Cmost Manual

Colon
Modeling with Open Source Tool (CMOST)

Notes and User Manual
Program generated by Meher Prakash and Benjamin Misselwitz

Table of content:
I. PROGRAM AND REQUIREMENTS 3
II. CMOST Folder Contents 4
II.2 CMOST applications 5
III. Opening the program 6
IV. CMOST Main Window 7
IV.1. M AIN W INDOW : P ATHS A ND SETTINGS 7
IV.2. Start, patients and additional settings 8
IV.3. Screening and Surveillance 9
IV.4. Output 10
IV.5. Scan variables 10
IV.6. Automated optimization 11
IV.6. Options 12
IV.6.1. Write CMOST batch instructions – Automatic tests 12
IV.6.2. Write CMOST batch instructions – Repeat identical settings 12
IV.6.3. Calibration Step 1, 2, 3 12
IV.6.3. Autocalibration Step 4 rectosigmo 13
V. CMOST output 13
V.1. CMOST graphical output 13
V.1.1. First page of CMOST graphical Results – adenoma prevalence, CRC incidence 14
V.1.2. Second page of CMOST graphical results: adenoma characteristics 14
V.1.3. Third page of CMOST graphical results: Cancer characteristics 17
V.1.4. Fourth page of CMOST graphical results -‐‑ CRC effects and CRC Screening 19
V.2. CMOST Results (Matlab variable) 20
V.3. CMOST Results (Excel File) 21
VI. Adjusting CMOST 22
VI.1. Risk 22
VI.2. Location 23
VI.3. Mortality 24
VI.4. Colonoscopy 25
VI.5. Costs 26
VI.6. Screening 26
VI.7. Adenoma dwell time 27
VII. Parameter optimization 28
Prakash et al. Manual for CMOST: Colon modeling with an open source tool. 1

VII.1. Step 1: Early adenomas 29
VII.1.1. Early adenoma benchmarks 29
VII.1.2. Optimizing early adenomas 30
VII.2. Step 2: Advanced adenomas 32
VII.2.1. Advanced adenoma benchmarks 32
VII.2.2. Optimizing advanced adenomas 33
VII.3. Step 3: Optimizing cancer 34
VII.3.1. Benchmarks for cancer optimization 34
VII.3.1. Optimizing cancer parameters 35
VII.4. Step 4: Adjusting direct cancer 36
VII.4.1. Benchmarks for adjusting direct cancer 36
VII.4.1. Optimizing direct cancer parameters 37
VII.5. Suggested scheme for automated calibration 38
VII.6. Alternative strategy for Step 4, adjustment of direct cancer 38
VII.7. Concomitant adjustment of Steps 1-‐‑3 39
VII.8. Manual adjustments 41
VII.9. Default benchmarks 42
VIII. Speed of calculations 42
VIII.1. Speed limit 42
VIII.2. Accelerating speed: the coder option 43
IX. Running CMOST in batch mode 45
IX.1. Using the STARTER option 45
IX.2. Parallel Calculations on a Linux cluster 46
IX.3. Generating multiple settings files with the “Scan Variables” option 48
IX.4. Simulating large populations 49


I. PROGRAM AND REQUIREMENTS

Checking out: CMOST program source code is uploaded to gitlab. The code is
available for the researchers under GNU Public license. The last version of the code
can be checked out in a LINUX/UNIX environment with the command:
$ git clone https://gitlab.com/cmostmodel/CMOST.git

or in a internet browser, visit the URL

https://gitlab.com/cmostmodel/CMOST
and click on the “Download Zip” option as shown below.

This will download the CMOST source code on your machine. Unzip the folder to
access the source files.

Software requirements:

CMOST program runs on Matlab R2011b or later versions (versions later than
2015b have not been tested).

The computationally intensive part of the Matlab program is converted into a C++
executable (MEX file, details in Section VIII.2. Accelerating speed, the Coder option
below). We provide compiled versions for Mac64, Windows64, Linux64. In case
another operating system is installed, coder generation should be done (otherwise
calculations for large population sizes will be slow). In order to achieve this
conversion Matlab requires the “coder toolbox” and compilers to be installed.
If no compiled versions of the time critical NumberCrunching subroutine are
available an error message is provided:

Some of the compilers include Microsoft Windows SDK 7.1, Microsoft Visual C++
2010 on windows, GNU gcc 4.3.x on Linux, Apple Xcode 4.1 on Mac OS X.

One can check the list of supported compilers for the version of Matlab at the
Mathworks website. For example, Matlab R2011b supports the following compilers.
http://www.mathworks.com/support/compilers/R2011b/win32.html

System requirements: A standard calculation of 100,000 individuals requires a 2
GB RAM and 2.5 GHz processing speed. Calculations with larger populations (a few
million might be a routine calculation of interest for health economists) require
larger RAM. To make the calculation easier, the job is split into sub populations of
100,000 and run in parallel on a large computer cluster.
II. CMOST Folder Contents

CMOST folder includes:

Software package implemented in MATLAB

1a. CMOST_Main GUI: Graphical User Interface which can be the starting point for
the microsimulation calculations

1b. CalculateSub: This subroutine processes the inputs including the risks of
adenomas, cancers as well as the preferences of screening method and passes this
data to the next module

1c. NumberCrunching: This module handles the most computationally intensive part
of the software. The module performs the microsimulation by tracking over the
entire population, all the adenomas that appeared and evolved in each individual
from the population

1d. Evaluation: This module processes the results from the microsimulation and
presents them as graphical comparisons to benchmarks, matlab data file for further
processing and as excel sheets.

1e. Other CMOST subroutines:
(to be explained below)

1f. Scripts to run the calculations
on cluster. The scripts are useful
for submitting multiple
calculations simultaneously on a
linux cluster.

2. Settings folder with pre-‐‑calibrated settings files

2a. Parameter set with dwell time 8 years (CMOST8.mat)
2b. Parameter set with dwell time 13 years (CMOST13.mat)
2c. Parameter set with dwell time 19 years (CMOST19.mat)

3. Cluster folder with scripts for submission to cluster
4. Codegen folder with MEX files compiled for running CMOST Matlab code
efficiently
5. Manual
II.2 CMOST applications

CMOST as an open source program, with pre-‐‑calibrated settings caters to the
following cases with the different levels of complexity.

User interest Manual Sections of How to do it Technical difficulty
interest
Repeat calculations with Sections III, IV, V Use any one of the None
same natural history for pre-‐‑calibrated
100,000 individuals settings from the
Settings folder
Repeat calculations with Sections III, IV, V. Use pre-‐‑calibrated None
same natural history for Additionally Section VI Settings and
100,000 individuals with for screening options, update required
updated Costs, costs, etc parameters
Screening Scenarios, etc
Repeat calculations with Sections III, IV, V. Use coder module Low. Requires
same benchmarks, but Additionally, Section in Matlab to checking supported
optimize the VIII to convert time convert one part of C++ compilers for
performance for faster consuming parts of the complete Matlab, and installing if
calculations program into faster program into a needed and Matlab
C++ equivalent faster MEX format command line usage
Repeat calculations with Sections III, IV, V. Use the pre-‐‑ Medium. Access to a
same or different natural Additionally Section IX calibrated settings linux cluster. Sufficient
history for much more for cluster scripts from the folder linux knowledge to use
than 100,000 individuals Settings the BASH scripts we
provide to execute
multiple jobs on a
cluster
Calibrate CMOST to a Sections III, IV, V. Update Medium. Our
different natural history Additionally, Section benchmarks in the automatic parameter
using a new choice of VI for parameter specified formats calibration works with
benchmarks calibration. (early, advanced a broad range of
adenomas, cancer, benchmarks. We

etc). Run cannot exclude that for
automatic some parameter
parameter settings, the heuristics
calibration. used in greedy-‐‑
algorithm may need to
be modified

III. Opening the program

The program CMOST_Main.m can be opened with the Matlab Editor and started
(press run, see red arrow).

This calls the function CMOST_Main.m in a graphical user interface.


IV. CMOST Main Window
After starting CMOST the following graphical user interface will appear:

Most basic functions of CMOST are accessible via the graphical user interface.
IV.1. MAIN WINDOW: PATHS AND SETTINGS

Settings name: Name of the current settings of CMOST
Save data path: Results of CMOST calculations will be saved under this path
Browse button: Browse for another path to save data
Comment: These comments will be saved with the settings
Default Settings: Since the current settings might be derived from a different set
of settings, the name of the original settings will be saved.
Load Settings button: Browse to load saved settings
Save Settings button: Save current settings for future use


Comment: Saved settings can be considered as instructions for an automated run by
CMOST; they can be used for an automatic run by CMOST either with the Starter
option in the graphical user interface or on the cluster.

