Vahdat, Vahab

Abstract Colorectal cancer is the second leading cause of cancer-related mortality in adults in the United States. Despite compelling evidence of improved outcomes in colorectal cancer, screening rates are not optimal. This study aimed to characterize colorectal cancer screening trends over the last two decades and assess the impact of various screening modalities on overall colorectal cancer screening rates. Using National Health Interview Survey data from 2005 to 2021, we examined colorectal cancer screening [colonoscopy, multitarget stool DNA (mt-sDNA), fecal occult blood test (FOBT)/fecal immunochemical test, sigmoidoscopy, CT colonography] rates among adults ages 50–75 years (n = 85,571). A pseudo-time-series cross-sectional (pseudo-TSCS) analysis was conducted including a random effects generalized least squares regression model to estimate the relative impact of each modality on changes in colorectal cancer screening rates. Among 50 to 75 year olds, the estimated colorectal cancer screening rate increased from 47.7% in 2005 to 69.9% in 2021, with the largest increase between 2005 and 2010 (47.7%–60.7%). Rates subsequently plateaued until 2015 but increased from 63.5% in 2015 to 69.9% in 2018. This was primarily driven by the increased use of mt-sDNA (2.5% in 2018 to 6.6% in 2021). Pseudo-TSCS analysis results showed that mt-sDNA contributed substantially to the increase in overall screening rates (77.3%; P < 0.0001) between 2018 and 2021. While colorectal cancer screening rates increased from 2005 to 2021, they remain below the 80% goal. The introduction of mt-sDNA, a noninvasive screening test may have improved overall rates. Sustained efforts are required to further increase screening rates to improve patient outcomes and offering a range of screening options is likely to contribute to achieving this goal. Prevention Relevance: This retrospective study highlights the importance of convenient stool-based colorectal cancer screening options to achieve the national goal of 80% for overall colorectal cancer screening rates. Empowering screening-eligible individuals with a choice for their colorectal cancer screening tests is imperative.

This cross-sectional study estimates the number of average-risk colorectal cancer screening–eligible individuals in the US since the US Preventive Services Task Force updated its recommendations in 2021.

67 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality among men and women combined in the United States (US). Although the national screening rate has increased over the years, it remains below the target of 80% recommended by the National Colorectal Cancer Roundtable for improved CRC outcomes. In most recent years, and particularly during COVID-19, screening-eligible individuals preferred at-home, non-invasive screening options over invasive tests such as colonoscopy due to convenience and accessibility. The objective of this study was to understand the CRC screening trends over the last two decades, and the impact of various screening modalities on the overall CRC screening rate. Methods: Using National Health Interview Survey (NHIS) data from 2005 onwards, we examined CRC screening (colonoscopy, mt-sDNA, FIT/FOBT, and sigmoidoscopy) rates among adults aged 50-75 years. A pseudo-time-series cross-sectional (pseudo TSCS) analysis was conducted including random effects Generalized Least Square (GLS) regression model to estimate the relative impact of each modality on the overall increase in CRC rates from 2018 to 2021. Results: Among 50-75 years old individuals, the estimated CRC screening use increased by 32% from 2005 to 2021 (47.7% to 69.9%). Between 2018 to 2021, the rates increased from 64% to 70%, driven largely by increased use of mt-sDNA, a 62.1% increase from 2018 to 2021 (2.5% to 6.6%). During this time period, colonoscopy utilization increased by 4.4% (61.2% to 64.0%), while FOBT/FIT utilization increased by 3.6% (5.3% to 5.5%). A pseudo-TSCS analysis showed that mt-sDNA contributed substantially to the overall CRC screening rate increase during years 2018-2021 (77.3%; p < 0.0001). Conclusions: While CRC screening rates are increasing, they remain below the national goal of 80%. Mt-sDNA as a home-based, non-invasive screening, recommended at a 3-year interval, has been leveraged to improve overall CRC screening rates, particularly to address the screening backlog created during the COVID-19 pandemic. A collaborative approach between healthcare providers and screening-eligible individuals is needed to empower patients with choice for their CRC screening modality to achieve the national goal.

