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Objective: To assess the risk for melanoma associated with moles and pigmentary characteristics. Methods: Representative melanoma cases (773) among non-Hispanic white residents under age 65 occurring between 1 June 1978 and 1 December 1983 in Los Angeles County were compared to controls (752) matched to cases by age, sex, race and neighborhood of residence. Factors considered include hair, eye, and skin color; numbers of freckles and moles; and propensity to burn and tan obtained during an in-person interview. Results: Five hundred and fifty-one cases were classified as superficial spreading melanoma (SSM) and 110 as nodular melanoma (NM). For SSM, the important risk determinants were hair and skin color, freckling, and mole prevalence. Light skin and more freckles were found to be more highly associated with SSM for younger compared to older subjects, whereas the associations between SSM and both hair color and moles remained independent of age. NM showed patterns of risk similar to SSM with the exception of skin color. NM showed no evidence of increasing risk with lighter skin, as compared to the strong association seen for SSM. Conclusion: Hair and skin color, freckling and, especially, numbers and size of moles are important determinants of melanoma risk.

A variant of the case-cohort design is proposed for the situation in which a correlate of the exposure (or prognostic factor) of interest is available for all cohort members, and exposure information is to be collected for a case-cohort sample. The cohort is stratified according to the correlate, and the subcohort is selected by stratified random sampling. A number of possible methods for the analysis of such exposure stratified case-cohort samples are presented, some of their statistical properties developed, and approximate relative efficiency and optimal allocation to the strata discussed. The methods are compared to each other, and to randomly sampled case-cohort studies, in a limited computer simulation study. We found that all of the proposed analysis methods performed well and were more efficient than a randomly sampled case-cohort study.

Objectives. This report is an update on the outcomes in the management of pathologic Stage C (T3N0) prostate cancer (CaP) with postoperative irradiation. Methods. Between 1976 and 1994, 311 patients with pathologic Stage C CaP were treated with radical prostatectomy. Pathologic stage was as follows: C1, 60 patients (19%), C2, 146 patients (47%), and C3, 105 patients (34%). Gleason score was 2 to 4 in 10 patients (3.2%), 5 to 6 in 121 (39%), 7 in 101 (32%), and 8 to 10 in 76 (24%); median prostate-specific antigen (PSA) level was 11.9 ng/mL. Postoperative irradiation consisted of a median dose of 48 Gy. Follow-up was up to 18 years (median 5). Results. The 10-year actuarial survival was 81% and 10-year disease-free survival was 51%. Pathologic stage and Gleason score were independently predictive of recurrence, each with P >0.001 after controlling for the other. Patients with pathologic Stage C3 and Gleason score 7 to 10 were in the worst prognostic category and had 5.4 times the risk of recurrence compared with patients with pathologic Stage C1–C2, Gleason score 2 to 6. Preoperative PSA was a good ( P = 0.02) predictor of disease-free survival. Clinical recurrence was seen in 28 patients (9%), including 10 (3.2%) with local recurrence. PSA recurrence (PSA greater than 0.05 ng/mL) developed in 68 patients (22%). Conclusions. With the known limitations of a nonrandomized clinical trial, on the basis of the experience of this study we recommend the use of moderate dose, limited-field postoperative radiotherapy in patients with pathologic Stage C disease with Gleason score greater than 4.

Background Latency effects are an important factor in assessing the public health implications of an occupational or environmental exposure. Usually, however, latency results as described in the literature are insufficient to answer public health related questions. Alternative approaches to the analysis of latency effects are warranted. Methods A general statistical framework for modeling latency effects is described. We then propose bilinear and exponential decay latency models for analyzing latency effects as they have parameters that address questions of public health interest. Methods are described for fitting these models to cohort or case-control data; statistical inference is based on standard likelihood methods. Application A latency analysis of radon exposure and lung cancer in the Colorado Plateau uranium miners cohort was performed. We first analyzed the entire cohort and found that the relative risk associated with exposure increases for about 8.5 years and thereafter decreases until it reaches background levels after about 34 years. The hypothesis that the relative risk remains at its peak level is strongly rejected (P > 0.001). Next, we investigated the variation in the latency effects over subsets of the cohort based on attained age, level and rate of exposure, and smoking. Age was the only factor for which effect modification was demonstrated (P > 0.014). We found that the decline in effect is much steeper at older ages (60> years) than younger. Conclusion The proposed methods can provide much more information about the exposure–disease latency effects than those generally used. Am. J. Ind. Med. 35:246–256, 1999. © 1999 Wiley-Liss, Inc.

