Appendix: Model Descriptions
We used the MISCAN and SimCRC models from the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) to compare strategies for colorectal cancer screening that vary by the age at which to begin screening, the age at which to end screening, and screening interval. The use of 2 models (that is, a comparative modeling approach) provides a sensitivity analysis on the model structure. Although the models were developed independently, they were calibrated to the same data on adenoma prevalence and colorectal cancer incidence, and they use the same assumptions regarding the sensitivity, specificity, and reach of the various screening tests. Accordingly, differences in findings across models may be attributed to differences in model structure and the assumptions about the natural history of colorectal cancer. Both models are described below.
MISCAN-COLON is a semi-Markov microsimulation program that simulates the effect of screening and other interventions on the incidence and mortality of colorectal cancer. With microsimulation, we mean that each individual in the population is simulated separately. The model is semi-Markov in the following regards: 1) distributions other than exponential are possible in each disease state; 2) transitions in one state can depend on transitions in earlier states; 3) transitions can be dependent on age and calendar time; and 4) all events in the model are discrete, but the durations in each state are continuous—thus, there are no annual transitions in the model.
Simulation of the Natural History of Colorectal Cancer
In the model, colorectal cancer is assumed to develop according to the adenoma-carcinoma sequence. This means that adenomas arise in the population, and some eventually develop into colorectal cancer. We assume that there are 2 types of adenomas: nonprogressive and progressive. Nonprogressive adenomas can grow in size but will never develop into cancer. Progressive adenomas have the potential to develop into cancer if the person in whom the adenoma develops lives long enough.
All adenomas start small (≤5 mm). They can grow in size to medium (6 to 9 mm) and large (≥10 mm) adenomas. Progressive medium-size and large adenomas can transform into malignant cancer stage I (not yet giving symptoms; preclinical cancer). The cancer then eventually progresses from stage I (localized) to stage IV (distant metastasis). In each stage there is a probability of symptoms developing and clinical detection of the cancer. An adenoma is assumed to take, on average, 20 years to develop into colorectal cancer and become detected by symptoms. However, because many adenomas do not progress to colorectal cancer before the person dies of other causes, the average time a lesion has been present before it is diagnosed as colorectal cancer is approximately 10 years. After clinical detection, a person can die of colorectal cancer or of other causes based on the survival rate. Survival from colorectal cancer is highly dependent on the stage in which the cancer was detected.
Simulation of an Individual
Appendix Figure 1 shows how the model generates an individual life history. MISCAN-COLON first generates a time of birth and a time of death from causes other than colorectal cancer for an individual. This is shown in the top line of Appendix Figure 1. This line constitutes the life history in the absence of colorectal cancer. Subsequently, the model generates adenomas for an individual. For most individuals, no adenomas are simulated, for some multiple. In this example, MISCAN-COLON has generated 2 adenomas for the individual. The first adenoma occurs at a certain age and grows from a small to a medium to a large adenoma. However, this is a nonprogressive adenoma and will never transform into cancer. The second adenoma is a progressive adenoma. After having grown to 6 to 9 mm, the adenoma transforms into a malignant carcinoma, causing symptoms and eventually resulting in an earlier death from colorectal cancer.
The life history without colorectal cancer and the development of the 2 adenomas are combined into a life history in the presence of colorectal cancer. This means that a person's state is the same as the state of the most advanced adenoma or carcinoma present. If the individual dies of colorectal cancer before dying of other causes, the death age is adjusted accordingly. The combined life history with colorectal cancer is shown in the bottom line of Appendix Figure 1.
Simulation of Screening
The complete simulation of an individual life history in Appendix Figure 1 depicts a situation in which screening does not take place. After the model has generated a life history with colorectal cancer but without screening, screening is overlaid. This is shown in Appendix Figure 2. The first 3 lines show the combined life history with colorectal cancer and the development of the 2 adenomas from Appendix Figure 1. At the moment of screening, both adenomas are present, then detected and removed. This results in a combined life history for colorectal cancer and screening (bottom line), where the person is free of adenomas and carcinomas after the screening intervention. Because the precursor lesion has been removed, this individual does not develop colorectal cancer and will therefore not die of colorectal cancer. The moment of death is delayed until the moment of death of other causes. The benefit of screening is equal to the difference between life-years lived in a situation without screening and the situation with screening.
