CISNET Publication Abstracts |
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Working Group: | Breast | Colorectal | Lung | Prostate | General Methods Breast Working GroupPlevritis SK, Kurian AW, Sigal BM, Daniel BL, Ikeda DM, Stockdale FE, Garber AM. Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging. JAMA 2006 May 24;295(20):2374-84. Context: Women with inherited BRCA1/2 mutations are at high risk for breast cancer, which mammography often misses. Screening with contrast-enhanced breast magnetic resonance imaging (MRI) detects cancer earlier but increases costs and results in more false-positive scans. Objective: To evaluate the cost-effectiveness of screening BRCA1/2 mutation carriers with mammography plus breast MRI compared with mammography alone. Design, Setting, and Patients: A computer model that simulates the life histories of individual BRCA1/2 mutation carriers, incorporating the effects of mammographic and MRI screening was used. The accuracy of mammography and breast MRI was estimated from published data in high-risk women. Breast cancer survival in the absence of screening was based on the Surveillance, Epidemiology and End Results database of breast cancer patients diagnosed in the prescreening period (1975-1981), adjusted for the current use of adjuvant therapy. Utilization rates and costs of diagnostic and treatment interventions were based on a combination of published literature and Medicare payments for 2005. Main Outcome Measures: The survival benefit, incremental costs, and cost-effectiveness of MRI screening strategies, which varied by ages of starting and stopping MRI screening, were computed separately for BRCA1 and BRCA2 mutation carriers. Results: Screening strategies that incorporate annual MRI as well as annual mammography have a cost per quality-adjusted life-year (QALY) gained ranging from less than 45,000 dollars to more than 700,000 dollars, depending on the ages selected for MRI screening and the specific BRCA mutation. Relative to screening with mammography alone, the cost per QALY gained by adding MRI from ages 35 to 54 years is 55,420 dollars for BRCA1 mutation carriers, 130,695 dollars for BRCA2 mutation carriers, and 98,454 dollars for BRCA2 mutation carriers who have mammographically dense breasts. Conclusions: Breast MRI screening is more cost-effective for BRCA1 than BRCA2 mutation carriers. The cost-effectiveness of adding MRI to mammography varies greatly by age. [top] [breast working group] [close] Plevritis SK, Salzman P, Sigal BM, Glynn PW. A natural history model of stage progression applied to breast cancer. Stat Med 2006 Apr 5; [Epub ahead of print]. Abstract: Invasive breast cancer is commonly staged as local, regional or distant disease. We present a stochastic model of the natural history of invasive breast cancer that quantifies (1) the relative rate that the disease transitions from the local, regional to distant stages, (2) the tumour volume at the stage transitions and (3) the impact of symptom-prompted detection on the tumour size and stage of invasive breast cancer in a population not screened by mammography. By symptom-prompted detection, we refer to tumour detection that results when symptoms appear that prompt the patient to seek clinical care. The model assumes exponential tumour growth and volume-dependent hazard functions for the times to symptomatic detection and stage transitions. Maximum likelihood parameter estimates are obtained based on SEER data on the tumour size and stage of invasive breast cancer from patients who were symptomatically detected in the absence of screening mammography. Our results indicate that the rate of symptom-prompted detection is similar to the rate of transition from the local to regional stage and an order of magnitude larger than the rate of transition from the regional to distant stage. We demonstrate that, in the even absence of screening mammography, symptom-prompted detection has a large effect on reducing the occurrence of distant staged disease at initial diagnosis. [top] [breast working group] [close] Stout NK, Rosenberg MA, Trentham-Dietz A, Smith MA, Robinson SM, Fryback DG. Retrospective Cost-effectiveness Analysis of Screening Mammography. J Natl Cancer Inst 2006;98(11):774-782. Background: Many guidelines recommend screening mammography every 1 – 2 years for women older than 40 years; more than 70% of women now participate in routine screening. No studies have examined the societal impact of screening practices over the past decade in the United States on costs and quality-adjusted life-years (QALYs). We performed a retrospective cost-effectiveness analysis comparing actual and alternative screening mammography scenarios. Methods: We used a discrete-event simulation model of breast cancer epidemiology to estimate the costs and the number of QALYs that were associated with observed screening mammography patterns in the United States from 1990 to 2000 for women aged 40 years or older. We also estimated costs and QALYS for no screening and for 64 alternative screening scenarios. Incremental cost-effectiveness ratios were computed. Sensitivity analyses were performed on key parameters. Results: Actual U.S. screening patterns from 1990 to 2000 accrued 947.5 million QALYs and cost $166 billion over the lifetimes of the screened women, resulting in a gain of 1.7 million QALYs for an additional cost of $62.5 billion compared with no screening. Among those polices that were not dominated — i.e., for which no alternative existed that produced more QALYs for lower costs — screening all women aged 40 – 80 years annually per some U.S. guidelines was the most expensive option, costing $58 000 per additional QALY gained compared with the next most costly alternative, screening all women aged 45 – 80 years annually. Many alternative screening scenarios generated more QALYs for less cost (with savings up to $6 billion) than actual screening patterns over the study period. Sensitivity analysis showed that conclusions about the costeffectiveness of screening mammography policies were highly sensitive to small, short-term detrimental effects on quality of life from the screening test itself. Conclusions: Choosing among the effi cient policies to guide current screening recommendations requires consideration of costs to promote participation in screening and measurement of acute quality-of-life effects of mammography. [top] [breast working group] [close] Cronin K.A.,Yu B., Krapcho M., Miglioretti D.L., Fay M.P.,Izmirlian G., Ballard-Barbash R., Geller B.M., Feuer E.J. Modeling The Dissemination Of Mammography In The United States. Cancer Causes Control 2005;16:701-712. Objective: This paper presents a methodology for piecing together disparate data sources to obtain a comprehensive model for the use of mammography screening in the US population for the years 1975-2000. Methods: Two aspects of mammography usage, the age that a woman receives her first mammography and the interval between subsequent mammograms, are modeled separately. The initial dissemination of mammography is based on cross-sectional self report data from national surveys and the interval length between screening exams is fit using longitudinal mammography registry data. Results: The two aspects of mammography usage are combined to simulate screening histories for individual women that are representative of the US population. Simulated mammography patterns for the years 1994-2000 were found to be similar to observed screening patterns from the state level mammography registry for Vermont. Conclusions: The model presented gives insight into screening practices over time and provides an alternative public health measure for screening usage in the US population. The comprehensive description of mammography use from its introduction represents an important first step to understanding the impact of mammography on breast cancer incidence and mortality. [top] [breast working group] [close] Mandelblatt JS, Schechter CB, Yabroff KR, Lawrence W, Dignam J, Extermann M, Fox S, Orosz G, Silliman R, Cullen J, Balducci L; Breast Cancer in Older Women Research Consortium. Toward optimal screening strategies for older women. J Gen Intern Med 2005 Jun;20(6):487-96. Context: Optimal ages of breast cancer screening cessation remain uncertain. Objective: To evaluate screening policies based on age and quartiles of life expectancy (LE). Design and Population: We used a stochastic model with proxies of age-dependent biology to evaluate the incremental U.S. societal costs and benefits of biennial screening from age 50 until age 70, 79, or lifetime. Main Outcome Measures: Discounted incremental costs per life years saved (LYS). Results: Lifetime screening is expensive (151,434 dollars per LYS) if women have treatment and survival comparable to clinical trials (idealized); stopping at age 79 costs 82,063 dollars per LYS. This latter result corresponds to costs associated with an LE of 9.5 years at age 79, a value expected for 75% of 79-year-olds, about 50% of 80-year-olds, and 25% of 85-year-olds. Using actual treatment and survival patterns, screening benefits are greater, and lifetime screening of all women might be considered (114,905 dollars per LYS), especially for women in the top 25% of LE for their age (50,643 dollars per LYS, life expectancy of approximately 7 years at age 90). Conclusions: If all women receive idealized treatment, the benefits of mammography beyond age 79 are too low relative to their costs to justify continued screening. However, if treatment is not ideal, extending screening beyond age 79 could be considered, especially for women in the top 25% of life expectancy for their age. [top] [breast working group] [close] Rosenberg J, Chia YL, Plevritis S. The effect of age, race, tumor size, tumor grade, and disease stage on invasive ductal breast cancer survival in the U.S. SEER database. Breast Cancer Res Treat Jan 2005;89(1):47-54. Purpose: To examine the effect of patient and tumor characteristics on breast cancer survival as recorded in the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 1998. Methods: A sample of 72,367 female cases from 1973 to 1998 aged 21-90 years with invasive ductal breast cancer were examined with Cox proportional hazards regression to determine the effect of age at diagnosis, race, tumor size, tumor grade, disease stage, and year of diagnosis on disease-specific survival. Results: Larger tumor size and higher tumor grade were found to have large negative effects on survival. Blacks had a 47 % greater risk of death than whites. Year of diagnosis had a positive effect, with a 15 % reduction