Adenocarcinoma of the prostate is the most common human cancer of internal organs. Radical surgery is regarded by many to be the treatment of choice for capsule confined disease. Since accurate preoperative assessment of tumor stage is difficult to define, many patients are subsequently found to have pathological stage C (T3) disease. These patients should be considered for adjuvant radiotherapy.A group of 201 PS C (T3) unselected patients, treated with radical prostatectomy and limited pelvic lymphadenectomy, received postoperative irradiation to the prostate bed. This radiotherapy was given between 42-90 days after surgery and consisted of a median dose of 48 Gy. Patient survival, disease free survival, time to clinical and chemical relapse and the incidence of local and systemic relapse were analyzed. The influence of multiple parameters on the treatment outcome including patient age, treatment period, clinical stage, pathological stage, Gleason's score, prostate specific antigen (PSA), radiotherapy techniques and radiation dose were examined using univariate and multivariate analysis. Follow-up ranged from 3 to 15 years, with a median of 5 years.The overall 5- and 10-year actuarial survival was 92% and 83% (median10 years), respectively and the 5- and 10-year disease-free survival (clinical and PSA) was 67% and 53% (median10 years), respectively. A total of 61 (30%) patients had a recurrence, including 23 (11%) patients who had clinical and 38 (19%) who had PSA recurrence. Of the 23 patients with clinical recurrence, 10 (5%) had local recurrence, including two patients who had local and systemic recurrence. Pathological stage and Gleason's score were independently predictive of recurrence (each with p0.001 after controlling for the other). Patients in the worst prognostic category with pathological stage C3 and Gleason's score 8-10 were predicted to be at 7.2 times the risk of recurrence, compared to stage C1 or C2 and Gleason's score 2-7 patients. Preoperative PSA level (25 ng/ml) was also an important independent factor predicting tumor recurrence, p = 0.05. All other investigated parameters were not significant in predicting tumor recurrence. This treatment program was very well tolerated by the study patients, with seven (3.5%) recorded with major and 18 (9%) with minor surgical complications, while 65% of patients had minor and clinically insignificant radiation complications.Surgery followed by moderate dose radiotherapy in patients with PS C (T3) prostatic carcinoma was well tolerated and resulted in excellent overall and disease free survival, with a low incidence of local recurrence. New treatment strategies need to be developed for patients with C3 tumors and those with high (8-10) Gleason's score and those with high (25 ng/ml) PSA level at diagnosis.

SUMMARY The counter-matching design for sampling from risk sets is presented in which each sampled risk set includes the failure and a random sample of controls from 'sampling strata' defined by exposure information available for all cohort subjects. Asymptotic relative efficiency comparisons indicate that this type of sampling has superior efficiency to simple nested case-control sampling in situations of practical interest. A simple extension of the method is given which allows for nonrepresentative sampling of failures. Analysis of data from counter-matched studies may be performed using standard conditional logistic likelihood software which allows for an 'offset' in the model.

Variation in the risk of insulin-dependent diabetes mellitus (IDDM) across alleles at HLA-A, B, and DR loci was investigated in a population-based study of 801 families of children with newly diagnosed IDDM in Finland nationwide. Parallel analyses assessed the relative frequencies of alleles in IDDM children compared with age-matched sibling controls and with the four possible genotypes which could have been inherited from the parents. The joint effects of DR3 and DR4 alleles were investigated under dominant, recessive, and additive models of gene expression. The additive model gave the best fit, though the relative risk for DR4 homozygotes was smaller than predicted. To investigate other alleles, we fitted the standard multiplicative model for alleles at each locus. After controlling for the correlation among alleles, significantly elevated risks were found for B13, DR3, DR4, and DR14. Subjects with these alleles have more than twice the risk of IDDM as those without. Alleles A24 and B62 incurred relative risks between one and two. DR2 and DR5 were significantly negatively associated with IDDM, incurring less than half the risk. These findings support an independent role of class I antigens in the etiology of IDDM.

We fitted models for the main effects of alleles at the HLA-A, B, and DR loci and their haplotypes on the risk of insulin-dependent diabetes mellitus (IDDM). Empirical Bayes methods were used, assuming independent exchangeable normal priors for effects at each locus separately and for haplotype effects. A pure main effects model, pure haplotype effects model, and a combined model were fitted using Gibbs sampling. The main effects model showed that the DR locus had the largest variation in risk between alleles, followed by the B locus; significance tests for each allele in this model were in general agreement with those in the companion paper [Langholz et al. (1995) Genet Epidemiol 12:441-453], although all relative risks were shrunk toward 1.0 in the empirical Bayes analysis. The variance estimate for pure haplotype effects was substantially larger than for any of the three main effects considered in this analysis, but in the combined model, the DR locus showed larger variability than the haplotype deviations. We confirmed that haplotype A2/B56/DR4 previously reported to be common in Finnish diabetics does indeed confer unusually high risk (relative risk = 7.6, P < 0.001), but found this to be only 1.9 times higher than predicted by its component main effects (P = 0.046). All of the other haplotypes could be adequately explained by their main effects. Empirical Bayes methods provide a natural means of dealing with the problems of multiple comparisons, multicolinearity, and sparse data that complicate the analysis of HLA data.

The role of SCT in pediatric oncology has continued to evolve with the introduction of new therapeutic agents and immunological insights into cancer. COG has focused its efforts on the study of hematopoietic stem cell transplantation in the treatment of pediatric malignancies in several major multi-institutional Phase II and Phase III studies. These studies include addressing the impact of allogenicity in ALL (ASCT0431), and establishing autologous stem cell transplant as the standard of care in neuroblastoma. Reducing transplant-associated toxicity was addressed in the ASCT0521 study, where the TNFα inhibitor etanercept was tested for the treatment of idiopathic pneumonia syndrome. Impact of cell dose was explored in the single versus tandem umbilical cord blood study CTN-0501, in close collaboration with the BMT-CTN.

Epidemiologic studies that collect detailed exposure histories often incorporate this information into a regression model through a time-dependent cumulative exposure metric. This summary metric obscures variations in exposure rates among people and within persons over time. To disentangle the effects of cumulative exposure and exposure rate, one standard approach is to simultaneously model both cumulative exposure and average exposure rate. We propose an alternative regression model that uses a person's detailed exposure history information to describe the effect of the history of exposure increments on the relative hazard function. We illustrate this approach using data from a cohort study of radon exposure and lung cancer mortality among uranium miners. Compared with a standard cumulative exposure-average exposure rate model, our proposed approach yielded somewhat stronger evidence that the radon-lung cancer mortality association is modified by exposure rate. At low exposure rates, the estimated excess relative hazard per 100 working-level months was 0.63 (95% confidence interval = 0.32-1.37) under the standard approach, whereas under the proposed approach it was 1.23 (0.53-3.76). The proposed approach may provide better understanding of relationships between a protracted exposure and disease and is readily implemented using existing statistical software.

