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 *k*_{d} ∼ Pois(*m*_{d}/2) driver mutations and *k*_{n} ∼ Pois(*m*_{n}/2) neutral mutations. For each type of mutation, *N*_{d} and *N*_{n} mutations can be accumulated at maximum. For a cell that has *n*_{d} (=∑*k*_{d}) mutations, cell division probability *g* is defined as *g* = *g*_{0}*f*^{nd}, where *g*_{0} 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 *m*_{d}, *m*_{n}, *f* and *P* to log scale, i.e., *m*_{d}' = log_{10} *m*_{d}',
*m*_{n}' = log_{10} *m*_{n}', *f*' = log_{10} *f* and *P*' = log_{10} *P*, and then tested every combination of
*m*_{d}' ∈ {-4,-3,-2,-1},
*m*_{n}' ∈ {-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 |
---|---|

k_{d} |
number of driver mutations obtained in a cell division |

k_{n} |
number of neutral mutations obtained in a cell division |

n_{d} |
number of driver mutations accumulated in a cell |

n_{n} |
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 |
---|---|---|

m_{d} |
expected number of driver mutations generated per cell division | {10^{-4}, 10^{-3}, 10^{-2},10^{-1}} |

m_{n} |
expected number of neutral mutations generated per cell division | {10^{-2}, 10^{-1}, 10^{0},10^{1}} |

N_{d} |
maximum number of driver mutations accumulated in a cell | 3 |

N_{n} |
maximum number of neutral mutations accumulated in a cell | 1000 |

f |
increase of the cell division probability per driver mutation | {10^{0.1}, 10^{0.15}, 10^{0.2},...,10^{1.0}} |

g_{0} |
base cell division probability | 10^{-4} |

P |
maximum population size | {10^{3}, 10^{4}, 10^{5}, 10^{6}} |

T |
maximum number of time steps | 10^{6} |