Search

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.

Microsimulation models are often used to predict long-term outcomes and guide policy decisions regarding cancer screening. The United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial examines a one-time intervention of flexible sigmoidoscopy that was implemented before a colorectal cancer (CRC) screening program was established. Long-term study outcomes, now a full 17 years following randomization, have been published. We use the outcomes from this trial to validate three microsimulation models for CRC to long-term study outcomes. We find that two of three models accurately predict the relative effect of screening (the hazard ratios) on CRC-specific incidence 17 years after screening. We find that all three models yield predictions of the relative effect of screening on CRC incidence and mortality (i.e., the hazard ratios) that are reasonably close to the UKFSS results. Two of the three models accurately predict the relative reduction in CRC incidence 17-years after screening. One model accurately predicted absolute incidence and mortality rates in the screened group. The models differ in their estimates related to adenoma detection at screening. While high-quality screening results help to inform models, trials are expensive, last many years, and can be complicated by ethical issues and technological changes across the duration of the trial. Thus, well-calibrated and validated models are necessary to predict outcomes for which data are not available. The results from this validation demonstrate the utility of models in predicting long-term outcomes, and in collaborative modeling to account for uncertainty.

Background: Population-based metastatic recurrence rates for patients diagnosed with nonmetastatic colorectal cancer cannot be estimated directly from population-based cancer registries because recurrence information is not reported. We derived population-based colorectal cancer recurrence rates using disease-specific survival data based on our understanding of the colorectal cancer recurrence-death process. Methods: We used a statistical continuous-time multistate survival model to derive population-based annual colorectal cancer recurrence rates from 6 months to 10 years after colorectal cancer diagnosis using relative survival data from the Surveillance, Epidemiology, and End Results Program. The model was based on the assumption that, after 6 months of diagnosis, all colorectal cancer–related deaths occur only in patients who experience a metastatic recurrence first, and that the annual colorectal cancer–specific death rate among patients with recurrence was the same as in those diagnosed with de novo metastatic disease. We allowed recurrence rates to vary by post-diagnosis time, age, stage, and location for two diagnostic time periods. Results: In patients diagnosed in 1975–1984, annual recurrence rates 6 months to 5 years after diagnosis ranged from 0.054 to 0.060 in stage II colon cancer, 0.094 to 0.105 in stage II rectal cancer, and 0.146 to 0.177 in stage III colorectal cancer, depending on age. We found a statistically significant decrease in colorectal cancer recurrence among patients diagnosed in 1994–2003 compared with those diagnosed in 1975–1984 for 6 months to 5 years after diagnosis (hazard ratios between 0.43 and 0.70). Conclusions: We derived population-based annual recurrence rates for up to 10 years after diagnosis using relative survival data. Impact: Our estimates can be used in decision-analytic models to facilitate analyses of colorectal cancer interventions that are more generalizable.

Background: Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be. Methods: The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiver-operating curve [AUC] of 0.60 and 0.65-0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40-60 years), end age (70-85 years), and interval (1-20 years). Results: With current discriminatory performance, optimal screening ranged from once-only colonoscopy at age 60 years for the lowest-risk group to six colonoscopies at ages 40-80 years for the highest-risk group. While maintaining the same health benefits, risk-stratified screening increased costs by $59 per person. Risk-stratified screening could become cost-effective if the AUC value would increase beyond 0.65, the price per polygenic test would drop to less than $141, or risk-stratified screening would lead to a 5% increase in screening participation. Conclusions: Currently, CRC screening based on polygenic risk is unlikely to be cost-effective compared with uniform screening. This is expected to change with a greater than 0.05 increase in AUC value, a greater than 30% reduction in polygenic testing costs, or a greater than 5% increase in adherence with screening. National Cancer Institute as part of the Cancer Intervention and Surveillance Modeling Network (CISNET) [U01CA152959] This work was supported by the National Cancer Institute (grant number U01CA152959) as part of the Cancer Intervention and Surveillance Modeling Network (CISNET), with a supplement from the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute or Centers for Disease Control and Prevention.

