Analysis and asymptotic theory for nested case-control designs under highly stratified proportional hazards models.

Nested case-control sampled event time data under a highly stratified proportional hazards model, in which the number of strata increases proportional to sample size, is described and analyzed. The data can be characterized as stratified sampling from the event time risk sets and the analysis approach of Borgan et al. (Ann Stat 23:1749-1778, 1995) is adapted to accommodate both the stratification and case-control sampling from the stratified risk sets. Conditions for the consistency and asymptotic normality of the maximum partial likelihood estimator are provided and the results are used to compare the efficiency of the stratified analysis to an unstratified analysis when the baseline hazards can be semi-parametrically modeled in two special cases. Using the stratified sampling representation of the stratified analysis, methods for absolute risk estimation described by Borgan et al. (1995) for nested case-control data are used to develop methods for absolute risk estimation under the stratified model. The methods are illustrated by a year of birth stratified analysis of radon exposure and lung cancer mortality in a cohort of uranium miners from the Colorado Plateau.

Area-Based Geocoding: An Approach to Exposure Assessment Incorporating Positional Uncertainty.

While the spatial resolution of exposure surfaces has greatly improved, our ability to locate people in space remains a limiting factor in accurate exposure assessment. In this case-control study, two approaches to geocoding participant locations were used to study the impact of geocoding uncertainty on the estimation of ambient pesticide exposure and breast cancer risk among women living in California's Central Valley. Residential and occupational histories were collected and geocoded using a traditional point-based method along with a novel area-based method. The standard approach to geocoding uses centroid points to represent all geocoded locations, and is unable to adapt exposure areas based on geocode quality, except through the exclusion of low-certainty locations. In contrast, area-based geocoding retains the complete area to which an address matched (the same area from which the centroid is returned), and therefore maintains the appropriate level of precision when it comes to assessing exposure by geography. Incorporating the total potential exposure area for each geocoded location resulted in different exposure classifications and resulting odds ratio estimates than estimates derived from the centroids of those same areas (using a traditional point-based geocoder). The direction and magnitude of these differences varied by pesticide, but in all cases odds ratios differed by at least 6% and up to 35%. These findings demonstrate the importance of geocoding in exposure estimation and suggest it is important to consider geocode certainty and quality throughout exposure assessment, rather than simply using the best available point geocodes.

General Relative Rate Models for the Analysis of Studies Using Case-Cohort Designs.

A standard approach to analysis of case-cohort data involves fitting log-linear models. In this paper, we describe how standard statistical software can be used to fit a broad class of general relative rate models to case-cohort data and derive confidence intervals. We focus on a case-cohort design in which a roster has been assembled and events ascertained but additional information needs to be collected on explanatory variables. The additional information is ascertained just for persons who experience the event of interest and for a sample of the cohort members enumerated at study entry. One appeal of such a case-cohort design is that this sample of the cohort may be used to support analyses of several outcomes. The ability to fit general relative rate models to case-cohort data may allow an investigator to reduce model misspecification in exposure-response analyses, fit models in which some factors have effects that are additive and others multiplicative, and facilitate estimation of relative excess risk due to interaction. We address model fitting for simple random sampling study designs as well as stratified designs. Data on lung cancer among radon-exposed men (Colorado Plateau uranium miners, 1950-1990) are used to illustrate these methods.

A case-control study of breast cancer risk and ambient exposure to pesticides.