Background stratified Poisson regression is an approach that has been used in the analysis of data derived from a variety of epidemiologically important studies of radiation-exposed populations, including uranium miners, nuclear industry workers, and atomic bomb survivors. We describe a novel approach to fit Poisson regression models that adjust for a set of covariates through background stratification while directly estimating the radiation-disease association of primary interest. The approach makes use of an expression for the Poisson likelihood that treats the coefficients for stratum-specific indicator variables as 'nuisance' variables and avoids the need to explicitly estimate the coefficients for these stratum-specific parameters. Log-linear models, as well as other general relative rate models, are accommodated. This approach is illustrated using data from the Life Span Study of Japanese atomic bomb survivors and data from a study of underground uranium miners. The point estimate and confidence interval obtained from this 'conditional' regression approach are identical to the values obtained using unconditional Poisson regression with model terms for each background stratum. Moreover, it is shown that the proposed approach allows estimation of background stratified Poisson regression models of non-standard form, such as models that parameterize latency effects, as well as regression models in which the number of strata is large, thereby overcoming the limitations of previously available statistical software for fitting background stratified Poisson regression models.

Data on lung cancer mortality in a cohort of 3,347 Colorado Plateau uranium miners was reanalyzed to investigate the role of time-related modifiers of the radon-smoking interaction. A nested case-control sample of the cohort was drawn, matching each of the 258 lung cancer deaths with 15 controls drawn at random from the subjects who were born in the same year and still alive at the time the case died. As reported earlier, the dose response was sublinear for both total radon and total smoking, and their joint effect was approximately multiplicative. We fitted linear multiplicative models to these data, transforming the radon and smoking variables to improve their fit, and then added variables testing various temporal modifying effects and interactions. The strongest modifiers of the main effects of each variable taken separately were latency and duration of exposure. The strongest modifier of the interaction effect was the timing of radon and smoking exposures: Exposure to radon followed by smoking produced a significantly more-than-multiplicative effect, whereas the reverse sequence produced a significantly less-than-multiplicative effect. These findings suggest that smoking may act as a promoter of radon-initiated cells.

Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.

Exposure lagging and exposure-time window analysis are 2 widely used approaches to allow for induction and latency periods in analyses of exposure-disease associations. Exposure lagging implies a strong parametric assumption about the temporal evolution of the exposure-disease association. An exposure-time window analysis allows for a more flexible description of temporal variation in exposure effects but may result in unstable risk estimates that are sensitive to how windows are defined. The authors describe a hierarchical regression approach that combines time window analysis with a parametric latency model. They illustrate this approach using data from 2 occupational cohort studies: studies of lung cancer mortality among 1) asbestos textile workers and 2) uranium miners. For each cohort, an exposure-time window analysis was compared with a hierarchical regression analysis with shrinkage toward a simpler, second-stage parametric latency model. In each cohort analysis, there is substantial stability gained in time window-specific estimates of association by using a hierarchical regression approach. The proposed hierarchical regression model couples a time window analysis with a parametric latency model; this approach provides a way to stabilize risk estimates derived from a time window analysis and a way to reduce bias arising from misspecification of a parametric latency model.

Lagging exposure information is often undertaken to allow for a latency period in cumulative exposure-disease analyses. The authors first consider bias and confidence interval coverage when using the standard approaches of fitting models under several lag assumptions and selecting the lag that maximizes either the effect estimate or model goodness of fit. Next, they consider bias that occurs when the assumption that the latency period is a fixed constant does not hold. Expressions were derived for bias due to misspecification of lag assumptions, and simulations were conducted. Finally, the authors describe a method for joint estimation of parameters describing an exposure-response association and the latency distribution. Analyses of associations between cumulative asbestos exposure and lung cancer mortality among textile workers illustrate this approach. Selecting the lag that maximizes the effect estimate may lead to bias away from the null; selecting the lag that maximizes model goodness of fit may lead to confidence intervals that are too narrow. These problems tend to increase as the within-person exposure variation diminishes. Lagging exposure assignment by a constant will lead to bias toward the null if the distribution of latency periods is not a fixed constant. Direct estimation of latency periods can minimize bias and improve confidence interval coverage.

Associations between infant-feeding patterns and risk of IDDM were investigated in a nationwide Finnish case-control study of 690 IDDM children

Information on 23,567 Non-Hispanic White, 2,539 Black, and 2,380 Hispanic breast cancer cases diagnosed between 1977 and 1985 was used to evaluate the risk of late stage diagnosis and long duration of symptoms prior to diagnosis in relation to ethnicity, socioeconomic status, age and year of diagnosis. All data were collected by the University of Southern California Cancer Surveillance Program, the comprehensive population-based incidence registry of Los Angeles County. The results indicate that lower socioeconomic status, Black or Hispanic ethnicity, younger age, and earlier year of diagnosis are risk factors for late stage diagnosis and long duration of symptoms. The effect of ethnicity was not explained by lower SES levels among Black or Hispanic women. After controlling for duration of symptoms, race and SES remained significantly predictive of more advanced stage. More recent diagnosis across the 9 year time frame was not associated with improved stage for those of low SES. These results suggest that increased efforts are needed to reach low SES and Black and Hispanic women with campaigns to improve the stage at which breast cancer is detected.