Objective Cerebrospinal fluid (CSF) biomarkers are shown to facilitate a risk identification of patients with mild cognitive impairment (MCI) into different risk levels of progression to Alzheimer’s disease (AD). Knowing a patient’s risk level provides an opportunity for earlier interventions, which could result in potential greater benefits. We assessed the cost effectiveness of the use of CSF biomarkers in MCI patients where the treatment decision was based on patients’ risk level. Methods We developed a state-transition model to project lifetime quality-adjusted life-years (QALYs) and costs for a cohort of 65-year-old MCI patients from a US societal perspective. We compared four test-and-treat strategies where the decision to treat was based on a patient’s risk level (low, intermediate, high) of progressing to AD with two strategies without testing, one where no patients were treated during the MCI phase and in the other all patients were treated. We performed deterministic and probabilistic sensitivity analyses to evaluate parameter uncertainty. Results Testing and treating low-risk MCI patients was the most cost-effective strategy with an incremental cost-effectiveness ratio (ICER) of US$37,700 per QALY. Our results were most sensitive to the level of treatment effectiveness for patients with mild AD and for MCI patients. Moreover, the ICERs for this strategy at the 2.5th and 97.5th percentiles were US$18,900 and US$50,100 per QALY, respectively. Conclusion Based on the best available evidence regarding the treatment effectiveness for MCI, this study suggests the potential value of performing CSF biomarker testing for early targeted treatments among MCI patients with a narrow range for the ICER. Electronic supplementary material The online version of this article (doi:10.1007/s41669-017-0054-z) contains supplementary material, which is available to authorized users.

We used cross-sectional data from the Aging, Demographics, and Memory Study linked to CMS Medicare data to examine the effect of three clinical features of dementia - cognition, function, and behavior - on Medicare expenditures and healthcare utilization (skilled nursing facility covered days, number of inpatient admission claims, and physician office visit claims). Cognition was evaluated using the Mini-Mental State Examination (0 – 30). Function was evaluated as the number of functional limitations (0 – 10). Behavior was evaluated as the number of behavioral symptoms (0 -12). Medicare expenditures were estimated with a generalized linear model (log-link and gamma distribution). Measures of healthcare utilization were estimated with a negative binomial regression. All models controlled for age, gender, race, education, marital status, and number of comorbidities. Following estimation, we calculated average marginal effects of clinical features on the outcomes of interest. On average, a one-unit increase in the measure of function (i.e., worse function) was associated with $160 (95% CI: $11 – $309) additional Medicare expenditures per month. Cognition and behavior were not significantly associated with expenditures or healthcare utilization. A one-unit increase in the measure of function was associated with 0.17 (95% CI: 0.03 – 0.31) more skilled nursing days per month. Function is an important predictor of expenditures/utilization and should be targeted by interventions.

Background Clinical features of dementia (cognition, function, and behavioral/psychological symptoms [BPSD]) may differentially affect Medicare expenditures/health care utilization. Methods We linked cross-sectional data from the Aging, Demographics, and Memory Study to Medicare data to evaluate the association between dementia clinical features among those with dementia and Medicare expenditures/health care utilization (n = 234). Cognition was evaluated using the Mini-Mental State Examination (MMSE). Function was evaluated as the number of functional limitations (0-10). BPSD was evaluated as the number of symptoms (0-12). Expenditures were estimated with a generalized linear model (log-link and gamma distribution). Number of hospitalizations, institutional outpatient visits, and physician visits were estimated with a negative binomial regression. Medicare covered skilled nursing days were estimated with a zero-inflated negative binomial model. Results Cognition and BPSD were not associated with expenditures. Among individuals with less than seven functional limitations, one additional limitation was associated with $123 (95% confidence interval: $19-$227) additional monthly Medicare spending. Better cognition and poorer function were associated with more hospitalizations among those with an MMSE less than three and less than six functional limitations, respectively. BPSD had no effect on hospitalizations. Poorer function and fewer BPSD were associated with more skilled nursing among individuals with one to seven functional limitations and more than four symptoms, respectively. Cognition had no effect on skilled nursing care. No clinical feature was associated with institutional outpatient care. Of individuals with an MMSE less than 15, poorer cognition was associated with fewer physician visits. Among those with more than six functional limitations, poorer function was associated with fewer physician visits. Conclusions Poorer function, not cognition or BPSD, was associated with higher Medicare expenditures.