in risk for each decade in the time period under study. The effects of patient age and disease stage violated the proportional hazards assumption, with distant disease having much poorer short-term survival than one would expect from a proportional hazards model, and younger age groups matching or even falling below the survival rate of the oldest group over time. Conclusion: Tumor size, grade, race, and year of diagnosis all have significant constant effects on disease-specific survival in breast cancer, while the effects of age at diagnosis and disease stage have significant effects that vary over time. [top] [breast working group] [close] Shen Y, Yang Y, Inoue LY, Munsell MF, Miller AB, Berry DA. Role of detection method in predicting breast cancer survival: analysis of randomized screening trials. J Natl Cancer Inst 17 Aug 2005;97(16):1195-203. Background: Screening mammography detects breast cancers earlier than those detected symptomatically, and so mammographically detected breast cancers tend to have better prognoses. The so-called stage shift that results from screen detection is subject to lead-time and length biases, and so earlier detection may not translate into longer survival. We used data from three large breast cancer screening trials--Health Insurance Plan (HIP) of New York and two Canadian National Breast Cancer Screening Studies (CNBSS)--to investigate survival benefits of breast cancer screening beyond stage shift. We also address whether method of detection is an independent prognostic factor in breast cancer. Methods: The HIP trial randomly assigned approximately 62,000 women to screening and control groups. The two CNBSS trial cohorts CNBSS-1 and CNBSS-2 included a total of 44,970 women in the screening group and 44,961 in the control group. After adjusting for stage and other tumor characteristics in a Cox proportional hazards model, survival distributions were compared by method of breast cancer detection with both univariate and multivariable analyses. All P values are two-sided. Results: Breast cancers detected by screening mammography had a shift in stage distribution to earlier stages (for HIP, P < .001; for CNBSS-1, P = .03; and for CNBSS-2, P < .001). After adjusting for tumor size, lymph node status, and disease stage in a Cox proportional hazards model, method of detection was a statistically significant independent predictor of disease-specific survival. Patients with interval cancers had a 53% (95% confidence interval [CI] = 17% to 100%) greater hazard of death from breast cancer than patients with screen-detected cancers, and patients with cancer in the control groups had a 36% (95% CI = 10% to 68%) greater hazard of death than patients with screen-detected cancer. Conclusion: There was an apparent survival benefit beyond stage shift for patients with screen-detected breast cancers compared with patients with breast cancers detected otherwise. Method of detection appears to be an important prognostic factor, even after adjusting for known tumor characteristics. This finding suggests that clinical trialists should routinely collect information about method of detection. [top] [breast working group] [close] Andersen LD, Remington PL, Trentham-Dietz A, Robert S. Community trends in the early detection of breast cancer in Wisconsin, 1980-1998. Am J Prev Med Jan 2004;26(1):51-5. Background: Early detection of breast cancer is an important public health goal. Rates of early detection have increased over the past several decades, contributing to recent declines in mortality. Despite these overall trends, however, some populations have experienced less progress than others. Methods: The rates of early detection, measured as the percentage of breast cancers diagnosed as breast carcinoma in situ, were calculated using data from Wisconsin's population-based tumor registry from 1980 to 1998. Trends in breast cancer (percent diagnosed in situ) were examined over time by socioeconomic characteristics of ZIP code of residence, using census data. Results: The percentage of breast cancer cases that were breast carcinoma in situ was more than five times greater in the later period (1994-1998) (13.9%), compared with the early period (1980-1984) (2.6%). In the middle period (1987-1991), breast cancer was diagnosed as breast carcinoma in situ about one-third less frequently among women in areas with the lowest urbanization, median family income, and percent educated beyond high school, compared with communities with the highest levels of these variables. Recently disparities in early detection rates by community income and education indicators declined slightly, whereas disparities in percent of breast carcinoma in situ by urbanization did not. Conclusions: Communities with lower levels of income, education, and urbanization lagged in the early detection of breast cancer during the 1980s and, despite some progress during the 1990s, continue to be underserved. Women in these communities should be targeted for interventions to improve the early detection of breast cancer. Boer R, Plevritis S, Clarke L. Diversity of model approaches for breast cancer screening: a review of model assumptions by the Cancer Intervention and Surveillance Network (CISNET) Breast Cancer Groups. Stat Methods Med Res 2004 Dec;13(6):525-38. Abstract: The National Cancer Institute-sponsored Cancer Intervention and Surveillance Network program on breast cancer is composed of seven research groups working largely independently to model the impact of screening and adjuvant therapy on breast cancer mortality trends in the US from 1975 to 2000. Each of the groups has chosen a different modeling methodology without purposeful attempt to be in contrast with each other. The seven groups have met biannually since November 2000 to discuss their methodology and results. This article investigates the differences in methodology. To facilitate this comparison, each of the groups submitted a description of their model into a uniformly structured web based 'model profiler'. Six of the seven models simulate a preclinical natural history that cannot be observed directly with parameters estimated from published evidence concerning screening and therapy effects. The remaining model regards published evidence on intervention effects as prior information and updates that with information from the US population in a Bayesian type analysis. In general, the differences between the models appear to be small, particularly among the models driven by natural history assumptions. However, we demonstrate that such apparently small differences can have a large impact on surveillance of population trends. We describe a systematic approach to evaluating differences in model assumptions and results, as well as differences in modeling culture underlying the differences in model structure and parameters. [top] [breast working group] [close] Chia L, Salzman P, Plevritis SK, Glynn PW. Simulation-based parameter estimation for complex models: a breast cancer natural history modeling illustration. Stat Methods Med Res 2004 Dec;13(6):507-24. Abstract: Simulation-based parameter estimation offers a powerful means of estimating parameters in complex stochastic models. We illustrate the application of these ideas in the setting of a natural history model for breast cancer. Our model assumes that the tumor growth process follows a geometric Brownian motion; the parameters are estimated from the SEER registry. Our discussion focuses on the use of simulation for computing the maximum likelihood estimator for this class of models. The analysis shows that simulation provides a straightforward means of computing such estimators for models of substantial complexity. [top] [breast working group] [close] Hanin LG, Yakovlev AY. Multivariate distributions of clinical covariates at the time of cancer detection. Stat Methods Med Res 2004 Dec;13(6):457-89. Abstract: Many screening trials conducted in the past have generated a wealth of interesting data. These data represent an invaluable source of information for furthering our knowledge about the natural history of the disease. The traditional approach to modeling cancer screening tends to describe the process of tumor development in only one dimension, that is, the time natural history. A broader methodological idea is to construct a stochastic model of cancer development and detection that yields the multivariate distribution of observable variables at the time of diagnosis. By focusing on such multivariate observations, rather than just on the age of patients at diagnosis, this idea seeks to invoke an additional source of information (available only at the time of detection) in order to improve an estimation of unobservable quantitative parameters of cancer latency. In this article, we discuss modeling techniques that make the above-mentioned problems approachable. A special focus is placed on analytical tools for deriving joint distributions of clinical covariates at the time of cancer detection under an arbitrary screening protocol. In addition, some future research avenues and public health implications of the proposed approach are discussed. [top] [breast working group] [close] Hu P, Zelen M. Planning of randomized early detection trials. Stat Methods Med Res 2004;13:491-506. Abstract: Consider a randomized clinical trial to evaluate the benefit of screening an asymptomatic population. Suppose that the subjects are randomized into a usual care and a study group. The study group receives one or more periodic early detection examinations aimed at diagnosing disease early, when there are no signs or symptoms. Early detection clinical trials differ from therapeutic trials in that power is affected by: (i) the number of exams, (ii) the time between exams and (iii) the ages at which exams will be given. These design options do not exist in therapeutic trials. Furthermore; long-term follow-up may result in a reduction of power. In general, power increases with number of examinations, and the optimal follow-up time is dependent on the spacing between examinations. Clinical trials in which the usual care group receives benefit are also discussed. Two designs are discussed, for example the 'up-front design' in which all subjects receive an initial exam and then are randomized to the usual care and study groups and the 'close-out design' in which the usual care group receives an exam which is timed to be given at the same time as the last exam in the study group. Both families of designs significantly reduce the power. Power calculations are made for two clinical trials, which actually used these two designs.
