Rob Boer

Biochemical markers of altered mineral metabolism have been associated with increased mortality in end stage renal disease patients. Several studies have demonstrated non-linear (U-shaped or J-shaped) associations between these minerals and mortality, though many researchers have assumed linear relationships in their statistical modeling. This analysis synthesizes the non-linear relationships across studies.

Objective To compare the risk of cervical cancer in women with histologically confirmed cervical intraepithelial neoplasia who returned to routine screening after having completed post-treatment follow-up with consecutive normal smear test results with women with a normal primary smear test result.Design Population based cohort study using data from a nationwide pathology register.Setting The Netherlands, 1994 to 2006.Population 38 956 women with histologically confirmed intraepithelial neoplasia grades 1 to 3 with completed follow-up after treatment.Intervention Routine post-treatment follow-up of cervical intraepithelial neoplasia, recommending smear tests at six, 12, and 24 months.Main outcome measure Incidence of cervical cancer in the period from completed follow-up with negative test results after cervical intraepithelial neoplasia to the next primary test. 10-year hazard ratios were compared with periods after normal results for the primary smear test, adjusted for year in follow-up.Results 20 cervical cancers were diagnosed during 56 956 woman years after completed follow-up of cervical intraepithelial neoplasia, whereas 1613 cervical cancers were diagnosed during 25 020 697 woman years after a normal primary smear test result. The incidence of 35.1 (95% confidence interval 21.4 to 54.2) per 100 000 woman years and 6.4 (6.1 to 6.8) per 100 000 woman years, respectively, led to an adjusted hazard ratio of 4.2 (95% confidence interval 2.7 to 6.5) for periods after completed follow-up compared with periods after normal primary smear test results. This hazard ratio was increased for all ages. No significant difference in risk of cervical cancer was observed by grade of cervical intraepithelial neoplasia.Conclusions An excess risk of cervical cancer previously observed for women treated for cervical intraepithelial neoplasia was also observed in the subgroup of women who completed their post-treatment follow-up with three consecutive normal smear test results. The overall corrected risk of cervical cancer in these women was increased fourfold 35 cases per 100 000 woman years) compared with women with normal primary smear test results (6 per 100 000 woman years).

The MISCAN‐lung model was designed to simulate population trends in lung cancer (LC) for comprehensive surveillance of the disease, to relate past exposure to risk factors to (observed) LC incidence and mortality, and to estimate the impact of cancer‐control interventions. MISCAN‐lung employs the technique of stochastic microsimulation of life histories affected by risk factors. It includes the two‐stage clonal expansion model for carcinogenesis and a detailed LC progression model; the latter is specifically intended for the evaluation of screenings. This article elucidates further the principles of MISCAN‐lung and describes its application to a comparative study within the CISNET Lung Working Group on the impact of tobacco control on U.S. LC mortality. MISCAN‐lung yields an estimate of the number of LC deaths avoided during 1975–2000. The potential number of avoidable LC deaths, had everybody quit smoking in 1965, is 2.2 million; 750,000 deaths (30%) were avoided in the United States due to actual tobacco control interventions. The model fits in the actual tobacco‐control scenario, providing credibility to the estimates of other scenarios, although considering survey‐reported smoking trends alone has limitations.

Background: A consortium of six research groups estimated the impact on lung cancer mortality of changes in smoking behavior that began around the publication of the Surgeon General's report (SGR). This chapter presents the results of that effort. We quantified the cumulative impact of changes in smoking behaviors on lung cancer mortality in the United States over the period 1975–2000. Methods: The six groups used common inputs and independent models to estimate the number of U.S. lung cancer deaths averted over the period 1975–2000 as a result of changes in smoking behavior beginning in the mid fifties, and the number of deaths that could have been averted if tobacco control had completely eliminated all smoking following issuance of the first SGR on Smoking and Health in 1964. Results: Approximately 795,000 deaths (550,000 men and 245,000 women) were averted over the period 1975–2000 as a result of changes in smoking behavior since in 1950s. In the year 2000 alone approximately 70,000 lung cancer deaths were averted (44,000 among men and 26,000 among women). However, these represent approximately 30% of lung cancer deaths that could have potentially been averted over the period 1975–2000 if smoking was eliminated completely. In the 10‐year period 1991–2000, this fraction increased to about 37%. Conclusions: Our results show the substantial impact of changes in smoking behavior since the 1950s. Despite a major impact of changing smoking behaviors, tobacco control effort are still needed to further reduce the burden of this disease.

