BACKGROUND:Fecal immunochemical test (FIT) performance for colorectal cancer screening varies by age and sex, yet most FIT-based screening programs use uniform positivity thresholds. This study assessed the potential benefits of stratifying FIT thresholds based on age and sex. METHODS:We conducted a meta-analysis of FIT sensitivity and specificity at various positivity thresholds by age and sex. We then used these estimates in 2 microsimulation models of colorectal cancer and projected lifetime clinical outcomes, incremental costs, and quality-adjusted life-years (QALYs) gained from age- and sex-stratified FIT strategies. FIT thresholds ranged from 10 to 50 µg hemoglobin per gram of feces. RESULTS:For current uniform FIT screening (20 µg hemoglobin/gram of feces), models projected 85.67 to 122.15 QALYs gained at incremental costs of ‒$982 to $504 per 1000 individuals compared with no screening. At equivalent costs to current uniform screening, only 1 model found stratified FIT approaches cost-effective, yielding a marginal increase of 1.04 and 1.10 QALYs gained/1000 female and male individuals, respectively. At a willingness-to-pay threshold of $100 000/QALYs gained, both models found stratified FIT cutoffs to be the best strategy, with cutoffs being equal to or higher for males and lowest at older ages (70-75 years). Uniform strategies showed comparable effectiveness, falling within 1 quality-adjusted life-day per person of efficient strategies at up to $112 more per person. Results were sensitive to FIT test performance characteristics and 1-time setup costs. CONCLUSION:Stratifying FIT thresholds by age and sex may be cost-effective compared to current screening. The gain in expected health benefits with stratified FIT screening, however, is likely small.

Background Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale.Development This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency.Application First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations.Conclusions The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs.

BACKGROUND & AIMS:Whether gastric cancer (GC) precursor lesions progress to invasive cancer at similar rates globally remains unknown. We conducted a systematic review and meta-analysis to determine the progression of precursor lesions to GC in countries with low versus medium/high incidence. METHODS:We searched relevant databases for studies reporting the progression of endoscopically confirmed precursor lesions to GC. Studies were stratified by low (<6 per 100,000) or medium/high (≥6 per 100,000) GC incidence countries. Random-effects models were used to estimate the progression rates of atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia to GC per 1000 person-years. RESULTS:Among the 5829 studies identified, 44 met our inclusion criteria. The global pooled estimates of the progression rate per 1000 person-years were 2.09 (95% confidence interval, 1.46-2.99), 2.89 (2.03-4.11), and 10.09 (5.23-19.49) for AG, IM, and dysplasia, respectively. The estimated progression rates per 1000 person-years for low versus medium/high GC incidence countries, respectively, were 0.97 (0.86-1.10) versus 2.47 (1.70-2.99) for AG (P < .01), 2.37 (1.43-3.92) versus 3.47 (2.13-5.65) for IM (P = .29), and 5.51 (2.92-10.39) versus 14.80 (5.87-37.28) for dysplasia (P = .08). There were no differences for progression of AG between groups when high-quality studies were compared. CONCLUSIONS:Similar progression rates of IM and dysplasia were observed among low and medium/high GC incidence countries. This suggests that the potential benefits of surveillance for these lesions in low-risk regions may be comparable with those of population-wide interventions in high-risk regions. Further prospective studies are needed to confirm these findings and inform global screening and surveillance guidelines.

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.

INTRODUCTION: The characteristics of gastric carcinoma in young individuals differ from that in older individuals. We conducted a systematic review and meta-analysis to explore the clinicopathological features and risk factors associated with young-onset (younger than 50 years) gastric carcinoma. METHODS: We searched for studies published between January 1, 1990, and September 1, 2023, on patients with young-onset gastric carcinoma in PubMed, EMBASE, Web of Science, and MEDLINE to explore clinicopathological characteristics among this specific patient group. Extracted information included the proportion of patients with symptoms or family history of gastric cancer, tumor location, and histological features such as Lauren or World Health Organization histological classification and degree of differentiation. Additional analyses were conducted on risk factors such as positive family history, Helicobacter pylori infection, or high-risk nutritional or behavioral factors. The estimates were derived using random or fixed-effect models and included subgroup analyses based on different sex and age groups. This study was registered in PROSPERO (CRD42023466131). RESULTS: We identified 5,696 records, 1,292 were included in the quality assessment stage. Finally, 84 studies from 18 countries or regions including 89,447 patients with young-onset gastric carcinoma were included. Young-onset gastric carcinoma has slight female predominance (53.7%, 95% confidence interval [CI]: 51.6–55.7%), with most having symptoms (87.0%, 95% CI: 82.4%–91.7%). Family history was reported in 12.1% (95% CI: 9.5%–14.7%). H. pylori infection was detected in 60.0% of cases (95% CI: 47.1%–72.8%). Most of these carcinomas were in the non-cardia region (89.6%, 95% CI: 82.4%–96.8%), exhibiting Lauren diffuse-type histology (71.1%, 95% CI: 66.8%–75.3%) and poor/undifferentiated features (81.9%, 95% CI%: 79.7–84.2%). A positive family history of gastric cancer was the most important risk factor associated with the development of gastric carcinoma in young individuals (pooled odds ratios 4.0, 95% CI: 2.8–5.2), followed by H. pylori infection (odds ratio 2.3; 95% CI: 1.4–3.2) and dietary and other lifestyle risk factors. DISCUSSION: Young-onset gastric carcinoma exhibits specific clinicopathological characteristics, with positive family history being the most important risk factor. Most of the patients were symptomatic at diagnosis. These findings could help to inform future strategies for the early detection of gastric carcinoma among young individuals.