[top] [breast working group] [close] Lee S, Huang H, Zelen M. Early detection of disease and the scheduling of examinations. Stat Methods Med Res 2004;13:443-56. Abstract: Special examinations exist for many chronic diseases, which can diagnose the disease while it is asymptomatic, with no signs or symptoms. The earlier detection of disease may lead to more cures or longer survival. This possibility has led to public health programs which recommend populations to have periodic screening examinations for detecting specific chronic diseases, for example, cancer, diabetes, cardiovascular disease and so on. Such examination schedules when embedded in a public health program are invariably costly and are ordinarily not chosen on the basis of possible trade-offs in costs and benefits for different screening schedules. The possible candidate number of examination schedules is so large that it is not feasible to carry out clinical trials to compare different schedules. Instead, this problem can be investigated by developing a theoretical model which can predict the eventual disease specific mortality for different examination schedules. We have developed such a model. It is a stochastic model which assumes that i) the natural history of the disease is progressive and ii) any benefit from earlier diagnosis is due to a change in the distribution of disease stages at diagnosis (stage shift). The model is general and can be applied to any chronic disease which satisfies our two basic assumptions. We discuss the basic ideas of schedule sensitivity and lifetime schedule Q1 sensitivity and its relation to the reduction in disease specific mortality. Our theory is illustrated by applications to screening breast cancer. The investigation of schedules compares not only examination schedules with equal intervals between examinations but also staggered schedules using the threshold method. (Examinations are carried out when an individual’s risk status reaches a preassigned threshold value.) [top] [breast working group] [close] Mandelblatt J, Schechter CB, Yabroff KR, Lawrence W, Dignam J, Muennig P. Benefits and costs of interventions to improve breast cancer outcomes in African American women. J Clin Oncol 2004 Jul 1;22(13):2554-66. Context: Historically, African American women have experienced
higher breast cancer mortality than White women despite lower incidence. Objective: To
evaluate whether costs of increasing rates of screening or application of intensive
treatment will be off set by survival benefits for African American women. Design
and Population:
We use a stochastic simulation model of the natural history of breast
cancer to evaluate the incremental societal costs and benefits of
status quo versus targeted biennial screening or treatment improvements
among African Americans 40 years and over. [top] [breast working group] [close] Lee SJ, Zelen M. Modeling the early detection of breast cancer. Ann Oncol 2003;14:1199-1202. Abstract: A mathematical model was developed to predict the outcome of early detection clinical trials or programs targeted at evaluating mortality benefit from earlier diagnosis of breast cancer. The model was applied to eight randomized breast cancer trials, which were carried out to evaluate the benefits of mammography, physical examination or their combination. The model assumes that breast cancer is a progressive disease and any mortality benefit from earlier diagnosis is generated from a favorable shift in the stage at diagnosis relative to usual care. The model predicted the reduction in mortality for seven of the eight trials within the reported confidence intervals. Input data required by the models are: stage shift distribution, examination schedules, population age distribution, follow up time, and survival conditional on stage at diagnosis. Survival distributions were obtained from the 1973-82 SEER database whereas the remaining data was obtained for each of the trials. Information on sensitivity and stage was ordinarily available during the early phase of the trials. The theoretical model has the promise of being able to predict the long-term outcome of early detection trials or programs during the initial examination phase. The theoretical model is general and may be applied to other chronic diseases, which satisfy the basic assumptions. [top] [breast working group] [close] Mandelblatt J, Saha S, Teutsch S. The cost-effectiveness of screening mammography beyond age 65 years: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2003 Nov 18;139(10):835-42. Context: Women older than 65 to 69 have been under-represented in mammography screening trials. There is also a paucity of data on breast cancer biology in this age group, and competing causes of mortality may offset any gains from screening. Objective: To review the evidence about the costs and benefits of screening after age 65. Methods: We used Medline and the National Health Service Economic Evaluation Database to conduct a search of published breast cancer cost-effectiveness research published between January 1989 and March 2002. We included research conducted from a societal or government perspective that included data on extending screening after age 65. We excluded reviews, duplicate publications, and analyses of other screening technologies. Results: We identified 115 studies; 10 met our inclusion criteria. Only one study modeled age-dependent assumptions of disease biology. None of the studies fully captured the potential harms of screening, including anxiety associated with positive results, over diagnosis, earlier knowledge of cancer, and living longer with the consequences of treatment. Models differed in the specific strategies compared and analytic approaches. All suggested that extending biennial screening to age 75 or 80 extends life at a reasonable cost, with costs per year of life gained ranging from about $34,000 to $88,000 in year 2002 dollars, compared to stopping at about age 65. Two studies suggested that was more cost-effective to target women with few comorbidities than those with greater competing risks of non-breast cancer mortality. Conclusions: Current estimates suggest that biennial breast cancer screening continues to save lives at reasonable costs for older women without significant comorbidity. More data is needed on the biology of disease in older women and preferences for potential benefits and harms. [top] [breast working group] [close] Polsky D, Mandelblatt JS, Weeks JC, Venditti L, Hwang YT, Glick HA, Hadley J, Schulman KA. Economic evaluation of breast cancer treatment: considering the value of patient choice. J Clin Oncol 15 Mar 2003;21(6):1139-46. Purpose: To use 5 years of primary data to compare the incremental cost-effectiveness of breast conservation and radiation versus mastectomy with the restriction of choice to a single therapy versus providing a choice of either therapy. Patients and Methods: We evaluated a random retrospective cohort of 2,517 Medicare beneficiaries treated for newly diagnosed stage I or II breast cancer from 1992 through 1994. The outcome measures were quality-adjusted life-years (QALYs) and 5-year medical costs. Risk and propensity score adjustments were used in the analysis. Results: A breast conservation and radiation regimen has significantly higher costs than mastectomy in the first year after surgery; the adjusted 5-year costs are $14,054 (95% confidence interval, $9,791 to $18,312) greater than those of mastectomy. The adjusted incremental cost-effectiveness ratio comparing breast conservation and radiation to mastectomy was $219,594 per QALY for the comparison of the two strategies. If the possibility of patient choice from maintaining the availability of multiple treatments versus restricting choice to mastectomy alone provides a quality-of-life gain of 0.031 QALYs, then the cost-effectiveness ratio of this choice option is $80,440 per QALY. Conclusion: The current system of providing a choice between mastectomy and breast conservation surgery is economically attractive when the economic analysis includes the benefit of patient choice of treatment. Tan SYGL, Oortmarssen GJ, van Piersma N. Estimating parameters of a microsimulation model for breast cancer screening using the score function method. Ann Oper Res 2003;119:43-61. Abstract: In developing decision-making models for the evaluation of medical procedures, the model parameters can be estimated by fitting the model to data observed in (randomized) trials. For complex models that are implemented by discrete event simulation (microsimulation) of individual life histories, the Score Function (SF) method can potentially be an appropriate approach for such estimation exercises. We test this approach for a microsimulation model for breast cancer screening that is fitted to data from the HIP randomized trial for early detection of breast cancer. Comparison of the parameter values estimated using the SF method and the analytical solution shows that method performs well on this simple model. The precision of the estimated parameter values depends (as expected) on the size of the sample of simulated life histories, and on the number of parameters estimated. Using analytical representations for parts of the microsimulation model can increase the precision of the estimated parameter values. Compared to the Nelder and Mead Simplex method which is often used in stochastic simulation because of its ease of implementation, the SF method is clearly more efficient (ratio computer time: precision of estimates). The additional analytical investment needed to implement the SF method in an (existing) simulation model may well be worth the effort. [top] [breast working group] [close] Yabroff KR, Washington KS, Leader A, Neilson E, Mandelblatt J. Is the promise of cancer-screening programs being compromised? Quality of follow-up care after abnormal screening results. Med Care Res Rev Sep 2003;60(3):294-331. Abstract: Cancer screening has increased dramatically in the United States, yet in some populations, particularly racial minorities or the poor, advanced disease at diagnosis remains high. One potential explanation is that follow-up of abnormal tests is suboptimal, and the benefits of screening are not being realized. The authors used a conceptual model of access to care and integrated constructs from models of provider and patient health behaviors to review published literature on follow-up care. Most studies reported that fewer than 75 percent of patients received some follow-up care, indicating that the promise of screening may be compromised. They identified pervasive barriers to follow-up at the provider, patient, and health care system levels. Interventions that address these barriers appear to be effective. Improvement of data infrastructure and reporting will be important objectives for policy makers, and further use of conceptual models by researchers may improve intervention development and, ultimately, cancer control. [top] [breast working group] [close] Lee SJ, Zelen M. Statistical models for screening: planning public health programs. In: Beam C, editor. Biostatistical applications in cancer research. Boston: Kluwer Academic Publishers; 2002. p. 19-36. Abstract: The Threshold Method and Schedule Sensitivity Method proposed by Lee and Zelen (JASA, 1998) were used to plan breast cancer screening programs. The Threshold Method constructs examination schedules so that the probability of being in the pre-clinical state (earlier stage of cancer) is bounded by a pre-selected value during the surveillance time. The Schedule Sensitivity Method is based on the ratio of the expected number of cases diagnosed on scheduled examinations to the expected total number of cases. The Threshold Method offers a way to choose the spacings of exams according to the risk of having disease. The Schedule Sensitivity Method can be used to compare the ''efficiency'' of different screening programs. Both methods were utilized to plan and evaluate public health programs for the early detection of cancer. [top] [breast working group] [close] Mariotto A, Feuer EJ, Harlan LC, Wun LM, Johnson KA, Abrams J. Trends in use of adjuvant multi-agent chemotherapy and tamoxifen for breast cancer in the United States: 1975-1999. J Natl Cancer Inst 2002 Nov 6;94(21):1626-34. Background: Estimate the complete history of the dissemination of adjuvant multi-agent chemotherapy, tamoxifen and the combined use of both for early stage breast cancer patients from 1975 to 1997. Data and methods: We have used data from 8 registries of the Surveillance, Epidemiology and End-Results (SEER) of patients diagnosed with stages I, II node negative (II-), II node positive (II+) and IIIA from 1975 to 1997 (192,518 patients). The SEER information on the use of adjuvant systemic therapy is incomplete. Data from a series of population-based patterns of care (POC) studies that randomly selected cases from the SEER registries