Background A cohort mortality study among 5886 chemical manufacturing workers was completed in 1987 and showed increased mortality due to pancreatic cancer. Purpose We conducted a nested case-control study of pancreatic cancer among these chemical manufacturing workers to identify risk factors for this disease. Methods Twenty-eight verified cases of pancreatic cancer and 112 matched controls were studied. Next of kin of each subject were interviewed to determine lifestyle factors, including tobacco, alcohol, and coffee consumption. Written work records and interviews with co-workers were used to determine chemical exposures at the plant under study. Results DDT was associated with pancreatic cancer (risk ratio [RR] for ever exposed compared with never exposed = 4.8; 95% confidence interval = 1.3-17.6). Among subjects who had a mean exposure to DDT of 47 months, the risk was 7.4 times that among subjects with no exposure. Two DDT derivatives, Ethylan and DDD, were additionally associated with pancreatic cancer (RR = 5.0 and 4.3, respectively); exposures to these two chemicals were correlated, and it was not possible to determine whether each acted independently of the other. Smoking was identified as an independent risk factor, but controlling for smoking (and other potential confounders) in the analyses did not appreciably alter the risks seen for DDT, DDD, or Ethylan. Conclusions Exposure to DDT was associated with pancreatic cancer. The association was not explained by exposure to lifestyle factors or other chemicals, and risk increased with both duration of exposure and latency since first exposure. Implications These results may indicate that DDT can cause pancreatic cancer in humans under circumstances of heavy and prolonged exposure.

Standard regression models for disease incidence data can be used to test for associations between a disease and measured genetic and environmental factors and their interactions. Complications arise when the gene is not observed, requiring segregation and linkage analysis approaches, or when the candidate gene(s) are found to be highly polymorphic, as in the HLA region. We propose a Bayesian approach to the latter problem, in which the log relative risks for all alleles at a given locus are taken to be independent and exchangeable, assuming there is no preferential zygotic assortment and negligible recombination. Multi-locus problems can be addressed either by adding exchangeable interaction terms or by adopting a multivariate prior for haplotype effects. Some simulations based on our current work on family studies of IDDM are discussed.

From 1988 to 1991, 21 patients with uveal melanoma were treated in a Phase I study with episcleral plaque radiotherapy (EPRT). This irradiation was combined with localized current field episcleral hyperthermia (LCFHT). Tumor stage was: T3 = 15 (71%) and T2 = 6 (29%). Follow-up ranged from 2 to 42 months (mean 9.2 months). EPRT was given using custom built I-125 gold plaques. Radiation doses to the tumor apex ranged from 13 to 123 Gy (mean dose 70.0 Gy) given at a mean dose rate of 55 cGy/hr. LCFHT was given with 500 KHz frequency for 45 min immediately before EPRT. The temperature was controlled on the scleral surface using four thermocouples. T mean ranged from 42.5 degrees C to 45 degrees C +/- 0.5 degrees C (mean 43.4 degrees C). The study patients showed rapid tumor necrosis. A 25% mean decrease of apical tumor dimension was noted, p = 0.0007. At least ambulatory vision (greater than 5/200) was maintained by 17/21 (81%) patients. Visual acuity was seen to improve greater than 6 months post-plaque therapy in 10 (48%) study patients. This was following an intermediate decrease in visual acuity. Severe complications, including large hemorrhagic retinal detachment and large vitreous hemorrhage, were seen in two (9.5%) of the early study patients. A mean scleral temperature reduction to less than or equal to 44 degrees C +/- 0.5 degrees C resulted in good treatment tolerance and a lack of serious complications in subsequently treated patients. A Phase II prospective randomized trial comparing LCFHT with 60 versus 80 Gy EPRT dose to the tumor apex is currently being activated for patients with choroidal melanoma.

We develop a class of smoothed χ 2 tests of distributional hypotheses based on Fourier coefficients used in the density estimation procedure of Fellner. Starting with the simple test of Fx = G, where G is a completely specified hypothesized continuous distribution, we develop tests of the composite null hypothesis Fx − Gα for some vector of unknown parameters α. Variances used in computing the tests vary according to the choice of distributional family and depend on estimators used to estimate the nuisance parameters α. Expressions are given that allow one to use fast Fourier transforms to compute the necessary quantities. Examples given include tests of exponential, normal, Laplace, Pareto, Weibull, and uniform distributions as well as a test of the normality of residuals in least squares regression. Simulation studies indicate fast convergence of the statistics’ distributions to the χ 2 distribution under the null hypothesis. The power of the test of normality was found to be competitive with o...

In this paper we examine the efficiency of a generalization of the traditional normal linear (LDA) or quadratic (QDA) discriminant analysis. This procedure (the generalized discriminant analysis, GDA) replaces each normal density used in the traditional classification rule by a Fourier series density estimator which 'adjusts' the normal density if the data deviate markedly from normality (for example, heavily skewed or multimodal). We derive the GDA in both the univariate and multivariate situations. In a simulation study for the univariate situation, we evaluate the relative efficiency of the GDA. In addition, we demonstrate the performance of the GDA through a series of multivariate applications. We conclude that if the distributions of the data do not deviate markedly from normality, the GDA is as efficient as the LDA or QDA. On the other hand, if either of the distributions deviates from normality, then the GDA, which performs as a semiparametric discriminant procedure, is more efficient than the LDA or QDA.

This is an analysis of treatment results over a 23-year period in 241 patients with carcinoma of the esophagus. The treatment for unresectable patients was external beam radiotherapy (EBRT) alone (mean dose 55 Gy) in 137 (57%) combined with brachytherapy (mean dose 50 + 40 Gy) in 46 (19%), and chemotherapy alone in 3 (1%) patients. In the 55 resectable patients, treatment was resection alone in 9 (4%), and combined with radiotherapy (mean dose 43 Gy) in 46 (19%) patients. The 1-, 2-, and 5-year survival for the 241 patients was 36, 15, and 5%, respectively (median 38 weeks). The 5-year survival was 18% for radiotherapy (RT)-surgery (S) patients, 11% for EBRT with brachytherapy, 2% for EBRT alone, and 0% for patients who had S alone, p less than 0.001. Survival correlated well with initial performance status, treatment, stage of disease, tumor size, radiation dose, and degree of response, p less than 0.001, but not with tumor location in the esophagus and patients' race and sex, p = 0.44. Serious complications occurred in 5 (2%) patients treated with RT alone and in 4 (7%) patients treated with S alone or combined with RT. The leading cause of death was persistent or recurrent tumor in the chest found in 39% patients.

