Our study demonstrates that annual screening with FIT, assuming mid-range test performance characteristics, is more effective and less costly than other CRC screening strategies, including the most commonly used stool-based CRC screening test, FOBT, and no screening. Among a cohort of 100,000 average risk individuals followed until death, 4,857 cancers and 1,782 cancer-related deaths would be expected with no screening. An annual FIT with high sensitivity for cancer (81%) and moderate sensitivity for advanced adenomas (54%) 
could reduce costs and decrease the number of CRCs and cancer-related deaths to 1,393 and 457, respectively. Screening with FIT was also more effective at reducing cancer and cancer-related deaths at lower costs compared with FOBT.
FIT represents a significant advance over the traditional guaiac-based FOBTs, in large part due to FITs improved sensitivity for identifying adenomatous polyps. Our findings underscore the importance of identifying patients with advanced adenomas and preventing cancer through the identification and removal of precancerous polyps. Indeed, changing the sensitivity of FIT for cancer had relatively little impact on our results, whereas reducing the sensitivity of FIT for advanced adenomas from 54% to below 45% resulted in FIT no longer being cost saving compared with no screening.
Although it may seem counter-intuitive that screening with FIT could be even more effective than colonoscopy, this is due to the more frequent screening interval with FIT. In base case analyses, and consistent with current guidelines 
, screening with FIT was done annually compared to every 10 y with colonoscopy. Therefore, even though the test performance of a single FIT test was inferior to colonoscopy, there were more opportunities to identify previously missed pathology with FIT compared to colonoscopy.
Our results are robust. FIT with mid-range performance (FIT-mid) remained optimal compared with no screening and all the other strategies except FIT with even better test performance (FIT-high) unless the cost of CRC treatment was reduced, or the sensitivity for advanced adenomas was decreased significantly. However, even with lower CRC treatment costs, FIT remained economically attractive. Many health jurisdictions now fund biologic chemotherapies for advanced-stage CRC and with further advances in CRC chemotherapy, it is unlikely that management costs for CRC will decrease 
. In addition, our modeled CRC treatment costs were lower than those used in a recent US study that had similar results 
, lending further support to the notion that CRC screening can indeed save money.
It is possible that the administrative costs of annual screening programs such as FIT would be more expensive over the long-run compared with those offered every 5 or 10 y. As these data are not known, we did not consider administrative costs or the costs to build and staff additional screening centers in our primary analysis. However, in sensitivity analysis, we noted that FIT-mid remained cost saving if the administration costs were <CAN$10 per test, and remained attractive compared with colonoscopy even if the administrative costs per test were CAN$30 per test. It should also be noted that the additional infrastructure required to implement primary screening with CTC, flexible sigmoidoscopy, or colonoscopy would likely counterbalance a substantial portion of these additional administrative costs of an annual screening program.
We assumed in the base case that adherence would be identical across all of the CRC screening strategies. Although this may not be true, we are unaware of a study that has evaluated screening uptake for all of the strategies we considered. However, fecal-based screening does not require a bowel preparation, is associated with lower patient-borne costs, and is safe to perform, which may be more appealing to the general population. Furthermore, FIT does not require any dietary restrictions. Indeed, in a recent randomized trial, FIT was associated with higher screening uptake than flexible sigmoidoscopy and FOBT 
. Of course, this finding only strengthens our conclusions as illustrated in our scenario analysis in which FIT had relatively higher adherence than all of the other strategies (). Recent data suggest that screening adherence with FOBT may drop by 50% after only 2 y in a biennial screening program 
; this may affect programs with frequent screening (i.e., annual fecal-based strategies) to a greater extent than programs requiring less frequent screening (i.e., colonoscopy). As expected, when we dropped our subsequent adherence rates for FOBT and FIT, FIT-mid became less effective, though it remained dominant compared with no screening. In contrast, colonoscopy became the most effective strategy when the subsequent adherence rates for FOBT and FIT were dropped from 63% to 40%, though it was associated with an unattractive incremental cost per QALY. It is clear that further information on long-term adherence rates for annual stool-based tests are needed.
Our study has limitations. As with most economic evaluations, our results are limited by available evidence. The natural history of adenomas and their progression to cancer is not clearly known. However, we populated our model with the best available evidence including a systematic review of adenoma and CRC prevalence rates 
and modeled new adenoma growth and adenoma progression over time to closely match high quality clinical datasets 
. We did not model cancers arising from lesions other than adenomas. However, most CRCs arising in average risk individuals are believed to develop via the traditional adenoma-carcinoma sequence. A small proportion of CRC may develop from undetectable lesions (i.e., flat or depressed adenomas), and it is known that some interval cancers can arise through a rapid adenoma-carcinoma sequence between screening studies 
. It should be noted that this potential issue would impact the effectiveness of all CRC screening modalities, and thus would be unlikely to impact the differential effectiveness between our modeled strategies. Given data limitations, we modeled identical CRC stage distributions for cancers detected using all of the stool-based strategies despite differences in testing characteristics. Given FIT's superior sensitivity compared to FOBT, patients diagnosed with CRC might be expected to have more earlier stage cancers, which again would make FIT appear more attractive. We assumed that the results of each screening test were independent of the prior test result. While not informed by evidence, it is possible that this is not entirely true; however, it is important to note that the results of our analysis were robust to small changes in the sensitivity and specificity of each of the screening tests. Finally, although we did model the most widely available and promising screening strategies, additional technologies are being developed and it is possible that other screening paradigms, including nurse-based endoscopy, may become viable in the future as a means to reduce the cost of delivering flexible sigmoidoscopy and potentially colonoscopy.
In conclusion, annual screening with FIT having test performance characteristics within the mid-range reported in the literature is both more effective and less costly than other CRC screening modalities, including FOBT and colonoscopy, and not screening for CRC. Even if this level of test performance is not attainable in clinical practice, annual screening with a lower performing FIT is still highly attractive with a cost per QALY gained of <CAN$5,000 compared to no screening. Our results are robust suggesting that screening for CRC with FIT should be considered the modality of choice for average risk patients between the ages of 50 and 75 in North America.