was used in order to verify with the treatment physicians information on treatment and to correct the SEER bias. The POC data included 7,117 breast cancer women diagnosed between 1987-1991 and 1995. Modeling and information on the start point of dissemination was also used. Results: The models revealed patterns of care compatible with results from clinical trials. The dissemination of multi-agent chemotherapy was higher among pre-menopausal women while the dissemination of tamoxifen was higher among post-menopausal. The dissemination of multi-agent chemotherapy for post-menopausal women diagnosed in stages II+/IIIA showed a distinct pattern. It reached a peak in 1983 and decreased from 1983 to 1987, indicating a clear substitution of multi-agent chemotherapy by tamoxifen. After 1986, the combined use of multi-agent chemotherapy and tamoxifen increased for almost all stages and ages. Conclusions: This work showed how modeling can be used to piece together disparate data sources, some of which having inherent biases, to estimate the curves that represent the dissemination of multi-agent chemotherapy, tamoxifen and the combined use of both for breast cancer patients from 1975 to 1997. These dissemination curves are important in understanding the relationship between medical research findings and translation of these results into general practice as well as measuring the impact of treatment advances on population mortality. [top] [breast working group] [close] Zelen M, Lee SJ. Models and the Early Detection of Disease: Methodological Consideration. In: Beam C, editor. Biostatistical applications in cancer research. Boston: Kluwer Academic Publishers; 2002. Abstract: This paper reviews the role of models in the early detection of disease. Among the topics discussed are: natural histories (progressive and non-progressive disease models, length and lead time biases, stable and non-stable disease models, theory of length biased sampling and it consequences, planning early detection clinical trials, parametric procedures for estimating sensitivity and the mean sojourn time in the pre-clinical state. Illustrations are drawn from breast cancer applications. [top] [breast working group] [close] Bartoszynski R, Edler L, Hanin L, Kopp-Schneider A, Pavlova L, Tsodikov A, Zorin A, Yakovlev AY. Modeling cancer detection: tumor size as a source of information on unobservable stages of carcinogenesis. Math Biosci 2001 Jun;171(2):113-42. Abstract: This paper is concerned with modern approaches to mechanistic modeling of the process of cancer detection. Measurements of tumor size at diagnosis represent a valuable source of information to enrich statistical inference on the processes underlying tumor latency. One possible way of utilizing this information is to model cancer detection as a quantal response variable. In doing so, one relates the chance of detecting a tumor to its current size. We present various theoretical results emerging from this approach and illustrate their usefulness with numerical examples and analyses of epidemiological data. An alternative approach based on a threshold type mechanism of tumor detection is briefly described. [top] [breast working group] [close] Hanin LG, Tsodikov AD, Yakovlev AY. Optimal regimens of cancer screening. Math Comput Model 2001;33:1419-30. Abstract: The goal of the present work is to study methodological, mathematical, and computational aspects of optimization procedure for screening regimens and discuss its biomedical significance with application to early detection of breast cancer. The problem of optimal screening design is set up as a search for optimal schedules of medical exams subject to certain constraints on their number and timing. The paper deals with a screening efficiency functional defined as the expected difference between tumor sizes at detection in the absence and presence of screening. It is assumed that in the absence of screening a tumor can be detected spontaneously, i.e. by symptomatic surfacing of the disease typically followed by appropriate medical exams, or asymptomatically as a result of unrelated medical tests, and that the same mechanism is in place also in the presence of screening and competes with the latter. Thus, the efficiency functional under study characterizes the net effect of screening and is completely determined by tumor natural history from the birth of a patient to the time of the last exam in the screening schedule. The functional coincides with the Kantorovich distance between tumor sizes at detection with and without screening which leads to a convenient computational formula. Optimal schedules are obtained by a numerical algorithm [top] [breast working group] [close] Saha S, Hoerger TJ, Pignone MP, Teutsch SM, Helfand M, Mandelblatt JS; Cost Work Group, Third US Preventive Services Task Force. The art and science of incorporating cost effectiveness into evidence-based recommendations for clinical preventive services. Am J Prev Med 2001 Apr;20(3 Suppl):36-43. Abstract: As medical technology continues to burgeon and the cost of using all effective clinical services exceeds available resources, decisions regarding the use of services may increasingly rely on assessments of the cost-effectiveness of medical technologies. Cost-effectiveness is particularly relevant when shaping policies regarding the implementation of preventive services, since these policies typically represent major investments in the future health of large populations, rather than smaller and more targeted investments in the management of acutely or chronically ill individuals. As such, decisions regarding the implementation of preventive services frequently involve implicit, if not explicit, reliance on cost-effectiveness data. Realizing this, the Third United States Preventive Services Task Force (USPSTF) has initiated a process for reviewing cost-effectiveness analyses with the intent of including relevant information from them in the next edition of the Guide to Clinical Preventive Services. In this paper, we provide an overview and examples of some potential roles for using cost-effectiveness analyses to complement preventive services recommendations, discuss the limitations of cost-effectiveness data in the context of shaping evidence-based preventive health care policies, outline the USPSTF approach to using cost-effectiveness analyses, and discuss the methods the USPSTF is developing to assess the quality and results of cost-effectiveness studies. While this paper focuses on clinical preventive services (i.e., screening, counseling, immunizations, and chemoprophylaxis), the framework we have developed should be broadly portable to other health care services. [top] [breast working group] [close] Shen Y, Zelen M. Screening sensitivity and sojourn time from breast cancer early detection clinical trials: mammograms and physical examinations. J Clin Oncol 2001 Aug 1;19(15):3490-9. Purpose: To estimate sensitivities of breast cancer screening modalities and preclinical duration of the disease from eight breast cancer screening clinical trials. Materials and Methods: Screening programs invariably lead to diagnosis of disease before signs or symptoms are present. Two key quantities of screening programs are the sensitivity of the disease detection modality, and the mean sojourn time. The knowledge of these quantities is related to potential benefit. The observed screening histories in a periodically screened cohort make it possible to estimate these quantities of interest. We applied recently developed statistical methods to data from eight randomized breast cancer screening trials to estimate the sensitivities of early detection modalities and mean sojourn time (MST). Moreover, when a screening trial involves two screening modalities, our methods enable the estimation of the individual sensitivity of each screening modality. Results: We analyzed breast cancer data from the HIP, Edinburgh, Swedish two-county, Malmö, Stockholm, Gothenburgh and Canadian (two) screening trials. Among these studies, we have relatively complete data from the HIP, Edinburgh and the two Canadian studies. The screening sensitivity for mammography, for physical exam, and MST are: the HIP: 0.39 (sd=.11), 0.47 (.14) and 2.5 (1.2) years; and Edinburgh: 0.63 (.13), 0.40 (.08) and 4.3 (.37) years; Canadian (age 40-49 at entry): 0.61 (.13), 0.59 (.12) and 1.9 (1.2) years; Canadian (age 50-59 at entry): 0.66 (.10), 0.39 (.06) and 3.1 (.94) years. Conclusion: The public debate on early breast cancer detection is mainly centered on mammograms. However, the current study indicates that a physical exam is of comparable importance. Public access to complete trial data will allow better understanding of screening benefits. Cautious interpretation of trial differences is required due to various experimental designs and the age-dependency of screening sensitivity and MST. [top] [breast working group] [close] Yabroff KR, O'Malley A, Mangan P, Mandelblatt J. Inreach and outreach interventions to improve mammography use. J Am Med Womens Assoc 2001;56(4):166-73, 188. Objective: to assess the effectiveness of patient-targeted interventions in increasing mammography use when performed outside (outreach) or inside the primary care medical setting (inreach). Methods: We performed a meta-analysis of controlled interventions to increase mammography use in patients in the United States published between 1980 and February 2001. Interventions were classified by setting (inreach or outreach), mechanism of action (behavioral, cognitive, sociologic, or a combination), type of control group (active or usual care), number of strategies, and mode of delivery (static or interactive). Summary estimates were calculated with DerSimonian and Laird random effects models for each group of interventions. Results: We included 66 studies with 98 separate interventions. Inreach and outreach interventions were equally effective in increasing mammography use. Compared to active controls, behavioral interventions with multiple strategies increased mammography use by 14.0% (95% CI, 8.7-19.2) in inreach and 18.7% (95% CI, 4.9-32.4) in outreach settings. Theory-based educational strategies delivered interactively increased mammography use by 10.7% (95% CI, 6.8-14.7) and 19.9% (95% CI, 10.6-29.1) in inreach and outreach settings, respectively. Interventions that combined behavioral and theory-based educational strategies with usual care controls increased mammography use by 14.0% (95% CI, 7.9-20.2) in inreach and 27.3% (95% CI, 14.7-40.0) in outreach settings. Finally, sociologic interventions increased mammography use by 10.7% (95% CI, 3.4-18.0) and 9.1% (95% CI, 1.7-13.3) in inreach and outreach settings, respectively. Conclusions: Inreach and outreach interventions to increase mammography use were similarly effective within intervention categories based on mechanism of action, mode of delivery, and type of control group. Ultimate decisions about intervention strategies will depend on the characteristics of the target population, practical considerations, and relative cost-effectiveness. [top] [breast working group] [close] Colorectal Working GroupJeon J, Meza R, Moolgavkar SH, Luebeck EG. Evaluation of screening strategies for pre-malignant lesions using a biomathematical approach. Math Biosci 2008:213;56-70. We derive mathematical expressions for the size distribution of screen-detectable pre-malignant lesions, both conditional and unconditional on no prior detection of cancer in the tissue of interest, based on a general multistage clonal expansion model of carcinogenesis. We apply these expressions to simulate the natural history of colorectal cancer and to evaluate the effect of a screen for adenomatous polyps and concomitant intervention on cancer risk. Our approach allows the efficient simulation of multiple screens and interventions and determination of the optimal timing of the screens. We further demonstrate the utility of our approach by computing the benefits of up to two colonoscopies on the lifetime risk of colorectal cancer. [top] [colorectal working group] [close] Miglioretti DL, Brown ER. A marginalized diffusion model for estimating age at first lower endoscopy use from current-status data. Journal of the Royal Statistical Society, Series C (Applied Statistics) 2008;57(1):61-74. We propose an approach for estimating the age at first lower endoscopy examination from current status data that were collected via two series of cross-sectional surveys. To model the national probability of ever having a lower endoscopy examination, we incorporate birth cohort effects into a mixed influence diffusion model.We link a state-specific model to the national level diffusion model by using a marginalized modelling approach. In future research, results from our model will be used as microsimulation model inputs to estimate the contribution of endoscopy examinations to observed