** Purpose: ** Modeling adherence with colorectal cancer (CRC) screening is challenging due to limited data on longitudinal adherence patterns. We assessed whether the manner in which imperfect adherence is simulated affects model-predicted conclusions about the effectiveness and cost-effectiveness of CRC screening.

** Method: ** Using a previously-developed microsimulation model of CRC, we predicted the fraction of 50-year-olds ever screened as well as the life-years gained (LYG), lifetime costs, and incremental cost-effectiveness ratios (ICERs) for two CRC screening strategies: five-yearly computed tomographic colonography (CTC) and ten-yearly colonoscopy (COL). We considered four approaches for simulating imperfect adherence (based on approaches used in the literature), each of which could be described as assuming 50% adherence: (1) fraction (50%) perfectly adherent and fraction (50%) completely nonadherent; imperfect random adherence at a constant rate (50%) (2) without and (3) with dropout; and (4) heterogeneity in imperfect adherence with constant rates within population subgroup (population average 50%).

** Result: ** The fractions ever screened were 50% for scenarios 1 and 3, and higher for at least one strategy in scenarios 2 and 4 (Table). In scenarios 1 and 3, COL was more effective than CTC, while in scenarios 2 and 4 CTC was more effective. CTC was the most costly strategy in scenarios 1 and 4 and less costly than COL in scenarios 2 and 3. CTC was dominated in scenario 1, COL was dominated in scenarios 2 and 4, and in scenario 3 the ICER of COL vs. CTC was $8,900/LYG.

** Conclusion: **The manner in which imperfect adherence is simulated affects the model-predicted relative effectiveness, cost, and cost-effectiveness of CTC vs. COL screening for CRC. To clarify the implications of adherence assumptions in the context of repeated screening, we recommend that modelers report the fraction of the population ever screened with each modality, as well as findings assuming perfect adherence. While unrealistic, the latter output enables direct comparison of alternative screening options among those willing to be screened and facilitates comparisons across models.

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