adams_bashforth(1:2)) , 1 )

% Convergence rate based on the first and last errors
m = length(dt_vals);
polyfit( log( [dt_vals(1),dt_vals(m)] ) ,...
    log( [errors_forward_euler(1),errors_forward_euler(m)]) , 1 )
polyfit( log( [dt_vals(1),dt_vals(m)] ) ,...
    log( [errors_adams_bashforth(1),errors_adams_bashforth(m)]) , 1 )

% Convergence rate based on all the errors
polyfit( log(dt_vals) , log(errors_forward_euler) , 1 )
polyfit( log(dt_vals) , log(errors_adams_bashforth) , 1 )

% Convergence rate based on all the errors but the outlier
polyfit( log(dt_vals(2:m)) , log(errors_forward_euler(2:m)) , 1 )
polyfit( log(dt_vals(2:m)) , log(errors_adams_bashforth(2:m)) , 1 )

Using the first two errors gives a convergence rate over 5 for Adams-Bashforth, and around 1.6 for forward Euler. Using first and last is better, but still over-estimates the convergence rates (1.15 and 2.37, FE and AB, respectively). Linear least squares is closer to reality: 1.12 for FE, 2.21 for AB. And lastly, linear least squares but excluding the outliers, we get 1.08 for forward Euler, and 2.03 for Adams-Bashforth. (As expected!)

Which convergence rates are “right”?

So, which values do you report as your convergence rates? Ideally, use all the errors to avoid bias and/or cherry-picking. It’s the most honest and straightforward way to present the work. However, you may have a good rationale to exclude the clear outliers in this case. But then again, if you have calculated the errors for enough values of \(\Delta t\), there’s no need to do this at all. There’s little value in (or basis for) reporting the convergence rate to three significant digits. I’d instead report these as approximately first-order convergence (forward Euler) and approximately second-order convergence (Adams-Bashforth); we get this result with either linear least squares fit, and using all your data points puts you on more solid ground.


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Building a Cellular Automaton Model Using BioFVM

Note: This is part of a series of “how-to” blog posts to help new users and developers of BioFVM. See below for guides to setting up a C++ compiler in Windows or OSX.

What you’ll need

Matlab or Octave for visualization. Matlab might be available for free at your university. Octave is open source and available from a variety of sources.

Our modeling task

We will implement a basic 3-D cellular automaton model of tumor growth in a well-mixed fluid, containing oxygen pO2 (mmHg) and a drug c (e.g., doxorubicin, μM), inspired by modeling by Alexander Anderson, Heiko Enderling, Jan PoleszczukGibin Powathil, and others. (I highly suggest seeking out the sophisticated cellular automaton models at Moffitt’s Integrated Mathematical Oncology program!) This example shows you how to extend BioFVM into a new cellular automaton model. I’ll write a similar post on how to add BioFVM into an existing cellular automaton model, which you may already have available.

Tumor growth will be driven by oxygen availability. Tumor cells can be live, apoptotic (going through energy-dependent cell death, or necrotic (undergoing death from energy collapse). Drug exposure can both trigger apoptosis and inhibit cell cycling. We will model this as growth into a well-mixed fluid, with pO2 = 38 mmHg (about 5% oxygen: a physioxic value) and c = 5 μM.

Mathematical model

As a cellular automaton model, we will divide 3-D space into a regular lattice of voxels, with length, width, and height of 15 μm. (A typical breast cancer cell has radius around 9-10 μm, giving a typical volume around 3.6×103 μm3. If we make each lattice site have the volume of one cell, this gives an edge length around 15 μm.)