changes in colorectal cancer incidence and mortality. [top] [colorectal working group] [close] Rutter CM, Miglioretti DM, Yu, O. A hierarchical non-homogeneous Poisson model for meta-analysis of adenoma counts. Statistics in Medicine, 2007; 26:98-109. Abstract: We use a hierarchical model for a meta-analysis that combines information from autopsy studies of adenoma prevalence and counts. The studies we included reported findings using a variety of adenoma prevalence groupings and age categories. We use a non-homogeneous Poisson model for multinomial bin probabilities. The Poisson model allows risk to depend on age and sex, and incorporates extra-Poisson variability. We evaluate model fit using the posterior predicted distribution of adenoma prevalence reported by the studies included in our analyses and validate our model using adenoma prevalence reported by more recent colonoscopy studies. For 1990, the estimated adenoma prevalence among Americans at age 60 is 40.3 per cent for men compared to 29.2 per cent for women. [top] [colorectal working group] [close] Vogelaar I, van Ballegooijen M, Schrag D, Boer R, Winawer SJ, Habbema JD, Zauber AG. How much can current interventions reduce colorectal cancer mortality in the U.S.: mortality projections for scenarios of risk-factor modification, screening, and treatment. Cancer 2006 Aug 24;107(7):1624-33. Background: Although colorectal cancer (CRC) is the second leading cause of cancer death in the U.S., available interventions to reduce CRC mortality are disseminated only partially throughout the population. This study assessed the potential reduction in CRC mortality that may be achieved through further dissemination of current interventions for risk-factor modification, screening, and treatment. Methods: The MISCAN-COLON microsimulation model was used to simulate the 2000 U.S. population with respect to CRC risk-factor prevalence, screening use, and treatment use. The model was used to project age-standardized CRC mortality from 2000 to 2020 for 3 intervention scenarios. Results: Without changes in risk-factor prevalence, screening use, and treatment use after 2000, CRC mortality would decrease by 17% by the Year 2020. If the 1995 to 2000 trends continue, then the projected reduction in mortality would be 36%. However, if trends in the prevalence of risk factors could be improved above continued trends, if screening use increased to 70% of the target population, and if the use of chemotherapy increased among all age groups, then a 49% reduction would be possible. Screening drove most (23%) of the projected mortality reduction with these optimistic trends; however, decreasing risk factors (16%) and increasing use of chemotherapy (10%) also contributed substantially. The contribution of risk factors may have been overestimated, because effect estimates could not be obtained from randomized controlled trials. Conclusions: Currently available interventions for risk-factor modification, screening, and treatment have the potential to reduce CRC mortality by almost 50% by the Year 2020. However, without action now to further increase the uptake of current effective interventions, the reduction in CRC mortality may be only 17%. [top] [colorectal working group] [close] Winawer SJ, Zauber AG, Fletcher RH, Stillman JS, O'Brien MJ, Levin B, Smith RA, Lieberman DA, Burt RW, Levin TR, Bond JH, Brooks D, Byers T, Hyman N, Kirk L, Thorson A, Simmang C, Johnson D, Rex DK, US Multi-Society Task Force on Colorectal Cancer, American Cancer Society. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology May 2006;130(6):1872-85. Abstract: Adenomatous polyps are the most common neoplastic findings discovered in people who undergo colorectal screening or who have a diagnostic work-up for symptoms. It was common practice in the 1970s for these patients to have annual follow-up surveillance examinations to detect additional new adenomas and missed synchronous adenomas. As a result of the National Polyp Study report in 1993, which showed clearly in a randomized design that the first postpolypectomy examination could be deferred for 3 years, guidelines published by a gastrointestinal consortium in 1997 recommended that the first follow-up surveillance take place 3 years after polypectomy for most patients. In 2003 these guidelines were updated and colonoscopy was recommended as the only follow-up examination, stratification at baseline into low risk and higher risk for subsequent adenomas was suggested. The 1997 and 2003 guidelines dealt with both screening and surveillance. However, it has become increasingly clear that postpolypectomy surveillance is now a large part of endoscopic practice, draining resources from screening and diagnosis. In addition, surveys have shown that a large proportion of endoscopists are conducting surveillance examinations at shorter intervals than recommended in the guidelines. In the present report, a careful analytic approach was designed to address all evidence available in the literature to delineate predictors of advanced pathology, both cancer and advanced adenomas, so that patients can be stratified more definitely at their baseline colonoscopy into those at lower risk or increased risk for a subsequent advanced neoplasia. People at increased risk have either 3 or more adenomas, high-grade dysplasia, villous features, or an adenoma 1 cm or larger in size. It is recommended that they have a 3-year follow-up colonoscopy. People at lower risk who have 1 or 2 small (<1 cm) tubular adenomas with no high-grade dysplasia can have a follow-up evaluation in 5-10 years, whereas people with hyperplastic polyps only should have a 10-year follow-up evaluation, as for average-risk people. There have been recent studies that have reported a significant number of missed cancers by colonoscopy. However, high-quality baseline colonoscopy with excellent patient preparation and adequate withdrawal time should minimize this and reduce clinicians concerns. These guidelines were developed jointly by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society to provide a broader consensus and thereby increase the use of the recommendations by endoscopists. The adoption of these guidelines nationally can have a dramatic impact on shifting available resources from intensive surveillance to screening. It has been shown that the first screening colonoscopy and polypectomy produces the greatest effects on reducing the incidence of colorectal cancer in patients with adenomatous polyps. [top] [colorectal working group] [close] de Visser M, van Ballegooijen M, Bloemers SM, van Deventer SJ, Jansen JB, Jespersen J, Kluft C, Meijer GA, Stoker J, de Valk GA, Verweij MF, Vlems FA. Report on the Dutch consensus development meeting for implementation and further development of population screening for colorectal cancer based on FOBT. Cell Oncol 2005;27(1):17-29. Abstract:A consensus development meeting was held to evaluate whether or not in the Netherlands all requirements were fulfilled for implementation of population screening with FOBT for colorectal cancer, or whether consensus was present that fulfilment by additional research or organisational actions could be obtained within 2-3 years. There was consensus that all classical Wilson and Jungner (1968) criteria, and six additional ones added more recently, had already been fulfilled or could be fulfilled within 2-3 years. Consequently, it was concluded that a national population screening for colorectal cancer should be implemented and carried out in the Netherlands in line with current national and European cancer screening programmes. A list of organisational actions to be taken was established. Research that is needed before the actual national launch of the screening within 2-3 years has been defined. Priorities have to be set for research and organisational actions for the coming 2-3 years for the implementation of population screening. In addition, research suggestions have been defined for the next 10-15 years for evaluation and/or improvement of implemented FOBT screening, and for future screening methodology. It was considered essential that infrastructure for future research would be embedded in the screening programme. A project group to arrange this should be formed. [top] [colorectal working group] [close] Loeve F, Boer R, Zauber AG, van Balleooijen M, van Oortmarssen GJ, Winawer SJ, Habbema JD. National Polyp Study data: evidence for regression of adenomas. Int J Cancer 2004;111:633-9. Abstract: The data of the National Polyp Study, a large longitudinal study on surveillance of adenoma patients, is used for testing assumptions on the adenoma-carcinoma sequence. The observed adenoma and colorectal cancer incidence in the National Polyp Study were compared with the simulated outcomes of the MISCAN-COLON model of epidemiology and control of colorectal cancer for the U.S. population based on expert opinion. Variants of this model were explored in order to identify assumptions on the adenoma-carcinoma sequence that are consistent with the study observations. The high observed adenoma detection rates at surveillance and low observed colorectal cancer incidence in the National Polyp Study could only be explained by assuming a high incidence rate of adenomas accompanied by regression of adenomas. The National Polyp Study data suggest that adenoma prevalence results from a dynamic process of both formation as well as regression of adenomas. This lowers the expectations for the effects of colorectal cancer screening strategies that focus on adenoma detection. [top] [colorectal working group] [close] Loeve F, van Ballegooijen M, Boer R, Kuipers EJ, Habbema JDF. Colorectal cancer risk in adenoma patients: a nation-wide study. Int J Cancer 2004:111(1):147-41. Abstract: Colorectal cancer incidence after adenoma removal has been studied in selected populations of adenoma patients. Our study estimates the trend in colorectal cancer incidence after adenoma removal in actual clinical practice. From PALGA, a nationwide network and registry of histo- and cytopathology in the Netherlands, we extracted data of all patients diagnosed with colorectal adenomas between 1 January 1988 and 1 October 1998. The data were used to calculate population-based colorectal cancer incidence rates after adenoma removal. A total of 78,473 adenoma patients were followed for a mean of 4.5 years after the first adenoma removal. The colorectal cancer incidence ratio compared with the general population matched by age and gender was 38.4 (37.3-39.5) in the first year after adenoma removal and 1.5 (95% confidence interval (CI): 1.4-1.6) after Year 1. The incidence ratio decreased from 2.8 (2.5-3.1) in Year 2 to 0.9 (0.6-1.2) in Years 9-11. This time trend is the opposite of the upward time trend that was expected after adenoma removal. Adenoma patients in the Netherlands are at increased risk for colorectal cancer compared to the general population. The high cancer incidence in Years 1-5 after polypectomy can be explained by a colonoscopic sensitivity for cancer of approximately 90%. [top] [colorectal working group] [close] Schrag D. The price tag on progress-chemotherapy for colorectal cancer. New Eng J Med 2004; 351(4):317-9. Abstract: From the 1960s until the mid-1990s, fluorouracil was the primary chemotherapeutic agent available for the treatment of colorectal cancer. During the past decade, the Food and Drug Administration (FDA) has approved five new drugs for metastatic colorectal cancer. Irinotecan (approved in 1996) and oxaliplatin (2002) are cytotoxic agents that interfere with DNA replication, and capecitabine (1998) is an oral formulation of fluorouracil. This spring, the monoclonal antibodies bevacizumab and cetuximab, targeting vascular endothelial growth factor and epithelial growth factor receptor, respectively, were approved by the FDA for use in conjunction with cytotoxic regimens. [top] [colorectal working group] [close] Lung Working GroupMeza R, Hazelton WD, Colditz GA, Moolgavkar SH. Analysis of lung cancer incidence in the nurses' health and the health professionals' follow-up studies using a multistage carcinogenesis model. Cancer Causes Control Apr 2008;19(3):317-28. Abstract: We analyzed lung cancer incidence among non-smokers, continuing smokers, and ex-smokers in the Nurses Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) using the two-stage clonal expansion (TSCE) model. Age-specific lung cancer incidence rates among non-smokers are identical in the two cohorts. Within the framework of the model, the main effect of cigarette smoke is on the promotion of partially altered cells on the pathway to cancer. Smoking-related promotion is somewhat higher among women, whereas smoking-related malignant conversion is somewhat lower. In both cohorts the relative risk for a given daily level of smoking is strongly modified by duration. Among smokers, the incidence in NHS relative to that in