While the estrogenic properties of certain pesticides have been established, associations between pesticide exposure and risk of breast cancer have been inconsistently observed. We investigated the relation between pesticide exposure and breast cancer risk using methods capable of objectively assessing exposure to specific pesticides occurring decades before diagnosis. METHODS: A case-control study was conducted to evaluate the risk of postmenopausal breast cancer associated with historic pesticide exposure in California's Central Valley, the most agriculturally productive region in the United States where pesticide drift poses a major source of nonoccupational exposure. Residential and occupational histories were linked to commercial pesticide reports and land use data to determine exposure to specific chemicals. Cases (N = 155) were recruited from a population-based cancer registry, and controls (N = 150) were obtained from tax assessor and Medicare list mailings. RESULTS: There was no association between breast cancer and exposure to a selected group of organochlorine pesticides thought to have synergistic endocrine-disrupting potential; however, breast cancer was three times as likely to occur among women exposed to chlorpyrifos compared with those not exposed, after adjusting for exposure to other pesticides including organochlorines (OR = 3.22; 95% CI = 1.38, 7.53). CONCLUSIONS: Organophosphate pesticides, such as chlorpyrifos, have rarely been evaluated in studies of breast cancer risk. Additional research is needed to confirm these findings and to better understand the underlying mechanisms given that chlorpyrifos has been detected in local air monitoring at levels of concern for residents living in the agricultural regions where it is used.

Cost-efficient case-control cluster sampling designs for population-based epidemiological studies.

Cost-efficient sampling schemes for population-based case-control studies are necessary for sampling subjects in geographically dispersed populations where in-house surveys are expensive to conduct due to high interviewer travel costs that may be associated with simple random sampling. Motivated by the original study conducted by Cockburn et al. (2011) that investigated the relationship between exposure to pesticides and prostate carcinogenesis, a set of cluster-based individually matched case-control designs is presented for cost-efficient sampling of additional controls. Based on cluster sampling from the field of survey sampling, the case-control study designs presented, where one case is individually matched to three controls, use case-control status in the sampling of the primary sampling clusters. In the secondary stage, interviewer travel costs are reduced by subsampling additional controls within primary sampling clusters as opposed to selecting additional controls purely at random, which would be highly inefficient from a cost perspective. Compared to the simple random sampling (SRS) 1:1 and SRS 1:3 (one case matched to: n SRS control(s)) designs, computer simulations demonstrate that these cluster-based designs provide unbiased rate ratio estimation and statistical efficiencies that are no worse than the SRS 1:1 design and moderately less than the SRS 1:3 design. Even under situations where the intracluster correlation for the exposure variable is extremely high for the exposure of interest, the cluster-based designs have statistical efficiencies that are comparable to that of the SRS 1:1 design. Furthermore, a cost-efficiency analysis is presented that demonstrates that the cluster-based designs are more cost-efficient compared to the SRS 1:3 design.

Impact of a Hypnotically-Based Intervention on Pain and Fear in Women Undergoing Labor.

The purpose of this study was to evaluate the effects of a hypnotically-based intervention for pain and fear in women undergoing labor who are about to receive an epidural catheter. A group of 155 women received interventions that included either (a) patient rocking, gentle touching, and hypnotic communication or (b) patient rocking, gentle touching, and standard communication. The authors found that the hypnotic communication intervention was more effective than the standard communication intervention for reducing both pain intensity and fear. The results support the use of hypnotic communication just before and during epidural placement for women who are in labor and also indicate that additional research to evaluate the benefits and mechanism of this treatment is warranted.

Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children's Oncology Group.

PURPOSE: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma. PATIENTS AND METHODS: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation. RESULTS: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy. CONCLUSIONS: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.

Exercise and Prognosis on the Basis of Clinicopathologic and Molecular Features in Early-Stage Breast Cancer: The LACE and Pathways Studies.