BACKGROUND: The Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees.OBJECTIVE: To evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services.DESIGN: Comparative microsimulation modeling study using 2 independently developed models.DATA SOURCES: Derived from literature.TARGET POPULATION: A cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied.TIME HORIZON: Lifetime.PERSPECTIVE: Third-party payer.INTERVENTION: Stool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies.OUTCOME MEASURES: Life expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs.RESULTS OF BASE-CASE ANALYSIS: Assuming a cost of $350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per-test cost of $40 to $60 for stool DNA testing every 3 years, depending on the simulation model used. There were no levels of sensitivity and specificity for which stool DNA testing would be cost-effective at its current cost of $350 per test. Stool DNA testing every 3 years would be cost-effective at a cost of $350 per test if the relative adherence to stool DNA testing were at least 50% better than that with other screening tests.RESULTS OF SENSITIVITY ANALYSIS: None of the results changed substantially when a cohort of persons aged 50 years was considered.LIMITATION: No pathways other than the traditional adenoma-carcinoma sequence were modeled.CONCLUSION: Stool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening.

Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.

Background/Objective. Modelers lack a tool to systematically and clearly present complex model results, including those from sensitivity analyses. The objective was to propose linear regression metamodeling as a tool to increase transparency of decision analytic models and better communicate their results. Methods. We used a simplified cancer cure model to demonstrate our approach. The model computed the lifetime cost and benefit of 3 treatment options for cancer patients. We simulated 10,000 cohorts in a probabilistic sensitivity analysis (PSA) and regressed the model outcomes on the standardized input parameter values in a set of regression analyses. We used the regression coefficients to describe measures of sensitivity analyses, including threshold and parameter sensitivity analyses. We also compared the results of the PSA to deterministic full-factorial and one-factor-at-a-time designs. Results. The regression intercept represented the estimated basecase outcome, and the other coefficients described the relative parameter uncertainty in the model. We defined simple relationships that compute the average and incremental net benefit of each intervention. Metamodeling produced outputs similar to traditional deterministic 1-way or 2way sensitivity analyses but was more reliable since it used all parameter values. Conclusions. Linear regression metamodeling is a simple, yet powerful, tool that can assist modelers in communicating model characteristics and sensitivity analyses. Key words: sensitivity analysis; cost-effectiveness; economic evaluation; decision analysis; design of experiments; metamodel; regression. (Med Decis Making 2013;33:880–890)

Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset < 40 years in six (10%) and > 60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (> 10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

Although gastric cancer incidence is declining in China, trends may differ from historical patterns in developed countries. Our aim was to (1) retrospectively estimate the effects of Helicobacter pylori (H. pylori) and smoking on past gastric cancer incidence and (2) project how interventions on these two risk factors can reduce future incidence.We used a population-based model of intestinal-type gastric cancer to estimate gastric cancer incidence between 1985 and 2050. Disease and risk factor data in the model were from community-based epidemiological studies and national prevalence surveys.Between 1985 and 2005, age-standardized gastric cancer incidence among Chinese men declined from 30.8 to 27.2 per 100,000 (12%); trends in H. pylori and smoking prevalences accounted for30% of overall decline. If past risk factor trends continue, gastric cancer incidence will decline an additional 30% by 2050. Yet, annual cases will increase from 116,000 to 201,000 due to population growth and aging. Assuming that H. pylori prevention/treatment and tobacco control are implemented in 2010, the decline in gastric cancer incidence is projected to increase to 33% with universal H. pylori treatment for 20-year-olds, 42% for a hypothetical childhood H. pylori vaccine, and 34% for aggressive tobacco control.The decline in gastric cancer incidence has been slower than in developed countries and will be offset by population growth and aging. Public health interventions should be implemented to reduce the total number of cases. Electronic supplementary material The online version of this article (doi:10.1007/s10552-009-9397-9) contains supplementary material, which is available to authorized users.