In voxels unoccupied by cells, we approximate a well-mixed fluid with Dirichlet nodes, setting pO2 = 38 mmHg, and initially setting c = 0. Whenever a cell dies, we replace it with an empty automaton, with no Dirichlet node. Oxygen and drug follow the typical diffusion-reaction equations:

\[ \frac{ \partial \textrm{pO}_2 }{\partial t} = D_\textrm{oxy} \nabla^2 \textrm{pO}_2 – \lambda_\textrm{oxy} \textrm{pO}_2 – \sum_{ \textrm{cells} i} U_{i,\textrm{oxy}} \textrm{pO}_2 \]

\[ \frac{ \partial c}{ \partial t }  = D_c \nabla^2 c – \lambda_c c – \sum_{\textrm{cells }i} U_{i,c} c \]

where each uptake rate is applied across the cell’s volume. We start the treatment by setting c = 5 μM on all Dirichlet nodes at t = 504 hours (21 days). For simplicity, we do not model drug degradation (pharmacokinetics), to approximate the in vitro conditions.

In any time interval [t,tt], each live tumor cell i has a probability pi,D of attempting division, probability pi,A of apoptotic death, and probability pi,N of necrotic death. (For simplicity, we ignore motility in this version.) We relate these to the birth rate bi, apoptotic death rate di,A, and necrotic death rate di,N by the linearized equations (from Macklin et al. 2012):

\[ \textrm{Prob} \Bigl( \textrm{cell } i \textrm{ becomes apoptotic in } [t,t+\Delta t] \Bigr)  = 1 – \textrm{exp}\Bigl( -d_{i,A}(t) \Delta t\Bigr) \approx d_{i,A}\Delta t \]

\[ \textrm{Prob} \Bigl( \textrm{cell } i \textrm{ attempts division in } [t,t+\Delta t] \Bigr)  = 1 – \textrm{exp}\Bigl( -b_i(t) \Delta t\Bigr) \approx b_{i}\Delta t \]

\[ \textrm{Prob} \Bigl( \textrm{cell } i \textrm{ becomes necrotic in } [t,t+\Delta t] \Bigr)  = 1 – \textrm{exp}\Bigl( -d_{i,N}(t) \Delta t\Bigr) \approx d_{i,N}\Delta t \]

Each dead cell has a mean duration Ti,D, which will vary by the type of cell death. Each dead cell automaton has a probability pi,L of lysis (rupture and removal) in any time span [t,t+Δt]. The duration TD is converted to a probability of cell lysis by

\[ \textrm{Prob} \Bigl( \textrm{dead cell } i \textrm{ lyses in } [t,t+\Delta t] \Bigr)  = 1 – \textrm{exp}\Bigl( -\frac{1}{T_{i,D}} \Delta t\Bigr) \approx \frac{ \Delta t}{T_{i,D}} \]

(Illustrative) parameter values

We use Doxy = 105 μm2/min (Ghaffarizadeh et al. 2016), and we set Ui,oxy = 20 min-1 (to give an oxygen diffusion length scale of about 70 μm, with steeper gradients than our typical 100 μm length scale). We set λoxy = 0.01 min-1 for a 1 mm diffusion length scale in fluid.

We set Dc = 300 μm2/min, and Uc = 7.2×10-3 min-1 (Dc from Weinberg et al. (2007), and Ui,c twice as large as the reference value in Weinberg et al. (2007) to get a smaller diffusion length scale of about 204 μm). We set λc = 3.6×10-5 min-1 to give a drug diffusion length scale of about 2.9 mm in fluid.

We use TD = 8.6 hours for apoptotic cells, and TD = 60 days for necrotic cells (Macklin et al., 2013). However, note that necrotic and apoptotic cells lose volume quickly, so one may want to revise those time scales to match the point where a cell loses 90% of its volume.

Functional forms for the birth and death rates

We model pharmacodynamics with an area-under-the-curve (AUC) type formulation. If c(t) is the drug concentration at any cell i‘s location at time t, then let its integrated exposure Ei(t) be

\[ E_i(t) = \int_0^t c(s) \: ds \]

and we model its response with a Hill function

\[ R_i(t) = \frac{ E_i^h(t) }{ \alpha_i^h + E_i^h(t) }, \]

where h is the drug’s Hill exponent for the cell line, and α is the exposure for a half-maximum effect.

