Background

Centers for Medicare and Medicaid Services (CMS) 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 CMS.

Design

Comparative microsimulation modeling study using two independently-developed models.

Data Sources

Derived from literature.

Target Population

65-year-old (Medicare eligible) individuals; 50-year old individuals as sensitivity analysis.

Time Horizon

Lifetime.

Perspective

Third-party payer.

Interventions

Stool DNA test every 3 or 5 years in comparison to currently-recommended colorectal cancer screening strategies.

Outcome Measures

Life expectancy, lifetime costs, incremental cost-effectiveness ratios, 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.

Results of Threshold Analysis

Screening with the stool DNA test would be cost-effective at per-test cost of $40 to $60 for 3-yearly stool DNA testing, 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 at 3-yearly intervals would be cost-effective at a cost of $350 per test if the relative adherence with stool DNA testing were at least 50% better than with other screening tests.

Results of Sensitivity Analysis

None of the above mentioned results changed significantly when considering a 50-year old cohort.

Limitations

We did not model other pathways than the traditional adenoma-carcinoma sequence.

Conclusions

Only if a significant reduction can be made to the test cost or if its availability would entice a large fraction of otherwise unscreened persons to be screened will stool DNA testing be a cost-effective alternative for colorectal cancer screening.

Primary Funding Source

Agency for Healthcare Research and Quality

Background

Microsimulation models are important decision support tools for screening. However, their complexity creates a barrier, making it difficult to understand models and, as a result, limiting realization of their full potential. Therefore, it is important to develop documentation that clarifies assumptions. We demonstrate this problem and explore a solution for the natural history, using three independently developed colorectal cancer screening models.

Methods

We begin by projecting the cost-effectiveness of colonoscopy screening for the three microsimulation models. Next, we provide a conventional presentation of each of them, including information that would usually be published with a decision analysis. Finally, for the three models, we provide the simulated reduction in clinical cancer incidence following a one-time complete removal of adenomas and preclinical cancers. We denote this measure as maximum clinical incidence reduction (MCLIR).

Results

There are considerable between-model differences in projected effectiveness. Conventional documentation describes model structure and associated parameter values. Given only this information, it is very difficult to compare models, largely because differences in structure make parameter values incomparable. In contrast, the MCLIR clearly shows the differences in assumptions on the key issue of the natural history: the dwell time of progressive preclinical disease, explaining between-model differences in projected effectiveness.

Conclusions

The simulated “maximum clinical incidence reduction” adds to the insight in dwell time, the critical characteristic of the natural history of disease, and how it differs between models. Inclusion of the MCLIR as a standard description would clarify the implications of assumptions for models applied to screening questions.

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.

Background

Omalizumab (trade name Xolair) is approved by the US Food and Drug Administration for treatment of moderate-to-severe allergic asthma. Given the high acquisition cost of omalizumab, its role and cost-effectiveness in disease management require definition.

Objective

We sought to identify the clinical and economic circumstances under which omalizumab might or might not be a cost-effective option by using a mathematic model.

Methods

We merged published data on clinical and economic outcomes (including acute event incidence, frequency/severity of hospitalizations, and health-related quality of life) to project 10-year costs, quality-adjusted life years (QALYs), and cost-effectiveness of treatment with omalizumab in addition to inhaled corticosteroids. Sensitivity analyses were conducted by using input data ranges from a variety of sources (published clinical trials and observational databases).

Results

For patients with baseline acute event rates, omalizumab conferred an additional 1.7 quality-adjusted months at an incremental cost of $131,000 over a 10-year planning horizon, implying a cost-effectiveness ratio of $821,000 per QALY gained. For patients with 5 times the baseline acute event rate, the cost-effectiveness ratio was $491,000 per QALY gained. The projected cost-effectiveness ratio could fall within a range of other programs that are widely considered to be cost-effective if the cost of omalizumab decreases to less than $200.