The Centers for Medicare & Medicaid Services (CMS) recommend covering blood-based tests meeting proposed minimum performance thresholds for colorectal cancer (CRC) screening. Outcomes were compared between currently available stool-based screening tests and a hypothetical blood-based test meeting CMS minimum thresholds. Using the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM), outcomes were simulated for average-risk individuals screened between ages 45 and 75 years with triennial multitarget stool DNA (mt-sDNA), annual fecal immunochemical test (FIT), and annual fecal occult blood test (FOBT). Per CMS guidance, blood-based CRC screening was modeled triennially, with 74% CRC sensitivity and 90% specificity. Although not specified by CMS, adenoma sensitivity was set between 10% and 20%. Published adenoma and CRC sensitivity and specificity were used for stool-based tests. Adherence was set at (1) 100%, (2) 30%–70%, in 10% increments, and (3) real-world rates for stool-based tests (mt-sDNA = 65.6%; FIT = 42.6%; FOBT = 34.4%). Assuming perfect adherence, a blood-based test produced ≥19 lower life-years gained (LYG) than stool-based strategies. At the best-case scenario for blood-based tests (100% adherence and 20% adenoma sensitivity), mt-sDNA at real-world adherence achieved more LYG (287.2 vs. 297.1, respectively) with 14% fewer colonoscopies. At 100% blood-based test adherence and real-world mt-sDNA and FIT adherence, the blood-based test would require advanced adenoma sensitivity of 30% to reach the LYG of mt-sDNA (297.1) and ∼15% sensitivity to reach the LYG of FIT (258.9). This model suggests that blood-based tests with CMS minimally acceptable CRC sensitivity and low advanced adenoma sensitivity will frequently yield inferior outcomes to stool-based testing across a wide range of adherence assumptions.

Objectives Machine learning (ML)–based emulators improve the calibration of decision-analytical models, but their performance in complex microsimulation models is yet to be determined. Methods We demonstrated the use of an ML-based emulator with the Colorectal Cancer (CRC)-Adenoma Incidence and Mortality (CRC-AIM) model, which includes 23 unknown natural history input parameters to replicate the CRC epidemiology in the United States. We first generated 15,000 input combinations and ran the CRC-AIM model to evaluate CRC incidence, adenoma size distribution, and the percentage of small adenoma detected by colonoscopy. We then used this data set to train several ML algorithms, including deep neural network (DNN), random forest, and several gradient boosting variants (i.e., XGBoost, LightGBM, CatBoost) and compared their performance. We evaluated 10 million potential input combinations using the selected emulator and examined input combinations that best estimated observed calibration targets. Furthermore, we cross-validated outcomes generated by the CRC-AIM model with those made by CISNET models. The calibrated CRC-AIM model was externally validated using the United Kingdom Flexible Sigmoidoscopy Screening Trial (UKFSST). Results The DNN with proper preprocessing outperformed other tested ML algorithms and successfully predicted all 8 outcomes for different input combinations. It took 473 s for the trained DNN to predict outcomes for 10 million inputs, which would have required 190 CPU-years without our DNN. The overall calibration process took 104 CPU-days, which included building the data set, training, selecting, and hyperparameter tuning of the ML algorithms. While 7 input combinations had acceptable fit to the targets, a combination that best fits all outcomes was selected as the best vector. Almost all of the predictions made by the best vector laid within those from the CISNET models, demonstrating CRC-AIM’s cross-model validity. Similarly, CRC-AIM accurately predicted the hazard ratios of CRC incidence and mortality as reported by UKFSST, demonstrating its external validity. Examination of the impact of calibration targets suggested that the selection of the calibration target had a substantial impact on model outcomes in terms of life-year gains with screening. Conclusions Emulators such as a DNN that is meticulously selected and trained can substantially reduce the computational burden of calibrating complex microsimulation models. Highlights Calibrating a microsimulation model, a process to find unobservable parameters so that the model fits observed data, is computationally complex. We used a deep neural network model, a popular machine learning algorithm, to calibrate the Colorectal Cancer Adenoma Incidence and Mortality (CRC-AIM) model. We demonstrated that our approach provides an efficient and accurate method to significantly speed up calibration in microsimulation models. The calibration process successfully provided cross-model validation of CRC-AIM against 3 established CISNET models and also externally validated against a randomized controlled trial.

