Background and Aims:Functional cure, which requires sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation, is currently the optimal treatment endpoint for chronic hepatitis B virus infection. We performed a systematic literature review (SLR) and meta-analyses to assess the association between HBsAg loss and long-term clinical outcomes. Methods:We performed a SLR of scientific literature published in Medline and Embase reporting the incidence of cirrhosis, hepatic decompensation (HD), hepatocellular carcinoma (HCC), liver-related mortality (LRM), and all-cause mortality (ACM) in relation to HBsAg status. Bayesian hierarchical commensurate prior meta-analyses synthesized evidence on the association between HBsAg loss and each outcome. Results:Thirty-eight studies, comprising 50,354 patients with 350,734 patient-years of follow-up, were included in the meta-analyses, reporting on cirrhosis (n = 12), HD (n = 12), HCC (n = 36), LRM (n = 12), and ACM (n = 16). Pooled incidence rate ratios (IRRs; vs HBsAg persistence) and respective credible intervals (Crls) were 0.28 (0.060-1.070) for cirrhosis, 0.13 (0.013-0.38) for HD, 0.27 (0.11-0.53) for HCC, 0.17 (0.028-0.61) for LRM, and 0.64 (0.24-1.17) for ACM. Single-predictor-adjusted IRRs remained consistent with those from the primary analyses for all outcomes except cirrhosis and LRM. Outcome incidence rates were modified by selected study, patient and infection characteristics, but trended in the same direction of reduced risk after loss. Conclusion:Overall, HBsAg loss was associated with a reduced risk of most clinically relevant outcomes. While the magnitude of the effect differed across subgroups, the direction of the association remained similar. Our results validate the need to develop new strategies to achieve HBsAg loss.

Table S2. Model cost inputs and references. All costs were inflated to April 2022 US dollars.

Abstract Medicare coverage of a follow-up colonoscopy after a positive stool-based colorectal cancer screening test with no patient cost-sharing started January 2, 2023, which may favorably affect screening behavior. This analysis estimated the clinical and economic effects of increased colorectal cancer screening participation potentially resulting from this policy change in Medicare beneficiaries. The validated Colorectal Cancer and Adenoma Incidence & Mortality (CRC-AIM) model simulated three guideline-endorsed colorectal cancer screening strategies for average-risk individuals (colonoscopy every 10 years, annual fecal immunochemical test, triennial multitarget stool DNA) from ages 65–75 years. The base-case scenario assumed 0% coinsurance for initial screening and follow-up colonoscopy, real-world screening test use (colonoscopy = 45.3%, stool-based test = 24.4%, unscreened = 30.3%), and real-world follow-up colonoscopy rates. Comparative scenarios assumed an increase in the overall screening rate from 0% to 15% (5% increments) and an increase in the follow-up colonoscopy rate from 0% to 15% (5% increments). The base-case scenario resulted in 128 life-years gained (LYG)/1,000 individuals versus no screening and total screening and treatment costs of $7,938/person. The changes resulted in an increase of up to 26 LYG/1,000 individuals and a decrease in total screening and treatment costs by as much as $128/person. Follow-up colonoscopy at $0 coinsurance became cost-saving with any increase in either overall screening or follow-up colonoscopy. Policies that remove cost barriers to completing colorectal cancer screening may increase rates of screening participation, potentially improving economic and clinical outcomes. Significance: A follow-up colonoscopy after a positive stool-based colorectal cancer screening test is necessary to complete the full screening process. Policies that remove cost barriers to completing colorectal cancer screening may lead to increases in overall participation rates and use of follow-up colonoscopy, improving clinical and economic outcomes.

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.

