Use three states of a continuous-time Markov chain: disease-free , pre-clinical , and clinical . The transition intensities are for onset and for progression. Clinical disease is an absorbing state. The mandatory pre-clinical phase excludes a direct jump, and this untreated progression model has no reverse transitions.
Figure 1.
Irreversible cancer progression from disease-free to pre-clinical to clinical states
. Details.
With row-vector probabilities and state order , the generator matrix is
Its rows sum to zero, so only the two off-diagonal transition intensities are unknown. This is a continuous-time multi-state model with sequential irreversible progression.

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