Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The prevalence of precursor lesions for gastric cancer (GC) and the differential burden between countries of varying GC risk is not well-understood. We conducted a systematic review and meta-analysis to estimate the global prevalence of precursor lesions. METHODS: We estimated the prevalence of atrophic gastritis (AG), gastric intestinal metaplasia (IM), and dysplasia in regions with low, medium, and high GC incidence. Because IM is an advanced manifestation of AG, we assessed the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. Prevalence was sub-stratified by Helicobacter pylori infection, symptomatology, and period (<2000, 2000-2010, and >2010). RESULTS: Among the 582 articles that underwent full-text review, 166 studies met inclusion criteria. The global prevalence estimates of AG, IM, and dysplasia were 25.4%, 16.2%, and 2.0%, respectively, on the basis of 126 studies that reported the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. The prevalence of all precursor lesions was higher in high and medium compared with low GC incidence countries (P < .01). Prevalence of AG and IM was significantly higher among H pylori-infected individuals (P < .01) but not statistically different between symptomatic and asymptomatic individuals (P > .17). All precursors demonstrated a secular decrease in prevalence over time. CONCLUSIONS: Gastric precursor lesions have differences in prevalence in regions with differential GC incidence and are associated with H pylori infection. Because of the substantial prevalence of precursor lesions in both symptomatic and asymptomatic individuals, symptomatic evaluation may not be sufficient to identify individuals at risk. These estimates provide important insights for tailoring GC prevention strategies.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Development and validation of colorectal cancer risk prediction tools: A comparison of models.

BACKGROUND: Identification of individuals at elevated risk can improve cancer screening programmes by permitting risk-adjusted screening intensities. Previous work introduced a prognostic model using sex, age and two preceding faecal haemoglobin concentrations to predict the risk of colorectal cancer (CRC) in the next screening round. Using data of 3 screening rounds, this model attained an area under the receiver-operating-characteristic curve (AUC) of 0.78 for predicting advanced neoplasia (AN). We validated this existing logistic regression (LR) model and attempted to improve it by applying a more flexible machine-learning approach. METHODS: We trained an existing LR and a newly developed random forest (RF) model using updated data from 219,257 third-round participants of the Dutch CRC screening programme until 2018. For both models, we performed two separate out-of-sample validations using 1,137,599 third-round participants after 2018 and 192,793 fourth-round participants from 2020 onwards. We evaluated the AUC and relative risks of the predicted high-risk groups for the outcomes AN and CRC. RESULTS: For third-round participants after 2018, the AUC for predicting AN was 0.77 (95% CI: 0.76-0.77) using LR and 0.77 (95% CI: 0.77-0.77) using RF. For fourth-round participants, the AUCs were 0.73 (95% CI: 0.72-0.74) and 0.73 (95% CI: 0.72-0.74) for the LR and RF models, respectively. For both models, the 5% with the highest predicted risk had a 7-fold risk of AN compared to average, whereas the lowest 80% had a risk below the population average for third-round participants. CONCLUSION: The LR is a valid risk prediction method in stool-based screening programmes. Although predictive performance declined marginally, the LR model still effectively predicted risk in subsequent screening rounds. An RF did not improve CRC risk prediction compared to an LR, probably due to the limited number of available explanatory variables. The LR remains the preferred prediction tool because of its interpretability.

Differential impact of test performance characteristics on burden-to-benefit tradeoffs for blood-based colorectal cancer screening: A microsimulation analysis.

OBJECTIVES: To inform the development and evaluation of new blood-based colorectal cancer (CRC) screening tests satisfying minimum United States (US) coverage criteria, we estimated the impact of the different test performance characteristics on long-term testing benefits and burdens. METHODS: A novel CRC-Microsimulation of Adenoma Progression and Screening (CRC-MAPS) model was developed, validated, then used to assess different screening tests for CRC. We compared multiple, hypothetical blood-based CRC screening tests satisfying minimum coverage criteria of 74% CRC sensitivity and 90% specificity, to measure how changes in a test's CRC sensitivity, specificity, and adenoma sensitivity (sizes 1-5 mm, 6-9 mm, ≥10 mm) affect total number of colonoscopies (COL), CRC incidence reduction (IR), CRC mortality reduction (MR), and burden-to-benefit ratios (incremental COLs per percentage-point increase in IR or MR). RESULTS: A blood test meeting minimum US coverage criteria for performance characteristics resulted in 1576 lifetime COLs per 1000 individuals, 46.7% IR and 59.2% MR compared to no screening. Tests with increased CRC sensitivity of 99% ( + 25%) vs. increased ≥10 mm adenoma sensitivity of 13.6% ( + 3.6%) both yielded the same MR, 62.7%. Test benefits improved the most with increases in all-size adenoma sensitivity, then size-specific adenoma sensitivities, then specificity and CRC sensitivity, while increases in specificity or ≥10 mm adenoma sensitivity resulted in the most favorable burden-to-benefit tradeoffs (ratios <11.5). CONCLUSIONS: Burden-to-benefit ratios for blood-based CRC screening tests differ by performance characteristic, with the most favorable tradeoffs resulting from improvements in specificity and ≥10 mm adenoma sensitivity.