10529 Background: The Centers for Medicare & Medicaid Services (CMS) recommends covering blood-based biomarker tests with proposed minimum performance thresholds for colorectal cancer (CRC) screening test every 3 years for average-risk, asymptomatic Medicare beneficiaries ages 50–85 years. A blood-based test is a non-invasive screening method to detect CRC but is limited by low sensitivity to detect adenomas. Using the CRC-AIM microsimulation model, predicted life-years gained (LYG) and CRC incidence and mortality reduction were compared between a blood-based test meeting the CMS minimum thresholds and stool-based screening tests (fecal immunochemical test [FIT], fecal occult blood test [FOBT], and multitarget stool DNA [mt-sDNA]). Methods: Outcomes of blood- and stool-based tests were simulated for average-risk individuals free of diagnosed CRC at age 40 and screened between ages 45–75 years per USPSTF recommendations. Per CMS proposed criteria, CRC sensitivity and specificity for a blood-based test were set at 74% and 90%, respectively, and adenoma sensitivity was set at 10%. Published adenoma and CRC sensitivity and specificity were used for each stool test. For the primary analysis, adherence was assumed to be 100%. For secondary analysis, adherence was set at 30–70%, in 10% increments. Outcomes were per 1000 individuals. Results: At 100% adherence, LYG was 229 for a blood test and ≥305 for stool tests, corresponding to at least 25% lower LYG for a blood test relative to all stool tests (Table). Absolute CRC incidence and mortality reductions were at least 19% and 18% lower, respectively, for a blood test vs all stool tests. Secondary analysis indicates that at identical adherence rates that are less than 100%, a blood test had lower LYG vs all stool tests (Table). When the adherence of any test was 50%–70%, a blood test resulted in at least 20% lower LYG vs any stool test, and absolute reductions in CRC incidence and mortality were at least 9% and 10% lower, respectively, vs any stool test. Conclusions: This model suggests that if blood-based CRC screening tests do not sufficiently detect advanced adenomas, clinical outcomes will be inferior to stool-based testing due to lack of cancer prevention. Further discovery efforts to identify blood-based markers associated with both invasive and preinvasive neoplasia are needed to address this deficiency. [Table: see text]

Table S3. Model utility inputs and references.

We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Studies that enrolled ≥ 75

Figure S1. Incremental LYG, incremental total screening and treatment costs, and ICERs by additional scenarios compared with the base-case scenario.

Table S1. Performance characteristic assumptions for the screening tests.

Introduction: Most commercial insurance plans in the US will be required to cover a follow-up colonoscopy after a positive stool test with no patient cost-sharing as of January 1, 2023. In Oregon, a policy that eliminated patient cost-sharing significantly increased the overall uptake of CRC screening and shifted screening modalities from colonoscopy to non-invasive methods. We estimated the clinical and economic effects of these outcomes that may stem from the policy on a cohort of US average-risk individuals newly eligible for CRC screening. Methods: CRC-AIM, a validated microsimulation model for CRC, was used to simulate 2 million individuals undergoing CRC screening (colonoscopy every 10 years, annual fecal immunochemical test [FIT], triennial multi-target stool DNA [mt-sDNA]) from ages 45-75. Individuals who completed initial CRC screening were assumed to also complete follow-up colonoscopies. Outcomes were aggregated according to the current proportional distribution of different modalities. The baseline scenario represented the utilization of CRC screening prior to implementation of state-level policy (46% colonoscopy, 23% stool test, and 31% unscreened; derived from published literature). Scenarios 1-5 assumed 10% shift from colonoscopy to stool-test utilization with 1, 2, 5, 10, and 15% absolute increase in overall screening rate, respectively. Results: When 10% shift from screening colonoscopy to stool-test utilization was modeled, an increase in overall screening as low as 1%, compared to the baseline led to lower total costs, and cost per patient screened and higher quality adjusted life years (QALYs) (Table). LYG increased by at least 5% while ≥1,200 cases and ≥900 deaths were averted per 1 million individuals with a modest (5%) uptake in total screening. Total colonoscopies were 1.7% lower than the baseline at 15% increase to total screening. All scenarios that included the alternate screening modality distributions were less costly and more effective compared to the baseline, regardless of percent changes to total screening uptake (Figure). Conclusion: Based on this modeling analysis, policies that remove cost barriers to completing CRC screening can lead to shifts in test utilization patterns, increase overall participation rates, and improve both economic and clinical outcomes.Figure 1.: Incremental cost-effectiveness ratio by absolute percent increase in total CRC screening rate. Screening rates were assumed to increase as a consequence of waiving patient cost-sharing leading to a shift from screening colonoscopy to non-invasive methods. Negative ICER indicates that the scenario is less costly and more effective than the baseline. (CRC: colorectal cancer; ICER: incremental cost-effectiveness ratio; QALY: quality-adjusted life year) Table 1. - Estimated Outcomes in Baseline Scenario and Scenarios 1-5 Assuming 10% Absolute Reduction in Colonoscopy Utilization and Increased Overall Screening Rate. LYG, CRC cases, CRC deaths, total colonoscopies, and stool tests were calculated per 1000 individuals. Total costs and total QALYS were calculated per person Scenario % COLs % Stool Tests % Screened LYG CRC Cases CRC Deaths Total COLs Stool Tests Total Costs Total QALYs ICER Baseline 46 23 69 246.4 36.9 15.6 2298.0 3442.1 $6,901 16.8482 NA (1) 10% shift from COL to stool-test and 1% increase in screening 36 34 70 245.2 37.8 15.8 2051.6 5080.8 $6,628 16.8483 Less costly and more effective (2) 10% shift from COL to stool-test and 2% increase in screening 36 35 71 248.5 37.3 15.5 2066.4 5229.8 $6,629 16.8492 Less costly and more effective (3) 10% shift from COL to stool-test and 5% increase in screening 36 38 74 258.3 35.7 14.7 2110.8 5676.7 $6,632 16.8520 Less costly and more effective (4) 10% shift from COL to stool-test and 10% increase in screening 36 43 79 274.7 33.0 13.3 2184.8 6421.6 $6,638 16.8565 Less costly and more effective (5) 10% shift from COL to stool-test and 15% increase in screening 36 48 84 291.1 30.3 12.0 2258.8 7166.5 $6,644 16.8611 Less costly and more effective COL: colonoscopy; CRC: colorectal cancer; ICER: incremental cost-effectiveness ratio; LYG: life-years gained; NA: not applicable; QALY: quality-adjusted life year.

