Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW.

Objective To estimate benefits and harms of different colorectal cancer screening strategies, stratified by (baseline) 15-year colorectal cancer risk. Design Microsimulation modelling study using MIcrosimulation SCreening ANalysis-Colon (MISCAN-Colon). Setting A parallel guideline committee ( BMJ Rapid Recommendations) defined the time frame and screening interventions, including selection of outcome measures. Population Norwegian men and women aged 50-79 years with varying 15-year colorectal cancer risk (1-7%). Comparisons Four screening strategies were compared with no screening: biennial or annual faecal immunochemical test (FIT) or single sigmoidoscopy or colonoscopy at 100% adherence. Main outcome measures Colorectal cancer mortality and incidence, burdens, and harms over 15 years of follow-up. The certainty of the evidence was assessed using the GRADE approach. Results Over 15 years of follow-up, screening individuals aged 50-79 at 3% risk of colorectal cancer with annual FIT or single colonoscopy reduced colorectal cancer mortality by 6 per 1000 individuals. Single sigmoidoscopy and biennial FIT reduced it by 5 per 1000 individuals. Colonoscopy, sigmoidoscopy, and annual FIT reduced colorectal cancer incidence by 10, 8, and 4 per 1000 individuals, respectively. The estimated incidence reduction for biennial FIT was 1 per 1000 individuals. Serious harms were estimated to be between 3 per 1000 (biennial FIT) and 5 per 1000 individuals (colonoscopy); harms increased with older age. The absolute benefits of screening increased with increasing colorectal cancer risk, while harms were less affected by baseline risk. Results were sensitive to the setting defined by the guideline panel. Because of uncertainty associated with modelling assumptions, we applied a GRADE rating of low certainty evidence to all estimates. Conclusions Over a 15 year period, all screening strategies may reduce colorectal cancer mortality to a similar extent. Colonoscopy and sigmoidoscopy may also reduce colorectal cancer incidence, while FIT shows a smaller incidence reduction. Harms are rare and of similar magnitude for all screening strategies.

Background: There is growing evidence for personalising colorectal cancer (CRC) screening based on risk factors. We compared the cost-effectiveness of personalised CRC screening based on polygenic risk and family history to uniform screening.Methods: Using the MISCAN-Colon model, we simulated a cohort of 100 million 40-year-olds, offering them uniform or personalised screening. Individuals were categorised based on polygenic risk and family history of CRC. We varied screening strategies by start age, interval and test and estimated costs and quality-adjusted life years (QALYs). In our analysis we: 1) assessed the costeffectiveness of uniform screening; 2) developed personalised screening scenarios based on optimal screening strategies by risk group; 3) compared the cost-effectiveness of both.Results: At a willingness-to-pay threshold of $50,000/QALY, the optimal uniform screening scenario was annual faecal immunochemical testing (FIT) from 50-74 years, whereas for personalised screening the optimal screening scenario consisted of annual and biennial FIT screening except for those at highest risk who were offered 5-yearly colonoscopy from age 50. Although these scenarios gained the same number of QALYs (17,887), personalised screening was not cost effective, costing an additional $428,953 due to costs associated with determining risk