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data.

BACKGROUND & AIMS: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death. METHODS: Risk predictions for CRC and competing causes of death from a large community-based cohort were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals and cost-effectiveness compared with uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses. RESULTS: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every 5 years from ages 40 to 85 for high-risk individuals. Nevertheless, on a population level, risk-stratified screening would increase net quality-adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening or reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test. CONCLUSIONS: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.

Impact and Recovery from COVID-19-Related Disruptions in Colorectal Cancer Screening and Care in the US: A Scenario Analysis.

BACKGROUND: Many colorectal cancer-related procedures were suspended during the COVID-19 pandemic. In this study, we predict the impact of resulting delays in screening (colonoscopy, FIT, and sigmoidoscopy) and diagnosis on colorectal cancer-related outcomes, and compare different recovery scenarios. METHODS: Using the MISCAN-Colon model, we simulated the US population and evaluated different impact and recovery scenarios. Scenarios were defined by the duration and severity of the disruption (percentage of eligible adults affected), the length of delays, and the duration of the recovery. During recovery (6, 12 or 24 months), capacity was increased to catch up missed procedures. Primary outcomes were excess colorectal cancer cases and -related deaths, and additional colonoscopies required during recovery. RESULTS: With a 24-month recovery, the model predicted that the US population would develop 7,210 (0.18%) excess colorectal cancer cases during 2020-2040, and 6,950 (0.65%) excess colorectal cancer-related deaths, and require 108,500 (8.6%) additional colonoscopies per recovery month, compared with a no-disruption scenario. Shorter recovery periods of 6 and 12 months, respectively, decreased excess colorectal cancer-related deaths to 4,190 (0.39%) and 4,580 (0.43%), at the expense of 260,200-590,100 (20.7%-47.0%) additional colonoscopies per month. CONCLUSIONS: The COVID-19 pandemic will likely cause more than 4,000 excess colorectal cancer-related deaths in the US, which could increase to more than 7,000 if recovery periods are longer. IMPACT: Our results highlight that catching-up colorectal cancer-related services within 12 months provides a good balance between required resources and mitigation of the impact of the disruption on colorectal cancer-related deaths.

Faecal occult blood loss accurately predicts future detection of colorectal cancer. A prognostic model.

OBJECTIVES: To examine the prognostic potential of repeated faecal haemoglobin (F-Hb) concentration measurements in faecal immunochemical test (FIT)-based screening for colorectal cancer (CRC). DESIGN: Prognostic model. SETTING: Dutch biennial FIT-based screening programme during 2014-2018. PARTICIPANTS: 265 881 participants completing three rounds of FIT, with negative test results (F-Hb <47 µg Hb/g faeces) in rounds 1 and 2. INTERVENTIONS: Colonoscopy follow-up in participants with a positive FIT (F-Hb ≥47 µg Hb/g faeces). MAIN OUTCOMES: We evaluated prognostic models for detecting advanced neoplasia (AN) and CRC in round 3, with as predictors, participant age, sex, F-Hb in rounds 1 and 2, and categories/combinations/non-linear transformations of F-Hb. Primary evaluation criteria included: risk prediction accuracy (calibration), discrimination of participants with versus without AN or CRC (optimism-adjusted C-statistics, range 0.5-1.0), the degree of risk stratification and C-statistics in external validation. RESULTS: Among study participants, 8806 (3.3%) had a positive FIT result, 3254 (1.2%) had AN detected and 557 (0.2%) had cancer. F-Hb concentrations in rounds 1 and 2 were the strongest outcome predictors, with adjusted ORs of up to 9.4 (95% CI 7.5 to 11.7) for the highest F-Hb category. Risk predictions matched the observed risk for most participants (calibration intercept -0.008 to -0.099; slope 0.982-0.998), and discriminated participants with versus without AN or CRC with C-statistics of 0.78 (95% CI 0.77 to 0.79) and 0.73 (95% CI 0.71 to 0.75), respectively. The predicted risk ranged from 0.4% to 36.7% for AN and from 0.0% to 5.5% for CRC across participants. In external validation, the model retained similar discrimination accuracy for AN (C-statistic 0.77, 95% CI 0.66 to 0.87) and CRC (C-statistic 0.78, 95% CI 0.66 to 0.91). CONCLUSION: Participants at lower versus higher risk of future AN or CRC can be accurately identified based on their age, sex and particularly, prior F-Hb concentrations. Risk stratification should be considered based on this information.