HPFS depends both on smoking intensity and duration. The age-adjusted risk is somewhat larger in NHS, but not significantly so. After smokers quit, the risk decreases over a period of many years and the temporal pattern of the decline is similar to that reported in other recent studies. Among ex-smokers, the incidence in NHS relative to that in HPFS depends both on previous levels of smoking and on time since quitting. The age-adjusted risk among ex-smokers is somewhat higher in NHS, possibly due to differences in the age-distribution between the two cohorts. [top] [lung working group] [close] Levy DT, Ross H, Powell L, Bauer J, Lee HR. The role of public policies in reducing smoking prevalence in Arizona: results from the Arizona tobacco policy simulation model. J Public Health Manag Pract 2007 Jan-Feb;13(1):59-67. Abstract: Arizona was one of the first few states to implement a comprehensive tobacco control program. The effect of that program is examined utilizing a computer-simulation model (SimSmoke) that was developed for the purposes of evaluation, planning and justifying policies. This approach assesses the impact to date of tobacco control policies on smoking prevalence and generates predictions about the effects of tobacco control policies on past and future smoking prevalence and associated future premature mortality. SimSmoke estimates indicate that tobacco control policies reduced smoking rates in Arizona by about 20% over the period 1993 to 2002. A previous CDC study obtains similar effects, but does not net out the effects of individual policies. SimSmoke attributes much of the reduction, about 61%, to price increases and attributes 38% of the overall effect to media policies, leaving only a small percent of the smoking reductions attributed to quitlines, youth access policies and the weak clean air laws. Tobacco control policies implemented as comprehensive strategies have significantly affected smoking rates in Arizona, which leads to large reductions in deaths attributable to smoking. It will be important to maintain these efforts over time to reduce or keep smoking prevalence down and to minimize smoking attributable deaths. [top] [lung working group] [close] Levy D, Mumford E, Cummings M, Gilpin B, Giovino G, Hyland A, Sweanor D, Warner K. The potential impact of a low-nitrosamine smokeless tobacco product on cigarette smoking in the United States: Estimates of a panel of experts. Addict Behav 2006 Jul;31(7):1190-200. Epub 2005 Oct 26. Objective: To predict the impact on tobacco use in the US of a "harm reduction" policy that requires that the smokeless tobacco product meet low nitrosamine standards, but could be marketed with a warning label consistent with the evidence of relative health risks. Methods: Low nitrosamine smokeless tobacco (LN-SLT) and cigarette use are predicted by a panel of experts using a modified Delphi approach. We specify a thought experiment to isolate the changes that would occur after the new LN-SLT policy was implemented. Results: The panel predicted that the new policy would accelerate a decrease in smoking prevalence from 1.3 to 3.1 percentage points over 5 years compared to the current SLT product policy, with greater effects on males than females. Introduction of the new product was also predicted to result in modest additional use of SLT overall, with the greatest increases among males who initiated tobacco use under the new policy. Conclusion: An overall consensus was reached that the introduction of a new LN-SLT product under strict regulations would increase SLT use, but reduce overall smoking prevalence. This reduction would likely yield substantial health benefits, but uncertainties surround the role of marketing and other tobacco control policies. [top] [lung working group] [close] Clements MS, Armstrong BK, Moolgavkar SH. Lung cancer rate predictions using generalized additive models. Biostatistics 2005 Oct;6(4):576-89. Epub 2005 Apr 28. Abstract: Predictions of lung cancer incidence and mortality are necessary for planning public health programs and clinical services. It is proposed that generalized additive models (GAMs) are practical for cancer rate prediction. Smooth equivalents for classical age-period, age-cohort, and age-period-cohort models are available using one-dimensional smoothing splines. We also propose using two-dimensional smoothing splines for age and period. Variance estimation can be based on the bootstrap. To assess predictive performance, we compared the models with a Bayesian age-period-cohort model. Model comparison used cross-validation and measures of predictive performance for recent predictions. The models were applied to data from the World Health Organization Mortality Database for females in five countries. Model choice between the age-period-cohort models and the two-dimensional models was equivocal with respect to cross-validation, while the two-dimensional GAMs had very good predictive performance. The Bayesian model performed poorly due to imprecise predictions and the assumption of linearity outside of observed data. In summary, the two-dimensional GAM performed well. The GAMs make the important prediction that female lung cancer rates in these countries will be stable or begin to decline in the future. [top] [lung working group] [close] Gorlova O, Peng B, Yankelevitz D, Henschke C, Kimmel M. Estimating the growth rates of primary lung tumours from samples with missing measurements. Stat Med 2005 Apr 15;24(7):1117-34. Abstract: .A method to estimate the population variability in tumour growth rate using incomplete data was developed. We assume exponential growth and lognormal distribution for the parameter of the growth curve. Estimates of growth rate obtained based on the cases with two measurements, one of which is obtained retrospectively, are biased towards lower growth rate. For the data sets where two measurements are available for some tumours and only one measurement for others (which means that no tumour was seen in retrospect for those cases), several approaches were developed that can eliminate or substantially reduce the bias. The relative error of the best estimates, as assessed by simulation, rarely exceeds 20 per cent. We found that the results of application of our estimation procedures to chest X-ray screening data agree well with the expectations. [top] [lung working group] [close] Hazelton WD, Clements MS, Moolgavkar SH. Multistage carcinogenesis and lung cancer mortality in three cohorts. Cancer Epidemiol Biomarkers Prev 2005 May;14(5):1171-81. Abstract: Experimental evidence indicates that tobacco smoke acts both as an initiator and a promoter in lung carcinogenesis. We used the two-stage clonal expansion model incorporating the ideas of initiation, promotion, and malignant conversion to analyze lung cancer mortality in three large cohorts, the British Doctors' cohort and the two American Cancer Society cohorts, to determine how smoking habits influence age-specific lung cancer rates via these mechanisms. Likelihood ratio tests indicate that smoking-related promotion is the dominant model mechanism associated with lung cancer mortality in all cohorts. Smoking-related initiation is less important than promotion but interacts synergistically with it. Although no information on ex-smokers is available in these data, the model with estimated variables can be used to project risks among ex-smokers. These projected risks are in good agreement with the risk among ex-smokers derived from other studies. We present 10-year projected risks for current and former smokers adjusted for competing causes of mortality. The importance of smoking duration on lung cancer risk in these cohorts is a direct consequence of promotion. Intervention and treatment strategies should focus on promotion as the primary etiologic mechanism in lung carcinogenesis. [top] [lung working group] [close] Levy DT, Nikolayev L, Mumford EA. Recent trends in smoking and the role of public policies: results from the SimSmoke Tobacco Control Policy Simulation Model. Addiction 2005;10(10):1526-37. Objectives: After a period of steady decline in smoking prevalence between 1976 and 1990, smoking rates leveled off between 1990 and 1997, but began falling at a more rapid rate between 1997 and 2003. Trends in smoking prevalence between 1993 and 2003, and the role of tobacco control policies in affecting those rates, are examined using a computer simulation model. Methods: A computer simulation model is used in which smoking rates evolve through initiation and cessation, which are in turn influenced by tobacco control policies. The results of the model are compared to measures of smoking prevalence from the National Health Interview Survey (NHIS). We then consider the effect of tax/price, clean air laws, media campaigns and youth access policies on predicted smoking rates over the period 1993-2003. Results: Both the SimSmoke model and data for recent years indicates that adult smoking prevalence changed little between 1993 and 1997, and even increased among youth. Between 1997 and 2003, smoking prevalence has been declining. Most age, gender and racial-ethnic groups show patterns similar to that of the entire population, with some important differences. When decomposed into policy changes, the predominant trends were mostly explained by changes in price/taxes, with some residual effect of clean air laws, media campaigns and enforcement of youth access laws. Conclusions: Among public tobacco control policies, price had the dominant effect on smoking prevalence between 1993 and 2002, because most states did not implement other policies to the degree necessary to affect much change. Through continued tax increases, stronger clean air laws, extensive media campaigns and broader cessation treatment programs, there is the potential to have much larger reductions in smoking prevalence than seen between 1993 and 2003, but sustained efforts will be required. [top] [lung working group] [close] Levy DT, Nikolayev L, Mumford EA, Compton C. The Healthy People 2010 smoking prevalence and tobacco control objectives: results from the SimSmoke tobacco control policy simulation model (United States). Cancer Causes Control 2005 May;16(4):359-71. Objectives: Healthy People 2010 (HP2010) set a goal of reducing the adult smoking prevalence to 12% by 2010. Smoking prevalence rates do not appear to be declining at or near the rate targeted in theHP2010 goals. The purpose of this paper is to examine the attainability ofHP2010 smoking prevalence objectives through the stricter tobacco control policies suggested in HP2010. Methods: Atested dynamic simulation model of smoking trends, known as SimSmoke, is applied. Smoking prevalence evolves over time through initiation and cessation, behaviors which are in turned influenced by tobacco control policies. We consider the effect of changes in taxes/prices, clean air laws, media campaigns, cessation programs and youth access policies on projected smoking prevalence over the period 2003–2020, focusing on the levels in 2010. Results: The SimSmoke model projects that the aging of older cohorts and the impact of policies in years prior to 2004 will yield a reduction in smoking rates to 18.4% by 2010, which is substantially above the 2010 target of 12%.When policies similar to the HP2010 tobacco control policy objectives are implemented, SimSmoke projects that smoking rates could be reduced to 16.1%. Further reductions might be realized by increasing the tax rate by $1.00. Conclusions: The SimSmoke model suggests that the HP2010 smoking prevalence objective is unlikely to be attained. Although we are unlikely to reach the goals by meeting the HP2010 policy objectives, they could get us much closer to the goal. Emphasis should be placed on meeting the tax, clean air, media/comprehensive campaigns, and cessation treatment objectives. [top] [lung working group] [close] Levy DT, Mumford EA, Cummings KM, Gilpin EA, Giovino G, Hyland A, Sweanor D, Warner KE. The relative risks of a low-nitrosamine smokeless tobacco product compared with smoking cigarettes: estimates of a panel of experts. Cancer Epidemiol Biomarkers Prev 2004 Dec;13(12):2035-42. Abstract: A 9-member panel of experts was asked to determine expert opinions of mortality risks associated with use of low-nitrosamine smokeless tobacco (LN-SLT) marketed for oral use. A modified Delphi approach was employed. For total mortality, the estimated median relative risk for individual users of LN-SLT ages 35 to 49 years was 9% of the risk associated with smoking and for those ages 50 years and older it was 5% of smoking risk. Median mortality risks relative to smoking were estimated to be 2%-3% for lung cancer, 10% for heart disease, and 15%-30% for oral cancer. While individual estimates often varied between 0% and 50%, most panel members were confident or very confident of their estimates by the last round of consultation. In