IMPORTANCE The fecal immunochemical test (FIT) is widely used for colorectal cancer (CRC) screening, but evidence of its effectiveness is limited. OBJECTIVE To evaluate whether FIT screening is associated with a lower risk of dying from CRC overall, according to cancer location, and within demographic groups. DESIGN, SETTING, AND PARTICIPANTS This nested case-control study in a cohort of screening-eligible people was conducted in 2 large, integrated health systems of racially, ethnically, and socioeconomically diverse members with long-term programs of mailed FIT screening outreach. Eligible participants included people aged 52 to 85 years who died from colorectal adenocarcinoma between 2011 and 2017 (cases); cases were matched in a 1:8 ratio based on age, sex, health-plan membership duration, and geographic area to randomly selected persons who were alive and CRC-free on case's diagnosis date (controls). Data analysis was conducted from January 2002 to December 2017. EXPOSURES Completing 1 or more FIT screenings in the 5-year period prior to the CRC diagnosis date among cases or the corresponding date among controls; in secondary analyses, 2- to 10-year intervals were evaluated. MAIN OUTCOMES AND MEASURES The primary study outcome was CRC death overall and by tumor location. Secondary analyses were performed to assess CRC death by race and ethnicity. RESULTS From a cohort of 2 127 128 people, a total of 10 711 participants (3529 aged 60-69 years [32.9%]; 5587 male [52.1%] and 5124 female [47.8%]; 1254 non-Hispanic Asian [11.7%]; 973 non-Hispanic Black [9.1%]; 1929 Hispanic or Latino [18.0%]; 6345 non-Hispanic White [59.2%]) was identified, including 1103 cases and 9608 controls. Among controls during the 10-year period prior to the reference date, 6101 (63.5%) completed 1 or more FITs with a cumulative 12.6% positivity rate (768 controls), of whom 610 (79.4%) had a colonoscopy within 1 year. During the 5-year period, 494 cases (44.8%) and 5345 controls (55.6%) completed 1 or more FITs. In regression analysis, completing 1 or more FIT screening was associated with a 33% lower risk of death from CRC (adjusted odds ratio [aOR], 0.67; 95% CI, 0.59-0.76) and 42% lower risk in the left colon and rectum (aOR, 0.58; 95% CI, 0.48-0.71). There was no association with right colon cancers (aOR, 0.83; 95% CI, 0.69-1.01) but the difference in the estimates between the right colon and left colon or rectum was statistically significant (P = .01). FIT screening was associated with lower CRC mortality risk among non-Hispanic Asian (aOR, 0.37; 95% CI, 0.23-0.59), non-Hispanic Black (aOR, 0.58; 95% CI, 0.39-0.85) and non-Hispanic White individuals (aOR, 0.70; 95% CI, 0.57-0.86) (P for homogeneity = .04 for homogeneity). CONCLUSIONS AND RELEVANCE In this nested case-control study, completing FIT was associated with a lower risk of overall death from CRC, particularly in the left colon, and the associations were observed across racial and ethnic groups. These findings support the use of FIT in population-based screening strategies.

ABSTRACTBackgroundMost research on obesity trends and projections has focused on changes across calendar years. However, as the risk of disease increases with cumulative exposure to obesity, it is crucial to characterize the obesity landscape through a life-course perspective and across birth cohorts.ObjectiveTo enhance the accuracy of obesity epidemic projections throughout life course and across birth cohorts in the US.DesignCross-sectional and cohort study.SettingUnited StatesParticipantsIndividuals participated in three National Health Examination Surveys (NHES) from 1959 to 1970 and 18 National Health and Nutrition Examination Surveys (NHANES) from 1971 to 2020.MeasurementsBody mass index (BMI) distributions by sex, race, and birth cohort.ResultsBy leveraging over 40 years of cross-sectional and longitudinal data from nationally representative surveys, we developed models to estimate historical and future BMI distributions in the US for both children and adults throughout their life course. We also calculated life-years of exposure to overweight and obesity, according to sex, race, and birth cohort. Our findings reveal significant increases in these metrics among birth cohorts since 1965 and highlight differential trends by sex and race for the 1965, 1985, and 2005 cohorts.LimitationsAssumption that model parameters will hold in the future.ConclusionOur approach significantly expands upon previous models by projecting life course with continuous BMI distributions informed by longitudinal trajectories, explicitly accounting for variations in birth cohorts.Primary Funding SourceNational Institutes of Health.