Clinically significant serrated polyp detection rates and risk for postcolonoscopy colorectal cancer: data from the New Hampshire Colonoscopy Registry.

BACKGROUND AND AIMS: Higher adenoma detection rates reduce the risk of postcolonoscopy colorectal cancer (PCCRC). Clinically significant serrated polyps (CSSPs; defined as any sessile serrated polyp, traditional serrated adenoma, large [≥1 cm] or proximal hyperplastic polyp >5 mm) also lead to PCCRC, but there are no data on associated CSSP detection rates (CSSDRs). We used data from the New Hampshire Colonoscopy Registry (NHCR) to investigate the association between PCCRC risk and endoscopist CSSDR. METHODS: We included NHCR patients with 1 or more follow-up events: either a colonoscopy or a colorectal cancer (CRC) diagnosis identified through linkage with the New Hampshire State Cancer Registry. We defined our outcome, PCCRC, in 3 time periods: CRC diagnosed 6 to 36 months, 6 to 60 months, or all examinations (6 months or longer) after an index examination. We excluded patients with CRC diagnosed at or within 6 months of the index examination, with incomplete examinations, or with inflammatory bowel disease. The exposure variable was endoscopist CSSDR at the index colonoscopy. Cox regression was used to model the hazard of PCCRC on CSSDR controlling for age, sex, index findings, year of examination, personal history of colorectal neoplasia, and having more than 1 surveillance examination. RESULTS: One hundred twenty-eight patients with CRC diagnosed at least 6 months after their index examination were included. Our cohort included 142 endoscopists (92 gastroenterologists). We observed that the risk for PCCRC 6 months or longer after the index examination was significantly lower for examinations performed by endoscopists with CSSDRs of 3% to <9% (hazard ratio [HR], .57; 95% confidence interval [CI], .39-.83) or 9% or higher (HR, .39; 95% CI, .20-.78) relative to those with CSSDRs under 3%. CONCLUSIONS: Our study is the first to demonstrate a lower PCCRC risk after examinations performed by endoscopists with higher CSSDRs. Both CSSDRs of 9% and 3% to <9% had statistically lower risk of PCCRC than CSSDRs of <3%. These data validate CSSDR as a clinically relevant quality measure for endoscopists.

Risk-stratified strategies in population screening for colorectal cancer.

Colorectal cancer (CRC) screening has been demonstrated to reduce CRC incidence and mortality. However, besides such benefits, CRC screening is also associated with potential harmful effects. In an ideal world, screening would only be directed to the small proportion of the population that might potentially benefit. Risk-based screening can be seen as a first step towards this ideal world, by redistributing screening resources from low-risk to high-risk individuals. In theory, this should result in scarce resources being used in individuals who benefit most, while intensity of screening is reduced in individuals who benefit less, hence improving the benefit-harm ratio among all invitees. Available strategies that have been proposed for risk-based CRC screening include using information on age, sex, prior screening history, lifestyle and/or genetic information. Implementation of risk-based screening requires careful consideration of reliable risk prediction models, participation with screening and informed decision-making. While it is important to recognise the limitations of current approaches, available evidence suggests that it might be feasible to start planning the introduction of tailored strategies within screening programmes. Implementing risk-based screening based on age, sex and prior screening history alone would already represent a substantial improvement over current uniform screening approaches. We propose that it is time that screening programmes start there and continue striving towards more comprehensive approaches embedding primary prevention as an effective approach to lower risk for everyone.