comparison to smoking, experts perceive at least a 90% reduction in the relative risk of LN-SLT. The risks of using LN-SLT products therefore should not be portrayed as comparable to those of smoking cigarettes, as has been the practice of some governmental and public health authorities in the past. Importantly, the overall public health impact of LN-SLT will reflect use patterns, its marketing, and governmental regulation of tobacco products. [top] [lung working group] [close] Zeliadt SB, Penson DF, Albertsen PC, Concato J, Etzioni RD. Race independently predicts prostate specific antigen testing frequency following a prostate carcinoma diagnosis. Cancer 1 Aug 2003;98(3):496-503. Abstract: A 9-member panel of experts was asked to determine expert opinions of mortality risks associated with use of low-nitrosamine smokeless tobacco (LN-SLT) marketed for oral use. A modified Delphi approach was employed. For total mortality, the estimated median relative risk for individual users of LN-SLT ages 35 to 49 years was 9% of the risk associated with smoking and for those ages 50 years and older it was 5% of smoking risk. Median mortality risks relative to smoking were estimated to be 2%-3% for lung cancer, 10% for heart disease, and 15%-30% for oral cancer. While individual estimates often varied between 0% and 50%, most panel members were confident or very confident of their estimates by the last round of consultation. In comparison to smoking, experts perceive at least a 90% reduction in the relative risk of LN-SLT. The risks of using LN-SLT products therefore should not be portrayed as comparable to those of smoking cigarettes, as has been the practice of some governmental and public health authorities in the past. Importantly, the overall public health impact of LN-SLT will reflect use patterns, its marketing, and governmental regulation of tobacco products. [top] [lung working group] [close] Levy DT, Chaloupka F, Gitchell J, Mendez D, Warner KE. The use of simulation models for the surveillance, justification and understanding of tobacco control policies. Health Care Manag Sci Apr 2002;5(2):113-20. Abstract: Debates over national tobacco legislation and the use of state settlement funds demonstrate a need for information on the effects of tobacco control policies. Computer simulation models that are based on empirical evidence and that account for the variety of influences on tobacco use can be useful tools for informing policy makers. They can identify the effects of different policies, convey the importance of policy approaches to tobacco control, and help policy planners and researchers to better understand policies. This paper examines the role of simulation models in public policy, and discusses several recent models and limitations of those models. [top] [lung working group] [close] Prostate Working GroupTsodikov A, Garibotti G. Profile information matrix for nonlinear transformation models. Lifetime Data Anal 2006 Oct 5; [Epub ahead of print]. Abstract: For semiparametric models, interval estimation and hypothesis testing based on the information matrix for the full model is a challenge because of potentially unlimited dimension. Use of the profile information matrix for a small set of parameters of interest is an appealing alternative. Existing approaches for the estimation of the profile information matrix are either subject to the curse of dimensionality, or are ad-hoc and approximate and can be unstable and numerically inefficient. We propose a numerically stable and efficient algorithm that delivers an exact observed profile information matrix for regression coefficients for the class of Nonlinear Transformation Models [A. Tsodikov (2003) J R Statist Soc Ser B 65:759–774]. The algorithm deals with the curse of dimensionality and requires neither large matrix inverses nor explicit expressions for the profile surface. Tsodikov A, Szabo A, Wegelin J. A population model of prostate cancer incidence. Stat Med 2006 Aug 30;25(16):2846-66. Abstract: Introduction of screening for prostate cancer using the prostate-specific antigen (PSA) marker of the disease led to remarkable dynamics of the incidence of the disease observed in the last two decades. A statistical model is used to provide a link between dissemination of PSA and the observed transient population responses. The model is used to estimate lead time, overdiagnosis and other relevant characteristics of prostate cancer screening. Draisma G, Postma R, Schröder FH, van der Kwast TH, de Koning HJ. Gleason score, age and screening: modeling dedifferentiation in prostate cancer. Int J Cancer 2006 Jul 20; [Epub ahead of print]. Abstract: Tumor differentiation as measured by the Gleason score is highly predictive of the course of prostatic cancer after diagnosis. Since the introduction of the prostate-specific antigen (PSA) test tumors are diagnosed with a favorable tumor stage and differentiation grade. Does screening with PSA just detect more tumors with favorable characteristics or is dedifferentiation actually being prevented by early detection and consequent treatment? The latter option implies that tumors dedifferentiate in the preclinical screen-detectable phase. To model the natural history of prostate cancer, we analyzed the age-specific distribution of clinical stage and Gleason score of 2,204 tumors diagnosed in the ERSPC-Rotterdam trial. We fitted two MISCAN simulation models to the observed data: Model I where tumors dedifferentiate before becoming screen-detectable and Model II where dedifferentiation occurs during the screen-detectable pre-clinical phase. The hypothesis of dedifferentiation during the screen-detectable phase was tested by a goodness of fit test of both models. In the first screening round we observed a significant relation between age and Gleason score in screen detected cancers: the percentage of Gleason scores less than 7 dropped from 76% in men aged 55-59 to 57% in men aged 70-74; Gleason scores greater than 7 rose from 9% to 32%. In the second round after 4 years and in the control arm the association between Gleason score and age was not significant. Model II fitted significantly better than Model I (p<0.001). This study provides epidemiological evidence of dedifferentiation as a major mechanism of progression in prostate cancer. Tumors dedifferentiate during the screen-detectable phase and consequently screening with PSA and early treatment can possibly prevent dedifferentiation. [top] [prostate working group] [close] Inoue L, Etzioni R, Slate E, Morrell C. Combining logitudinal studies of PSA. Biostat 2004;5:483-500. Abstract: Prostate-Specific Antigen (PSA) is a biomarker commonly used to screen for prostate cancer. Several studies have examined PSA growth rates prior to prostate cancer diagnosis. However, the resulting estimates are highly variable. In this article we propose a non-linear Bayesian hierarchical model to combine longitudinal data on PSA growth from three different studies. Our model enables novel investigations into patterns of PSA growth that were previously impossible due to sample size limitations. The goals of our analysis are two-fold. First, to characterize growth rates of PSA accounting for differences when combining data from different studies. Second, to investigate the impact of clinical covariates such as advanced disease and unfavorable histology on PSA growth rates. [top] [prostate working group] [close] Shaw PA, Etzioni R, Zeliadt SB, Mariotto A, Karnofski K, Penson DF, Weiss NS, Feuer EJ. An ecologic study of prostate-specific antigen screening and prostate cancer mortality in nine geographic areas of the United States. Am J Epidemiol 2004 Dec 1;160(11):1059-69. Abstract: Ecologic studies of cancer screening examine cancer mortality rates in relation to use of population screening. These studies can be confounded by treatment patterns or influenced by choice of outcome and time horizon. Interpretation can be complicated by uncertainty about when mortality differences might be expected. The authors examined these issues in an ecologic analysis of prostate-specific antigen (PSA) screening and prostate cancer mortality across nine cancer registries in the United States. Results suggested a weak trend for areas with greater PSA screening rates to have greater declines in prostate cancer mortality; however, the magnitude of this trend varied considerably with the time horizon and outcome measure. A computer model was used to determine whether divergence of mortality declines would be expected under an assumption of a clinically significant survival benefit due to screening. Given a mean lead time of 5 years, the model projected that differences in mortality between high- and low-use areas should be apparent by 1999 in the absence of other factors affecting mortality. The authors concluded that modest differences in PSA screening rates across areas, together with additional sources of variation, could have produced a negative ecologic result. Ecologic analyses of the effectiveness of PSA testing should be interpreted with caution. [top] [prostate working group] [close] Zeliadt SB, Potosky AL, Etzioni R, Ramsey SD, Penson DF. Racial disparity in primary and adjuvant treatment for nonmetastatic prostate cancer: SEER-Medicare trends 1991 to 1999. Urology 2004 Dec;64(6):1171-6. Objectives: To assess trends in the initial care of nonmetastatic prostate cancer, including the use of primary and adjuvant androgen deprivation therapy (ADT), using population-based treatment claims from 1991 to 1999. Methods: We used a database linking the Surveillance, Epidemiology, and End Results (SEER) registry with Medicare claims to extract treatment information for 90,128 men aged 65 years and older, who were newly diagnosed with nonmetastatic prostate cancer. Results: The use of aggressive therapy has increased among white men over time; but aggressive therapy has recently declined among African-American men. Accounting for age, grade, socioeconomic status, and comorbidity, African-American men were 26% less likely to receive aggressive therapy than white men (odds ratio 0.74; 95% confidence interval 0.70 to 0.79). The use of ADT has increased substantially in both the primary and the adjuvant settings. By 1999, 45.6% of white men and 35.8% of African-American men who selected conservative management received primary ADT; among men treated with external beam radiotherapy, the proportion receiving adjuvant ADT was 53.7% for white men and 42.4% for African-American men (P <0.001). Conclusions: Racial differences in the use of aggressive and conservative therapies are increasing. ADT is becoming a widely adopted component of initial treatment for localized prostate cancer. It is crucial to understand the impact of treatment patterns, including the increased use of ADT, on patient survival, morbidity, and costs of care. [top] [prostate working group] [close] Etzioni R, Berry KM, Legler J, Shaw P. Prostate-specific antigen testing in black and white men: an analysis of Medicare claims from 1991-1998. Urology 2002 Feb;59(2):251-255. Background: The objective of this study was to describe trends in PSA utilization, and associated cancer detection among black and white Medicare beneficiaries over the age of 65 during the calendar period from January 1991 through December 1998. Methods: Medicare claims data were linked with cancer registry data from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. Data from a five percent random sample of men without a diagnosis of prostate cancer were combined with data from prostate cancer cases diagnosed during the calendar period from 1991-1998. PSA tests conducted after a diagnosis of prostate cancer were excluded. Results: PSA utilization has stabilized among white men, reaching an annual rate of 38 percent by 1995 and remaining at this level through 1998. Annual rates of use among black men reached 32 percent by 1998, but were still increasing at this time. By 1996, at least 80 percent of tests in both blacks and whites were second or later tests. By the end of 1996, 35 percent of white men and 25 percent of black men were undergoing testing at least biannually or more frequently. In 1996, 83 percent of diagnoses in whites and 77 percent in blacks were preceded by a PSA test. Conclusions: Older black men lag slightly behind older white men in their utilization of the PSA test, however, annual testing rates in blacks have yet to stabilize. In both race groups, an overwhelming majority of diagnoses are associated with a PSA test, whether for screening or diagnostic purposes. Regular screening rates in blacks are substantially lower than in whites, but the regular screening rates are relatively low in both race groups. Should PSA testing prove efficacious, efforts to promote regular screening among both black and white men will likely be needed. [top] [prostate working group] [close] Etzioni R, Penson DF, Legler JM, di Tommaso D, Boer R, Gann PH, Feuer EJ. Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends. J Natl Cancer Inst 2002 Jul 3;94(13):981-90. Background: Overdiagnosis of clinically insignificant prostate cancer is considered a major potential drawback of Prostate-Specific Antigen (PSA) screening. Unfortunately quantitative estimates of the magnitude of this problem are lacking. The objective of this study was to provide estimates of overdiagnosis rates due to PSA testing that are consistent with prostate cancer incidence trends observed in the US from 1988 through 1996. Methods: We developed a computer simulation model of PSA testing, subsequent prostate cancer diagnosis, and death. The model uses data from Medicare and the Surveillance, Epidemiology and End Results registry on PSA testing patterns and associated cancer detection rates, together with data from the literature on expected lead time, which is the time by which PSA advances diagnosis. Given these inputs as well as an assumption regarding the incidence of prostate cancer that would have been anticipated in the absence of PSA, the model provides projections of prostate cancer incidence and overdiagnosis among men aged 65 and above and undergoing PSA testing from 1988 through 1996. By comparing the model-projected incidence with observed incidence trends, overdiagnosis rates are estimated. Results: Assuming that prostate cancer incidence in the absence of PSA would reflect the consequences of a movement away from surgical toward medical management of benign prostatic hyperplasia, overdiagnosis rates consistent with observed incidence ranged from 25% to 35% for Caucasians and 30% to 40% for African Americans. Conclusions: The observed incidence trends are consistent with non-trivial rates of overdiagnosis among PSA-detected cases aged 65 and above. However, these overdiagnosis rates are considerably lower than might be anticipated given the prevalence of autopsy-detectable prostate cancer in the population. The results suggest that the majority of PSA-detected cancers detected in this population between 1988 and 1996 would have presented clinically within the lifetime of the patient, and that the minority of PSA-detected cancers appear to arise from the pool of trivial indolent cases that are visible only on autopsy. [top] [prostate working group] [close] General MethodsHanin L, Yakovlev A. Identifiability of the joint distribution of age and tumor size at detection in the presence of screening. Math Biosci Aug 2007;208(2):644-57. Abstract: In recent years, a stochastic model of cancer development and detection allowing for arbitrary screening schedules has been developed and applied to analysis of screening trials and population-based cancer incidence and mortality data. The model is entirely mechanistic, builds on a minimal set of biologically plausible assumptions, and yields the joint distribution of tumor size and age of a patient at the time of diagnosis. Whether or not parameters of the model can be estimated from data generated by cohort studies depends on model identifiability. The present paper provides a proof of this important property of the model. [top] [general methods section] [close] Holford TR. Approaches to fitting age-period-cohort models with unequal intervals. Stat Med 2006 Mar 30;25(6):997-993. Abstract: Age-period-cohort models have provided useful insights into the analysis of time trends for disease rates, in spite of the well known identifiability problem. Unique parameter estimates that avoid arbitrary constraints are provided by estimable functions of the parameter estimates. For data that are generated using equal interval widths for age and period, the identifiability issue may be expressed in terms of the age, period and cohort slopes. However, when the interval widths are not the same for age and period, additional identifiability problems arise. These may be represented in terms of macro trends, which have the identical identifiability problem seen in the equal interval case, and micro trends, which are the source of the additional problems. A framework for testing estimability is presented, and a variety of potentially interesting functions of the parameters considered. Unlike the equal interval case, drift is not estimable for unequal intervals, but local drift is. In addition, the available functions for forecasting are much more restrictive in the latter case. This estimability problem induces cyclical patterns in the estimates of trend as is demonstrated using data on leukemia in Connecticut males, but this can be avoided through the use of smoothing splines. These methods of are illustrated for three year period and five year age intervals using data on lung cancer mortality in Californian women. [top] [general methods section] [close] Pignone M, Saha S, Hoerger T, Lohr KN, Teutsch S, Mandelblatt J. Challenges in systematic reviews of economic analyses. Ann Intern Med 21 Jun 2005;142(12 Pt 2):1073-9. Abstract: Economic analyses can provide valuable information for health care decision makers. Systematic reviews of economic analyses can integrate information from multiple studies and provide important insights by systematically examining how differences between models lead to different results. We use our experience in developing and implementing systematic reviews of economic analyses for the U.S. Preventive Services T ask Force, particularly our systematic review of the cost-effectiveness of colorectal cancer screening, to illustrate key methodologic challenges and suggest a framework for other researchers in this area. [top] [general methods section] [close] Shen Y, Zelen M. Robust modeling in screening studies: estimation of sensitivity and preclinical sojourn time distribution. Biostatistics 2005; 6:604-14. Abstract: In early-detection clinical trials, quantities such as the sensitivity of the screening modality and the preclinical duration of the disease are important to describe the natural history of the disease and its interaction with a screening program. Assume that the schedule of a screening program is periodic and that the sojourn time in the preclinical state has a piecewise density function. Modeling the preclinical sojourn time distribution as a piecewise density function results in robust estimation of the distribution function. Our aim is to estimate the piecewise density function and the examination sensitivity using both generalized least squares and maximum likelihood methods. We carried out extensive simulations to evaluate the performance of the methods of estimation. The different estimation methods provide complimentary tools to obtain the unknown parameters. The methods are applied to three breast cancer early-detection trials. [top] [general methods section] [close] Broët P, Tsodikov A. De Rycke Y, Moreau T. Two-sample statistics for testing the equality of survival functions against improper semi-parametric accelerated failure time alternatives: An application to the analysis of a breast cancer clinical trial. Lifetime Data Anal 2004;10:103-20. Abstract: This paper presents two-sample statistics suited for testing equality of survival functions against improper semi-parametric accelerated failure time alternatives. These tests are designed for comparing either the short- or the long-term effect of a prognostic factor, or both. These statistics are obtained as partial likelihood score statistics from a time-dependent Cox model. As a consequence, the proposed tests can be very easily implemented using widely available software. A breast cancer clinical trial is presented as an example to demonstrate the utility of the proposed tests. [top] [general methods section] [close] Davidov O, Zelen M. Overdiagnosis in early detection programs. Biostatistics 2004;5:603-13. Abstract: Overdiagnosis refers to the situation
where a screening exam detects a disease that would have
otherwise been undetected in a person's lifetime. The disease
would have not have been diagnosed because the individual
would have died of other causes prior to its clinical onset.
Although the probability of overdiagnosis is an important
quantity for understanding early detection programs it has
not been rigorously studied. We analyze an idealized early
detection program and derive the mathematical expression
for the probability of overdiagnosis. The results are studied
numerically for prostate cancer and applied to a variety
of screening schedules. Our investigation indicates that
the probability of overdiagnosis is remarkably high. [top] [general methods section] [close] Feuer EJ, Etzioni R, Cronin KA, Mariotto A. The use of modeling to understand the impact of screening on U.S. mortality: examples from mammography and PSA testing. Stat Methods Med Res 2004 Dec;13(6):421-42. Abstract: Surveillance data represent a vital resource for understanding the impact of cancer control interventions on the population cancer burden. However, population cancer trends are a complex product of many factors, and estimating the contribution of any one of these factors can be challenging. Surveillance modeling is a technique for estimating the contribution of one or more interventions of interest to trends in disease incidence and mortality. In this article, we present several approaches to surveillance modeling of cancer screening interventions. We classify models as biological or epidemiological, depending on whether they model the full unobservable aspects of disease onset and progression, or models which reduce the complex process to simpler terms by summarizing portions of the disease process using population level measures. We also describe differences between macrolevel models, microsimulation models and mechanistic models. We discuss procedures for model calibration and validation, and methods for presenting model results which are robust with respect to certain types of biased model estimates. As examples, we present several models of the impact of mammography screening on breast cancer mortality, and PSA screening on prostate cancer mortality. Both these examples are appropriate uses of surveillance modeling, even though for mammography there is extensive (although somewhat controversial) randomized trial evidence, whereas for PSA this biomarker has seen extensive use as a screening test prior to any controlled trial evidence of its efficacy. Some of the models presented here were developed as part of the National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network. [top] [general methods section] [close] Tsodikov A. Generalized self-consistency methods for cure models. INSERM Workshop 154, 2004. Abstract: A large class of semiparametric survival models can be represented by the survival function G(t | z) given covariates z treated as a function of an unspecifed baseline survival function F (or the corresponding cumulative hazard function H = -log F), and a vector of regression coeffients . With such semiparametric models, we present a unifed approach for model building and construction of numerically effcient algorithms for maximum likelihood inference. The approach is based on a generalization of the idea of self-consistency and is motivated by frailties and the EM algorithm. Composition technique is developed for building hierarchical model families compatible with the algorithms. An algorithm is provided to obtain the exact profile information matrix for the parametric part of the model. The approach is illustrated using cure models and real data. [top] [general methods section] [close] Zelen M. Forward and backward recurrence times and length biased sampling: Age specific models. Lifetime Data Anal 2004; 10:325-34. Abstract: Consider a chronic disease process which is beginning to be observed at a point in chronological time. The backward recurrence and forward recurrence times are defined for prevalent cases as the time with disease and the time to leave the disease state, respectively, where the reference point is the point in time at which the disease process is being observed. In this setting the incidence of disease affects the recurrence time distributions. In addition, the survival of prevalent cases will tend to be greater than the population with disease due to length biased sampling. A similar problem arises in models for the early detection of disease. In this case the backward recurrence time is how long an individual has had disease before detection and the forward recurrence time is the time gained by early diagnosis, i.e., until the disease becomes clinical by exhibiting signs or symptoms. In these examples the incidence of disease may be age related resulting in a non-stationary process. The resulting recurrence time distributions are derived as well as some generalization of length-biased sampling. [top] [general methods section] [close] Davidov O, Zelen M. The theory of case-control studies for early detection programs. Biostatistics 2003;4:411-21. |