IV.2. Start, patients and additional settings

(upper left part of main window)

Number patients: Adjust the number of patients for the next run of CMOST. For
technical reasons (usage of the coder programming module in Matlab) only 4
options are available: 10’000, 25’000, 50’000 and 100’000 patients. A larger number
of patients will be difficult for Matlab due to limitations in memory. If necessary,
several runs with 100’000 patients should be combined.
START: Start a run of Matlab with current settings

Starter: Starter option allows loading several saved runs of CMOST which can
be calculated sequentially
Start batch: Start calculations of the files selected with Starter option

Risk: Opens menu to adjust risk distribution of individual risk of adenoma
development and early and advanced adenoma progression (see
below)
Location: Opens menu to adjust behavior of CMOST in various locations within
the colon (i.e. adenoma appearance, progression, detection by
colonoscopy); see below.
Mortality: Opens menu to adjust CRC mortality according to age
Colonoscopy: Opens menu to adjust CMOST settings regarding colonoscopy
(for instance complications)
Costs: Opens menu to adjust costs for interventions and CRC treatment
Screening: Opens a menu to adjust settings for CRC screening

IV.3. Screening and Surveillance
(lower left in main window)

Enable CRC screening: If this box is checked, CRC screening will be performed
(screening parameters will be adjusted in Screening window)
Enable adenoma surveillance: If this box is checked, surveillance colonoscopies
will be performed (5 years after detection of 1 or 2 early adenomas, 3 years after
detection of an advanced adenomas and 5 years henceforward)
Enable cancer surveillance: CRC surveillance colonoscopies will be performed 1
and 4 years after CRC detection and henceforward every 5 years.
Special scenarios: If this box is checked one of the special scenarios below will be
considered during CMOST calculations

Special scenarios: The text indicates the special scenario. Several strings are
known to CMOST (see below). If a different string is entered the special scenario will
be ignored. Several special scenarios are hard coded:
-‐‑ “RS-‐‑Atkin”: simulation of the rectosigmoidoscopy study by Atkin et al.,
Lancet 2012), treatment arm
-‐‑ “RS-‐‑Atkin_Mock”: simulation the rectosigmoidoscopy study by Atkin et
al., Lancet 2012), control arm without screening
-‐‑ “RS-‐‑Schoen”: simulation of rectosigmoidoscopy study by Schoen et al.
NEJM 2012, treatment arm
-‐‑ “RS-‐‑Schoen_Mock” simulation of the rectosigmoidoscopy study by Schoen
et al. NEJM 2012, control arm without screening
-‐‑ “RS-‐‑Holme”: simulation of rectosigmoidoscopy study by Holme et al.
JAMA 2014, treatment arm
-‐‑ RS-‐‑Holme_Mock”: simulation of rectosigmoidoscopy study by Holme et al.
JAMA 2014, control arm without screening
-‐‑ RS-‐‑Segnan”: simulation of rectosigmoidoscopy study by Segnan et al. JNCI
2011, treatment arm
-‐‑ RS-‐‑Segnan_Mock”: RS-‐‑Segnan”: simulation of rectosigmoidoscopy study
by Segnan et al. JNCI 2011, control arm without screening
-‐‑ “perfect”, perfect intervention: simulation “maximum clinical incidence
reduction. At age 65 all colonic lesions will be removed and the evolution

of new lesions will be followed (van Ballegooijen et al., Med. Dec Making
2011)
-‐‑ “Po+-‐‑55”: at age 55 all individuals with and without adenomas will be
marked to be able to distinguish differences of both populations
-‐‑ “Po+-‐‑55treated”: as above, only adenomas will be removed; thereby,
individuals with treated adenomas at age 55 can be compared with
individuals without adenomas. (Kuntz et al., Med. Dec Making 2011)
-‐‑ “Kolo1”: A single colonoscopy at a given age will be performed
(technical comment: age can be found at the third position in the
colonoscopy screening window or at:
handles.Variables.Screening.Colonoscopy(3))
-‐‑ “Kolo2”: Two colonoscopies will be performed at pre-‐‑specified ages
The year of the second colonoscopy can be found at the fourth position in
the colonoscopy screening window or at:
-‐‑ “Kolo3”: Two colonoscopies will be performed at pre-‐‑specified ages
The year of the third colonoscopy can be found at the fifth position in the
colonoscopy screening window or at:
IV.4. Output

During a run of CMOST the program can generate a results file (Matlab variable), an
Excel file and/ or .pdf figures. Output will be saved in the Results-‐‑Folder (compare
Paths and Settings above)

IV.5. Scan variables

Variables Scan: enables systematic scanning of CMOST parameters. Thereby up to
5 parameters can be modified in parallel or 2 or 3 individual parameters can be
scanned independently (thus generating a 2D or 3D matrix of parameters). The
result will be a number of settings files which could be run on a Linux cluster or by
using the Start option.

IV.6. Automated optimization

Optimization of parameters required for calibrating the model will be done in 4
separate steps. Step 1 deals with early adenoma prevalence, progression and
distribution. Step 2 deals with advanced adenoma prevalence and distribution. Step
3 deals with carcinoma incidence, fast cancer (derived from adenoma precursors
other than P6) and rectum carcinoma. Step 4 adjusts the direct cancer rate (cancer
without adenomatous precursors).
Step 1 bench marks: opens a window to adjust benchmarks for Step 1

Optimize step 1: opens a window for automatic parameter adjustment step 1

Manual adjustments: Opens a window to visualize and manually adjust all
parameters important for a run of CMOST (these are the parameters automatically
adjusted by Step 1 – Step 4).

Default benchmarks: No window will be opened. The current benchmarks will be
replaced by benchmarks provided by the authors


IV.6. Options

Some functionality is available via this dropdown menu
IV.6.1. Write CMOST batch instructions – Automatic tests

A larger series of instruction files for CMOST is written enabling testing of standard
features of CMOST. These includes most of the tests from the CMOST manuscripts.
The user is asked to select the folder where the files will be saved and the number of
replicas.
Tests include:
-‐‑ Screening colonoscopy (ages 50-‐‑70, every 10 years with follow up)
-‐‑ Rectosigmoidoscopy screening (ages 50-‐‑70, every 10 years with follow
up)
-‐‑ Screening with FOBT, I-‐‑FOBT, Hemoccult Sensa, no intervention for
comparison
-‐‑ Simulation of randomized controlled trials for rectosigmoidoscopy
screening (according to Atkin et al., Schoen et al., Holme et al. and Segnan
et al.) with intervention and Mock
-‐‑ Comparison of individuals with and without adenomas at age 55, treated
and untreated
-‐‑ “perfect intervention” (i.e. “maximum clinical incidence reduction”, see
CMOST for details)
These instruction files could either be transferred to a linux cluster or calculated
using the (see appropriate section of this Manual). In the folder “Scripts” in the
CMOST-‐‑folder the file “Evaluate standard settings” will be helpful for evaluations
(please note that writing Excel file does not work on a Mac computer).
IV.6.2. Write CMOST batch instructions – Repeat identical settings

You are allowed to select a folder and the number of replicas. After that the current
settings of CMOST will be saved with the chosen number of copies. This is for
instance useful if a number of parallel calibrations will be needed.
IV.6.3. Calibration Step 1, 2, 3

Autocalibration 123

Will perform automated calibrations step 1-‐‑3 without graphical output and without
detailed reporting of results in one procedure. This might need several hours. See
section VII.7. for more detail.

Autocalibration 123 bootstrapping
As above with bootstrapping (see VII.7. for more detail). Please note that
bootstrapping has not been sufficiently tested and usage is not recommended.
IV.6.3. Autocalibration Step 4 rectosigmo

Autocalibration RS tests writing
Writes a battery of tests for titrating the best CancerVariable for direct cancer which
appears without adenomatous precursors (Step 4 of Autocalibration). These files
can be calculated using the Starter option or the Cluster. See Section “VII.7.
Alternative strategy for Step 4, adjustment of direct cancer” for more detail.

Autocalibration RS tests writing
The user is asked to select a folder with calculated files for RS tests (see above). The
results will be plotted, the best CancerVariable selected and transferred to the
current settings (if user agrees). See Section “VII.7. Alternative strategy for Step 4,
adjustment of direct cancer” for more detail.
V. CMOST output

Running CMOST calculation generates three different types of outputs -‐‑

1. Graphical output of the natural history, comparing to the benchmarks used.
The output is saved in PDF format as OUTPUT_NAME_1.pdf, …_2.pdf, …_3.pdf,
OUTPUT_NAME_4.pdf.
2. Excel format results file, summarizing the number of colonoscopies, number
of cancers, etc. This is saved as OUTPUT_NAME.xls.
3. Matlab format results file, which has all the detailed results including
developed or detected adenomas, cancers, costs, etc. This results file is saved
under the name OUTPUT_NAME_Results.mat and can be used for incidence,
cost calculations, etc.
All these results are saved in the results folder (see IV.1).
V.1. CMOST graphical output

If the “generate pdf file” option is checked, after a run of CMOST (i.e. after pressing
“Start”) 4 different pdf files are generated. CMOST also generates Matlab figures. For
convenience these figures are not closed after saving the pdf files.