Conclusion

Omalizumab is not cost-effective for most patients with severe asthma. The projected cost-effectiveness ratios could fall within a favorable range if the cost of omalizumab decreases significantly.

Clinical implications

Based on the high cost of omalizumab, it is especially important that clinicians explore alternative medications for asthma before initiating omalizumab.

Objective

The purpose of this study was to estimate the ratio of cancers prevented to induced (benefit-risk ratio) for CT colonography screening every five years from age 50-80.

Materials and methods

Radiation-related cancer risk was estimated using risk projection models based on the National Research Council's BEIR VII committee's report and screening protocols from the American College of Radiology Imaging Network's National CT Colonography Trial. Uncertainty limits (UL) were estimated using Monte-Carlo simulation methods. Comparative modelling with three colorectal cancer microsimulation models was used to estimate the potential reduction in colorectal cancer cases and deaths.

Results

The estimated mean effective dose per CT colonography screen was 8mSv for females and 7mSv for males. The estimated number of radiation-related cancers from CT colonography screening every 5 years from age 50-80 was 150 cases/100,000 individuals (95%UL:80-280) for males and females. The estimated number of colorectal cancers prevented by CT colonography every 5 years from age 50-80 ranged across the three microsimulation models from 3580 to 5190/100,000, yielding a benefit-risk ratio that varied from 24:1(95%UL=13:1-45:1) to 35:1(95%UL=19:1-65:1). The benefit-risk ratio for cancer deaths was even higher than the ratio for cancer cases. Inclusion of radiation-related cancer risks from CT scans following-up extracolonic findings did not materially alter the results.

Conclusions

Concerns have been raised about recommending CT colonography as a routine screening tool because of the potential harms, including the radiation risks. Based on these models the benefits from CT colonography screening every five years from age 50-80 clearly outweigh the radiation risks.

Background

As the complexity of microsimulation models increases, however, concerns about model transparency are heightened.

Methods

We conducted model “experiments” to explore the impact of variations in “deep” model parameters using three colorectal cancer (CRC) models. All natural history models were calibrated to match observed data on adenoma prevalence and cancer incidence, but varied in their underlying specification of the adenoma-carcinoma process. We projected CRC incidence among individuals with an underlying adenoma or preclinical cancer vs. those without any underlying condition and examined the impact of removing adenomas. We calculated the percentage of simulated CRC cases arising from adenomas that developed within 10 or 20 years prior to cancer diagnosis, and estimated dwell time – defined as the time from the development of an adenoma to symptom-detected cancer in the absence of screening among individuals with a CRC diagnosis.

Results

The 20-year CRC incidence among 55-year-old individuals with an adenoma or preclinical cancer was 7 to 75 times greater than in the condition-free group. The removal of all adenomas among the subgroup with an underlying adenoma or cancer resulted in a reduction of 30% to 89% in cumulative incidence. Among CRCs diagnosed at age 65, the proportion arising from adenomas formed within 10 years ranged between 4% and 67%. The mean dwell time varied from 10.6 years to 25.8 years.

Conclusions

Models that all match observed data on adenoma prevalence and cancer incidence can produce quite different dwell times and very different answers with respect to the effectiveness of interventions. When conducting applied analyses to inform policy, using multiple models provides a sensitivity analysis on key (unobserved) “deep” model parameters and can provide guidance about specific areas in need of additional research and validation.

Our purpose was to project and compare clinical and quality-adjusted life year (QALY) outcomes of adjuvant radiotherapy (ART) vs. salvage radiotherapy (SRT) after radical prostatectomy for men with locally advanced prostate cancer.

We constructed a Markov model to simulate the randomized studies of observation vs. ART, assuming 75% of observation patients would receive SRT at prostate specific antigen (PSA) recurrence. Transition probabilities and utility inputs were drawn from randomized trials of ART and cohort studies of SRT. We projected 10-year PSA recurrence-free survival, metastasis-free survival and overall survival.