Helicobacter pylori (H. pylori) infection is classified as a human carcinogen by the International Agency for Research on Cancer (IARC) and is associated with an estimated 65–80% of gastric cancer.1-3 Gastric cancer is the second leading cause of cancer-related deaths worldwide and a major public health problem with over 40% of all cases occurring in China. On the basis of current age-specific rates of gastric cancer and projected demographic changes, the annual number of expected cases in the country alone will increase from 393,000 in 2002 to 795,700 in 2030.4 Over the past 30 years, the understanding of gastric carcinogenesis has advanced. Specifically, the role of H. pylori and the development of gastric cancer through a series of precancerous lesions have shifted the focus of gastric cancer research from palliative strategies to the development of preventive strategies, including screening for H. pylori, especially in China where nearly 60% are infected, the majority of whom are asymptomatic.5,6 Although the infection is relatively easy to detect and treat with a non-invasive diagnostic test and course of antibiotics, the effectiveness of treatment to prevent gastric cancer is uncertain and screening thus far has not been recommended. Ideally, the strongest evidence would come from randomized controlled trials that use gastric cancer incidence as the primary outcome. Several clinical trials are underway7 and results from the first of such studies showed that after 7.5 years, treatment for H. pylori reduces cancer incidence among individuals without preexisting precancerous lesions, defined as atrophy, intestinal metaplasia and dysplasia, at time of treatment.8 Studies measuring intermediate outcomes also provide indirect support for a benefit on cancer risk via reduced progression of precancerous lesions to cancer. To estimate the public health benefits of a H. pylori screening program, several factors must be considered: the underlying natural history of H. pylori-associated disease; the heterogeneity of risk conferred by gender, age and country; the effectiveness of treatment for H. pylori in interrupting the pathway to cancer; and the feasibility of implementing a secondary prevention program at the population level. As no single empirical study can evaluate all possible H. pylori screening and treatment strategies, by integrating the best biologic, epidemiologic and economic data, mathematical simulation models can assist in decision making by leveraging available data on intermediate outcomes to estimate the avertable burden of disease expected with different strategies, identify influential factors for which better empirical data would be most valuable, and provide insight into the potential cost-effectiveness of different strategies.9 The feasibility of introducing a new public health intervention in any country, especially one that is resource-constrained, is complex given competing health priorities. Cost-effectiveness analysis when used in conjunction with other equally important information on affordability, political will and cultural preferences and distributional and equity considerations can provide useful information to decision makers considering alternative public health interventions and policies. By quantifying the relative health and economic consequences of one investment compared with another, cost-effectiveness analyses provide information on the investment’s “value for money.” To inform the dialogue and debate about the potential value of gastric cancer prevention programs, we explored the health benefits and economic consequences associated with screening for H. pylori in China.

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from I to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateratized topography of degeneration across all affected individuals. (C) 2007 Elsevier Inc. All rights reserved.