V.1.1. First page of CMOST graphical Results – adenoma prevalence,

CRC incidence
The first page deals with early adenoma prevalence (left column), advanced
adenoma prevalence (middle column) and carcinoma incidence (right column).
Results are indicated separately for males (upper row), females (middle row) and
overall (lower row).

early polyps present advanced polyps present cancer incidence overall
60 14 400
12 350
50
300
per 100'000 per year

10
40
% of survivors
% of survivors
250
8
30 200
6
150
20
4
100
10 2 50
0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
year year
year
Early and advanced adenoma prevalence and CRC incidence for the overall
early polyps present male advanced polyps present male cancer incidence male
population.
60 Similar graphs are
20 generated for males
500and females. Benchmarks (as
adjusted in the benchmark windows) are indicated in blue; actual results of CMOST
50
calculations are indicated by
15 the black line. Data
400
points corresponding to the
benchmarks are plotted separately in green (if the

40
respective point is situated
% of survivors
% of survivors
300
within an arbitrary 20% tolerance from the benchmark) or in red (if the data point
30 10
is outside this tolerance range). Note: no tolerance is indicated for cancer incidence
200
20
<20 years. 5
10 100
0 0 0
V.1.2.
0
Second
20 40 60
year
page of
80 100 0 20
CMOST
40 60
year
graphical
80 100 0 20
results:
40 60
year
adenoma
80 100
characteristics
early polyps present female advanced polyps present female cancer incidence female
50 12 350
10 300
40
250
8
% of survivors
% of survivors
30 200
6
20 150
4
100
10
2 50
0 0 0
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
year year year

Page 2 upper row: distribution of adenomas-‐‑1
all early Adenoma 3mm 1 adenoma
at least P2 Adenoma 5mm 2 adenomas
at least P4
Adenoma 9mm 4 adenomas
at least P5
P6 Adv Adenoma P5 >4 adenomas
Adv Adenoma P6
% of patients with adenomas

all adenomas present number of adenomas
60 100 100
% of survivors
% of adenomas
40
50 50
20
0 0 0
0 20 40 60 80 100 Ear.Ad. BM Adv.Ad. BM 0 50 100
year
year
Left: Fraction o f p atients

young population (40-54y)
w ith a t l east 1 early a
intermediate population (55-74y)
denoma o f a t l east t he i
old population (75-90y)
ndicated s tage
is indicated as a function of age (P1: 3mm, P2: 5mm, P3: 7mm, P4: 9mm, P5: 1cm or
20 40 50
advanced histology, P6: 2cm. 35

40
Middle: 15 Adenoma all stage early distribution.
30 Fraction
Adenoma 3mm of 3mm, 5mm, 7mm, 1 adenoma 9mm early
% of population
% of population
% of population
adenomas of all atatearly adenomas is indicated; BM: benchmark. The green line
least P3 25 Adenoma 7mm 30 3 adenomas
least P4
indicates 10 agreement at least with
P6
P5 the benchmark,
20 the red
Adenoma 9mm
Adv Adenoma P5 line indicates >4a adenomas deviation of at
4 adenomas
least 20%. The right bars indicate 15 fraction of

Adv Adenoma P6
>1cm (or
20 advanced histology) and
% of patients with adenomas

>2cm 60adenomas
5
all adenomas and the respective
present
10010 benchmarks (BM). 100 number of adenomas
10
Right: Fraction of adenoma patients with only 1 adenoma, 2 adenomas etc., plotted
% of survivors
% of adenomas
5
40
as a function
0 of age. 50 0 50 0
20 1 2 3
min number polyps
4 5 1 2 3
min number polyps
4 5 1 2 3
min number polyps
4 5
0 0 0
Page 2 0middle
20 40
ryear
ow:
60
d80istribution
100
of adenomas-‐‑
Ear.Ad. BM Adv.Ad. BM
2 0 50
year
100
summary number polyps Relative danger adenomas
40-49y: 1.22 (0.59)
Ad 3mm 0.009 0.021 red
Adenoma 3mm
Adenoma 5mm
50-59y: 1.55 (1.15)
Ad 3mm 0.12 0.214 red Adenoma 7mm
young population (40-54y) intermediate population
Ad 3mm 0.285 (55-74y)
0.342 green old populationAdenoma
(75-90y)
9mm
20 60-69y: 1.94 (1.8) 40 Ad 3mm 0.593 50
70-79y: 2.19 (2.15) 1.069 red Adv Ad P5
80-89y: 2.43 (2.46) Adv P5 8.571 12.829 red Adv Ad P6
35 Adv P6 90.421 85.525 green direct
screening population (50-80y) 40
15 30
adenoma prevalvence : 32.8% origin of cancer
% of population
% of population
allpopulation
advanced adenoma prev.:5.7% 100

25 30
cancer
carcinoma prevalence:0.5%
10 20
50
20
of of
15
%%
5 10
10 0
0 5 10
5
decade
0 0 0
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
min number polyps min number polyps min number polyps

Left: Distribution of adenomas in the young population (age 40-‐‑54 years). The
fraction summary
of the population with Relative
number polyps
1, 2, 3, 4 0.021
danger adenomas
Ad 3mm 0.009
and 5
red
or more adenomas is indicated.
Adenoma 3mm
Adenoma 5mm
Benchmarks are indicated in blue. Please note that for the young population
40-49y: 1.22 (0.59)
50-59y: 1.55 (1.15)
60-69y: 1.94 (1.8) Ad 3mm 0.285 0.342 green Adenoma 9mm
benchmarking h
70-79y: 2.19 (2.15)
80-89y: 2.43 (2.46)
as b een inactivated a nd
Ad 3mm 0.593
Adv P5 8.571
t he c olor
1.069
12.829
red
red
o f t he m arkers is m eaningless.
Adv Ad P5
Adv Ad P6
Middle: screening
Fraction of individuals
population (50-80y) with a 85.525
Adv P6 90.421
given
green
number of adenomas direct
for the
intermediate population (55-‐‑
adenoma prevalvence : 32.8%
advanced adenoma prev.:5.7%
7 4 years) with benchmarks (blue) and agreement with
origin of cancer
100
benchmarks (green) or disagreement (red) with a tolerance of 20%. Please note that
% of all cancer
Prakash et al. Manual for CMOST: Colon modeling with a50 n open source tool. 15

0
0 5 10
decade
year year
young population (40-54y) intermediate population (55-74y) old population (75-90y)

20 40 50
35
40
15 30
% of population
% of population
% of population
25
5 indicates 5 or more adenomas. Only this plot (but
30
not the young or the old
10 20
population) will be used for automated calibration in 20Step 1.
15
Right: Fraction of Fraction of individuals with a given number of adenomas for the
old population (75-‐‑90 years).
5 10
Colors and labels as for 10the intermediate population.
5
0 0 0
1 2 3 4 5 1 2 3 4 5 1 2 3 4 5
Page 2 lower row: adenoma summary, origin of cancer min number polyps
min number polyps min number polyps

summary number polyps Relative danger adenomas Adenoma 3mm
40-49y: 1.22 (0.59)
50-59y: 1.55 (1.15)
60-69y: 1.94 (1.8) Ad 3mm 0.285 0.342 green Adenoma 9mm
70-79y: 2.19 (2.15) Ad 3mm 0.593 1.069 red Adv Ad P5
80-89y: 2.43 (2.46) Adv P5 8.571 12.829 red Adv Ad P6
Adv P6 90.421 85.525 green direct
screening population (50-80y)
adenoma prevalvence : 32.8% origin of cancer

advanced adenoma prev.:5.7% 100
% of all cancer
50
0
0 5 10
decade

Right: Average number of adenomas for individuals of a given age (mean and
standard deviation). The fraction of individuals of the screening population (50-‐‑
80years) with adenomas, advanced adenomas and cancer is also indicated.
Middle: Relative danger adenomas. CMOST assumes that most cancers derive from
advanced adenomas (P6). However, a fraction of cancers will also derive from
smaller adenomas (“fast cancer”). Relative danger indicates the origin of all cancers
with adenomatous precursors (most from large adenomas, very few also from small
adenomas). The left column indicates numbers from the current run, the middle
column benchmarks and the right column agreement with benchmarks (within 20%
tolerance – green, outside 20% tolerance – red).
Right: Origin of carcinomas. The origin of carcinomas either “direct, i.e. without
adenomatous precursors or an adenoma of a given stage (3, 5, 7, 9 mm, P5 or P6) is
indicated as a function of age.


V.1.3. Third page of CMOST graphical results: Cancer
characteristics
Page 3 upper row: stage distribution of colorectal cancer
Stage I Stage I Stage I
Stage II Stage II Stage II
Stage III Stage III Stage III
Stage IV Stage IV Stage IV
stage distribution screening stage distribution symptomatic cancer stage distribution follow up
100 100 100
% of affected patients
80 80 80
60 60 60
40 40 40
20 20 20
0 0 0
<50 50+ 60+ 70+ 80+ 90+ all b-mark <50 50+ 60+ 70+ 80+ 90+ all b-mark <50 50+ 60+ 70+ 80+ 90+ all b-mark

year year year
Stage I Stage I Stage I
The distribution Stage of
II cancer stages (stage
StageI…
II stage IV) are labeled
Stage II by colors as
Stage distributionStage III Stage III male Stage III female
indicated in the legend. Stage distribution is provided per decade (<50y, 50-‐‑
100
per location
Stage IV 100
fraction rectum carcinoma
Stage IV 100
fraction rectum carcinoma
Stage IV 59, 60-‐‑
69, 70-‐‑stage
79, 80-‐‑ 89, ≥90), for all patients and the benchmark is indicated (very left of
distribution screening stage distribution symptomatic cancer stage distribution follow up
each panel, b-‐‑
80
100
mark). Green color indicates agreement with the benchmark (within
80
100 80
100
% rectum of all ca
% rectum of all ca
20% 80
60
tolerance), red color indicates
80
60
disagreement with 60
80
the benchmark.
CMOST provides results for cancers detected 40during screening (left), for
60 60 60
40 40
spontaneous
40
20
( i.e. symptomatic) 40
20
cancer and for cancer 4020detected during surveillance.
0 0 0
Page
20
3 <50
m50+iddle row: b-mark
60+ 70+ 80+ 90+ all
year
CRC location
20 <50 50+ 60+ 70+ 80+ 90+ all
year
b-mark 20 <50 50+ 60+ 70+ 80+ 90+ all
year
b-mark
0 0 0
all Rectum Right Rest 0 50carcinoma male
100 0
Stage distribution per location fraction rectum fraction rectum50 100
carcinoma female
100 year 100 year 100 year
80
fraction of all carcinoma without polyp precursor 80 80
of affected patients
100 dwell time all Ca