We found that observation with selective SRT yielded slightly worse outcomes than ART for post-RT PSA recurrence-free survival (47% and 52%), metastasis-free survival (69% and 70%) and overall survival (72% and 73%). Findings were robust to sensitivity analyses. After adjusting for the disutility of RT, observation plus SRT yielded better QALYs at 10 years than ART (6.80 and 6.13 QALYs).

Thus, observation plus SRT may be optimal for men likely to comply with surveillance who wish to minimize treatment side effects. These findings reflect outcomes for the average patient given the current level of evidence and are meant to help inform current decision-making as we await future clinical studies of comparative effectiveness.

Background

The Centers for Medicare and Medicaid Services (CMS) considered whether to reimburse computed tomographic colonography (CTC) for colorectal cancer screening of Medicare enrollees. To help inform its decision, we evaluated the reimbursement rate at which CTC screening could be cost-effective compared with the colorectal cancer screening tests that are currently reimbursed by CMS and are included in most colorectal cancer screening guidelines, namely annual fecal occult blood test (FOBT), flexible sigmoidoscopy every 5 years, flexible sigmoidoscopy every 5 years in conjunction with annual FOBT, and colonoscopy every 10 years.

Methods

We used three independently developed microsimulation models to assess the health outcomes and costs associated with CTC screening and with currently reimbursed colorectal cancer screening tests among the average-risk Medicare population. We assumed that CTC was performed every 5 years (using test characteristics from either a Department of Defense CTC study or the National CTC Trial) and that individuals with findings of 6 mm or larger were referred to colonoscopy. We computed incremental cost-effectiveness ratios for the currently reimbursed screening tests and calculated the maximum cost per scan (ie, the threshold cost) for the CTC strategy to lie on the efficient frontier. Sensitivity analyses were performed on key parameters and assumptions.

Results

Assuming perfect adherence with all tests, the undiscounted number life-years gained from CTC screening ranged from 143 to 178 per 1000 65-year-olds, which was slightly less than the number of life-years gained from 10-yearly colonoscopy (152–185 per 1000 65-year-olds) and comparable to that from 5-yearly sigmoidoscopy with annual FOBT (149–177 per 1000 65-year-olds). If CTC screening was reimbursed at $488 per scan (slightly less than the reimbursement for a colonoscopy without polypectomy), it would be the most costly strategy. CTC screening could be cost-effective at $108–$205 per scan, depending on the microsimulation model used. Sensitivity analyses showed that if relative adherence to CTC screening was 25% higher than adherence to other tests, it could be cost-effective if reimbursed at $488 per scan.

Conclusions

CTC could be a cost-effective option for colorectal cancer screening among Medicare enrollees if the reimbursement rate per scan is substantially less than that for colonoscopy or if a large proportion of otherwise unscreened persons were to undergo screening by CTC.

Background

While surveillance for Barrett’s esophagus and other gastrointestinal precancerous conditions is recommended, no analogous guidelines exist for gastric lesions. We sought to estimate the clinical benefits and cost-effectiveness of treatment and endoscopic surveillance to prevent gastric cancer.

Methods

We developed a state-transition decision model for a cohort of U.S. men with a recent incidental diagnosis of gastric precancerous lesions (dysplasia, intestinal metaplasia, or atrophy). Strategies included (1) no treatment or surveillance, and (2) referral for treatment and surveillance, and varied by treatment for dysplastic and cancerous lesions (surgery or endoscopic mucosal resection (EMR)) and surveillance frequency (none, every 10, 5, or 1 years). We restrict the term ‘post-treatment surveillance’ to surveillance in individuals after treatment. Data were based on published literature and databases. Outcomes included lifetime gastric cancer risk, quality-adjusted-life-expectancy, lifetime costs, and incremental cost-effectiveness ratios.

Results

For a 50-year-old cohort of men with dysplasia, lifetime gastric cancer risk was 5.9%. EMR with annual surveillance reduced lifetime cancer risk by 90% and cost $39,800 per quality-adjusted-life-year (QALY). Addition of post-treatment surveillance every 10 years provided little incremental benefit (~5%), but cost >$1 million per QALY. Results were most sensitive to surgical risks and proportion of lesions completely removed with EMR.