A total of 15 patients with severe symptoms of prostadynia who were refractory to therapy were treated with transurethral microwave hyperthermia (TUHT) in a phase I trial. All patients had pain as the predominant symptom, 9 (60%) patients gave a history of psychological problems while frequency, urgency, dysuria, nocturia, and impotence were less common symptoms. Treatment consisted of TUHT at 915 MHz given weekly for 5 weeks with a total of 68 treatment sessions and a mean of 4.5 treatments per patient. Each treatment lasted for 60 minutes. The aim was to increase the temperature measured on the urethral surface to greater than or equal to 44 degrees C. T mean for all sessions was 45.5 degrees C. In 91% of treatments, the temperature was greater than or equal to 44 degrees C. Treatment was well tolerated in 87% patients and acute toxicity was mild. Of the 15 patients treated, 2 (13%) did not complete the treatment course due to discomfort during TUHT. Good treatment response, manifested by complete pain relief and a decrease in dysuria, was noted in 7 (47%) patients. A higher (greater than or equal to 46 degrees C) treatment temperature correlated well with good response, P less than .01. Similarly, relief of pain correlated well with the absence of a history of psychological problems, P less than .01. A decrease of obstructive micturition problems was noted in 5 of the 7 patients who had this upon presentation. This study showed evidence of therapeutic activity with the use of TUHT in patients with prostadynia refractory to therapy. The response obtained was limited to less than one-half of the patients. Complete pain relief was obtained in 4 (27%) patients. It is of interest to note that patients who had major benefit did not show evidence of psychological problems and were able to tolerate higher treatment temperatures. The latter could suggest a temperature-related response.

BACKGROUND. Histopathologic diagnosis of endometrial biopsies is used to estimate the risk of progression to carcinoma and guide clinical management. Problems with the widely used World Health Organization (WHO) system for classifying endometrial hyperplasia (EH) have prompted the development of an alternative system based on endometrial intraepithelial neoplasia (EIN). The authors estimated progression risk associated with EIN among endometrial biopsies in a nested case-control study of EH progression. METHODS. Index biopsies with original community pathology diagnoses of disordered proliferative endometrium (DPEM) or EH that were independently confirmed by a panel of pathologists were independently reviewed and assigned EIN classifications (inadequate, benign, EIN, or cancer) by a second panel of pathologists. Cases (N = 138) progressed to carcinoma at least 1 year (median, 6 years) after their index biopsy. Controls (N = 241) also had EH, did not progress to carcinoma, and were individually matched to cases based on age at EH, date of EH, and length of follow-up. By using conditional logistic regression, the authors estimated relative risks (RRs) with 95% confidence intervals (95% CIs) for progression to carcinoma for EIN versus benign. RESULTS. In the EIN system, 71 (52.6%) cases and 159 (66.8%) controls were classified as benign and 42 (31.1%) cases and 65 (27.3%) controls were classified as EIN. The RR for EIN versus benign was 7.76 (95% CI, 3.36-17.91). In the WHO system, the RR for atypical hyperplasia (AH) versus DPEM, simple hyperplasia, or complex hyperplasia was 9.19 (95% CI, 3.87-21.83). CONCLUSIONS. Among women observed for at least 1 year after receiving a biopsy-based EH diagnosis, EIN and AH were both found to have similarly increased risks of progression to carcinoma. Cancer 2008. © Published 2008 by American Cancer Society

Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3–0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3–0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1–0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1–0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53. [Cancer Res 2008;68(16):6486–91]

Inactivation of PTEN tumor suppressor gene is common in endometrial carcinoma and its precursor, atypical endometrial hyperplasia (EH). We compared PTEN expression via immunohistochemistry in endometrial biopsies diagnosed as EH in 138 cases, who were diagnosed with EH and then endometrial carcinoma at least 1 year later (median, 6 years), and 241 individually matched controls, who were diagnosed with EH but did not progress to carcinoma during equivalent follow-up. We assessed PTEN status (normal versus null) in index biopsies containing EH to estimate the relative risk (RR) of developing endometrial carcinoma up to 25 years later. Analysis of 115 cases and 193 controls with satisfactory assays revealed PTEN-null glands in index biopsies of 44% of cases and 49% of controls [P = 0.85; RR, 1.51; 95% confidence interval (CI), 0.73–3.13]. For predicting progression to carcinoma, PTEN-null status had low sensitivity (44%; 95% CI, 45–54%) and specificity (51%; 95% CI, 44–58%). Among 105 cases with PTEN results for both index biopsy and carcinoma, 16% had a PTEN-null index biopsy, 23% had PTEN-null carcinoma, and 26% had both a PTEN-null index biopsy and carcinoma. Loss of PTEN expression in endometrial biopsies was neither associated with nor a sensitive and specific marker of subsequent progression to endometrial carcinoma. [Cancer Res 2008;68(14):6014–20]

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

Context The risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers. Objectives To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics. Design, Setting, and Participants Probands were identified from a population-based, case-control study (Women’s Environmental Cancer and Radiation Epidemiology [WECARE]) of asynchronous contralateral breast cancer conducted during the period of January 2000 to July 2004. Participants previously diagnosed with contralateral breast cancer or unilateral breast cancer were genotyped for mutations in BRCA1 and BRCA2. All participants had their initial breast cancer diagnosed during the period of January 1985 to December 2000, before the age of 55 years. Main Outcome MeasureIncidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families.Results Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P = .04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P = .28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics. Conclusion There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

