Colorectal cancer models overview

Overall Model Structure: Individuals in all three models can move through several disease states: They can develop one or more adenomas which can grow in size and might eventually develop into cancer. Cancers may progress through stages I to IV. However, during each stage, colorectal cancer (CRC) may also be clinically diagnosed (i.e. because of symptoms). Survival after clinical diagnosis is determined by the stage at diagnosis, the localization of the cancer, and the person's age.

All three models are stochastic microsimulation models. The term "stochastic" implies that the models simulate sequences of events by drawing from distributions of probabilities or durations, rather than using fixed values. Hence the results of the models are subject to random variation. The term "microsimulation" implies that persons are moved through the model one at a time, rather than as proportions of a cohort. This allows future state transitions to depend on past transitions, giving the models a "memory". Further, unlike most traditional Markov models, the models do not use yearly transition probabilities; instead they generate durations in states, thereby increasing model flexibility and computational performance.

Time Scale: All models describe events in continuous time.

Population Structure: All models can simulate life histories for either a distinct cohort or a full cross-section of a hypothetical population via multiple-cohort modeling.

Adenoma Risk: All models allow adenoma risk to vary stochastically across individuals and by age, though the models use different distributions to describe variability in risk. All models allow multiple adenomas within individuals, though the models use different mechanisms to generate the number of adenomas within individuals. None of the models allow detectable adenomas in individuals <20 years of age. Both MISCAN-CRC and SimCRC allow adenoma risk to vary by birth cohort. In MISCAN-CRC, the average adenoma risk varies for a birth cohort based on the prevalence of risk factors within that cohort; in SimCRC the individual adenoma risk varies based on the presence of risk factor within an individual. The prevalence of risk factors in MISCAN-CRC and the presence of risk factors in SimCRC are varied through secular trends in risk factors.

Distribution of Adenomas in the Colorectum: All models have or can generate specific distributions for the location of adenomas in the colorectum. SimCRC and CRC-SPIN inform these distributions using data on the location of adenomas from autopsy studies; MISCAN-CRC assumes the distribution of adenomas in the colorectum is the same as the distribution of clinically detected CRCs (Table 3.4).

Adenoma Growth: All models allow adenoma growth to vary stochastically across individuals, and across adenomas within individuals, though the models use different distributions to describe variability in growth. None of the models specify correlation of adenoma growth within individuals. MISCAN-CRC and SimCRC define adenoma size categorically (<5mm, 6-9mm, 10+mm) and do not explicitly specify a minimum or maximum size. CRC-SPIN models adenoma growth continuously, with a minimum size of 1mm and maximum size of 50mm. Adenoma growth depends on location in the SimCRC and CRC-SPIN models, with SimCRC distinguishing between adenomas in the proximal colon, distal colon, and rectum, and CRC-SPIN distinguishing between adenomas in the colon and rectum. MISCAN-CRC can allow adenoma regression, although until now this feature has been ‘turned off' because there was not strong empirical evidence of adenoma regression. The SimCRC and CRC-SPIN models do not currently allow regression.

Progression to Preclinical Colorectal Cancer (CRC): All models allow for multiple preclinical cancers and allow the progression of adenomas to preclinical disease to vary stochastically across individuals and across adenomas within individuals, though the models use different distributions to describe variability in adenoma progression. All models assume independence of adenoma progression rates within individuals. The MISCAN-CRC and SimCRC models do not allow progression to preclinical cancer in adenomas that are less than 6mm. CRC-SPIN models progression as a function of continuous size, with a very small (but non-zero) probability of progression to preclinical cancer in adenomas less than 6mm in size. In the MISCAN-CRC and CRC-SPIN models, the probability that an adenoma progresses to preclinical cancer depends on age at adenoma initiation. In the SimCRC and CRC-SPIN models, adenoma progression depends on location in the colorectum. MISCAN-CRC specifies two types of adenomas, nonprogressive adenomas, which have no potential of becoming cancerous, and progressive adenomas which have this potential. The SimCRC and CRC-SPIN models do not explicitly model nonprogressive adenomas; these models simulate slow growing adenomas that would not progress, even for individuals living more than 100 years after adenoma initiation.

Progression to Clinically Detected CRC (Sojourn Time): All models allow sojourn times through preclinical CRC stages to vary stochastically across individuals, though the models use different distributions to describe variability in sojourn time. All models allow multiple adenomas to transition through preclinical and clinical detection states. All three models also allow multiple preclinical cancers. When one is detected (either by symptoms or by screening), all are assumed to be detected. Currently, none of the models allow metachronous primary CRC after CRC detection.

Risk Factor Modeling: Both the MISCAN-CRC and SimCRC models can include risk factors, and their basic models can describe CRC by race. CRC-SPIN has a general risk factor model, but it is not calibrated and does not currently include specific risk factors.

MISCAN-CRC and SimCRC include the same set of eight risk factors. MISCAN-CRC includes all risk factors using binary indicators and only allows risk factors to influence adenoma onset. SimCRC uses a mix of dichotomous and continuous risk factors and they may affect both adenoma onset and adenoma progression. Both MISCAN-CRC and SimCRC use the SimCRC module to describe risk factor prevalence, which accounts for correlation among the risk factors using NHANES data. The SimCRC risk factor module was calibrated using data from the National Health Interview Survey (NHIS) and Health Professionals Follow-Up Study (HPFS). MISCAN-CRC used published relative risks from the same datasets to estimate the effect of risk factors on adenoma on`set.

CRC Death: All three models stochastically assign CRC death using survival probabilities based on Cox proportional hazards models for relative survival applied to Surveillance, Epidemiology, and End Results (SEER) survival data for cases diagnosed from 1/1/1975 to 12/31/2003 with follow-up through 12/31/2010 (Rutter and colleagues, (2013)) Time to CRC death depends on stage, location (colon or rectum), age at diagnosis, year of diagnosis, sex, and (optionally) race. The SimCRC model also has a separate post-CRC-diagnosis model that simulates the risk of subsequent metastatic recurrence and only allows CRC deaths to occur following an unresectable metastatic recurrence.

Non-CRC Death: All models stochastically assign non-CRC death using life-tables from the National Center for Health Statistics. In addition as part of SimCRC's collaborative CISNET work, Dr. Wang developed life table adjustments that allow the models to incorporate the effects of obesity and smoking behavior on the risks of non-CRC death (Wang and colleagues, (2013); Dr. Cho developed life table adjustments that allow incorporation of the effects of comorbidity conditions on non-CRC death (Cho and colleagues, (2013).

Table 3.4. Distribution of Adenomas in the Colorectum, by Model

Table 3.4. Distribution of Adenomas in the Colorectum, by Model
LocationMISCAN-CRCSimCRCCRC-SPIN
Cecum0.160.100.08
Ascending colon0.080.230.23
Transverse colon0.120.290.24
Descending colon0.060.090.12
Sigmoid colon0.360.210.24
Rectum0.210.080.09