Conclusions

EMR with surveillance every 1 to 5 years for gastric dysplasia is promising for secondary cancer prevention, and has a cost-effectiveness ratio that would be considered attractive in the U.S. Endoscopic surveillance of less advanced lesions does not appear to be cost-effective, except possibly for immigrants from high-risk countries.

Background

The availability of human papillomavirus (HPV) DNA testing and vaccination against HPV types 16 and 18 (HPV-16,18) motivates questions about the cost-effectiveness of cervical cancer prevention in the United States for unvaccinated older women and for girls eligible for vaccination.

Methods

An empirically calibrated model was used to assess the quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (2004 US dollars per QALY) of screening, vaccination of preadolescent girls, and vaccination combined with screening. Screening varied by initiation age (18, 21, or 25 years), interval (every 1, 2, 3, or 5 years), and test (HPV DNA testing of cervical specimens or cytologic evaluation of cervical cells with a Pap test). Testing strategies included: 1) cytology followed by HPV DNA testing for equivocal cytologic results (cytology with HPV test triage); 2) HPV DNA testing followed by cytology for positive HPV DNA results (HPV test with cytology triage); and 3) combined HPV DNA testing and cytology. Strategies were permitted to switch once at age 25, 30, or 35 years.

Results

For unvaccinated women, triennial cytology with HPV test triage, beginning by age 21 years and switching to HPV testing with cytology triage at age 30 years, cost $78 000 per QALY compared with the next best strategy. For girls vaccinated before age 12 years, this same strategy, beginning at age 25 years and switching at age 35 years, cost $41 000 per QALY with screening every 5 years and $188 000 per QALY screening triennially, each compared with the next best strategy. These strategies were more effective and cost-effective than screening women of all ages with cytology alone or cytology with HPV triage annually or biennially.

Conclusions

For both vaccinated and unvaccinated women, age-based screening by use of HPV DNA testing as a triage test for equivocal results in younger women and as a primary screening test in older women is expected to be more cost-effective than current screening recommendations.

Purpose

When using state-transition Markov models to simulate risk of recurrent events over time, incorporating dependence on higher numbers of prior episodes can increase model complexity, yet failing to capture this event history may bias model outcomes. This analysis assessed the tradeoffs between model bias and complexity when evaluating risks of recurrent events in Markov models.

Methods

We developed a generic episode/relapse Markov cohort model, defining bias as the percentage change in events prevented with two hypothetical interventions (prevention and treatment) when incorporating 0–9 prior episodes in relapse risk, versus a model with 10 such episodes. We evaluated magnitude and sign of bias as a function of event and recovery risks, disease-specific mortality, and risk function.

Results

Bias was positive in the base case for a prevention strategy, indicating that failing to fully incorporate dependence on event history overestimated the prevention’s predicted impact. For treatment, the bias was negative, indicating an underestimated benefit. Bias approached zero as number of tracked prior episodes increased, and average bias over 10 tracked episodes was greater with the exponential than linear functions of relapse risk and with treatment than prevention strategies. With linear and exponential risk functions, absolute bias reached 33% and 78%, respectively, in prevention, and 52% and 85% in treatment.

Conclusion

Failing to incorporate dependence on prior event history in subsequent relapse risk in Markov models can greatly impact model outcomes, overestimating the impact of prevention and treatment strategies by up to 85%, and underestimating impact in some treatment models by up to 20%. When at least four prior episodes are incorporated, bias does not exceed 26% in prevention or 11% in treatment.

Objective

To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), emphasizing the unique clinical features in this kindred.

Design

Clinical, radiologic, pathologic, and genetic characterization of a kindred with a familial neurodegenerative disorder.

Setting

Multispecialty group academic medical center.

Patients

Affected members of a kindred with dementia +/- parkinsonism associated with a unique mutation in PGRN.