We model the microenvironment-dependent birth rate by:

\[ b_i(t) = \left\{ \begin{array}{lr} b_{i,P} \left( 1 – \eta_i R_i(t) \right) & \textrm{ if } \textrm{pO}_{2,P} < \textrm{pO}_2 \\  \\ b_{i,P} \left( \frac{\textrm{pO}_{2}-\textrm{pO}_{2,N}}{\textrm{pO}_{2,P}-\textrm{pO}_{2,N}}\right) \Bigl( 1 – \eta_i R_i(t) \Bigr) & \textrm{ if } \textrm{pO}_{2,N} < \textrm{pO}_2 \le \textrm{pO}_{2,P} \\ \\ 0 & \textrm{ if } \textrm{pO}_2 \le \textrm{pO}_{2,N}\end{array} \right. \]

where pO2,P is the physioxic oxygen value (38 mmHg), and pO2,N is a necrotic threshold (we use 5 mmHg), and 0 < η < 1 the drug’s birth inhibition. (A fully cytostatic drug has η = 1.)

We model the microenvironment-dependent apoptosis rate by:

\[ d_{i,A}(t)  = d_{i,A}^* + \Bigl( d_{i,A}^\textrm{max} – d_{i,A}^* \Bigr) R_i(t)  \]

where di,Amax is the maximum apoptotic death rate. We model the microenvironment-dependent necrosis rate by:

\[ d_{i,N}(t) = \left\{ \begin{array}{lr} 0 & \textrm{ if } \textrm{pO}_{2,N} < \textrm{pO}_{2} \\ \\ d_{i,N}^* &  \textrm{ if } \textrm{pO}_{2} \le \textrm{pO}_{2,N} \end{array}\right. \]

for a constant value di,N*.
(Illustrative) parameter values

We use bi,P = 0.05 hour-1 (for a 20 hour cell cycle in physioxic conditions), di,A* = 0.01 bi,P, and di,N* = 0.04 hour-1 (so necrotic cells survive around 25 hours in low oxygen conditions).

We set α = 30 μM*hour (so that cells reach half max response after 6 hours’ exposure at a maximum concentration c = 5 μM), h = 2 (for a smooth effect), η = 0.25 (so that the drug is partly cytostatic), and di,Amax = 0.1 hour^-1 (so that cells survive about 10 hours after reaching maximum response).

Building the Cellular Automaton Model in BioFVM

BioFVM already includes Basic_Agents for cell-based substrate sources and sinks. We can extend these basic agents into full-fledged automata, and then arrange them in a lattice to create a full cellular automata model. Let’s sketch that out now.

Extending Basic_Agents to Automata

The main idea here is to define an Automaton class which extends (and therefore includes) the Basic_Agent class. This will give each Automaton full access to the microenvironment defined in BioFVM, including the ability to secrete and uptake substrates. We also make sure each Automaton “knows” which microenvironment it lives in (contains a pointer pMicroenvironment), and “knows” where it lives in the cellular automaton lattice. (More on that in the following paragraphs.)

So, as a schematic (just sketching out the most important members of the class):

class Standard_Data; // define per-cell biological data, such as phenotype, 
	// cell cycle status, etc..
class Custom_Data; // user-defined custom data, specific to a model.

class Automaton : public Basic_Agent
{
	private:
		Microenvironment* pMicroenvironment; 
		
		CA_Mesh* pCA_mesh; 
		int voxel_index; 
		
	protected:
	public:
		// neighbor connectivity information
		std::vector<Automaton*> neighbors; 
		std::vector<double> neighbor_weights; 
		
		Standard_Data standard_data; 
		void (*current_state_rule)( Automaton& A , double ); 
	
		Automaton();  
		void copy_parameters( Standard_Data& SD  ); 
		void overwrite_from_automaton( Automaton& A );  

		void set_cellular_automaton_mesh( CA_Mesh* pMesh );  
		CA_Mesh* get_cellular_automaton_mesh( void ) const;  
		
		void set_voxel_index( int ); 
		int get_voxel_index( void ) const;  
		
		void set_microenvironment( Microenvironment* pME );  
		Microenvironment* get_microenvironment( void );  

