## Composite model

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