Objective: Cinacalcet has been used in controlling secondary hyperparathyroidism (SHPT) in dialysis patients since 2004, but its full economic evaluation has not been conducted from the US perspective. This study assesses the cost-effectiveness of cinacalcet and low-dose vitamin D for the treatment of SHPT in dialysis patients compared with flexible vitamin D. Methods: A lifetime patient-level simulation model was developed using ADVANCE trial data, including biomarker levels: parathyroid hormone, calcium, and phosphorus. The impact of the biomarkers on mortality, cardiovascular events, fractures, and parathyroidectomy were estimated from literature: Block, an observational study; Cunningham, a combined analysis of four randomized trials of cinacalcet; and Danese, a study investigating the effect of duration in recommended targets. Baseline event rates were derived from the large dialysis organizations registries. One-way and probabilistic sensitivity analyses (PSA) were conducted. Results: The cost-effectiveness ratio for cinacalcet compared with standard of care (vitamin D and phosphate binders) was $54,560 and $72,456/quality-adjusted-life-year (QALY) gained or an incremental cost of $3155 and $2638 per year alive for the Block and Danese variants, respectively. In the Cunningham variant, cost-effectiveness ratio for cinacalcet was $5064/QALY gained or a cost saving of $1068 per year. The difference in the results of the Cunningham variant vs other variants can be explained by the favorable impact of cinacalcet on outcomes, specifically cardiovascular events observed in the Cunningham study. The PSA showed 98% likelihood for cinacalcet to be cost-effective at $100,000/QALY threshold. Limitations: Observational data assessing effects on clinical outcomes, trial restriction to use calcium-containing phosphate binders, no utility data in SHPT dialysis population, and insufficient evidence on long-term impact of cinacalcet and vitamin D on biochemical markers. Conclusions: Cinacalcet treatment is cost-effective for treatment of SHPT in the US. Due to cost offsets, cinacalcet can reduce annual costs in some scenarios.

Background: Because the efficacy of mammography screening had been shown in randomized controlled trials, the focus has turned on its effectiveness within the daily practice. Using individual data of women invited to screening, we conducted a case–control study to assess the effectiveness of the Dutch population–based program of mammography screening.

Background. Microsimulation models are important decision support tools for screening. However, their complexity makes them difficult to understand and limits realization of their full potential. Therefore, it is important to develop documentation that clarifies their structure and assumptions. The authors demonstrate this problem and explore a solution for natural history using 3 independently developed colorectal cancer screening models. Methods. The authors first project effectiveness and cost-effectiveness of colonoscopy screening for the 3 models (CRC-SPIN, SimCRC, and MISCAN). Next, they provide a conventional presentation of each model, including information on structure and parameter values. Finally, they report the simulated reduction in clinical cancer incidence following a one-time complete removal of adenomas and preclinical cancers for each model. They call this new measure the maximum clinical incidence reduction (MCLIR). Results. Projected effectiveness varies widely across models. For example, estimated mortality reduction for colonoscopy screening every 10 years from age 50 to 80 years, with surveillance in adenoma patients, ranges from 65% to 92%. Given only conventional information, it is difficult to explain these differences, largely because differences in structure make parameter values incomparable. In contrast, the MCLIR clearly shows the impact of model differences on the key feature of natural history, the dwell time of preclinical disease. Dwell times vary from 8 to 25 years across models and help explain differences in projected screening effectiveness. Conclusions. The authors propose a new measure, the MCLIR, which summarizes the implications for predicted screening effectiveness of differences in natural history assumptions. Including the MCLIR in the standard description of a screening model would improve the transparency of these models.

The Mayo Lung Project (MLP), a randomized controlled clinical trial of lung cancer screening conducted between 1971 and 1986 among male smokers aged 45 or above, demonstrated an increase in lung cancer survival since the time of diagnosis, but no reduction in lung cancer mortality. Whether this result necessarily indicates a lack of mortality benefit for screening remains controversial. A number of hypotheses have been proposed to explain the observed outcome, including over-diagnosis, screening sensitivity, and population heterogeneity (initial difference in lung cancer risks between the two trial arms). This study is intended to provide model-based testing for some of these important arguments.