% rectum of all ca
% rectum of all ca
present
70 diagnosed
60 60 60 multiple cancer
80 60
% cancer
40 40 50 40 cumulative cancer
60 8
40
years
% of all patients
% direct
20 20 30 6
20
40
20 4
0 0 0
20 all Rectum Right Rest 0 10 50 100 0 50 100
2
year
0 year year
Left: 0Percentage o f
all Ca right side
carcinoma a nd
all s
10tage
20 30 40d 50istribution
60 70 80 90100 of
0
0
cancer
20 40
a ccording
60 80 100
t o l ocation
decade
(all, 100rectum, right colon, remaining cdwell olon) is allindicated.
fraction of all carcinoma without polyp precursor
time Ca year
present
Middle/ right: Rectum carcinoma 70
as a fraction of all carcinoma in males (left) and
diagnosed
multiple cancer
80
females (right) is indicated according to age. The black line indicates (noisy) raw
60
% direct cancer
numbers,
60 blue markers indicate 50benchmarks. Red or g8reen cumulative markers indicate an
cancer
average of 5 years around the year of the benchmark. G

40
reen color indicates that the
years
% of all patients
6
value
40 is within 20% tolerance of the benchmark, red colors indicate a value outside
30
that tolerance.
20 4
20 10
Prakash et al. Manual for CMOST: 0
Colon modeling with 2an open source tool. 17
0 all 10 20 30 40 50 60 70 80 90100 0
all Ca right side decade 0 20 40 60 80 100
year
60 60 60
% of affected p
% rectum of
% rectum of
40 40 40
20 20 20
0 0 0
Page 3 lower row:
all Rectum Right dRest
irect cancer,
0 dwell 50time, cumulative
100 0 cancer
50 100
year year year

fraction of all carcinoma without polyp precursor
100 dwell time all Ca
present
diagnosed
80 multiple cancer
80
% direct cancer
60 cumulative cancer
60 8
years
% of all patients
40 6
40
4
20
20
2
0
0 all 10 20 30 40 50 60 70 80 90100 0
all Ca right side decade 0 20 40 60 80 100
year

Left: Fraction of direct cancer (i.e. cancer without adenomatous precursors) from all
cancer (left bar) and right-‐‑sided cancer (right bar). The green line indicates 20%,
the red line indicates a 50% value.
Please note that CMOST assumes that many serrated/ flat/ hard-‐‑to-‐‑detect lesions
preferentially reside in the right colon. Since direct cancer also represents these
lesions, direct cancer is located preferentially within the right colon.
Middle: Box plots of adenoma dwell time is indicated (dwell time is defined as the
time from appearance of an adenoma to appearance of colon cancer) for each
decade. The box indicates the 25th and 75th percentile of adenoma dwell times.
Outliers are indicated by red crosses.
Right: Cumulative cancer as a function of age. The black line indicates the fraction of
patients with cancer (present or past, diagnosed or undiagnosed). The blue line
indicates the fraction of patients with a past or present diagnosis of cancer. The
green line indicates the fraction of patients with multiple cancers.


V.1.4. Fourth page of CMOST graphical results -‐‑ CRC effects and CRC
Screening
Page 4 upper row: CRC mortality
Cancer mortality per year male Cancer mortality per year female Cancer mortality per year overall
300 250 250
250
200 200
per 100 000 per year per 100 000 per year
200
150 150
150
Cancer mortality per year male Cancer mortality per year female Cancer mortality per year overall
300 100
250 100
250
100
250 50 50
200 200
50
200
0 0
150 0
150
0 20 40 60 80 100 0 20 40 60 80 100 0 20 40 60 80 100
150
year year year
100 100
CRC related mortality (according to the SEERS data base) is indicated as a function
100
of the
50 age of the all patient for males (left),
50
natural females (middle) and
50 overall (right).
symptoms
Benchmarks are indicated a s b lue m arkers, a greement ( within 2 0%) is indicated by
excl. Ca
Man
cancer screening
0 excl. Ca 0 colonoscopy 0 follow up
a green 0color.
20 40 Woman
60
excl. Ca
80 100 0 20 40 60 80 100 0 20 40 baseline
60 80 100
year causeyear
of death year
10 5 reasons for colonoscopies
Page 4 middle row: Survival, cause of death, indication
Survival 10 4 colonoscopy
number patients
100
number patients
% of all patients
all natural symptoms

excl. Ca
cancer screening
50 Man 10 2
excl. Ca colonoscopy follow up
Woman baseline
excl. Ca
0 cause of death
0 10
10 5 10 0
0 20 40 60
Survival 80 100 1 2 3 4 5 6 7 8 9 10+ 0 reasons for 50
colonoscopies
100
10 4
number patients
100 year decade year

number patients
% of all patients
50 10 2
early all cost
population: 100000 patients
advanced treatment age: all: 74.6, male: 73.1, female: 76.11
follow up 0 screening colos performed
0 10 0 10 0 5488 symptom colos performed
0 20 40 removed
adenomas 60 80 100 1 2 3 4 5 screening
6 7 8 9 10+ 0
13022 follow up colos 50performed 100
800 year decade 0 custom tests performed
year
dollars spent per person
2182 patients died of CRC
number adenomas
26711.2 years lost to CRC

Left: 600
Survival. Percentage of all surviving patients (black), males (blue), female 150 0 pat. died due to colo
0 years lost to colo
(red)
400at a given age.
early Please 100
note that due to the low CRC incidence changes in 3.2324e+08 total CRR rel costs
US Dollar
all cost comment: no comment please

population:
settings: 100000 patients
Default_Settings_March_2016
CRC related survival are usually not detectable
advanced treatment
follow up
in this plot. age: all: 74.6, male: 73.1, female: 76.11
0 screening colos performed
50
Middle: Causes of death (natural, CRC related, endoscopy related) are indicated.
200
adenomas removed screening 5488 symptom colos performed
13022 follow up colos performed
800
Please 0 note the logarithmic y-‐‑s0cale.
0 custom tests performed
0 dollars spent 50 per person100
number adenomas
0 50 100 26711.2 years lost to CRC

Right:
600Indications (reasons) f150
year or colonoscopy
year (either for CRC related symptoms, CRC 0 pat. died due to colo
screening, CRC surveillance (i.e. follow up of adenoma or carcinoma) are indicated. 3.2324e+08 total CRR rel costs
US Dollar
400 100 comment: no comment please
Please note the logarithmic y-‐‑scale.

settings: Default_Settings_March_2016
200 50
0 0
0 50 100 0 50 100
year year

number patie
number patien
% of all patient
50 10 2
0 10 0 10 0
0 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10+ 0 50 100
year decade year
Page 4 lower row: adenomas removed, dollars spent, summary

early all cost
population: 100000 patients
advanced treatment age: all: 74.6, male: 73.1, female: 76.11
follow up 0 screening colos performed
5488 symptom colos performed
adenomas removed screening 13022 follow up colos performed
800 0 custom tests performed
dollars spent per person
number adenomas
26711.2 years lost to CRC

600 150 0 pat. died due to colo
3.2324e+08 total CRR rel costs
US Dollar
400 100 comment: no comment please
settings: Default_Settings_March_2016
200 50
0 0
0 50 100 0 50 100
year year

Left: Total number of early (red) and advanced (black) adenomas removed.
Middle: CRC related health care costs (related to CRC treatment, CRC screening and
CRC follow up) are indicated.
Right: Verbal summary of the current run of CMOST.
V.2. CMOST Results (Matlab variable)

Most of the results presented by the graphical user interphase are also available as a
Matlab output file. The results file OUTPUT_NAME_Results.mat stores the results in
a Matlab structure format. The variables stored in this structure can be seen by first
loading the results file into Matlab and then looking up the names of the fields:


The description of the benchmarks, benchmark values and the corresponding
results from CMOST calculations are stored in the fields BM_Description,
Benchmark, and BM_Value. The number of early cancers appearing, for example, is
retrieved by typing OUTPUT_NAME_Results.Early_Cancer. Check out Matlab
documentation for more detail.

V.3. CMOST Results (Excel File)

CMOST also provides results of a given calculation as an EXCEL-‐‑file with self-‐‑
explaining headlines. Please note that the Mac-‐‑version of Matlab does not support
the xlswrite-‐‑function and generation of Excel-‐‑files is not possible using a Macintosh.


VI. Adjusting CMOST
VI.1. Risk

Individual risk (upper left): At birth, an individual adenoma risk is assigned to each
patient. This risk determines the likelihood of the appearance of a new adenoma
(other factors determining adenoma risk are age, gender). A distribution of relative
risks is plotted and the relative risk for a given percentage of individuals is indicated
(12 bins: 0%, 10%, 20%... 97%, 100%).
At birth, for each individual a specific risk is drawn from the distribution indicated
by the graph. Thereby, 0 indicates no risk of ever getting an adenoma. A high
number (compared to the other numbers in this plot) indicate a high adenoma (and
subsequently a high cancer risk).
Note: Individual risk is adjusted during Step 1 of automated parameter calibration.
Thereby, anchor points are automatically adjusted
Adenoma risk – early progression (upper right): Risk for progression for an early
adenoma. At adenoma initiation, an early adenoma progression risk and an
advanced adenoma progression risk is assigned to each adenoma. This risk is
randomly drawn from a distribution of risks indicated by the graph and remains
constant throughout the lifetime of an adenoma. A low number indicates slow
progression of early adenoma, a high number fast progression (and a dangerous
adenoma quickly transforming to an advanced adenoma). The distribution of risks
can be adjusted as described for individual adenoma risk.