Main Outcome Measure

Genotype-phenotype correlation.

Results

Ten affected individuals were identified, among whom six presented with initial amnestic complaints resulting in initial diagnoses of AD or amnestic mild cognitive impairment (MCI). A minority of individuals presented with features characteristic of FTD. The ages of onset of generation II (mean 75.8 years, range 69-80 years) were far greater than those of generation III (mean 60.7 years, range 55-66 years). The pattern of cerebral atrophy varied widely among affected individuals. Neuropathology in six individuals showed frontotemporal lobar degeneration with ubiquitin positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U + NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), causing a frameshift (p.Thr52Hisfs×2) and therefore creation of a premature termination codon and likely null allele.

Conclusions

We describe a large kindred in which the majority of affected individuals had clinical presentations resembling AD or amnestic MCI in association with a mutation in PGRN and underlying FTLD-U + NII neuropathology. This is in distinct contrast to previously reported kindreds, where clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age of onset between generations will require further study.

Objective

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.

Methods

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.

Results

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 for >30% 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.

Conclusions

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.

Purpose

Survivors of Hodgkin's lymphoma (HL) who received mediastinal irradiation have an increased risk of coronary heart disease. We evaluated the cost effectiveness of lipid screening in survivors of HL and compared different screening intervals.

Methods

We developed a decision-analytic model to evaluate lipid screening in a hypothetical cohort of 30-year-old survivors of HL who survived 5 years after mediastinal irradiation. We compared the following strategies: no screening, and screening at 1-, 3-, 5-, or 7-year intervals. Screen-positive patients were treated with statins. Markov models were used to calculate life expectancy, quality-adjusted life expectancy, and lifetime costs. Baseline probabilities, transition probabilities, and utilities were derived from published studies and US population data. Costs were estimated from Medicare fee schedules and the medical literature. Sensitivity analyses were performed.

Results

Using an incremental cost-effectiveness ratio (ICER) threshold of $100,000 per quality-adjusted life-year (QALY) saved, lipid screening at every interval was cost effective relative to a strategy of no screening. When comparing screening intervals, a 3-year interval was cost effective relative to a 5-year interval, but annual screening, relative to screening every 3 years, had an ICER of more than $100,000/QALY saved. Factors with the most influence on the results included risk of cardiac events/death after HL, efficacy of statins in reducing cardiac events/death, and costs of statins.

Conclusion

Lipid screening in survivors of HL, with statin therapy for screen-positive patients, improves survival and is cost effective. A screening interval of 3 years seems reasonable in the long-term follow-up of survivors of HL.

Gastric cancer is the second leading cause of cancer-related deaths worldwide. Treatment for Helicobacter pylori infection, the leading causal risk factor, can reduce disease progression, but the long-term impact on cancer incidence is uncertain. Using the best available data, we estimated the potential health benefits and economic consequences associated with H. pylori screening in a high-risk region of China. An empirically calibrated model of gastric cancer was used to project reduction in lifetime cancer risk, life-expectancy and costs associated with (i) single lifetime screening (age 20, 30 or 40); (ii) single lifetime screening followed by rescreening individuals with negative results and (iii) universal treatment for H. pylori (age 20, 30 or 40). Data were from the published literature and national and international databases. Screening and treatment for H. pylori at age 20 reduced the mean lifetime cancer risk by 14.5% (men) to 26.6% (women) and cost less than $1,500 per year of life saved (YLS) compared to no screening. Rescreening individuals with negative results and targeting older ages was less cost-effective. Universal treatment prevented an additional 1.5% to 2.3% of risk reduction, but incremental cost-effectiveness ratios exceeded $2,500 per YLS. Screening young adults for H. pylori could prevent one in every 4 to 6 cases of gastric cancer in China and would be considered cost-effective using the GDP per capita threshold. These results illustrate the potential promise of a gastric cancer screening program and provide rationale for urgent clinical studies to move the prevention agenda forward.

Background

The U.S. Preventive Services Task Force requested a decision analysis to inform their update of the recommendations for colorectal cancer screening.

