Colorectal cancer (CRC) accounts for one in 10 new cancer cases worldwide. CRC risk is determined by a complex interplay of constitutional, behavioral, and environmental factors. Patients with ulcerative colitis (UC) are at increased risk of CRC, but effect estimates are heterogeneous, and many studies are limited by small numbers of events. Furthermore, it has been challenging to distinguish the effects of age at UC diagnosis and duration of UC. Multistate models provide a useful statistical framework for analyses of cancers and premalignant conditions. This thesis has three aims: to review the mathematical and statistical background of multistate models; to study maximum likelihood estimation in the illness-death model with piecewise constant hazards; and to apply the illness-death model to UC and CRC in a population-based cohort study in Finland in 2000–2017, considering UC as a premalignant state that may precede CRC.
A likelihood function is derived for multistate models under noninformative censoring. The multistate process is considered as a multivariate counting process, and product integration is reviewed. The likelihood is constructed by partitioning the study time into subintervals and finding the limit as the number of subintervals tends to infinity. Two special cases of the illness-death model with piecewise constant hazards are studied: a simple Markov model and a non-Markov model with multiple time scales. In the latter case, the likelihood is factorized into terms proportional to Poisson likelihoods, which permits estimation with standard software for generalized linear models.
The illness-death model was applied to study the relationship between UC and CRC in a population-based sample of 2.5 million individuals in Finland in 2000–2017. Dates of UC and CRC diagnoses were obtained from the Finnish Care Register for Health Care and the Finnish Cancer Registry, respectively. Individuals with prevalent CRC were excluded from the study cohort. Individuals in the study cohort were followed from January 1, 2000, to the date of first CRC diagnosis, death from other cause, emigration, or December 31, 2017, whichever came first. A total of 23,533 incident CRCs were diagnosed during 41 million person-years of follow-up. In addition to 8,630 patients with prevalent UC, there were 19,435 cases of incident UC. Of the 23,533 incident CRCs, 298 (1.3%) were diagnosed in patients with pre-existing UC. In the first year after UC diagnosis, the HR for incident CRC was 4.67 (95% CI: 3.07, 7.09) in females and 7.62 (95% CI: 5.65, 10.3) in males. In patients with UC diagnosed 1–3 or 4–9 years earlier, CRC incidence did not differ from persons without UC. When 10–19 years had passed from UC diagnosis, the HR for incident CRC was 1.63 (95% CI: 1.19, 2.24) in females and 1.29 (95% CI: 0.96, 1.75) in males, and after 20 years, the HR was 1.61 (95% CI: 1.13, 2.31) in females and 1.74 (95% CI: 1.31, 2.31) in males. Early-onset UC (age <40 years) was associated with a markedly increased long-term risk of CRC. The HR for CRC in early-onset UC was 4.13 (95% CI: 2.28, 7.47) between 4–9 years from UC diagnosis, 4.88 (95% CI: 3.46, 6.88) between 10–19 years, and 2.63 (95% CI: 2.01, 3.43) after 20 years.
In this large population-based cohort study, we estimated CRC risk in persons with and without UC in Finland in 2000–2017, considering both the duration of UC and age at UC diagnosis. Patients with early-onset UC are at increased risk of CRC, but the risk is likely to depend on disease duration, extent of disease, attained age, and other risk factors. Increased CRC risk in the first year after UC diagnosis may be in part due to detection bias, whereas chronic inflammation may underlie the long-term excess risk of CRC in patients with UC