Impact of assumptions on future costs, disutility and mortality in cost-effectiveness analysis; a model exploration.

INTRODUCTION: In cost-effectiveness analyses, the future costs, disutility and mortality from alternative causes of morbidity are often not completely taken into account. We explored the impact of different assumed values for each of these factors on the cost-effectiveness of screening for colorectal cancer (CRC) and esophageal adenocarcinoma (EAC). METHODS: Twenty different CRC screening strategies and two EAC screening strategies were evaluated using microsimulation. Average health-related expenses, disutility and mortality by age for the U.S. general population were estimated using surveys and lifetables. First, we evaluated strategies under default assumptions, with average mortality, and no accounting for health-related costs and disutility. Then, we varied costs, disutility and mortality between 100% and 150% of the estimated population averages, with 125% as the best estimate. Primary outcome was the incremental cost per quality-adjusted life-year (QALY) gained among efficient strategies. RESULTS: The set of efficient strategies was robust to assumptions on future costs, disutility and mortality from other causes of morbidity. However, the incremental cost per QALY gained increased with higher assumed values. For example, for CRC, the ratio for the recommended strategy increased from $15,600 with default assumptions, to $32,600 with average assumption levels, $61,100 with 25% increased levels, and $111,100 with 50% increased levels. Similarly, for EAC, the incremental costs per QALY gained for the recommended EAC screening strategy increased from $106,300 with default assumptions to $198,300 with 50% increased assumptions. In sensitivity analyses without discounting or including only above-average expenses, the impact of assumptions was relatively smaller, but best estimates of the cost per QALY gained remained substantially higher than default estimates. CONCLUSIONS: Assumptions on future costs, utility and mortality from other causes of morbidity substantially impact cost-effectiveness outcomes of cancer screening. More empiric evidence and consensus are needed to guide assumptions in future analyses.

Cost-effectiveness of prevention and early detection of gastric cancer in Western countries.

Gastric cancer (GC) is a significant global health problem, with Helicobacter pylori infection estimated to be responsible for 89% of non-cardiac GC cases, or 78% of all GC cases. The International Agency for Research on Cancer has called for Helicobacter pylori test-and-treat strategies in countries with high rates of GC. However, for countries with low rates of GC, such as most Western countries, the balance between benefits, harms and costs of screening is less clear-cut. GC is a disease with a well-characterized precancerous process, providing the basis for primary and secondary prevention efforts. However, rigorous data assessing the impact of such interventions in Western countries are lacking. In the absence of clinical trials, modelling offers a unique approach to evaluate the potential impact of various screening and surveillance interventions. In this paper, we provide an overview of modelling studies evaluating the cost-effectiveness of GC screening and surveillance in Western countries.

Colorectal Cancer Screening: An Updated Modeling Study for the US Preventive Services Task Force.

Importance: The US Preventive Services Task Force (USPSTF) is updating its 2016 colorectal cancer screening recommendations. Objective: To provide updated model-based estimates of the benefits, burden, and harms of colorectal cancer screening strategies and to identify strategies that may provide an efficient balance of life-years gained (LYG) from screening and colonoscopy burden to inform the USPSTF. Design, Setting, and Participants: Comparative modeling study using 3 microsimulation models of colorectal cancer screening in a hypothetical cohort of 40-year-old US individuals at average risk of colorectal cancer. Exposures: Screening from ages 45, 50, or 55 years to ages 70, 75, 80, or 85 years with fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy alone or with FIT, computed tomography colonography, or colonoscopy. All persons with an abnormal noncolonoscopy screening test result were assumed to undergo follow-up colonoscopy. Screening intervals varied by test. Full adherence with all procedures was assumed. Main Outcome and Measures: Estimated LYG relative to no screening (benefit), lifetime number of colonoscopies (burden), number of complications from screening (harms), and balance of incremental burden and benefit (efficiency ratios). Efficient strategies were those estimated to require fewer additional colonoscopies per additional LYG relative to other strategies. Results: Estimated LYG from screening strategies ranged from 171 to 381 per 1000 40-year-olds. Lifetime colonoscopy burden ranged from 624 to 6817 per 1000 individuals, and screening complications ranged from 5 to 22 per 1000 individuals. Among the 49 strategies that were efficient options with all 3 models, 41 specified screening beginning at age 45. No single age to end screening was predominant among the efficient strategies, although the additional LYG from continuing screening after age 75 were generally small. With the exception of a 5-year interval for computed tomography colonography, no screening interval predominated among the efficient strategies for each modality. Among the strategies highlighted in the 2016 USPSTF recommendation, lowering the age to begin screening from 50 to 45 years was estimated to result in 22 to 27 additional LYG, 161 to 784 additional colonoscopies, and 0.1 to 2 additional complications per 1000 persons (ranges are across screening strategies, based on mean estimates across models). Assuming full adherence, screening outcomes and efficient strategies were similar by sex and race and across 3 scenarios for population risk of colorectal cancer. Conclusions and Relevance: This microsimulation modeling analysis suggests that screening for colorectal cancer with stool tests, endoscopic tests, or computed tomography colonography starting at age 45 years provides an efficient balance of colonoscopy burden and life-years gained.