Objective

To assess life-years gained and colonoscopy requirements for colorectal cancer screening strategies and identify a set of recommendable screening strategies.

Design

Decision analysis using 2 colorectal cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network.

Data Sources

Derived from the literature.

Target Population

U.S. average-risk 40-year-old population.

Perspective

Societal.

Time Horizon

Lifetime.

Interventions

Fecal occult blood tests (FOBTs), flexible sigmoidoscopy, or colonoscopy screening beginning at age 40, 50, or 60 years and stopping at age 75 or 85 years, with screening intervals of 1, 2, or 3 years for FOBT and 5, 10, or 20 years for sigmoidoscopy and colonoscopy.

Outcome Measures

Number of life-years gained compared with no screening and number of screening tests required.

Results of Base-Case Analysis

Beginning screening at age 50 years was consistently better than at age 60. Decreasing the stop age from 85 to 75 years decreased life-years gained by 1% to 4%, whereas colonoscopy use decreased by 4% to 15%. Assuming equally high adherence, 4 strategies provided similar life-years gained: colonoscopy every 10 years, annual Hemoccult SENSA (Beckman Coulter, Fullerton, California) testing or fecal immunochemical testing, and sensitive FOBT every 2 to 3 years with 5-yearly sigmoidoscopy. Hemoccult II and flexible sigmoidoscopy every 5 years alone were less effective.

Results of Sensitivity Analysis

The results were most sensitive to beginning screening at age 40 years.

Limitations

The stopping age for screening was based only on chronological age.

Conclusions

The findings support colorectal cancer screening with the following: colonoscopy every 10 years, annual screening with a sensitive FOBT, or high sensitivity FOBT every 2 to 3 years with5-yearly flexible sigmoidoscopy every 5 years. from ages 50 to 75 years.

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.

OBJECTIVE

To assess the ability of echocardiographic data to predict important functional status outcomes in patients with chest pain.

DESIGN

Prospective cohort study.

SETTING

A large, urban teaching hospital.

PATIENTS

Three hundred thirty-three patients admitted from the Emergency Department for evaluation of chest pain.

MEASUREMENTS AND MAIN RESULTS

Patients underwent two-dimensional and Doppler echocardiography as well as a face-to-face interview during their initial hospitalization and a telephone interview 1 year thereafter. The interview included the Medical Outcomes Study 36-Item Short Form (SF-36) health inventory, a generic health status instrument with a physical function subscale. The relation between clinical and echocardiographic factors and functional status was explored by univariable and multivariable linear regression and logistic regression analyses. Multiple clinical and echocardiographic factors correlated significantly with functional status measures at 1 year. For the SF-36 score at 1 year, age, male gender, white race, the presence of rales, and a comorbidity score were independently predictors in multivariate analysis; echocardiographic findings of severe left ventricular dysfunction (parameter estimate [PE] −27.6; 95% confidence interval [CI] −43.1, −12.2) and aortic insufficiency (PE −16.7; 95% CI −26.4, −7.0) added independent predictive information. Explanatory power (r2) for models using clinical and demographic variables was .27 and increased after inclusion of echocardiographic data to an r 2of .35. Results in the subset of patients (n =148) with acute coronary syndromes such as unstable angina or myocardial infarction were qualitatively similar. Selected factors (rales on examination, electrocardiographic changes suggestive of ischemia, and moderate to severe mitral regurgitation) also predicted which patients would die or have a decline in their functional status. In multivariate analysis, only rales remained an independent predictor of poor outcome (odds ratio 2.4; 95% CI 1.2, 4.5).

CONCLUSIONS

Echocardiographic data are correlated with measures of functional status in patients with chest pain, but the ability to predict future functional status from clinical or echocardiographic information is limited. Because functional status cannot be predicted adequately from either patients' characteristics or echocardiographic testing, it must be assessed directly.

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.

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 1 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 lateralized topography of degeneration across all affected individuals.