Adenoma risk – advanced progression (lower right): Risk for progression of an
advanced adenoma and subsequent transformation to cancer. The progression risk
is randomly drawn at the initiation of an adenoma and remains constant throughout
the lifetime of an adenoma. Adjustment as described above.
Correlate: if this box is checked, early and advanced progression for a given
adenoma will correlate (i.e. if the 50th percentile of early adenoma progression will
be selected, the 50th percentile of advanced adenoma will also be selected, resulting
in an adenoma of intermediate progression speed). Default and recommended
option: ON
Note 1: The risk distribution for early and advanced adenoma is a critical parameter.
A steep curve or uneven distribution of early and advanced progression risks result
in a short adenoma dwell time. Vice versa, a flat curve will result in a long adenoma
dwell time.
Note 2: The risk distributions for early and advanced adenomas have to be manually
adjusted (no automated adjustment is available). The only way to adjusted adenoma
dwell time remains adjustment of the risk curve followed by automated parameter
calibration. Since Parameter calibration will also influence adenoma dwell time the
effect of adjusting the risk might partially bounce back and several rounds for
adjusting the risk curves and parameter calibration might be necessary.
Note 3: We provide 3 preset versions of CMOST with 8, 13 and 19 years dwell time.
We did not succeed calibrating a version of CMOST with <8 years dwell time.

Technical comment: The chance of actual adenoma progression is the product of the
individual adenoma-‐‑specific progression rate, age specific adenoma progression
rate, the gender specific progression rate and the location specific progression rate
(this is true for early and advanced adenomas).
VI.2. Location


This window allows for adjustments in adenoma behavior according to the location
of the adenoma. In CMOST, 13 colon segments are considered (1: cecum – 13:
rectum).
New adenoma: the numbers indicated the fraction of new adenomas to be situated
in each colon segment.
Adenoma progression, early/ advanced: Progression of early and advanced
adenomas can be adjusted. In the current version of CMOST progression of rectal
adenomas differs from adenomas in the remaining colon to account for a high rate of
rectal carcinomas.
Direct cancer: Location specific probability for the appearance of direct cancer (i.e.
cancer without adenomatous precursors. CMOST assumes direct cancer to be
situated preferentially within the right colon.
Detection during colonoscopy: Allows for the adjustment of different adenoma
detection rates in various segments of the colon.
Detection during rectosigmoidoscopy: Allows for the adjustment of different
adenoma detection rates in during rectosigmoidoscopy in various segments of the
colon.
Note: With the current settings, CMOST assumes an identical detection rate of
rectosigmoidscopy and colonoscopy
Reach of colonoscopy: Probablity that a colonosocpy will reach a certain colon
segment
Reach of rectosigmoidoscopy: Probablity that a rectosigmoidoscopy will reach a
certain colon segment
Return: Return to main window.
VI.3. Mortality
Allows for the adjustment of age dependent CRC
specific mortality. To reduce discrepancies in
calculated and reported mortality rates, CMOST
assumes a 45% increase in CRC mortality beyond age
86 years.


VI.4. Colonoscopy

Allows for the adjustment of critical settings for colonoscopy for the risks for
perforation during colonoscopy and rectosigmoidoscopy, death following
perforation, serosa burn (i.e. post-‐‑polypectomy syndrome), risks for bleeding and
severe bleeding.
Colo-‐‑detection: allows for the adjustment of the probability for detection of the
indicated lesions during colonoscopy.
Rectosigmo-‐‑detection: allows for the adjustment of the probability for detection of
the indicated lesions during rectosigmoidoscopy.
Note: With the current settings, CMOST assumes the detection rate of
rectosigmoidscopy for early adenomas to be 25% lower, for advanced adenomas to
be 12.5% lower than for colonoscopy
Colonoscopy rate (base line colonoscopy rate) will be implemented in a later
version of CMOST.

VI.5. Costs

Allows for the adjustment of costs of the indicated interventions (upper left
corner), complications of interventions (lower left corner) and cancer
treatment. Cancer treatment is thereby divided in an initial year (1st year), a
terminal year (the year before the patient will die if applicable) and continuous
care (time after the first year until year 5 or terminal year).

VI.6. Screening


Screening: allows for the adjustment of screening interventions.
7 screening interventions are implemented (colonoscopy, rectosigmoidoscopy,
FOBT, I-‐‑FOBT, Septin-‐‑9, other). These interventions can be combined but the
selected fraction of the population will adhere to the indicated screening test for the
rest of its life. For each screening intervention the following parameters can be
adjusted:
Left side:
-‐‑ Fraction of population (0…1): fraction of the population that will chose a
given screening test
-‐‑ adherence: fraction of population that will use the screening test at each
indicated time point (0…1)
-‐‑ follow-‐‑up: adherence to the follow up investigation (i.e. colonoscopy after
a positive screening test; 0…1).
-‐‑ y start: year at which screening will be started
-‐‑ y end: year at which screening will end
-‐‑ interval: interval at which screening tests will be applied (for instance 1,
2 or 5 years)
-‐‑ y after colo: time interval in years that CMOST will wait for another round
of screening after the last colonoscopy (performed for whatever reasons)
-‐‑ specificity: for detection of colonic lesions (determines the false positive
rate)
Right side: Sensitivity for the detection of the indicated lesions.
Fraction not screened: determines the fraction of the population which will not
undergo a screening test.
VI.7. Adenoma dwell time

Dwell time is the time from the appearance of a clinically detectable adenoma to it
developing into cancer. The graphical outputs show dwell time on page 3. Further,
loading the results file OUTPUT_NAME_Results.mat, loads a Matlab structured
variable Results. In it, Results.Variable{18} gives the dwell time.

Dwell time is a result of the time spent by the adenoma in several stages, and if a
model with different dwell time is desired, it is not straight-‐‑forward to precisely
adjust the dwell time. CMOST8, CMOST13, CMOST19 are preset with 8 years, 13
years and 19 years of dwell time. This range covers the range of dwell time covered
by other microsimulations.

We recommend adjusting the risks for early and advanced adenoma progression
(see VI.1. Risk). However, this step will not only change adenoma dwell time but
also several additional parameters. Therefore, all remaining parameters need to be
re-‐‑adjusted (preferentially automatically, see VII. Parameter optimization). The

adjustment will partially reverse the dwell time. Therefore, several rounds of risk
adjustment and parameter optimization might be necessary to achieve the desired
dwell time.
VII. Parameter optimization

This section is specifically for advanced users, who would like to use their own
benchmark parameters to create the CMOST settings file and to perform
calculations using them. An early user wanting to reproduce the calculations with
the default CMOST settings can ignore this section.

Parameterization approach: CMOST is a very detailed model with many different
parameters. For example, the new polyp appearance is a sigmoid function
parameterized by three parameters. The early polyp progression is assumed to be of
Gaussian form and is parameterized by three additional parameters. Inclusion of all
parameters used for describing the model would make it difficult if not impossible
to obtain an automated parameter estimation.

In order to achieve the results in a quick way, two strategies were adopted –
● The comparison of the calculated results to benchmarks is made in four
steps. It was observed during the calculations that these four-‐‑steps behaved
almost independently of each other. Making this step-‐‑wise parameterization
reduces the complexity from simultaneously optimizing twenty parameters
to fewer parameters in each step.
● The parameter space was not explored with all possible combinations of the
parameter values, but instead, in an initial step the parameters were
corrected iteratively, depending on how far the calculated results were from
the predictions. This greedy algorithm approach makes the exploration of the
parameter space directed towards achieving the benchmarks provided. For
some key parameters this is followed by a systematic unbiased search using
the Nelder-‐‑Mead simplex algorithm.

While the biology of colorectal cancer is complicated, at a very simple level of
description, colorectal cancer has two kinds of origins – adenomatous polyps that
can be detected in a colonoscopy, and flat/ serrated polyps (or non-‐‑polyp lesions)
that are hard to be detected by colonoscopy. The latter kind of lesions are accounted
for by the “direct cancer” pathways, i.e. cancer without adenomatous precursors.

Evolution from adenomas or without adenomas as well as the incidence of
colorectal cancer defines the natural history of colorectal cancer, in the absence
of any screening interventions.