		// standard state changes
		bool attempt_division( void ); 
		void become_apoptotic( void ); 
		void become_necrotic( void ); 
		void perform_lysis( void ); 
		
		// things the user needs to define
		
		Custom_Data custom_data;
		
		// use this rule to add custom logic 
		void (*custom_rule)( Automaton& A , double); 		
};

So, the Automaton class includes everything in the Basic_Agent class, some Standard_Data (things like the cell state and phenotype, and per-cell settings), (user-defined) Custom_Data, basic cell behaviors like attempting division into an empty neighbor lattice site, and user-defined custom logic that can be applied to any automaton. To avoid lots of switch/case and if/then logic, each Automaton has a function pointer for its current activity (current_state_rule), which can be overwritten any time.

Each Automaton also has a list of neighbor Automata (their memory addresses), and weights for each of these neighbors. Thus, you can distance-weight the neighbors (so that corner elements are farther away), and very generalized neighbor models are possible (e.g., all lattice sites within a certain distance).  When updating a cellular automaton model, such as to kill a cell, divide it, or move it, you leave the neighbor information alone, and copy/edit the information (standard_data, custom_data, current_state_rule, custom_rule). In many ways, an Automaton is just a bucket with a cell’s information in it.

Note that each Automaton also “knows” where it lives (pMicroenvironment and voxel_index), and knows what CA_Mesh it is attached to (more below).

Connecting Automata into a Lattice

An automaton by itself is lost in the world–it needs to link up into a lattice organization. Here’s where we define a CA_Mesh class, to hold the entire collection of Automata, setup functions (to match to the microenvironment), and two fundamental operations at the mesh level: copying automata (for cell division), and swapping them (for motility). We have provided two functions to accomplish these tasks, while automatically keeping the indexing and BioFVM functions correctly in sync. Here’s what it looks like:

class CA_Mesh{
	private:
		Microenvironment* pMicroenvironment; 
		Cartesian_Mesh* pMesh; 

		std::vector<Automaton> automata; 
		std::vector<int> iteration_order; 
	protected:
	public:
		CA_Mesh();  
	
		// setup to match a supplied microenvironment 
		void setup( Microenvironment& M ); 
		// setup to match the default microenvironment 
		void setup( void );  
		
		int number_of_automata( void ) const; 
		
		void randomize_iteration_order( void );

		void swap_automata( int i, int j ); 
		void overwrite_automaton( int source_i, int destination_i ); 
		
		// return the automaton sitting in the ith lattice site 
		Automaton& operator[]( int i ); 
		
		// go through all nodes according to random shuffled order 
		void update_automata( double dt ); 
};

So, the CA_Mesh has a vector of Automata (which are never themselves moved), pointers to the microenvironment and its mesh, and a vector of automata indices that gives the iteration order (so that we can sample the automata in a random order). You can easily access an automaton with operator[], and copy the data from one Automaton to another with overwrite_automaton() (e.g, for cell division), and swap two Automata’s data (e.g., for cell migration) with swap_automata().  Finally, calling update_automata(dt) iterates through all the automata according to iteration_order, calls their current_state_rules and custom_rules, and advances the automata by dt.

Interfacing Automata with the BioFVM Microenvironment

The setup function ensures that the CA_Mesh is the same size as the Microenvironment.mesh, with same indexing, and that all automata have the correct volume, and dimension of uptake/secretion rates and parameters. If you declare and set up the Microenvironment first, all this is take care of just by declaring a CA_Mesh, as it seeks out the default microenvironment and sizes itself accordingly:

// declare a microenvironment
Microenvironment M;
// do things to set it up -- see prior tutorials
// declare a Cellular_Automaton_Mesh
CA_Mesh CA_model;
// it's already good to go, initialized to empty automata:
CA_model.display();

If you for some reason declare the CA_Mesh fist, you can set it up against the microenvironment:

// declare a CA_Mesh
CA_Mesh CA_model;
// declare a microenvironment
Microenvironment M;
// do things to set it up -- see prior tutorials
// initialize the CA_Mesh to match the microenvironment
CA_model.setup( M );
// it's already good to go, initialized to empty automata:
CA_model.display();