Many other scenarios could have occurred. A person could have developed a third adenoma after the screening moment and could still have died of colorectal cancer. Another possibility is that one of the adenomas was missed, but in the presented example the individual really benefited from the screening intervention.
The effectiveness of screening depends on the performance characteristics of the test: sensitivity, specificity, and reach. In the model, 1 - specificity is defined as the probability of a positive test result in an individual regardless of any adenomas or cancers present. For a person without any adenomas or cancers, the probability of a positive test result is therefore equal to 1 - specificity. In individuals with adenomas or cancer, the probability of a positive test result depends on the lack of specificity and the sensitivity of the test for the present lesions. Sensitivity in the model is lesion-specific, where each adenoma or cancer contributes to the probability of a positive test result. The model provides the opportunity to consider the possibility of systematic test results.
The SimCRC model of colorectal cancer was developed to evaluate the effect of past and future interventions on the incidence and mortality of colorectal cancer in the United States. The model is population based, meaning that it simulates the life histories of multiple cohorts of individuals of a given year of birth. These cohorts can be aggregated to yield a full cross-section of the population in a given calendar year. For this analysis, we simulated the life histories of only 1 cohort—those age 40 years in 2005. SimCRC is a hybrid model, a cross between a Markov model and a discrete-event simulation. Although annual (often age-specific) probabilities define the likelihood of transitioning through a series of health states, the model does not have annual cycles. Instead, the age at which a given transition takes place for each simulated individual is drawn from a cumulative probability function.
Simulation of the Natural History of Colorectal Cancer
The SimCRC natural history model describes the progression of underlying colorectal disease (that is, the adenoma-carcinoma sequence) in an unscreened population. Each simulated individual is assumed to be free of adenomas and colorectal cancer at birth. Over time, each person is at risk for forming 1 or more adenomas. Each adenoma may grow in size from small (≤5 mm) to medium (6 to 9 mm) to large (≥10 mm). Medium-size and large adenomas may progress to preclinical colorectal cancer, although most will not in an individual's lifetime. Preclinical cancers may progress in stage (I to IV) and may be detected by the presence of symptoms, becoming a clinical case. Individuals with colorectal cancer may die of their cancer or of other causes.
The SimCRC model allows for heterogeneity in growth and progression rates across multiple adenomas within an individual. Although all adenomas have the potential to develop into colorectal cancer, most will not. The likelihood of adenoma growth and progression to colorectal cancer is allowed to vary by location in the colorectal tract (that is, proximal colon vs. distal colon vs. rectum). Appendix Figure 1 shows how the SimCRC model constructs an individual's life history in the absence of screening for colorectal cancer.
Simulation of Screening
The screening component of the SimCRC model is superimposed on the natural history model. It allows for the detection and removal of adenomas and the diagnosis of preclinical colorectal cancer (Appendix Figure 2). In a screening year, a person with an underlying (that is, undiagnosed) adenoma or preclinical cancer faces the chance that the lesion is detected on the basis of the sensitivity of the test for adenomas by size or for cancer and the reach of the test. Individuals who do not have an underlying adenoma or preclinical cancer also face the risk for having a positive screening test result (and for undergoing unnecessary follow-up procedures) because of the imperfect specificity of the test. While the model does not explicitly simulate nonadenomatous polyps, they are accounted for through the specificity of the test. In addition, individuals with false-negative screening test results (that is, individuals with an adenoma or preclinical cancer that was missed by the screening test) may be referred for follow-up because of the detection of nonadenomatous polyps. The model incorporates the risk for fatal and nonfatal complications associated with various screening procedures. It also accounts for the fact that not all individuals adhere to colorectal cancer screening guidelines and that adherence patterns are correlated within an individual.
The SimCRC model incorporates treatment for invasive cancer, such as adjuvant chemotherapy with 5-fluorouracil, and other improvements in cancer-specific mortality after diagnosis of colorectal cancer. Patients given a diagnosis of colorectal cancer, either by symptom detection or by a positive colonoscopy result, face a monthly cancer-specific mortality rate that is a function of the stage at diagnosis, age at diagnosis (<75 years, ≥75 years), time since diagnosis, and whether the patient received chemotherapy.