Parameter calibration is done in 4 separate steps:
1. Early adenoma prevalence and distribution
2. Advanced adenoma prevalence and distribution
3. Cancer incidence
4. Direct cancer
Number and size (or stage) distribution of adenomas and cancer as a function of age
and gender – observed either in colonoscopy studies or in autopsy studies are used
as benchmarks. Direct cancer (step 4) is benchmarked in an indirect way using the
data of a rectosigmoidoscopy randomized control trials.
VII.1. Step 1: Early adenomas

VII.1.1. Early adenoma benchmarks

Left (overall): Prevalence of early adenoma overall (i.e. males and females). The
number indicates the fraction of individuals with at least one (early or advanced)
adenoma. To add another benchmark just add a new year and an adenoma
prevalence. The sort button (lower right in this window) will sort all benchmarks
according to age. Below all benchmarks are illustrated with a graph
Second from left (male): As above, male population
Middle (female): As above, female population
Second from right – Multiple adenoma: Numbers indicate the fraction of individuals
with exactly 1 adenoma, 2, 3, 4 adenomas or 5 or more adenomas. Here the
population 55-‐‑74 years of age is considered.
Right graph -‐‑ Distribution of adenoma stage: Distribution of adenoma stages (i.e.
fraction or percentage of adenomas at a given stage (i.e. 3mm, 5mm, 7mm, 9mm)

Technical comment: for optimization step 1 only adenoma stages I-‐‑IV are
considered (the sum of the number adenoma stages I-‐‑IV is used as 100%); for
optimization step 2 only adenoma V and VI will be considered.
Sort: sort benchmarks according to age.
Return: return to main window.
VII.1.2. Optimizing early adenomas

CMOST will try to optimize overall, male and female adenoma prevalence,
distribution of multiple adenomas within the population and adenoma stage
distribution I-‐‑IV.
In the first set of iterations heuristic, customized algorithms will be used to
approach an optimum. In the second set of algorithm a Nelder-‐‑Mead simplex
algorithm will be used to refine this optimum. After an optimum is found the user
will be asked, whether the parameters found should be kept.
1st iteration: number of calculations for first set of iteration (heuristic algorithms)
2nd iteration: number of calculations for second set of iteration (Nelder-‐‑Mead)
Start: start optimization procedure
Stop: stop optimization procedure (the current run will be finished)
Technical comment 1:
-‐‑ For adenoma prevalence the age dependent new adenoma rate is
adjusted (3 coefficients of a sigmoid curve, see manuscript). In addition,

CMOST adjusts a scaling factor for adenoma appearance in females to
minimize the differences to the benchmarks in males and females.
-‐‑ For distribution of multiple adenomas the distribution of individual risks
for the population is adjusted
-‐‑ For the adenoma stage distribution, the stage specific adenoma
progression rates are adjusted according to the square root of the ratio of
observed vs. expected relative prevalence.
Technical comment 2:
Using these benchmarks, the following two internal vectors are adjusted:
-‐‑ New polyp appearance, which is a vector with the relative likelihood of
appearance of adenomas for each year between ages 0 and 99.
-‐‑ Individual Risk (vector with 500 numbers): This vector determines the
distribution of individual risks. This distribution might be flat (i.e. very
similar cancer and adenoma risks between individuals) or steep (i.e.
uneven, highly different adenoma and carcinoma risks). CMOST assumes
each simulated individual to have a person specific risk for adenoma
appearance. This individual risk is drawn from a distribution of these 500
numbers. This risk may be due to heredity, nutrition, or other factors. A
distribution of individual risks is calculated and benchmarked using the
distribution of multiple adenomas (a high frequency of multiple
adenomas can only be achieved if an uneven distribution of individual
risks are assumed (i.e., many high-‐‑risk individuals compared to average)


VII.2. Step 2: Advanced adenomas
VII.2.1. Advanced adenoma benchmarks

Left: prevalence of advanced adenomas (percentage of individuals with at least 1
advanced adenoma 1cm or 2cm; i.e. P5 or P6).
Middle left: same as above, male population
Middle right: same as above, female population
Right: distribution of adenoma, compare Benchmarks Step 1, above
Sort: will sort benchmarks according to the year

VII.2.2. Optimizing advanced adenomas

General strategy: CMOST will optimize overall, male and female advanced adenoma
prevalence, and adenoma stage distribution of advanced adenomas (P5: advanced
adenoma >1cm or advanced histology, P6: advanced adenoma >2cm).
In the first set of iterations customized heuristic algorithms will be used to approach
an optimum. In the second set of algorithm a Nelder-‐‑Mead simplex algorithm will be
used to refine this optimum. After an optimum is found the user will be asked,
whether the parameters found should be kept.
In addition, a scaling factor for adenoma progression for females will be adjusted to
account for different advanced adenoma distributions for females and males. This
scaling factor is not reported.

1st iteration: number of calculations for first set of iterations
2nd iteration: number of calculations for second set of iterations
Adjust Adv. Adenoma, Adjust adenoma distribution: adjustments can be activated/
inactivated separately.
Technical comments:

-‐‑ For advanced adenoma prevalence the age dependent early adenoma
progression rate is adjusted (3 coefficients of a Gaussian curve, see
manuscript). In addition, CMOST adjusts a correction factor for adenoma
appearance in females to minimize the differences to the benchmarks in
males and females.
-‐‑ For the adenoma stage distribution P5/ P6 the stage specific adenoma
progression rates is adjusted according to the square root of the ratio of
observed vs. expected relative prevalence.
VII.3. Step 3: Optimizing cancer

VII.3.1. Benchmarks for cancer optimization

Left: incidence of carcinoma whole population
Middle left: same as above, male population
Middle right: same as above, female population
Upper right -‐‑ relative danger of adenoma. This parameter is benchmarked reversely;
we estimate that the indicated fraction of carcinoma were derived from an adenoma

of the indicated stage. For instance, 1% of all carcinoma originated directly within
an adenoma of 9mm size (stage IV = P4), skipping the P5 stage (>1cm) and the P6
stage (>2cm).
Lower right – fraction of rectum carcinoma: A disproportionate fraction of
carcinoma is observed in the rectum. Benchmarks can be added for adjustment of
the fraction of rectum carcinoma (only the second and the third benchmark, i.e. the
5 year span around year 62 and 72 will be used).
Sort: will sort incidence benchmarks according to the year
Return: return to main window

VII.3.1. Optimizing cancer parameters

General strategy: CMOST will optimize overall, male and female carcinoma adenoma
prevalence, the relative danger of adenomas (i.e. the fraction of carcinomas derived
from each type of adenomas other than P6-‐‑adenoma (>2cm)) and the fraction of
rectum carcinoma.
In the first set of iterations customized heuristic algorithms will be used to approach
an optimum. In the second set of algorithm a Nelder-‐‑Mead simplex algorithm will be

used to refine this optimum. After an optimum is found the user will be asked,
whether the parameters found should be kept.
1st iteration: number of calculations for first set of iteration
2nd iteration: number of calculations for second set of iteration
Adjust fraction rectum, Adjust cancer, Adjust relative danger adenoma: adjustments
can be activated/ inactivated separately.
Technical comments:
-‐‑ For carcinoma incidence the age dependent advanced adenoma
progression rate is adjusted (3 coefficients of a Gaussian curve, see
manuscript). In addition, CMOST adjusts a correction factor for advanced
adenoma progression in females to minimize the differences to the
benchmarks in males and females.
-‐‑ For the relative danger adenoma a conversion factor for each type of
adenoma is adjusted according to the square root of the ratio of observed
vs. expected relative prevalences.
-‐‑ For adjusting the fraction of rectum carcinoma the location specific
progression rate of rectum adenomas (early and advanced) will be
adjusted.

VII.4. Step 4: Adjusting direct cancer

VII.4.1. Benchmarks for adjusting direct cancer


Incidence reduction overall: incidence reduction by sigmoidoscopy screening. This
parameter will be used for benchmarking.
Incidence reduction right/ left, mortality reduction: the respective outcomes in the
rectosigmoidoscopy study. These parameters are not used for benchmarking.
Comment: due to specific differences in the rectosigmoidoscopy studies (i.e. age of
population, 1 or 2 screening interventions (Schoen et al., NEJM 2012), adherence to
screening etc.) incidence reduction only makes sense in connection with the
selection of the study (see VII.4.1., below).
VII.4.1. Optimizing direct cancer parameters

General strategy: CMOST uses data from randomized controlled rectosigmoidoscopy
studies for the adjustment of direct cancer. Direct cancer is assumed to be localized
mainly in the right-‐‑sided colon, modeled by a sigmoid curve (see manuscript).
CMOST adjusts only the maximum of this sigmoid curve. Thereby, the variable
“DirectCancerSpeed” (direct cancer variable) will be adjusted using the square root
of the expected vs. observed incidence reduction rates for overall carcinoma.
Graph incidence reduction: for the calculations the trends in incidence reduction
overall (yellow), incidence reduction left colon (blue) and incidence reduction right
colon (red) are indicated.
Graph direct cancer variable: Trends in the variable “DirectCancerSpeed” are
indicated.
Max. iterations: Number of iterations
Number averaging: At the end of the calculations the last n individual direct cancer
speeds will be averaged (to reduce noise) and the resulting number used further on.
Scenario: 3 scenarios are modeled by CMOST, the user can choose either: “Atkin et
al., Lancet 2010”, “Schoen et al., NEJM 2012”, “Holme et al., JAMA 2014” or “Segnan,
JNCI 2011”.
Start: start calculations
Stop: stop calculations (the current run will be finished)
Return: return to main window


VII.5. Suggested scheme for automated calibration
We suggest to run all 4 optimization steps sequentially and adjust the number of
trials and the size of the patient population:
• Step 1: 25’000 patients, 10 trials first iteration, 30 trials second iteration
• Step 4: 100’000 patients, 30 trials first iteration, averaging the last 10
iterations
Comments:
-‐‑ Variables will only be transferred if the user applies the “Return” button
in each window, not simply by closing the windows.
-‐‑ Calculations for step 1 and 2 will be fast. Step 3 can take one hour. If
calculations are excessively slow please check that the coder option has
been appropriately used (section VII).
VII.6. Alternative strategy for Step 4, adjustment of

direct cancer
Since simulation of even a population as large as 100’000 results in some noise in
the data, we designed another way to adjust direct cancer. Thereby the “direct
cancer variable” will be systematically varied to span the range of reasonable values
with a selected number of repeats; results will be averaged and the most
appropriate value used.