Because each Automaton is in the microenvironment and inherits functions from Basic_Agent, it can secrete or uptake. For example, we can use functions like this one:

void set_uptake( Automaton&amp; A, std::vector<double>& uptake_rates )
{
	extern double BioFVM_CA_diffusion_dt; 
	// update the uptake_rates in the standard_data 
	A.standard_data.uptake_rates = uptake_rates; 
	// now, transfer them to the underlying Basic_Agent
	*(A.uptake_rates) = A.standard_data.uptake_rates; 
	// and make sure the internal constants are self-consistent 
	A.set_internal_uptake_constants( BioFVM_CA_diffusion_dt ); 
}

A function acting on an automaton can sample the microenvironment to change parameters and state. For example:

void do_nothing( Automaton& A, double dt )
{ return; }

void microenvironment_based_rule( Automaton& A, double dt )
{
	// sample the microenvironment 
	std::vector<double> MS = (*A.get_microenvironment())( A.get_voxel_index() );
 
	// if pO2 < 5 mmHg, set the cell to a necrotic state
	if( MS[0] < 5.0 ) { A.become_necrotic(); } // if drug > 5 uM, set the birth rate to zero
	if( MS[1] > 5 )
	{ A.standard_data.birth_rate = 0.0; }
 
	// set the custom rule to something else
	A.custom_rule = do_nothing;
 
	return;
}

Implementing the mathematical model in this framework

We give each tumor cell a tumor_cell_rule (using this for custom_rule):

void viable_tumor_rule( Automaton& A, double dt )
{
	// If there's no cell here, don't bother.
	if( A.standard_data.state_code == BioFVM_CA_empty )
	{ return; }
	
	// sample the microenvironment
	std::vector<double> MS = (*A.get_microenvironment())( A.get_voxel_index() );

	// integrate drug exposure 
	A.standard_data.integrated_drug_exposure += ( MS[1]*dt ); 
	A.standard_data.drug_response_function_value = pow( A.standard_data.integrated_drug_exposure,
		A.standard_data.drug_hill_exponent );  
	double temp = pow( A.standard_data.drug_half_max_drug_exposure,
		A.standard_data.drug_hill_exponent );  
	temp += A.standard_data.drug_response_function_value; 
	A.standard_data.drug_response_function_value /= temp; 
	
	// update birth rates (which themselves update probabilities) 
	update_birth_rate( A, MS, dt ); 
	update_apoptotic_death_rate( A, MS, dt ); 
	update_necrotic_death_rate( A, MS, dt );
	
	return; 
}

The functional tumor birth and death rates are implemented as:

void update_birth_rate( Automaton& A, std::vector<double>& MS, double dt )  
{
	static double O2_denominator = BioFVM_CA_physioxic_O2 - BioFVM_CA_necrotic_O2;
	
	A.standard_data.birth_rate = 	A.standard_data.drug_response_function_value;
		// response
	A.standard_data.birth_rate *= A.standard_data.drug_max_birth_inhibition;
		// inhibition*response; 
	A.standard_data.birth_rate *= -1.0;
		// - inhibition*response
	A.standard_data.birth_rate += 1.0;
		// 1 - inhibition*response
	A.standard_data.birth_rate *= viable_tumor_cell.birth_rate; 
		// birth_rate0*(1 - inhibition*response)
	
	double temp1 = MS[0] ; // O2 
	temp1 -= BioFVM_CA_necrotic_O2; 
	temp1 /= O2_denominator; 
	
	A.standard_data.birth_rate *= temp1; 
	if( A.standard_data.birth_rate < 0 )
	{ A.standard_data.birth_rate = 0.0; }