It has recently been shown that the relative risks of the order of 2 to 4 that are frequently found for cancer among relatives of affected cases are unlikely to be explainable by shared environmental risk factors. Classical methods of epidemiological analysis are not well suited to such analysis because they assume that the outcomes of each individual are independent. Classical methods of genetic analysis, on the other hand, are limited in their handling of environmental factors and variable ages of onset. The recent development of random effects models for survival analysis, however, appears to bridge this gap. Specifically, a proportional hazards model is postulated for the effects of measured covariates and of one or more components of frailty that are unmeasured but assumed to have some common distribution and known covariance structure within each family. From these assumptions, the posterior expectation of the hazard for each individual can be derived, given the covariate value and the observed and expected disease history of the family. These are then treated as known in a standard partial likelihood analysis; this is essentially a form of expectation-maximization algorithm. However, this does not provide a valid estimate of the covariance matrix because it fails to take account of the variability in the estimates of the frailties; an alternative approach using the imputation-posterior algorithm is suggested. This paper describes extensions of this approach to multivariate frailty distributions, modifications for application to pedigree and case-control studies, some simulation results, and applications to studies of breast cancer in twins and of lung cancer in relation to family smoking habits.

SUMMARY A test of an effect in matched case-control studies, natural in an analysis of variance context, compares within matched set case-control mean differences to the within matched set variances after removing the case-control effect. For large odds ratios, heuristic reasoning suggests that this new test should be more powerful than the standard score test when two or more controls are matched to any case. Asymptotic theory confirms this in some important situations. Simulation results reveal, however, that the differences in power at sample sizes relevant to epidemiological studies are small.

Classic methods in genetics for the analysis of binary attributes, based on an assumption of a "threshold" on a normally distributed latent variable called "liability," estimate the strength of genetic and environmental effects from differences in correlations between relatives of differing genetic relatedness. Two problems that are not easily addressed by these methods are the need to take the age of onset into account (particularly in chronic diseases in which incidence rates vary considerably with age and the lengths of time at risk can vary between individuals) and the desirability of incorporating measured covariates (genetic or environmental). The standard methods of cohort analysis used in epidemiology allow for both of these features, but until recently have been restricted to independent individuals. Recent developments in survival analysis have extended the widely used "proportional hazards" model of Cox by the addition of latent variable, epsilon, reflecting the shared susceptibility of related subjects because of their shared genes or shared environment. We show how this approach can be combined with more traditional models of gene-environment interaction to allow the main effects of measured genetic markers and environmental variables to be estimated, as well as the residual variance of genetic and environment and their interactions. The approaches are applied to a cohort of female twin births in Sweden from 1886 to 1958, linked with the Swedish cancer registry from 1961 to 1982.

The recently developed case-cohort method of sampling from a cohort is compared with the nested case-control method. Corrected asymptotic relative efficiency results show that the case-cohort design for single "disease" outcomes offers less improvement for intervention trials for which there is no random censoring than originally suggested. Furthermore, simulation results indicate that if there is moderate random censoring or staggered entry, the case-cohort method can do substantially worse than the nested case-control method.

A recent analysis showed that the excess odds ratio (EOR) for lung cancer due to smoking can be modeled by a function which is linear in total pack-years and exponential in the logarithm of smoking intensity and its square. Below 15-20 cigarettes per day, the EOR/pack-year increased with intensity (direct exposure rate or enhanced potency effect), suggesting greater risk for a total exposure delivered at higher intensity (for a shorter duration) than for an equivalent exposure delivered at lower intensity. Above 20 cigarettes per day, the EOR/pack-year decreased with increasing intensity (inverse exposure rate or reduced potency effect), suggesting greater risk for a total exposure delivered at lower intensity (for a longer duration) than for an equivalent exposure delivered at higher intensity. The authors applied this model to data from 10 case-control studies of cancer, including cancers of the lung, bladder, oral cavity, pancreas, and esophagus. At lower intensities, there was enhanced potency for several cancer sites, but narrow ranges for pack-years increased uncertainty, precluding definitive conclusions. At higher intensities, there was a consistent reduced potency effect across studies. The intensity effects were statistically homogeneous, indicating that after accounting for risk from total pack-years, intensity patterns were comparable across the diverse cancer sites.

Background: Women with an initial breast cancer diagnosis are at elevated risk of developing subsequent cancer in the contralateral breast. Studies of reproductive factors and contralateral breast cancer (CBC) have provided inconsistent results. Methods: We employed a case-control study nested within five population-based cancer registries in the United States and Denmark to examine associations between reproductive history and CBC risk. Cases were women with asynchronous CBC who had their first primary invasive breast cancer before age 55 years. Two controls, who had only one primary breast cancer diagnosis, were individually matched to each case on age and year of diagnosis, race, and registry. A total of 694 case-control triplets and 11 case-control pairs were enrolled. Information regarding possible CBC risk factors was obtained via telephone interviews. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% confidence intervals (95% CI) associated with risk factors of interest. Results: Increasing number of full-term pregnancies (FTP) was inversely associated with CBC risk (P trend, 0.001). Women who reported menarche before age 13 years had an increased risk of CBC (RR, 1.26; 95% CI, 1.01-1.58). Age at first FTP, breastfeeding history, and age at menopause were not significantly associated with CBC risk. Conclusions: These results suggest age at menarche and parity, which are established risk factors for first primary breast cancer, are associated with CBC, whereas other reproductive risk factors associated with first primary breast cancer, such as age at first FTP, are less important factors in the development of CBC. (Cancer Epidemiol Biomarkers Prev 2007;16(5):906–11)

Introduction The Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting. Methods A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score. Results After adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values. Conclusion In this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.

