Appendix 1: Model Descriptions
Microsimulation models. The MISCAN, SimCRC, and CRC-SPIN models from the NCI CISNET consortium were used to address the question of the cost-effectiveness of screening with CT colonography. The models used common inputs and assumptions concerning the screening tests but use their independently developed natural history models in addressing these questions.
Appendix 1a. Description of the MISCAN-COLON model for natural history and intervention
MISCAN Model overview
MISCAN-COLON is a semi-Markov microsimulation program to simulate the effect of screening and other interventions on colorectal cancer (CRC) incidence and mortality. With microsimulation we mean that each individual in the population is simulated separately. The model is semi-Markov in the sense that:
- Distributions other than exponential are possible in each disease state.
- Transitions in one state can depend on transitions in earlier states.
- Transitions can be age and calendar time dependent.
All events in the model are discrete, but the durations in each state are continuous. Hence, there are no annual transitions in the model.
The development of CRC in the model is assumed to occur according to the adenoma carcinoma sequence. This means that adenomas arise in the population, some of which eventually develop into CRC. We assume that there are two types of adenomas: progressive and non-progressive adenomas. Non-progressive adenomas can grow in size, but will never develop into a cancer. Progressive adenomas have the potential to develop into cancer, if the person in whom the adenoma develops lives long enough.
All adenomas start as a small (1-5 mm) adenoma. They can grow in size to medium (6-9 mm) and large (10+ mm) adenoma. Progressive medium and large adenomas can transform into a malignant cancer stage I, not yet giving symptoms (preclinical cancer). The cancer then progresses from stage I (localized) eventually to stage IV (distant metastasis). In each stage there is a probability of the cancer giving symptoms and being clinically detected. The time between the onset of a progressive adenoma and the clinical detection of CRC is assumed to be on average 20 years. After clinical detection a person can die of CRC, or of other causes based on the survival rate. The survival from CRC is highly dependent on the stage in which the cancer was detected.
MISCAN Simulation of an individual
Figure 2a shows how the model generates an individual life history. First MISCAN-COLON generates a time of birth and a time of death of other causes than CRC for an individual. This is shown in the top line of figure 1a. This line constitutes the life history in the absence of CRC. Subsequently, MISCAN-COLON generates adenomas for an individual. For most individuals no adenomas are simulated, for some multiple. In this example MISCAN-Colon has generated two adenomas for the individual. The first adenoma occurs at a certain age and grows in size from small to medium and large adenoma. However this is a non-progressive adenoma, so this adenoma will never transform into cancer. The second adenoma is a progressive adenoma. After having grown to 6-9 mm, the adenoma transforms into a malignant carcinoma, causing symptoms and eventually resulting in an earlier death from CRC.
Figure A.1.1a: Modeling natural history into life
The life history without CRC and the development of the two adenomas are combined into a life history in the presence of CRC. This means that the state a person is in is the same as the state of the most advanced adenoma or carcinoma present. If he dies from CRC before he dies from other causes, his death age is adjusted accordingly. The combined life history with CRC is shown in the bottom line of figure 1b.
MISCAN Simulation of screening
The complete simulation of an individual life history in figure 2a is in a situation without screening taking place. After the model has generated a life history with CRC but without screening, screening is overlaid. This is shown in figure 2b. The first three lines show the combined life history with CRC and the development of the two adenomas from figure 2a. At the moment of screening both adenomas are present, detected and removed. This results in a combined life history for CRC and screening (bottom line), where the person is adenoma-carcinoma free after the screening intervention. Because the precursor lesion has been removed this individual does not develop CRC and will therefore not die of CRC. 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 with screening and the situation with screening.
Figure A.1.1b: Modeling screening into life history
Many other scenarios could have occurred. A person could have developed a third adenoma after the screening moment and could still have died of CRC. Another possibility would have been that one of the adenomas was missed, but in the presented example the individual really benefited of the screening intervention.
The effectiveness of screening depends on the performance characteristics of the test performed: sensitivity, specificity and reach. In the model, one minus the specificity is defined as the probability of a positive test result in an individual irrespective 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 one minus the specificity. In individuals with adenomas or cancer the probability of a positive test result is dependent 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.