	A.standard_data.probability_of_division = A.standard_data.birth_rate;
	A.standard_data.probability_of_division *= dt; 
		// dt*birth_rate*(1 - inhibition*repsonse) // linearized probability 
	return; 
}
	
void update_apoptotic_death_rate( Automaton& A, std::vector<double>& MS, double dt )  
{
	A.standard_data.apoptotic_death_rate = A.standard_data.drug_max_death_rate; 
		// max_rate
	A.standard_data.apoptotic_death_rate -= viable_tumor_cell.apoptotic_death_rate; 
		// max_rate - background_rate
	A.standard_data.apoptotic_death_rate *= A.standard_data.drug_response_function_value; 
		// (max_rate-background_rate)*response 
	A.standard_data.apoptotic_death_rate += viable_tumor_cell.apoptotic_death_rate; 
		// background_rate + (max_rate-background_rate)*response 

	A.standard_data.probability_of_apoptotic_death = A.standard_data.apoptotic_death_rate;
	A.standard_data.probability_of_apoptotic_death *= dt; 
		// dt*( background_rate + (max_rate-background_rate)*response ) // linearized probability
	return;
} 

void update_necrotic_death_rate( Automaton& A, std::vector<double>& MS, double dt )   
{
	A.standard_data.necrotic_death_rate = 0.0; 
	A.standard_data.probability_of_necrotic_death = 0.0; 
	
	if( MS[0] > BioFVM_CA_necrotic_O2 )
	{ return; }

	A.standard_data.necrotic_death_rate = perinecrotic_tumor_cell.necrotic_death_rate; 
	A.standard_data.probability_of_necrotic_death = A.standard_data.necrotic_death_rate; 
	A.standard_data.probability_of_necrotic_death *= dt; 
		// dt*necrotic_death_rate

	return;
} 

And each fluid voxel (Dirichlet nodes) is implemented as the following (to turn on therapy at 21 days):

void fluid_rule( Automaton& A, double dt )
{
	static double activation_time = 504; 
	static double activation_dose = 5.0; 
	static std::vector<double> activated_dirichlet( 2 , BioFVM_CA_physioxic_O2 );
	static bool initialized = false; 
	if( !initialized )
	{
		activated_dirichlet[1] = activation_dose; 
		initialized = true; 
	}

	if( fabs( BioFVM_CA_elapsed_time - activation_time ) < 0.01 ) { int ind = A.get_voxel_index(); if( A.get_microenvironment()->mesh.voxels[ind].is_Dirichlet )
		{
			A.get_microenvironment()->update_dirichlet_node( ind, activated_dirichlet );
		}
	}
}

At the start of the simulation, each non-cell automaton has its custom_rule set to fluid_rule, and each tumor cell Automaton has its custom_rule set to viable_tumor_rule. Here’s how:

void setup_cellular_automata_model( Microenvironment& M, CA_Mesh& CAM )
{
	// Fill in this environment 
	double tumor_radius = 150;  
	double tumor_radius_squared = tumor_radius * tumor_radius; 
	
	std::vector<double> tumor_center( 3, 0.0 ); 
	
	std::vector<double> dirichlet_value( 2 , 1.0 );
	dirichlet_value[0] = 38; //physioxia
	dirichlet_value[1] = 0; // drug 
	
	for( int i=0 ; i < M.number_of_voxels() ;i++ )
	{
		std::vector<double> displacement( 3, 0.0 );
		displacement = M.mesh.voxels[i].center; 
		displacement -= tumor_center; 
		double r2 = norm_squared( displacement ); 
		
		if( r2 > tumor_radius_squared ) // well_mixed_fluid
		{
			M.add_dirichlet_node( i, dirichlet_value ); 
			CAM[i].copy_parameters( well_mixed_fluid );
			CAM[i].custom_rule = fluid_rule; 
			CAM[i].current_state_rule = do_nothing; 	
		}
		else // tumor 
		{
			CAM[i].copy_parameters( viable_tumor_cell );
			CAM[i].custom_rule = viable_tumor_rule; 
			CAM[i].current_state_rule = advance_live_state; 		
		}
		
	}
}

Overall program loop

There are two inherent time scales in this problem: cell processes like division and death (happen on the scale of hours), and transport (happens on the order of minutes). We take advantage of this by defining two step sizes:

double BioFVM_CA_dt = 3;
std::string BioFVM_CA_time_units = "hr";
double BioFVM_CA_save_interval = 12;
double BioFVM_CA_max_time = 24*28;
double BioFVM_CA_elapsed_time = 0.0;

double BioFVM_CA_diffusion_dt = 0.05;

std::string BioFVM_CA_transport_time_units = "min";
double BioFVM_CA_diffusion_max_time = 5.0;