Abstract Commercial insurance covers a follow-up colonoscopy after a positive colorectal cancer–screening test with no patient cost-sharing. Instituting a similar policy for Medicare beneficiaries may increase screening adherence and improve outcomes. The cost-effectiveness of stool-based colorectal cancer screening was compared across adherence scenarios that assumed Medicare coinsurance status quo (20% for follow-up colonoscopy) or waived coinsurance. The CRC-AIM model simulated previously unscreened eligible Medicare beneficiaries undergoing stool-based colorectal cancer screening at age 65 for 10 years. Medicare costs, colorectal cancer cases, colorectal cancer–related deaths, life-years gained (LYG), and quality-adjusted life-years (QALY) were estimated versus no screening. Scenario 1 (S1) assumed 20% coinsurance for follow-up colonoscopy. Scenario 2 (S2) assumed waived coinsurance without adherence changes. Scenarios 3–7 (S3–S7) assumed that waiving coinsurance increased real-world stool-based screening and/or follow-up colonoscopy adherence by 5% or 10%. Sensitivity analyses assumed 1%–4% increased adherence. Cost-effectiveness threshold was ≤$100,000/QALY. Waiving coinsurance without adherence changes (S2) did not affect outcomes versus S1. S3–S7 versus S1 over 10 years estimated up to 3.6 fewer colorectal cancer cases/1,000 individuals, up to 2.1 fewer colorectal cancer deaths, up to 20.7 more LYG, and had comparable total costs per-patient (≤$6,478 vs. $6,449, respectively) as reduced colorectal cancer medical costs offset increased screening and colonoscopy costs. In sensitivity analyses, any increase in adherence after waiving coinsurance was cost-effective and increased LYG. In simulated Medicare beneficiaries, waiving coinsurance for follow-up colonoscopy after a positive stool-based test improved outcomes and was cost-effective when assumed to modestly increase colorectal cancer screening and/or follow-up colonoscopy adherence. Prevention Relevance: Follow-up colonoscopy after a positive stool-based test is necessary to complete the colorectal cancer-screening process. This analysis demonstrated that in a simulated Medicare population, waiving coinsurance for a follow-up colonoscopy improved estimated outcomes and was cost-effective when it was assumed that waiving the coinsurance modestly increased screening adherence. See related Spotlight, p. 641