Load the settings for which you want to adjust the direct cancer variable.
à Menu Option
à autocalibration step 4 rectosigmo
à Automatic RS tests writing
You will be able to choose the number of repeats. For the settings calculated for
CMOST we used 25 repeats, resulting in 15x25 = 375 calculations.
Calculations can be done on a Linux cluster (recommended, see section VII.2) or
using the Starter Option (Section VII.1).

After calculations are finished, results can be summarized:
à Menu Option
à autocalibration step 4 rectosigmo
à Automatic RS tests reading

Results might look as follows:

In the plot above, results of an individual repeat are shown in blue, the averaged
value in red, the trendline is indicated by a blue line. The benchmark for overall
incidence reduction is indicated by a thin blue line. The point where the both lines
cross is calculated and the best value for cancer variable extracted.
The user will be asked, whether the calculated Cancer variable should be kept, if yes
it will be replaced in the settings.
VII.7. Concomitant adjustment of Steps 1-‐‑3

Steps 1-‐‑3 can be run subsequently (see above) with graphical representation of key
parameters. However, CMOST also supports optimization of Steps 1-‐‑3 in a single
procedure. This can be done from the CMOST Main window or on the cluster.

à Menu Option
à Calibration step 1, 2, 3
à Autocalibration step 123
The current settings will be used as a starting point. CMOST will perform the
following steps:
-‐‑ Step 1: With population size 25’000, 10 and 30 repeats for the first and
second set of iterations, respectively

-‐‑ Step 2+3 with population size 100’000, 100 iterations
CMOST will start running the calculations; no graphical output is provided. The
results of the calculations will be put back to CMOST main window. Calculations
might need several hours. For best results we suggest performing this automated
calibration on a Linux cluster; thereby, several calculations can be run in parallel
(see section X.2).

Note: For the combination of step 2 + 3 the Nelder-‐‑Mead simplex algorithm will be
used only. It can be useful to achieve even more precise fitting since some
interferences between steps 2 and 3 are present. This combined mode is not
available with a graphical user interphase.

We also developed automated calibration using bootstrapping. Thereby, for each
settings parameter an artificial population with the size of the original study (source
data) with the same distribution of the parameter as in the original study (source
data) will be generated. For each parameter individuals will be randomly drawn and
a new study population is generated (with the size of the original study). Since each
individual can be drawn more than once, some fluctuation of each parameter will be
present. Bootstrapping addresses the uncertainty of calculations. Bootstrapping has
not been sufficiently tested and usage is currently not recommended.

VII.8. Manual adjustments

CMOST also supports visualization and manual adjustment of all parameters.
This would be an alternative strategy to automated calibration. The user would
need to manually change parameters in this window, press Return to transfer
parameters to main window and press Start in the main window, followed by
inspection of the matlab figures or .pdf files. With experience, with 30-‐‑50 iterations
good agreement of all parameters can be achieved.
Manual calibration results in slightly better agreement with benchmarks and
ultimately provides an intuitive understanding of the model parameters. However,
we recommended the objective approach provided by the automated calibration.
New polyp rate: for each increment of 5 years an age-‐‑specific adenoma appearance
rate can be entered. CMOST will interpolate the rates for the years in between.
Technical comment: for the automated settings a sigmoid curve with 3 parameters
is assumed and the individual points will be calculated.
Early polyp progression: as for new polyp, only the age specific early adenoma
progression rate can be adjusted.
Advanced polyp progression: as for new polyp, only the age specific advanced
adenoma progression rate can be adjusted.

Direct cancer: The age specific direct cancer rate can be adjusted separately for
males and for females. For the settings provided by the authors, the direct cancer
rate follows the cancer incidence benchmarks. Direct cancer refers to cancer
without adenomatous precursors.
Technical comment:
-‐‑ The probability of direct cancer will be the result of the direct cancer rate
and “direct cancer speed”.
-‐‑ In the current settings the direct cancer rate equals the carcinoma
incidence
Progression: adenoma stage specific progression rates can be adjusted. These rates
determine the probability of progression for instance from a polyp 5mm (stage II,
P2) to a polyp 7mm (stage III, P3).
Technical comment: The rate of actual progression will be the product of stage-‐‑
specific progression rate, age-‐‑specific early or advanced adenoma progression rate,
gender-‐‑specific correction factor and a location specific correction factor.
Fast cancer: Refers to cancer directly derived from adenoma stages other than P6
(advanced adenoma >2cm). The probabilities of conversion to cancer for each
adenoma stage can be adjusted here (very low for small adenomas and relevant only
for large adenomas P5, >1cm).
Healing: CMOST assumes a low probability of adenoma regression, to be adjusted in
this windows. Adenoma healing is not calibrated.
Female gender: Correction factors to control for the fraction of females within the
general population (at birth), appearance of new adenoma, progression of early
adenoma and progression of advanced adenoma.
Direct cancer speed: allows for adjusting the fraction of direct cancer (i.e. without
adenomatous precursors) in the population.
VII.9. Default benchmarks

No new window will open, but all benchmarks will be reverted to the default
settings provided by the authors.
VIII. Speed of calculations

VIII.1. Speed limit
CMOST calculation handles large arrays. It loops over a population of (say) 100,000
individuals, following each of them over 100 years, and the number of adenomas
which can be up to 50. Handling the large data and calculations in Matlab makes it
slow, requiring about 20 minutes to finish such a calculation on a 2.5 GHz and 4 GB
RAM machine. This is because calculations by Matlab codes can be much slower
than their C or C++ counterparts.

VIII.2. Accelerating speed: the coder option

The computationally intensive part of CMOST is a function NumberCrunching.m
which is called from the subroutine Calculate_Sub.m.
Matlab offers a way to accelerate the calculations to achieve speeds comparable to C
programs. This option called coder and is called with the Matlab function “codegen”.
Important note: CMOST is provided with converted files for PC and Macintosh,for
some machines (64-‐‑bit machines). For best performance it might be necessary to
generate NumberCrunching.mex anew. Conversion is also necessary after each
modification in the NumberCrunching function. If no appropriate .mex file is
available, a warning will appear.
Due to technical requirements of the Matlab function “codegen”, it is necessary to
compile NumberCrunching for each number of patients (i.e. 10’000, 25’000, 50’000,
100’000). One additional routine (QuickRS, evaluating results of the simulated
randomized rectosigmoidoscopy studies) also needs to be converted.
Specifically, the conversion is achieved by the following steps:
1. Start Matlab
2. Change path to the CMOST folder
cd /Users/USERNAME/Documents/CMOST
(the command pwd will print the current path, cd .. moves on step up in the folder hierarchy,
cd FOLDERNAME one step down, consult Matlab documentation for details)
3. Change to the codegen folder

cd codegen
4. Load variables
load Variables_100000.mat
5. Change to CMOST path

cd ..
6. Use Matlab command “codegen” on NumberCrunching

codegen NumberCrunching_100000 -‐‑args All
7. Repeat these steps for 50000, 25000, 10000 patients

cd codegen, load Variables_50000.mat, cd .., codegen NumberCrunching_50000 -‐‑args All
8. Do codegen for one subprogram evaluating results of the simulated

randomized rectosigoidsocopy studies
cd codegen /, load RS_Variables_100000, cd .., codegen QuickRS -‐‑args All

After NumberCrunching.m module is converted to NumberCrunching_mex.mex, it is
called in the function Calculate_Subroutine.m exactly with the same arguments, with
only a difference in the name. NumberCrunching_mex is capable of performing
faster calculations (in our experience 20X faster).

IX. Running CMOST in batch mode
IX.1. Using the STARTER option
Press the “starter” button in the main window for following window:

The starter option allows to select individual saved settings_files as a pipeline. These
settings files can then be subsequently run by CMOST (settings files can also be
considered instruction files for a run of CMOST). One convenient way to generate
settings files would be the “Scan Variable” option.
Add item: Browse and select for Settings files
Add folder: a folder with all settings files can be added to the pipeline
Delete: delete individual files

Up, Down: change order of files
Comment: If files have been selected the “start batch” button will be active and the
pipeline can be started.
IX.2. Parallel Calculations on a Linux cluster

Calculations can be performed on a linux cluster. This allows parallel processing of
many jobs and tremendously increases the power of CMOST. However, the setup of
each cluster is different and not general solution can be provided. The following
steps will work on the Linux cluster Euler at ETH Zurich. If the setup of your cluster
differs, consult the cluster administration for support. Matlab and appropriate
compiler need to be installed on the cluster.
1. Adjust Foldernames in CMOSTCluster.m
Open CMOSTCluster.m in the Matlab Editor (if you do not know what this
means, consult Matlab documentation)
Adapt line 25:
addpath ('/cluster/home/USERNAME/CMOST')
2. Adjust Foldernames in CMOSTCluster_Calibration_Step123.m
Open CMOSTCluster_Calibration_Step123.m in the Matlab Editor
Adapt line 25:
addpath ('/cluster/home/USERNAME/CMOST')
3. Copy CMOST from your computer to the Linus-‐‑Cluster
From a Mac Terminal the following commands will work:
scp –r /Users/USERNAME/Documents/CMOST
USERNAME@euler.ethz.ch:/cluster/home/USERNAME
Note: paths on your computer or Linux cluster might look quite different.
4. Copy bash scripts to cluster
We will setup the cluster to be able to do 2 things: 1) calculations using a provided settings-‐‑
file (i.e. instruction file). 2) automated parameter calibration. For that 4 scripts need to be
copied:
a) submit_standard, Calib_submit (for automated submission of jobs)
b) CMOSTClusterSub, CMOSTClusterSub_Calib (subroutine called by the previous programs)