Every time the simulation advances by BioFVM_CA_dt (on the order of hours), we run diffusion to quasi-steady state (for BioFVM_CA_diffusion_max_time, on the order of minutes), using time steps of size BioFVM_CA_diffusion time. We performed numerical stability and convergence analyses to determine 0.05 min works pretty well for regular lattice arrangements of cells, but you should always perform your own testing!

Here’s how it all looks, in a main program loop:

BioFVM_CA_elapsed_time = 0.0;
double next_output_time = BioFVM_CA_elapsed_time; // next time you save data

while( BioFVM_CA_elapsed_time < BioFVM_CA_max_time + 1e-10 )
{
	// if it's time, save the simulation
	if( fabs( BioFVM_CA_elapsed_time - next_output_time ) < BioFVM_CA_dt/2.0 )
	{
		std::cout << "simulation time: " << BioFVM_CA_elapsed_time << " " << BioFVM_CA_time_units
			<< " (" << BioFVM_CA_max_time << " " << BioFVM_CA_time_units << " max)" << std::endl;
		char* filename;
		filename = new char [1024];
		sprintf( filename, "output_%6f" , next_output_time );
		save_BioFVM_cellular_automata_to_MultiCellDS_xml_pugi( filename , M , CA_model ,
			BioFVM_CA_elapsed_time );

		cell_counts( CA_model );
		delete [] filename;
		next_output_time += BioFVM_CA_save_interval;
	}

	// do the cellular automaton step
	CA_model.update_automata( BioFVM_CA_dt );
	BioFVM_CA_elapsed_time += BioFVM_CA_dt;

	// simulate biotransport to quasi-steady state

	double t_diffusion = 0.0;
	while( t_diffusion < BioFVM_CA_diffusion_max_time + 1e-10 )
	{
		M.simulate_diffusion_decay( BioFVM_CA_diffusion_dt );
		M.simulate_cell_sources_and_sinks( BioFVM_CA_diffusion_dt );
		t_diffusion += BioFVM_CA_diffusion_dt;
	}
}

Getting and Running the Code

  1. Start a project: Create a new directory for your project (I’d recommend “BioFVM_CA_tumor”), and enter the directory. Place a copy of BioFVM (the zip file) into your directory. Unzip BioFVM, and copy BioFVM*.h, BioFVM*.cpp, and pugixml* files into that directory.
  2. Download the demo source code: Download the source code for this tutorial: BioFVM_CA_Example_1, version 1.0.0 or later. Unzip its contents into your project directory. Go ahead and overwrite the Makefile.
  3. Edit the makefile (if needed): Note that if you are using OSX, you’ll probably need to change from “g++” to your installed compiler. See these tutorials.
  4. Test the code: Go to a command line (see previous tutorials), and test:
    make 
    ./BioFVM_CA_Example_1
    

    (If you’re on windows, run BioFVM_CA_Example_1.exe.)

Simulation Result

If you run the code to completion, you will simulate 3 weeks of in vitro growth, followed by a bolus “injection” of drug. The code will simulate one one additional week under the drug. (This should take 5-10 minutes, including full simulation saves every 12 hours.)

In matlab, you can load a saved dataset and check the minimum oxygenation value like this:

MCDS = read_MultiCellDS_xml( 'output_504.000000.xml' );
min(min(min( MCDS.continuum_variables(1).data )))

And then you can start visualizing like this:

contourf( MCDS.mesh.X_coordinates , MCDS.mesh.Y_coordinates , ...
MCDS.continuum_variables(1).data(:,:,33)' ) ; 
axis image; 
colorbar
xlabel('x (\mum)' , 'fontsize' , 12 );
ylabel( 'y (\mum)' , 'fontsize', 12 ); 
set(gca, 'fontsize', 12 );
title('Oxygenation (mmHg) at z = 0 \mum', 'fontsize', 14 ); 
print('-dpng', 'Tumor_o2_3_weeks.png' ); 
plot_cellular_automata( MCDS , 'Tumor spheroid at 3 weeks');

