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Tumor Model IMA 2017

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tumormodeling's Introduction

This repository contains the code for the following paper: Guiding dose selection of monoclonal antibodies using a new parameter (AFTIR) for characterizing ligand binding systems

Parameter Files

The parameter files are stored in the data directory and are called "ModelF_DRUG.xlsx" where DRUG can be Atezolizumab, Bevacizumab, Pembrolizumab, or Trastuzumab.

Key R Scripts and Rmarkdown files

These are short Tasks in Rmarkdown or R for generating key figures for the manuscript. They are stored in the ModelF folder.

Task10 - illustrates some simple graphs for how code can be executed
Task09f - Varying dose and checking AFTIR for each drug
Task09dV2 - comparison of simple formulation of AFTIR to the full formulation of AFTIR
Task05e - Varying other parameters and checking AFTIR accuracy for each drug
Task04 - look at how changing target accumulation affects AFTIR

Key helper files and functions

These contain the key functions that are called by multiple scripts above. They are also located in the ModelF folder.

AFIRT_calculation.R
- read.param.file() = read parameter file from Excel
- lumped.parameters.theory() = calculates AFTIR from theory
- lumped parameters.simulation() = calculates AFTIR from simulation
- simulation() - simulates model for one set of parmeters
ams_graphics_v2.R - Contains some useful graphics functions
scale.x.log10(), scale.y.log10() - for properly labeling log scaling
ams_initialize_scrpt.R - To be called at the top of every Rmd file. Initialization code and some useful constants.
ams_tmdd_helper.R - Could potentially be helpful for doing sensitivity analysis.
ivsc_4cmtc_shedct.R - ODE for Model F, written to work with RxODE

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tumormodeling's Issues

Append additional AFIRT terms for soluble target

Maybe do AFIRTM and AFIRTS, etc.

Create Parameter file which causes to M3totss accumulate

Andy thinks decreasing kshedDM3 would do it

M3 is not at steady state before first dosing.

Sameed noticed typos in initial conditions which could be causing this.

Should only be using key model parameters from excel, not all parameters

Param file could lead to confusion because we define CL, keD1 and VD1, but keD1=CL/VD1. Should have a function that strips the extraneous variables from the parameter vector.

Miandra to demonstrate Github Projects for creating minutes

Split Rmd file into Task01, Task02 etc. + external functions

This file currently does a lot of different things and is quite long. But it's exploring two different data files. I propose that we simplify into more modular Rmd files where

The functions are defined in a seperate R script (so they can be called by different Rmd files)
The Rmd files are made more modular (at least focusing on a aparticular data file or set of data files for now)

Perform sensitivity analysis for AFIRT.

Parameters to explore:

Determine if the time it takes for the concentration in the central compartment to reach a steady state could cause error in B.

To test this create a model with just D1, D2 and D3.

functions should not use global variables

Theoretical calculation and simulation functions should require dose.nmol, tau, and p as inputs. This will improve readability and robustness of code.

Check if changing the free formula in the code affects accuracy.

free_old = K_d/C
free_new = K_d/(C +K_d)

Don't know how to compute Cavg3

The title speaks for itself, I don't know how to compute Cagv3 from the parameters.

Confusion about Cavg1

I am confused about these two lumped parameters. For Cavg1, the formula is
[
Cavg1 = \frac{F \times dose.nmol}{CL \times \tau}
]
and $CL$ is computed as
[
CL = \frac{keD1}{VD1}
]
When I use the parameters for Atezolizumab to compute CL, I get 0.0185. However, CL is actually
given in ModelF_Atezolizumab_Params.xlsx, and its value is 0.2. I am not sure which one should we use to compute Cavg1.

AFIRT Sensitivity analysis duplicated functionality

File: TumorModeling\ModelF\AFIRTSensitivityAnalysis

Remove AFIRT_theory function and use only lumped.parameters.theory
Add B, Cavg1, Cavg3, and AFIRT to lumped.parameters.theory, and lumped.parameters.simulation and compare.

Combine individual plots of M3, Mfree, Mtot3, etc. into 1

Use ggplot2 + facet + tidyr::gather to do this.

First issue

The code does not wrong, I get this error message

There is VDi and VSi, but no VMi

I noticed that in the model file, the differential equations for M3, DM3, etc. should have volumes VM1, VM3 instead of VD1, VD3, as is the case for the S parameter. We will likely assume that the volumes are equal, but right now, it's confusing as written because there are VS1 parameters, but not VM1 parameters.

Changes in ivsc_4cmtct_shedct() not reflected

In "Sameed" branch is the file "sameed_scrap.rmd". Running this file simulates the model and plots the output.

I change something in "ivsc_4cmtct_shedct()" (e.g. on line 24, change "init["M3"] = unlist(x[4])" to "init["M3"] = unlist(x[3])"). Then in the console, I run "ivsc_4cmtct_shedct()". Then I run "sameed_scrap.rmd". The variable "out" in "sameed_scrap.rmd" does not change from the previous run.

Seriously what is the Thiele Modulus?

Elimination/Distribution =[(keDM3+kshedDM3)M3]/[PS/VD1avg] =
[(keDM3+kshedDM3)M3]/[P2πRcapL/(πRkrogh^2L)D1avg]
[(keDM3+kshedDM3)M3]/[P2Rcap/(Rkrogh^2)*D1avg]