Here, by combining the driver and neutral model, we build the composite model that, as expected, reproduces ITH more similar to those in real tumors. In a unit time, a cell divides into two daughter cells with a constant probability g without dying. In each cell division, each of the two daughter cells acquires kd ∼ Pois(md/2) driver mutations and kn ∼ Pois(mn/2) neutral mutations. For each type of mutation, Nd and Nn mutations can be accumulated at maximum. For a cell that has nd (=∑kd) mutations, cell division probability g is defined as g = g0fnd, where g0 is a base division probability. The simulation started from one cell without mutations and ended when the population size p reached P or time t reached T.
Information of variables and parameters are listed in Tables 1 and 2. In MASSIVE, we converted md, mn, f and P to log scale, i.e., md' = log10 md', mn' = log10 mn', f' = log10 f and P' = log10 P, and then tested every combination of md' ∈ {-4,-3,-2,-1}, mn' ∈ {-2,-1,0,1}, f' ∈ {0.1, 0.15, 0.2...,1.0} and P' ∈ {3, 4, 5, 6}. All results are explorable in the focused and comparative view modes of the MASSIVE viewer.
Table 1. a list of the variabes
symbol | description |
---|---|
kd | number of driver mutations obtained in a cell division |
kn | number of neutral mutations obtained in a cell division |
nd | number of driver mutations accumulated in a cell |
nn | number of neutral mutations accumulated in a cell |
p | population size |
t | number of time steps |
g | cell division probability |
Table 1. a list of the parameters
symbol | description | value |
---|---|---|
md | expected number of driver mutations generated per cell division | {10-4, 10-3, 10-2,10-1} |
mn | expected number of neutral mutations generated per cell division | {10-2, 10-1, 100,101} |
Nd | maximum number of driver mutations accumulated in a cell | 3 |
Nn | maximum number of neutral mutations accumulated in a cell | 1000 |
f | increase of the cell division probability per driver mutation | {100.1, 100.15, 100.2,...,101.0} |
g0 | base cell division probability | 10-4 |
P | maximum population size | {103, 104, 105, 106} |
T | maximum number of time steps | 106 |