Simulation plots

Here are some plots, showing (left from right) pO2 concentration, a cross-section of the tumor (red = live cells, green = apoptotic, and blue = necrotic), and the drug concentration (after start of therapy):

1 week:

o2_1 weekTumor_spheroid_at_1_week__cross_section

Oxygen- and space-limited growth are restricted to the outer boundary of the tumor spheroid.

2 weeks:

o2_2 weeks Tumor_spheroid_at_2_weeks__cross_section

Oxygenation is dipped below 5 mmHg in the center, leading to necrosis.

3 weeks:

o2_3 weeks Tumor_spheroid_at_3_weeks__cross_section

As the tumor grows, the hypoxic gradient increases, and the necrotic core grows. The code turns on a constant 5 micromolar dose of doxorubicin at this point

Treatment + 12 hours:

o2_Treatment + 12 hours Tumor_spheroid_at_Treatment_+_12_hours__cross_section drug_Treatment + 12 hours

The drug has started to penetrate the tumor, triggering apoptotic death towards the outer periphery where exposure has been greatest.

Treatment + 24 hours:

o2_Treatment + 24 hoursTumor_spheroid_at_Treatment_+_24_hours__cross_section drug_Treatment + 24 hours
The drug profile hasn’t changed much, but the interior cells have now had greater exposure to drug, and hence greater response. Now apoptosis is observed throughout the non-necrotic tumor. The tumor has decreased in volume somewhat.

Treatment + 36 hours:

o2_Treatment + 36 hours Tumor_spheroid_at_Treatment_+_36_hours__cross_sectiondrug_Treatment + 36 hours
The non-necrotic tumor is now substantially apoptotic. We would require some pharamcokinetic effects (e.g., drug clearance, inactivation, or removal) to avoid the inevitable, presences of a pre-existing resistant strain, or emergence of resistance.

Treatment + 48 hours:

o2_Treatment + 48 hours Tumor_spheroid_at_Treatment_+_48_hours__cross_sectiondrug_Treatment + 48 hours
By now, almost all cells are apoptotic.

Treatment + 60 hours:

o2_Treatment + 60 hours Tumor_spheroid_at_Treatment_+_60_hours__cross_sectiondrug_Treatment + 60 hours
The non-necrotic tumor is nearly completed eliminated, leaving a leftover core of previously-necrotic cells (which did not change state in response to the drug–they were already dead!)

Source files

You can download completed source for this example here: https://sourceforge.net/projects/biofvm/files/Tutorials/Cellular_Automaton_1/

This file will include the following:

  1. BioFVM_cellular_automata.h
  2. BioFVM_cellular_automata.cpp
  3. BioFVM_CA_example_1.cpp
  4. read_MultiCellDS_xml.m (updated)
  5. plot_cellular_automata.m
  6. Makefile

What’s next

I plan to update this source code with extra cell motility, and potentially more realistic parameter values. Also, I plan to more formally separate out the example from the generic cell capabilities, so that this source code can work as a bona fide cellular automaton framework.

More immediately, my next tutorial will use the reverse strategy: start with an existing cellular automaton model, and integrate BioFVM capabilities.


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Moving the blog to MathCancer.org

Hi, everyone!

Blogspot has been a great platform for me, but in the end, editing posts with source code and mathematics has been too much of a headache in the neglected blogspot and google UIs.

Elsewhere in the universe, WordPress has developed and encouraged a great ecosystem of plugins that let you do LaTeX and code syntax highlighting directly in your posts with ease. I can’t spend hours and hours on fixing mangled posts. It’s time to move on.

So as of today, I am moving to a self-hosted blog at http://MathCancer.org/blog/

I will leave old posts at http://MathCancer.blogspot.com and gradually migrate them here to MathCancer.org/blog. Thanks for following me over the last few years.


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