Experimental studies have consistently shown a protective effect of nonsteroidal antiinflammatory drugs (NSAIDs) against nonmelanoma skin cancers (NMSC). However, little human epidemiological research has been done in this regard. We used data from the Skin Cancer Chemoprevention Study to explore the association of NSAID use and with the risk of basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC). 1,805 subjects with a recent history of NMSC were randomized to placebo or 50 mg of daily beta-carotene. Participants were asked about their use of over-the-counter and prescription medications at baseline and every 4 months during the trial. Skin follow-up examinations were scheduled annually with a study dermatologist; confirmed lesions were the endpoints in the study. We used a risk set approach to the analysis of grouped times survival data and unconditional logistic regression to compute odds ratios [ORs] for various exposures to NSAIDs. The use of NSAIDs was reported in over 50% of questionnaires. For BCC, NSAIDs exhibited a weak protective effect in crude analyses, which attenuated markedly after adjustment. For SCC, the use of NSAIDs in the year previous to diagnosis reduced the odds by almost 30% (adjusted OR=0.71, 95% CI 0.48-1.04). When we accounted for frequency of use, results for BCC were not striking, and there were inconsistent suggestions of an inverse association with SCC. There were some indications of a modest, nonsignificant reduction on the number of BCCs and SCCs with NSAID use. Our data suggest a weak and inconsistent chemopreventive effect of NSAIDs on BCC and SCC.

reported that a haplotype composed of the alleles 5557G>A andIVS38-8T>C was statistically significantly associated with bilat-eral breast cancer. They observed 5 haplotype carriers among 16(31.3%) bilateral breast cancer patients studied when comparedto 7 carriers among 160 (4.4%) unilateral breast cancer patients(OR 5 9.9). The observed frequency of the haplotype in a sampleof cancer-free female blood donors from the same geographicalarea did not differ statistically from that observed among unilat-eral cases (4.2% vs. 4.4%, respectively). These findings led Heik-kinen et al.

The case-cohort study method is a sampling technique used in epidemiologic research of rare diseases. In this article, the design and its use in medical research is described. Two real examples are provided and a discussion of computer software to analyze case-cohort data is included. Keywords: case-control studies; clinical trials; cohort studies; failure time data; epidemiology; proportional hazards model; sampling

To investigate the associations of maternal and grandmaternal smoking before, during, and after pregnancy with childhood asthma.We conducted a case-control study nested within the Children's Health Study in southern California. The case patients consisted of 338 children with asthma that had been diagnosed in the first 5 years of life, and 570 control subjects were countermatched on in utero exposure to maternal smoking within grade, sex, and community of residence.Detailed maternal and household smoking histories and other asthma risk factor information was obtained by telephone interview.The participation rates were 72.3% and 82.5%, respectively, for control subjects and case patients. In utero exposure to maternal smoking was associated with increased risk for asthma diagnosed in the first 5 years of life (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0 to 2.3), and for persistent asthma (OR, 1.5; 95% CI, 1.0 to 2.3). The associations did not differ in children with early transient asthma compared to those with early persistent asthma. Relative to never-smokers, children whose mothers smoked throughout the pregnancy had an elevated risk of asthma in the first 5 years of life (OR, 1.6; 95% CI, 1.0 to 2.6). Children of mothers who quit smoking prior to the pregnancy showed no increased risk (OR, 0.9; 95% CI, 0.5 to 1.5). We were unable to assess the association of smoking cessation during pregnancy because very few mothers were reported to have done so (15%). Asthma risk did not increase in a monotonic pattern with smoking intensity during pregnancy. Postnatal secondhand smoke exposure was not independently associated with asthma. Grandmaternal smoking during the mother's fetal period was associated with increased asthma risk in her grandchildren (OR, 2.1; 95% CI, 1.4 to 3.2).Maternal and grandmaternal smoking during pregnancy may increase the risk of childhood asthma.

Let I_1,...,I_n be independent but not necessarily identically distributed Bernoulli random variables, and let X_n=\sum_{j=1}^nI_j. For \nu in a bounded region, a local central limit theorem expansion of P(X_n=EX_n+\nu) is developed to any given degree. By conditioning, this expansion provides information on the high-order correlation structure of dependent, weighted sampling schemes of a population E (a special case of which is simple random sampling), where a set d\subset E is sampled with probability proportional to \prod_{A\in d}x_A, where x_A are positive weights associated with individuals A\in E. These results are used to determine the asymptotic information, and demonstrate the consistency and asymptotic normality of the conditional and unconditional logistic likelihood estimator for unmatched case-control study designs in which sets of controls of the same size are sampled with equal probability., Comment: Published at http://dx.doi.org/10.1214/009053604000000706 in the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Nested case–control studies refer to a class of cohort sampling designs used in epidemiologic research. This article describes the general principles, analysis methods, statistical properties, and relationship to other approaches. Methods are illustrated by studies from the epidemiological literature. Keywords: case–control studies; cohort studies; failure time data; epidemiology; martingales; matching; partial likelihood; proportional hazards model; sampling; stochastic processes

Methods for the analysis of unmatched case-control data based on a finite population sampling model are developed. Under this model, and the prospective logistic model for disease probabilities, a likelihood for case-control data that accommodates very general sampling of controls is derived. This likelihood has the form of a weighted conditional logistic likelihood. The flexibility of the methods is illustrated by providing a number of control sampling designs and a general scheme for their analyses. These include frequency matching, counter-matching, case-base, randomized recruitment, and quota sampling. A study of risk factors for childhood asthma illustrates an application of the counter-matching design. Some asymptotic efficiency results are presented and computational methods discussed. Further, it is shown that a 'marginal' likelihood provides a link to unconditional logistic methods. The methods are examined in a simulation study that compares frequency and counter-matching using conditional and unconditional logistic analyses and indicate that the conditional logistic likelihood has superior efficiency. Extensions that accommodate sampling of cases and multistage designs are presented. Finally, we compare the analysis methods presented here to other approaches, compare counter-matching and two-stage designs, and suggest areas for further research.To whom correspondence should be addressed.