Goldhaber-Fiebert et al. (1) presented a convincing model for the natural history of cervical cancer. The results of this study should be considered by all policy makers in taking decisions about the preventive strategies for cervical cancer. The evaluation of this model was made by comparing the observed incidence curve by age of cervical cancer onset with the predicted incidence curve. In industrialized countries, this incidence curve is the result of a complex interaction involving the clinical history of the disease, sexual behaviors, and the screening habits of the different cohorts of women. The model reproduces the observed curve perfectly, and this reproduction is the result of a mixture of five populations with different cervical cancer screening behaviors and age distributions. The sum of these five populations produces the observed figures of screening behaviors by age in the United States and the number of invasive cancers that occurred (2). The preventive strategies proposed are based mainly on two interventions: vaccination and screening. Both of these interventions have two main factors that determine their effectiveness: the technical characteristics of vaccine and screening test (ie, the protection against infection and the types of human papillomaviruses that the vaccine is directed against and the sensitivity and specificity of the test) and the compliance of the population (ie, the vaccine coverage and test uptake). To better understand the role that each factor plays in determining effectiveness and also to have a valid target that is sensitive to the model characteristics, we believe that the proportion of cancer occurring in screened women, in unscreened people, and in vaccinated and unvaccinated women should be one of the most important outcomes to be presented for validation of a model for the natural history of cervical cancer. Given the structure of the model, it should be very easy to provide this output. Unfortunately, for the United States, there are few data on screening history for invasive cervical cancers (3,4) that could be used to validate the model; however, these data are available for other countries (5–7). All of these studies conclude that lack of participation in screening is still a major risk factor for invasive cancer in industrialized countries. Will lack of participation still be the major failure for the future preventive programs?

Despite recent declines in both incidence and mortality (1), colorectal cancer remains the second most common cause of cancer death in the United States (2). Screening for colorectal cancer reduces mortality by allowing physicians to detect cancer at earlier, more treatable stages, as well as to identify and remove adenomatous polyps (asymptomatic benign precursor lesions that may lead to colorectal cancer). Many tests are available for screening, such as fecal occult blood tests (FOBTs), flexible sigmoidoscopy, and colonoscopy. Screening with FOBT (Hemoccult II, Beckman Coulter, Fullerton, California) has been shown to reduce colorectal cancer mortality by 15% to 33% in randomized, controlled trials (3--5), and screening with more sensitive FOBTs, flexible sigmoidoscopy, colonoscopy, or combinations of these tests may reduce the burden of colorectal cancer even more (6, 7). In the absence of adequate clinical trial data on several recommended screening strategies, microsimulation modeling can provide guidance on the risks, benefits, and testing resources required for different screening strategies to reduce the burden of colorectal cancer. In July 2002, the U.S. Preventive Services Task Force (USPSTF) concluded that there was sufficient evidence to recommend strongly that all average-risk adults 50 years of age and older should be offered colorectal cancer screening (8). However, the logistics of screening, such as the type of screening test, screening interval, and age at which to stop screening, were not evaluated in terms of the balance of benefits and potential harms. The USPSTF has again addressed recommendations for colorectal cancer screening with a systematic review of the evidence (9) on screening tests. For this assessment, the USPSTF requested a decision analysis to project expected outcomes of various strategies for colorectal cancer screening. Two independent microsimulation modeling groups from the Cancer Intervention and Surveillance Modeling Network (CISNET), funded by the National Cancer Institute, used a comparative modeling approach to compare life-years gained relative to resource use of different strategies for colorectal cancer screening.