BACKGROUND:Blood-based biomarker tests can potentially change the landscape of colorectal cancer (CRC) screening. We characterize the conditions under which blood test screening would be as effective and cost-effective as annual fecal immunochemical testing or decennial colonoscopy. METHODS:We used the 3 Cancer Information and Surveillance Modeling Network-Colon models to compare scenarios of no screening, annual fecal immunochemical testing, decennial colonoscopy, and a blood test meeting Centers for Medicare & Medicaid (CMS) coverage criteria (74% CRC sensitivity and 90% specificity). We varied the sensitivity to detect CRC (74%-92%), advanced adenomas (10%-50%), screening interval (1-3 years), and test cost ($25-$500). Primary outcomes included quality-adjusted life-years (QALY) gained from screening and costs for a US average-risk cohort of individuals aged 45 years. RESULTS:Annual fecal immunochemical testing yielded 125-163 QALY gained per 1000 at a cost of $3811-$5384 per person, whereas colonoscopy yielded 132-177 QALY gained at a cost of $5375-$7031 per person. A blood test with 92% CRC sensitivity and 50% advanced adenoma sensitivity yielded 117-162 QALY gained if used every 3 years and 133-173 QALY gained if used every year but would not be cost-effective if priced above $125 per test. If used every 3 years, a $500 blood test only meeting CMS coverage criteria yielded 83-116 QALY gained at a cost of $8559-$9413 per person. CONCLUSION:Blood tests that only meet CMS coverage requirements should not be recommended to patients who would otherwise undergo screening by colonoscopy or fecal immunochemical testing because of lower benefit. Blood tests need higher advanced adenoma sensitivity (above 40%) and lower costs (below $125) to be cost-effective.

BACKGROUND & AIMS:A blood-based colorectal cancer (CRC) screening test may increase screening participation. However, blood tests may be less effective than current guideline-endorsed options. The Centers for Medicare & Medicaid Services (CMS) covers blood tests with sensitivity of at least 74% for detection of CRC and specificity of at least 90%. In this study, we investigate whether a blood test that meets these criteria is cost-effective. METHODS:Three microsimulation models for CRC (MISCAN-Colon, CRC-SPIN, and SimCRC) were used to estimate the effectiveness and cost-effectiveness of triennial blood-based screening (from ages 45 to 75 years) compared to no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with an FIT assay, and colonoscopy screening every 10 years. The CMS coverage criteria were used as performance characteristics of the hypothetical blood test. We varied screening ages, test performance characteristics, and screening uptake in a sensitivity analysis. RESULTS:Without screening, the models predicted 77-88 CRC cases and 32-36 CRC deaths per 1000 individuals, costing $5.3-$5.8 million. Compared to no screening, blood-based screening was cost-effective, with an additional cost of $25,600-$43,700 per quality-adjusted life-year gained (QALYG). However, compared to FIT, triennial stool DNA testing combined with FIT, and colonoscopy, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT remained more effective (+5-24 QALYG) and less costly (-$3.2 to -$3.5 million) than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT. CONCLUSION:Even with higher screening uptake, triennial blood-based screening, with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with established strategies for colorectal cancer screening.

The Affordable Care Act (ACA) eliminated patient cost-sharing for United States Preventive Service Task Force (USPSTF) recommended services. However, if the US Court of Appeals for the Fifth Circuit fully upheld a US District Court ruling in Braidwood Management v. Becerra, 666 F. Supp. 3d 613 (N.D. Tex 2023), cost-sharing for USPSTF recommendations made after ACA passage would have been reinstated for more than 150 million people. The case would have reinstated cost-sharing for colorectal cancer (CRC) screening for ages 45-49 years and for polyp removal during (diagnostic) colonoscopy across all ages. Using the MISCAN-Colon model, we simulated the potential impact on CRC outcomes, assuming early-onset CRC trends and lower screening participation. An 8-percentage-point decline in screening participation could increase CRC incidence by 5.1% and CRC mortality by 9.1%, with slightly lower costs due to increased cost-sharing. Larger decreases in screening participation can result in higher costs from increased incidence and delayed diagnoses.