PURPOSE: To investigate the relationship between traffic density and the risk of childhood leukemia. METHODS: The study group consisted of 212 cases and 202 controls from the London et al. (1991) study of childhood leukemia conducted in the Los Angeles area during 1978 to 1984. Using GIS methods, traffic counts on all streets within 1500 feet of each subject's residence of longest duration were determined. From these counts, an integrated distance-weighted traffic density measure was calculated for each subject for use as the analytic variable. Additional information, including magnetic fields and wire-code, was obtained from the original case-control study. Association between traffic density and leukemia, and confounding and effect modification by other variables, were assessed using standard matched case-control analyses. RESULTS: Although the unadjusted traffic density-childhood leukemia rate ratios were slightly elevated, this weak association was explained by confounding by wire code. Wire code remained associated with leukemia after controlling for traffic density. There was little evidence of effect modification between traffic density and magnetic fields, wire code or other variables. CONCLUSIONS: There is no evidence of an association of traffic density with childhood leukemia in the Los Angeles case-control study.

To evaluate the treatment outcome in pT3N0 patients with adenocarcinoma of the prostate treated with an elective course of postoperative irradiation (RT).During a 22-year period, a total of 423 pT3N0 prostate cancer patients were treated at a single medical center with prostatic fossa RT, which was the only adjuvant therapy given. The patient characteristics were as follows: median age 66 years; Stage pT3aN0 in 296 (70%) and pT3bN0 in 127 (30%); Gleason score 2-4 in 12 (2.8%), 5-6 in 157 (37.1%), 7 in 151 (35.7%), and 8-10 in 100 (23.6%); and the median and mean preoperative prostate-specific antigen (PSA) level was 10 and 15.9 ng/mL, respectively. Radiotherapy consisted of a median dose of 48 Gy delivered to the prostatic fossa and its immediate vicinity. The median follow-up was 7 years.The 5- and 10-year actuarial survival rate was 92% and 73%, respectively, and the 5- and 10-year disease-free survival rate (PSA0.05 ng/mL) was 69% and 51%, respectively. In multivariate analysis, the Gleason score was the most important predictor for survival (p = 0.00005), and pathologic stage and Gleason score were independently predictive of disease-free survival (p = 0.00007 and 0.0003, respectively). The worst prognostic category was represented by pT3bN0, Gleason score 7-10 patients who had a 5.3 times greater risk of tumor recurrence than those with pT3aN0, Gleason score 2-6. A high (25 ng/mL) preoperative PSA level was also a predictor of tumor recurrence (p = 0.03). A total of 43 patients (10.2%) developed clinical recurrence. This included 30 patients (7%) with distant metastases alone and 13 (3%) with local recurrence, which included 2 patients who also had distant disease. An additional 88 patients (20%) had PSA elevation (0.05 ng/mL). This treatment program was well tolerated, with acute toxicity common (62%) but of no clinical significance. No late or severe toxicity was recorded.Adjuvant radiotherapy, as given in this study, appears to substantially reduce the expected incidence of local tumor recurrence in pT3N0 prostate cancer patients. The treatment outcome was poor in pT3bN0 and Gleason score 7-10 patients, with80% showing evidence of clinical or PSA recurrence at 10 years after therapy. This group should be the target of a prospective trial of systemic therapy.

We examined potential confounding factors that, if unaccounted for, could possibly produce a spurious association in a study of breast cancer among women occupationally exposed to magnetic fields. For each risk factor, we estimated strength of association, prevalence in the general population, and prevalence of the risk factor in the exposed group required to explain completely hypothetical odds ratios between occupational exposure to magnetic fields and breast cancer. We performed similar analyses for two, three, four, and five confounding factors acting simultaneously. Factors numerically capable of substantial confounding included obesity, continent of birth, family history of breast cancer in a first-degree relative, densities on the mammogram, benign proliferative breast disease, history of cancer in one breast, and consumption of at least two alcoholic drinks per day. Nevertheless, only continent of birth, history of cancer, obesity, and consumption of alcohol could potentially be related to occupation. Uncontrolled confounders, either alone or in combination, could possibly account for odds ratios in the 1.2-1.3 range but were very unlikely to produce an odds ratio of more than 1.5. A spurious negative association between magnetic fields and breast cancer could occur if the exposed group included a large number of immigrants from Asia and Africa.

Summary. Motivated by a Finnish case-control study of early onset diabetes in which diabetic children are matched to sibling controls, we investigate ascertainment bias of the usual rate ratio estimator from case-control data under simplex complete ascertainment of families during a fixed interval of time. Analytic results indicate that the assumptions necessary for valid estimation are that the disease is rare and the factors under study are exchangeable–essentially that the covariate distribution does not depend on calendar time or birth order. Further, we found that the rare disease assumption could be dropped by restricting to cases that were diagnosed during the enrollment period of the study or including all cases but eliminating the proband as a control for non-enrollment-period cases. An important consequence of this work is that standard family-based case-control studies are subject to ascertainment bias if exchangeability of the covariates under investigation does not hold.