10580 Background: Blood-based tests are an emerging option for non-invasive colorectal cancer (CRC) screening for which the Centers for Medicare & Medicaid Services (CMS) has proposed coverage every 3 years for average-risk individuals. Analyses with the CRC-AIM microsimulation model demonstrated that triennial screening with blood-based tests with CMS minimum performance often yields inferior outcomes to stool-based CRC screening (fecal immunochemical test [FIT] and multi-target stool DNA [mt-sDNA]). CRC-AIM was used to explore the impact of blood-based screening intervals, using reported performance characteristics from the ECLIPSE study (Guardant Health, Inc.)1, on estimated clinical outcomes vs FIT and mt-sDNA screening. Methods: Outcomes were simulated for average-risk individuals screened between ages 45-75 years. Intervals were set at 1, 2, or 3 years for blood-based, 3 years for mt-sDNA and annually for FIT screening. The blood-based test was modeled at 83% CRC sensitivity, 13% advanced adenoma sensitivity, and 90% specificity. Perfect adherence (100%) was modeled for blood-based tests and real-world adherence rates used for CRC initial screening tests (mt-sDNA=65.6%; FIT=42.6%) and follow-up colonoscopy (mt-sDNA=72.1%; FIT=46.0%). Primary outcomes were life-years gained (LYG) and colonoscopies (COL) per 1000 individuals for blood-based screening compared to mt-sDNA and FIT. As a secondary analysis, estimates were generated with perfect (100%) adherence assumed for initial screening and follow-up colonoscopy for mt-sDNA and FIT as well. Results: Blood-based testing at a 3-year interval with 100% adherence led to 11% fewer LYG than mt-sDNA at RWE adherence (240 vs 270, respectively), and 9% more COL (1402/1000 vs 1288/1000). Meanwhile, blood-based testing at a 1-year interval and perfect adherence (best case scenario) resulted in the lowest LYG per COL ratio across all scenarios (16% more LYG and 87% more COL compared to mt-sDNA at RWE adherence). Blood-based test results showed similar trends when compared to FIT. Conclusions: Outcomes for blood-based screening every 3 years based on reported test performance characteristics and unrealistic perfect adherence demonstrate fewer LYG as compared to either mt-sDNA or FIT. When compared to real-world adherence for mt-sDNA and FIT, blood-based tests with 1- and 2-year intervals and perfect adherence had higher LYG with the tradeoff of a greater number of diagnostic colonoscopies. [Table: see text]

10567 Background: Average-risk screening for colorectal cancer (CRC) is effective and recommended. The U.S. Preventive Services Task Force issued grade A and B recommendations for screening ages 50-75 and 45-49, respectively, however the recommendation for the older population (ages 76-85) is grade C (moderate certainty that the net benefit is small). With emerging blood-based CRC screening, we evaluated the benefits of screening the older population with continued multi-target stool DNA (mt-sDNA) or FIT strategies and/or with a modality shift to blood-based tests after age 75. Methods: Using the validated CRC-AIM microsimulation model, triennial mt-sDNA and annual FIT screening (ages 45-75) followed by four strategies for ages 76-85 (no screening, continued mt-sDNA/FIT, or a modality shift to blood-based screening using either CMS criteria [CMS] or recently reported blood test data from the ECLIPSE study1 [BT; Guardant Health, Inc.] were considered. For CMS criteria and BT, CRC sensitivity were set at 74% and 83%; and adenoma sensitivity was set to 20%, and 13%; and CRC specificity was set to 90% for both tests. Real-world (RWE) adherence for initial screening was set to 80% (CMS, BT), 65.6% (mt-sDNA), and 42.6% (FIT). Adherence for follow-up colonoscopy was set to 72.1% (mt-sDNA, CMS, BT) and 46.0% (FIT). Results: Screening among the population aged 45-85 resulted in 281 life years gained (LYG) with continued mt-sDNA as compared to 193 with continued FIT. Furthermore, mt-sDNA reduced CRC mortality by 70% as compared to 49% by FIT (Table). When screening modality was shifted to CMS (76-85 year olds), mt-sDNA/CMS resulted in 279 LYG as compared to 196 for FIT/CMS. CRC incidence was reduced by 59% (mt-sDNA/CMS) as compared to 38% (FIT/CMS), and mortality declined by 69% (mt-sDNA/CMS) as compared to 51% (FIT/CMS). Reductions in disease burden were lower when modality was switched to BT after age 75 due to reduced test performance. Conclusions: Extending CRC screening to the older population with continued mt-sDNA demonstrated the best health outcomes compared to other modalities. A modality shift after age 75 to blood-based testing resulted in greater LYG as compared to no screening, with performance at CMS criteria yielding better results than BT. Therefore, despite inferior performance, blood-based tests may offer a CRC screening option for older patients who are unable to complete stool testing. [Table: see text]