From a Mac terminal the following commands would work:
scp /Users/USERNAME/Documents/CMOST/Cluster/bash_Scripts/submit_standard
scp /Users/USERNAME/Documents/CMOST/Cluster/bash_Scripts/Calib_submit
scp /Users/USERNAME/Documents/CMOST/Cluster/bash_Scripts/CMOSTClusterSub
scp /Users/USERNAME/Documents/CMOST/Cluster/bash_Scripts/CMOSTClusterSub_Calib

5. Login to the cluster
ssh USERNAME@euler.ethz.ch
6. Make bash scripts executable

chmod +x submit_standard
chmod +x Calib_submit
chmod +x CMOSTClusterSub
chmod +x CMOSTClusterSub_Calib
7. Generate Data folder and folders for output

mkdir Data
mkdir JobOutput
mkdir Data_Calib
mkdir JobOutput_Calib
8. Copy data to the cluster

Copy files for calculations:
scp –r /Users/USERNAME/Documents/YOURDATAFOLDER
USERNAME@euler.ethz.ch:/cluster/home/USERNAME/Data
(this will copy a whole folder with settings files = instruction files to the cluster, this might
be settings files systematically varying for the year of the screening colonoscopy)

AND/ OR copy files for automated parameter calibration:
scp –r /Users/USERNAME/Documents/YOURDATAFOLDER
USERNAME@euler.ethz.ch:/cluster/home/USERNAME/Data_Calib
(this files will be used as starting points for automated parameter calibration)
9. Start Matlab
module load matlab/8.5 (loads matlab to be started)
matlab –nojvm
(this will start Matlab without java virtual machine and thus without the graphical user
interphase which usually does not work on a busy Linux login node. However, operating
Matlab from the command line will work)
10. do codegen for all files necessary (see also VII.2 the coder option)
in Matlab:
cd /cluster/home/USERNAME/CMOST
cd codegen, load Variables_100000.mat, cd .., codegen NumberCrunching_100000 –args All
cd codegen /, load RS_Variables_100000, cd .., codegen QuickRS –args All
11. Start calculations

./submit_standard (for submitting files for calculations)
./Calib_submit (for submitting files for calibrations)

Notes:
-‐‑ You can use bjobs to follow how many jobs are currently running
-‐‑ During calculations for each settings file one results file in the form
ORIGINALFILENAME_Results.mat will be generated.
-‐‑ By checking the data folder you can also follow progress
cd ./Data/YOURDATAFOLDER

ls
for each original settings file one results file should be present.
-‐‑ You can follow the JobOutput folder for troubleshooting
cd ./JobOutput
vi YOURDATAFILE
12. Copy data back to your local computer and summarize data
IX.3. Generating multiple settings files with the

“Scan Variables” option

Purpose: “Scan variables” generates a number of settings files which differ
systematically in only 1 parameter (or several parameters as specified below). This
parameter could for instance be the year of a screening colonoscopy. This option
efficiently generates settings files (=instruction files) without the need of manually
changing one parameter and saving the file.
Scan: 1 CMOST parameter (or 2…5 parameters) will be changed
2D scan: 2 parameters will be individually changed (generating a 2D matrix of
parameters)
3D scan: 3 parameters will be individually changed (generating a 3D matrix of
parameters)
Number variables: only active for “scan” (single variable). Up to 5 individual
variables can be chosen (Variable 1…5).
Number steps: Determines the number of individual steps a variable will be tested
(for instance, for testing a single screening colonoscopy could be tested in 50
individual steps from age 30 to age 79). Therefore, 50 settings files would be
generated.

Number steps 2 and 3: Number of individual steps for the 2nd and 3rd variable (for
instance, 3 individual screening colonoscopies could be tested at age 30 to 79 and
50x50x50 = 125’000 individual settings files that would be generated.
Choose: Choose an individual parameter that will be varied. However, this requires
navigating through the variables of CMOST. However, naming of the variables is
usually self-‐‑explanatory and follows mainly the structure of the various graphical
user interphases. In case of a doubt the settings files generated can be reloaded in
CMOST and the graphical user interphases can be inspected .
Subposition: Several variables have subpositions (for instance screening has options
for percentage of population, adherence etc. as in the “Screening” graphical user
interphase). In the example with 3 screening colonoscopies the variable name
would be “Sreening.Colonoscopy” and the subpositions 3, 4 and 5.
Minimum, Maximum: minimum and maximum value of the respective variable (for
the example with screening colonoscopies, minimum would be 30 and maximum
79).
Adjust: before files can be generated CMOST wants the user to confirm (possibly
after adjustment) the individual values for each step (for instance, for screening
colonoscopies year 29.1 would be meaningless).
Filename: base filename for the files to be generated.
Linker: for the naming of the files, positioned between baseline and the number for
an individual file
Browse: Browse for a path to save the settings files to be generated
Economy: if checked double positions (for instance 2 colonoscopies at age 50/ 60
and 60/ 50 will be avoided. This reduces the number of files and the time for
calculations.
Number repeats: Each settings file can be generated once or with a given number of
repeats. Repeating calculations (and subsequent averaging) will reduce noise.
Linker repeats: Each file generated as a repeat will have in the file name the repeat
number attached with a linker string between filename and this number. This linker
can be selected.
Create files: create settings files in the respective folder.
Return: return to main menu.
IX.4. Simulating large populations

Colorectal cancer incidence is approximately 5%. And the incidence reduction could
be about 30% of this, which is about 1.5%. The risks of colonoscopy are even
smaller. Performing calculations on a small group of 100,000 can lead to stochastic
errors because of the small percentages. Since it is a theoretical model, it is better to
perform the calculations on large populations of a few million in order to get the
predictions right.


However, the memory requirements are very high, and a typical calculation for a
population of 100,000 requires more than 2 GB memory. In avoid memory and
processing limitations in performing the calculations on large populations, we split
the population into multiple jobs. For example, to perform a calculation of 300,000
using the settings of CMOST13.mat, CMOST13 can be saved as CMOST13_1,
CMOST13_2 and CMOST13_3 and calculated using the cluster or the Starter option.

Results have to be summarized using custom made scripts. Examples for these
scripts can be found in the Scripts folder in the CMOST folder. These scripts can be
used as a guide and modified for generation of scripts for different purposes.


Cmost Manual

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Cmost Manual

Uploaded by

Copyright:

Available Formats

Colon

Modeling with Open Source Tool (CMOST)

II. CMOST Folder Contents

II.2 CMOST applications

III. Opening the program

IV.1. MAIN WINDOW: PATHS AND SETTINGS

IV.2. Start, patients and additional settings

IV.5. Scan variables

IV.6.1. Write CMOST batch instructions – Automatic tests

IV.6.2. Write CMOST batch instructions – Repeat identical settings

IV.6.3. Calibration Step 1, 2, 3

IV.6.3. Autocalibration Step 4 rectosigmo

V.1. CMOST graphical output

V.1.1. First page of CMOST graphical Results – adenoma prevalence,

per 100'000 per year

benchmarks are plotted separately in green (if the

% of patients with adenomas

Left: Fraction o f p atients

advanced histology, P6: 2cm. 35

least 20%. The right bars indicate 15 fraction of

% of patients with adenomas

advanced adenoma prev.:5.7% 100

young population (40-54y) intermediate population (55-74y) old population (75-90y)

adenoma prevalvence : 32.8% origin of cancer

100 dwell time all Ca

average of 5 years around the year of the benchmark. G

all natural symptoms

100 year decade year

26711.2 years lost to CRC

all cost comment: no comment please

0 50 100 26711.2 years lost to CRC

400 100 comment: no comment please

Please note the logarithmic y-­‐‑scale.

Page 4 lower row: adenomas removed, dollars spent, summary

26711.2 years lost to CRC

V.2. CMOST Results (Matlab variable)

V.3. CMOST Results (Excel File)

VI.7. Adenoma dwell time

VII. Parameter optimization

VII.1. Step 1: Early adenomas

VII.1.2. Optimizing early adenomas

VII.3. Step 3: Optimizing cancer

VII.3.1. Optimizing cancer parameters

VII.4. Step 4: Adjusting direct cancer

VII.4.1. Optimizing direct cancer parameters

VII.6. Alternative strategy for Step 4, adjustment of

VII.7. Concomitant adjustment of Steps 1-­‐‑3

VII.9. Default benchmarks

VIII. Speed of calculations

VIII.2. Accelerating speed: the coder option

3. Change to the codegen folder

5. Change to CMOST path

6. Use Matlab command “codegen” on NumberCrunching

7. Repeat these steps for 50000, 25000, 10000 patients

8. Do codegen for one subprogram evaluating results of the simulated

IX.2. Parallel Calculations on a Linux cluster

6. Make bash scripts executable

7. Generate Data folder and folders for output

8. Copy data to the cluster

11. Start calculations

IX.3. Generating multiple settings files with the

IX.4. Simulating large populations

You might also like

Please note the logarithmic y-‐‑scale.

VII.7. Concomitant adjustment of Steps 1-‐‑3