Background: Many noninvasive tests exist to determine whether patients should undergo coronary angiography. The routine use of coronary angiography without previous noninvasive testing is typically not advocated. Objective: To determine the cost-effectiveness of diagnostic strategies for patients with chest pain. Design: Cost-effectiveness analysis, Data Sources: Published data. Target Population: Patients who present with chest pain, have no history of myocardial infarction, and are able to perform an exercise stress test. Time Horizon: Lifetime. Perspective: Societal. Interventions: No testing, exercise electrocardiography, exercise echocardiography, exercise single-photon emission computed tomography (SPECT), and coronary angiography alone. Outcome Measures: quality-adjusted life expectancy, lifetime cost, and incremental cost-effectiveness. Results of Base-Case Analysis: The incremental cost-effectiveness ratio of routine coronary angiography compared with exercise echocardiography was $36 400 per quality-adjusted life-year (QALY) saved for 55-year-old men with typical angina. For 55-year-old men with atypical angina, exercise echocardiography compared with exercise electrocardiography cost $41 900 per QALY saved. If adequate exercise echocardiography was not available, exercise SPECT cost $54 800 per QALY saved compared with exercise electrocardiography for these patients. For 55-year-old men with nonspecific chest pain, the incremental cost-effectiveness ratio of exercise electrocardiography compared with no testing was $57 700 per QALY saved. Results of Sensitivity Analysis: On the basis of a probabilistic sensitivity analysis, there is a 75% chance that exercise echocardiography costs less than $50 900 per QALY saved for 55-year-old men with atypical angina. Conclusions: Exercise electrocardiography or exercise echocardiography resulted in reasonable cost-effectiveness ratios for patients at mild to moderate risk for coronary artery disease in terms of age, sex, and type of chest pain. Coronary angiography without previous noninvasive testing resulted in reasonable cost-effectiveness ratios for patients with a high pretest probability of coronary artery disease.

The role of models to support recommendations on the cost-effective use of medical technologies and pharmaceuticals is controversial. At the heart of the controversy is the degree to which experimental or other empirical evidence should be required prior to model use. The controversy stems in part from a misconception that the role of models is to establish truth rather than to guide clinical and policy decisions. In other domains of public policy that involve human life and health, such as environmental protection and defense strategy, models are generally accepted as decision aids, and many models have been formally incorporated into regulatory processes and governmental decision making. We formulate an analytical framework for evaluating the role of models as aids to decision making. Implications for the implementation of Section 114 of the Food and Drug Administration Modernization Act (FDAMA) are derived from this framework.

Objectives The Commonwealth of Massachusetts increased the copayment for prescription drugs by $1.50 for Medicaid (MassHealth) beneficiaries in 2003. We sought to determine the likely health outcomes and cost shifts attributable to this copayment increase using the example of inhaled corticosteroids (ICS) use among adult asthmatic Medicaid beneficiaries. Method We compared the predicted costs and health outcomes projected over a 1-year time horizon with and without the increase in copayment from the perspective of MassHealth, providers, pharmacies, and MassHealth beneficiaries by employing decision analysis simulation model. Results In a target population of 17,500 adult asthmatics, increased copayments from 50¢ to $2.00 would result in an additional 646 acute events per year, caused by increased drug nonadherence. Annual combined net savings for the state and federal governments would be $2.10 million. Projected MassHealth savings are attributable to both decreased drug utilization and lower pharmacy reimbursement rates; these more than offset the additional costs of more frequent acute exacerbations. Pharmacies would lose $1.98 million in net revenues, MassHealth beneficiaries would pay an additional $0.28 million, and providers would receive additional $0.16 million. Conclusion Over its first year of implementation, increase in the prescription drug copayment is expected to produce more frequent acute exacerbations among asthmatic MassHealth beneficiaries who use ICS and to shift the financial burden from government to other stakeholders.

Advances in hematopoietic cell transplantation (HCT) have led to an increasing number of transplant survivors. To adequately support their healthcare needs, there is a need to know the prevalence of HCT survivors. We used data on 170,628 recipients of autologous and allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research from 1968 to 2009 to estimate the current and future number of HCT survivors in the United States. Stacked cohort simulation models were used to estimate the number of HCT survivors in the United States in 2009 and to make projections for HCT survivors by the year 2030. There were 108,900 (range, 100,500 to 115,200) HCT survivors in the United States in 2009. This included 67,000 autologous HCT and 41,900 allogeneic HCT survivors. The number of HCT survivors is estimated to increase by 2.5 times by the year 2020 (242,000 survivors) and 5 times by the year 2030 (502,000 survivors). By 2030, the age at transplant will be