Abstract Aims To evaluate the cost-effectiveness of vibegron compared with other oral pharmacologic therapies as treatment for overactive bladder (OAB). Methods A semi-Markov model with monthly cycles was developed to support a lifetime horizon of vibegron 75 mg from a US commercial payor or Medicare perspective. The model incorporated efficacy (reductions in daily micturitions and urinary incontinence episodes), adverse events, OAB-related comorbidities, drug–drug interactions, anticholinergic burden, and treatment persistence. Direct costs and quality-adjusted life years (QALY) were accumulated over time. The primary outcome was the cost per QALY incremental cost-effectiveness ratio (ICER). One-way (OWSA) and probabilistic sensitivity analyses (PSA) were performed. Results For commercial payors, vibegron was cost-effective at a willingness-to-pay (WTP) threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $9,311) and at a WTP threshold of $150,000/QALY versus mirabegron 25 mg (ICER, $141,957) and versus an anticholinergic basket based on market share (ICER, $118,121). For Medicare, vibegron was cost-effective at a WTP threshold of $50,000/QALY versus mirabegron 50 mg (ICER, $12,154) and at a WTP threshold of $100,000/QALY versus mirabegron 25 mg (ICER, $99,150) and versus an anticholinergic market basket (ICER, $60,756). For commercial payors and Medicare, OWSAs for vibegron versus mirabegron indicated cost-effectiveness was most sensitive to vibegron persistence at 1 and 12 months. PSAs indicated that vibegron was cost-effective versus mirabegron 50 mg 98.6% and 100% of the time at $50,000/QALY for commercial payors and Medicare payors, respectively. Limitations Due to lack of real-world data available on persistence, vibegron was assumed to have the same persistence as mirabegron 50 mg. Long-term efficacy was assumed to be sustained beyond 52 weeks in the absence of clinical trials longer than 52 weeks. Conclusions Vibegron is cost-effective from a commercial payor (WTP threshold $150,000/QALY) and Medicare (WTP threshold $100,000/QALY) perspective when compared with other oral pharmacologic treatments for OAB. PLAIN LANGUAGE SUMMARY Overactive bladder (OAB) affects more than 30 million adults in the United States. OAB is a condition associated with frequent and sudden urges to urinate. Drugs for treating OAB may improve symptoms for patients. Anticholinergic drugs are one type of drug available for treating OAB. Anticholinergic drugs may cause side effects such as dry mouth and constipation. Newer types of drugs called β3-adrenergic receptor agonists are available for treating OAB symptoms. Vibegron is a member of the β3-adrenergic receptor agonist class of drugs. Vibegron does not cause the same side effects related to anticholinergic drugs such as dry mouth and constipation. β3-adrenergic receptor agonists work well for OAB symptoms but may be more expensive than anticholinergic drugs. It is important to choose drugs that work well and that are a reasonable price. This study assessed if vibegron is cost-effective for people enrolled in US private insurance and Medicare plans. Compared with other common drugs such as anticholinergic drugs for OAB, vibegron is cost-effective for people enrolled in private insurance and Medicare plans. This was in part because vibegron works better for longer and causes fewer adverse effects than other drugs. Vibegron may be considered “good value for money” for patients with OAB.