An Evolutionary Algorithm to Personalize Stool-Based Colorectal Cancer Screening.

BACKGROUND: Fecal immunochemical testing (FIT) is an established method for colorectal cancer (CRC) screening. Measured FIT-concentrations are associated with both present and future risk of CRC, and may be used for personalized screening. However, evaluation of personalized screening is computationally challenging. In this study, a broadly applicable algorithm is presented to efficiently optimize personalized screening policies that prescribe screening intervals and FIT-cutoffs, based on age and FIT-history. METHODS: We present a mathematical framework for personalized screening policies and a bi-objective evolutionary algorithm that identifies policies with minimal costs and maximal health benefits. The algorithm is combined with an established microsimulation model (MISCAN-Colon), to accurately estimate the costs and benefits of generated policies, without restrictive Markov assumptions. The performance of the algorithm is demonstrated in three experiments. RESULTS: In Experiment 1, a relatively small benchmark problem, the optimal policies were known. The algorithm approached the maximum feasible benefits with a relative difference of 0.007%. Experiment 2 optimized both intervals and cutoffs, Experiment 3 optimized cutoffs only. Optimal policies in both experiments are unknown. Compared to policies recently evaluated for the USPSTF, personalized screening increased health benefits up to 14 and 4.3%, for Experiments 2 and 3, respectively, without adding costs. Generated policies have several features concordant with current screening recommendations. DISCUSSION: The method presented in this paper is flexible and capable of optimizing personalized screening policies evaluated with computationally-intensive but established simulation models. It can be used to inform screening policies for CRC or other diseases. For CRC, more debate is needed on what features a policy needs to exhibit to make it suitable for implementation in practice.

Comparing the Cost-Effectiveness of Innovative Colorectal Cancer Screening Tests.

BACKGROUND: Colorectal cancer (CRC) screening with colonoscopy and the fecal immunochemical test (FIT) is underused. Innovative tests could increase screening acceptance. This study determined which of the available alternatives is most promising from a cost-effectiveness perspective. METHODS: The previously validated Microsimulation Screening Analysis-Colon model was used to evaluate the cost-effectiveness of screening with capsule endoscopy every 5 or 10 years, computed tomographic colonography every 5 years, the multi-target stool DNA test every 1 or 3 years, and the methylated SEPT9 DNA plasma assay (mSEPT9) every 1 or 2 years. We also compared these strategies with annual FIT screening and colonoscopy screening every 10 years. Quality-adjusted life-years gained (QALYG), number of colonoscopies, and incremental cost-effectiveness ratios were projected. We assumed a willingness-to-pay threshold of $100 000 per QALYG. RESULTS: Among the alternative tests, computed tomographic colonography every 5 years, annual mSEPT9, and annual multi-target stool DNA screening had incremental cost-effectiveness ratios of $1092, $63 253, and $214 974 per QALYG, respectively. Other screening strategies were more costly and less effective than (a combination of) these 3. Under the assumption of perfect adherence, annual mSEPT9 screening resulted in more QALYG, CRC cases averted, and CRC deaths averted than annual FIT screening but led to a high rate of colonoscopy referral (51% after 3 years, 69% after 5 years). The alternative tests were not cost-effective compared with FIT and colonoscopy. CONCLUSIONS: This study suggests that for individuals not willing to participate in FIT or colonoscopy screening, mSEPT9 is the test of choice if the high colonoscopy referral rate is acceptable to them.