Objective To perform a cost-effectiveness analysis of three immunomodulatory treatments for newly diagnosed nonprimary progressive MS: interferon beta-1a, interferon beta-1b, and glatiramer acetate. Methods We developed a state-transition model to estimate the health effects and costs associated with interferon beta-1a, interferon beta-1b, glatiramer acetate, and no treatment for hypothetical cohorts of men and women with non-primary progressive MS. We used the Expanded Disability Status Scale as the measure of disability and included both relapses and disease progression in the model. We evaluated treatment strategies assuming a 10-year treatment duration using the societal perspective. We elicited preferences for disability and treatment states using standard-gamble questions and modeled the disutility associated with treatment administration and side effects explicitly. Main outcome measures were net gains in quality-adjusted life expectancy and incremental cost-effectiveness ratios in dollars per quality-adjusted life year (QALY) gained. Results For treatment duration of 10 years for newly diagnosed non-primary progressive MS, interferon beta-1a yielded the largest gain in quality-adjusted life expectancy with an incremental cost-effectiveness ratio of $2,200,000/QALY for women and $1,800,000/QALY for men, compared with no treatment. For a 5-year treatment duration, a "no treatment" strategy yielded more quality-adjusted life years than any of the treatment strategies. Cost-effectiveness ratios were similar for all three immunomodulatory treatments evaluated. Conclusions Cost-effectiveness results for all three immunomodulatory treatments for MS were unfavorable in the simulated study population under a wide range of assumptions. For treatment duration less than or equal to 5 years, expected benefits of treatment may not outweigh disutility associated with side effects and treatment discomfort.

Background To provide quantitative insight into current U.S. policy choices for cervical cancer prevention, we developed a model of human papillomavirus (HPV) and cervical cancer, explicitly incorporating uncertainty about the natural history of disease. Methods We developed a stochastic microsimulation of cervical cancer that distinguishes different HPV types by their incidence, clearance, persistence, and progression. Input parameter sets were sampled randomly from uniform distributions, and simulations undertaken with each set. Through systematic reviews and formal data synthesis, we established multiple epidemiologic targets for model calibration, including age-specific prevalence of HPV by type, age-specific prevalence of cervical intraepithelial neoplasia (CIN), HPV type distribution within CIN and cancer, and age-specific cancer incidence. For each set of sampled input parameters, likelihood-based goodness-of-fit (GOF) scores were computed based on comparisons between model-predicted outcomes and calibration targets. Using 50 randomly resampled, good-fitting parameter sets, we assessed the external consistency and face validity of the model, comparing predicted screening outcomes to independent data. To illustrate the advantage of this approach in reflecting parameter uncertainty, we used the 50 sets to project the distribution of health outcomes in U.S. women under different cervical cancer prevention strategies. Results Approximately 200 good-fitting parameter sets were identified from 1,000,000 simulated sets. Modeled screening outcomes were externally consistent with results from multiple independent data sources. Based on 50 good-fitting parameter sets, the expected reductions in lifetime risk of cancer with annual or biennial screening were 76% (range across 50 sets: 69–82%) and 69% (60–77%), respectively. The reduction from vaccination alone was 75%, although it ranged from 60% to 88%, reflecting considerable parameter uncertainty about the natural history of type-specific HPV infection. The uncertainty surrounding the model-predicted reduction in cervical cancer incidence narrowed substantially when vaccination was combined with every-5-year screening, with a mean reduction of 89% and range of 83% to 95%. Conclusion We demonstrate an approach to parameterization, calibration and performance evaluation for a U.S. cervical cancer microsimulation model intended to provide qualitative and quantitative inputs into decisions that must be taken before long-term data on vaccination outcomes become available. This approach allows for a rigorous and comprehensive description of policy-relevant uncertainty about health outcomes under alternative cancer prevention strategies. The model provides a tool that can accommodate new information, and can be modified as needed, to iteratively assess the expected benefits, costs, and cost-effectiveness of different policies in the U.S.