Overactive bladder (OAB) is associated with considerable clinical and economic burden. Treatment of patients with OAB using anticholinergics is limited by tolerability issues and increased anticholinergic burden, which is associated with increased risk of dementia and falls/fractures. This analysis assessed the budget impact of introducing the β3-adrenergic agonist vibegron for the treatment of patients with OAB from US commercial payor and Medicare perspectives. A budget impact model (BIM) with a 5-year time horizon was developed using a top-down, prevalence-based approach and projected market shares for 1-million-member US commercial and Medicare plans. The BIM included vibegron, mirabegron, and anticholinergics, incorporating changes in clinical outcomes (efficacy, drug–drug interactions, anticholinergic burden (ACB), OAB-related comorbidities, and adverse events (AEs)). Costs per member per month (PMPM) and per treated member per month (PTMPM) were determined. One-way sensitivity analyses quantified the impact of changes in key variables. The introduction of vibegron was associated with a modest increase in PMPM cost over 5 years of $0.12 (range for years 1‒5, $0.01‒$0.26) for commercial payors and $0.24 ($0.01‒$0.52) for Medicare (PTMPM cost: $2.70 ($0.17‒$4.85) and $3.15 ($0.19‒$5.82), respectively). Costs were partially offset by savings related to decreased third-line treatment use, yearly decreases in AE and comorbidity incidence, reduced drug–drug interactions, and reduced ACB associated with vibegron introduction. PMPM costs were most sensitive to vibegron market share assumptions, OAB prevalence, and vibegron persistence at 1 month for private payors and Medicare and additionally vibegron persistence at 12 months for Medicare. Vibegron may address unmet needs in treating OAB and is a useful addition to health plans while minimizing risks of anticholinergic AEs, ACB, and drug–drug interactions, which may partially offset increased pharmacy costs. Adults with overactive bladder (OAB) experience frequent and sudden urges to urinate. OAB affects more than 100 million men and women in the USA. In 2020, the projected cost of OAB was $82.6 billion. One of the standard treatments for OAB includes a class of drugs called anticholinergics. Anticholinergic drugs can cause side effects such as dry mouth and constipation. Over time, taking a lot of anticholinergic drugs may lead to increased risk of cognitive impairment or dementia. Vibegron is from a different class of drug for the treatment of OAB known as β3-adrenergic receptor agonists. Adding a new drug to the market may have a financial impact on healthcare plans. This study assessed if adding vibegron for treating OAB is affordable in US commercial and Medicare plans. Adding vibegron to a health plan somewhat increased monthly costs over 5 years. For commercial insurance plans, monthly costs over 5 years increased $0.12 per person enrolled in the plan. For Medicare plans, monthly costs over 5 years increased $0.24 per person enrolled in the plan. However, adding vibegron to the market lowered overall costs not directly related to OAB by lowering healthcare costs related to taking a lot of anticholinergic drugs or costs of outpatient visits. Vibegron for treating OAB may be a helpful addition to health plans. Vibegron may reduce some healthcare costs for patients with OAB.

e18827 Background: Despite proven effectiveness in reducing colorectal cancer (CRC) cases, screening for CRC remains underutilized, including those enrolled in Medicare Advantage. A mailed fecal immunochemical test (FIT) outreach program may increase CRC screening adherence. This study examined the cost-effectiveness of stool-based tests (FIT and multi-target stool DNA [mt-sDNA]), with FIT offered via a mailed outreach program, in a Medicare Advantage population. Methods: The validated CRC-AIM microsimulation model was used to simulate the costs and clinical outcomes of 2 million average-risk individuals, free of diagnosed CRC at age 40, who initiated CRC screening at age 65. Annual mailed FIT outreach and triennial mt-sDNA were assessed. Test sensitivity and specificity inputs were based on the 2021 United States Preventative Services Task Force modeling study. FIT outreach program cost ($25.92) and direct costs for screening tests, colonoscopies (COLs), complications, and CRC care were included. The model employed a lifetime horizon, 3% discount rates, and a Medicare Advantage perspective. The primary analysis used published real-world adherence rates for stool-based tests and follow-up COLs (FIT/COL: 29%/53%; mt-sDNA/COL: 69.8%/71.5%). Secondary analyses assumed 100% adherence for stool-based tests and/or follow-up COLs and 20% higher than primary analysis for FIT and the corresponding follow-up COLs. Results: In the primary analysis, mt-sDNA had the greatest life-years gained (LYG), incidence reduction (IR), and mortality reduction (MR) and was cost-effective at a willingness-to-pay threshold of $50,000/QALY compared to mailed FIT outreach (Table). This was true when 100% adherence was assumed for follow-up COL and when FIT had 20% higher adherence than the primary analysis. mt-sDNA had 64-129% greater LYG, 79-150% greater IR, and 68-146% greater MR than mailed FIT outreach. When assuming 100% adherence for both screening test and follow-up COL, mt-sDNA was dominated by mailed FIT outreach. Conclusions: Adherence to CRC screening modality and follow-up COL greatly impacts clinical and cost-effectiveness outcomes. Future analysis should consider evidence-based, health plan-specific data to accurately reflect outcomes that aid in payer decision making.[Table: see text]

To assess the budget impact of introducing the β3-adrenergic agonist vibegron for the treatment of patients with overactive bladder (OAB) from US commercial payor and Medicare perspectives. A budget impact model (BIM) with 5-year time horizon was developed using a top-down, prevalence-based approach and projected market shares for 1-million-member US commercial and Medicare plans. The BIM included vibegron, mirabegron, and anticholinergics and incorporated changes in clinical outcomes, including efficacy defined by mean daily incontinence episodes, drug-drug interactions, anticholinergic burden, OAB-related comorbidities, and adverse events (AEs). Economic outcomes are provided as costs per member per month (PMPM) and per treated member per month (PTMPM). One-way sensitivity analyses (OWSA) were performed to quantify impact in response to changes in key variables. Adding vibegron to a health plan formulary was associated with a modest increase in PMPM cost over 5 years of $0.12 (range for years 1‒5, $0.01‒$0.26) for commercial payors and $0.24 (range for years 1‒5, $0.01‒$0.52) for Medicare and in PTMPM cost of $2.70 (range for years 1‒5, $0.17‒$4.85) and $3.15 (range for years 1‒5, $0.19‒$5.82), respectively. Costs were partially offset by savings related to decreased use of third-line treatments, yearly decreases in incidence of AEs and comorbidities, reduced drug-drug interactions, and reduced anticholinergic burden associated with the introduction of vibegron. OWSAs indicated that PMPM costs were most sensitive to vibegron market share assumptions, OAB prevalence, and vibegron persistence at 1 month for both private payors and Medicare and additionally vibegron persistence at 12 months for Medicare. Vibegron may address an unmet need in treating OAB and may be a useful addition to health plans by improving clinical outcomes and reducing costs associated with third-line treatments, which may partially offset modest increases in pharmacy costs.

Model-based analyses for comparative analyses within medical decision making require the development of a model of the disease that is being examined. This involves the specification of the model structure and the calibration of model parameters so that model outcomes are consistent with observable disease-related data. There is rarely a unique set of model parameters that are consistent with observable data, and such parameter sets can vary significantly. This phenomenon is known as “calibration uncertainty” and is especially prevalent when models address preclinical phases of the disease. Because model parameters influence comparative analyses, examination of the impact of calibration uncertainty on recommendations derived from the analysis is crucial to developing confidence in the recommendations. In this chapter, we present an approach to the characterization and systematic examination of the set of models that provide plausible representations of the disease. We illustrate our approach within the context of ovarian cancer. In doing so, we illustrate the impact of calibration uncertainty on the potential for early detection of ovarian cancer.

In model-based analysis for comparative evaluation of strategies for disease treatment and management, the model of the disease is arguably the most critical element. A fundamental challenge in identifying model parameters arises from the limitations of available data, which challenges the ability to uniquely link model parameters to calibration targets. Consequently, the calibration of disease models leads to the discovery of multiple models that are similarly consistent with available data. This phenomenon is known as calibration uncertainty and its effect is transferred to the results of the analysis. Insufficient examination of the breadth of potential model parameters can create a false sense of confidence in the model recommendation, and ultimately cast doubt on the value of the analysis. This paper introduces a systematic approach to the examination of calibration uncertainty and its impact. We begin with a model of the calibration process as a constrained optimization problem and introduce the notion of plausible models which define the uncertainty region for model parameters. We illustrate the approach using a fictitious disease, and explore various methods for interpreting the outputs obtained.

Store-operated calcium entry (SOCE) has been proposed as the main process controlling Ca2+ entry in non-excitable cells. Although recent breakthroughs in experimental studies of SOCE have been made, its mathematical modeling has not been developed. In the present work, SOCE is viewed as a feedback control system subject to an extracellular agonist disturbance and an extracellular calcium input. We then design a dynamic output feedback controller to reject the disturbance and track Ca2+ resting levels in the cytosol and the endoplasmic reticulum (ER). The constructed feedback control system is validated by published experimental data and its global asymptotic stability is proved by using the LaSalle’s invariance principle. We then simulate the dynamic responses of STIM1 and Orai1, two major components in the operation of the store-operated channels, to the depletion of Ca2+ in the ER with thapsigargin, which show that: (1) Upon the depletion of Ca2+ in the ER, the concentrations of activated STIM1 and STIM1–Orai1 cluster are elevated gradually, indicating that STIM1 is accumulating in the ER–PM junctions and that the cytosolic portion of the active STIM1 is binding to Orai1 and driving the opening of CRAC channels for Ca2+ entry; (2) after the extracellular Ca2+ addition, the concentrations of both STIM1 and STIM1–Orai1 cluster decrease but still much higher than the original levels. We also simulate the system responses to the agonist disturbance, which show that, when a sequence of periodic agonist pulses is applied, the system returns to its equilibrium after each pulse. This indicates that the designed feedback controller can reject the disturbance and track the equilibrium.