To investigate whether the impact of postdiagnosis exercise on breast cancer outcomes in women diagnosed with early-stage breast cancer differs on the basis of tumor clinicopathologic and molecular features. Using a prospective design, 6,211 patients with early-stage breast cancer from two large population-based cohort studies were studied. Age-adjusted and multivariable Cox regression models were performed to determine the relationship between exercise exposure (total MET-hours/week) and recurrence and breast cancer-related death for: (i) all patients ("unselected" cohort), and on the basis of (ii) classic clinicopathologic features, (iii) clinical subtypes, (iv) PAM50-based molecular intrinsic subtypes, and (v) individual PAM50 target genes. After a median follow-up of 7.2 years, in the unselected cohort (n = 6,211) increasing exercise exposure was not associated with a reduction in the risk of recurrence (adjusted Ptrend = 0.60) or breast cancer-related death (adjusted Ptrend = 0.39). On the basis of clinicopathologic features, an exercise-associated reduction in breast cancer-related death was apparent for tumors <2 cm [HR, 0.50; 95% confidence interval (CI), 0.34-0.72], well/moderately differentiated tumors (HR, 0.63; 95% CI, 0.43-0.91), and ER-positive tumors (HR, 0.72; 95% CI, 0.53-0.97). Stratification by clinical subtype indicated that the ER(+)/PR(+)/HER2(-)/low-grade clinical subtype was preferentially responsive to exercise (recurrence: adjusted HR, 0.63; 95% CI, 0.45-0.88; breast cancer-related death: adjusted HR, 0.57; 95% CI, 0.37-0.86). The impact of exercise on cancer outcomes appears to differ as a function of pathologic and molecular features in early-stage breast cancer. Cancer Res; 76(18); 5415-22. ©2016 AACR.

Correlation of Insurance, Race, and Ethnicity with Pathologic Risk in a Controlled Retinoblastoma Cohort: A Children's Oncology Group Study.

PURPOSE: To determine whether insurance status, race, and ethnicity correlate with increased retinoblastoma invasiveness as a marker of both risk and time to diagnosis. DESIGN: Retrospective case-control study. PARTICIPANTS: All 203 patients from the United States enrolled in the Children's Oncology Group (COG) trial ARET0332, a study of patients with unilateral retinoblastoma requiring enucleation. MAIN OUTCOME MEASURES: All surgical specimens underwent pathologic review to determine the presence of well-defined histopathologic features correlating with a higher risk of disease progression. Insurance status, race, and ethnicity were compiled from the study record for each patient. RESULTS: On institutional pathologic review, nonprivate insurance, nonwhite race, and Hispanic ethnicity all correlated significantly with a greater rate of high-risk pathologic findings. Hispanic ethnicity remained a significant predictor on multivariate analysis. On central pathologic review, these correlations remained but did not reach statistical significance. The differences in results from institutional versus central pathologic reviews appeared to be due to a higher likelihood of patients in minority groups of being misclassified as high risk by institutional pathologists. CONCLUSIONS: In this controlled study population of patients with retinoblastoma who had central pathologic review, our findings suggest a higher rate of more advanced disease associated with nonprivate insurance, nonwhite race, and Hispanic ethnicity; these findings may be due to delays in diagnosis for these groups. Future work should use direct methods to study the impact of other variables, including English-language proficiency and socioeconomic status. Further effort also should focus on where in the diagnostic process potential delays exist, so that interventions can be designed to overcome barriers to care for these groups. In addition, potential systematic differences in pathologic reads based on demographic variables deserve further study.

A post-hoc Unweighted Analysis of Counter-Matched Case-Control Data.

Informative sampling based on counter-matching risk set subjects on exposure correlated with a variable of interest has been shown to be an efficient alternative to simple random sampling; however, the opposite is true when correlation between the two covariates is absent. Thus, the counter-matching design will entail substantial gains in statistical efficiency compared to simple random sampling at a first stage of analyses focused by design on variables correlated with the counter-matching variable but will lose efficiency at a second stage of analyses aimed at variables independent of the counter-matching variable and not conceived as a part of the initial study. In an effort to recover efficiency in such second stage of analyses scenarios, we considered a naive analysis of the effect of a dichotomous covariate on the disease rates in the population that ignores the underlying counter-matching sampling design. We derive analytical expressions for the bias and variance and show that when the counter-matching and the new dichotomous variable of interest are uncorrelated and a multiplicative main effects model holds, such an analysis is advantageous over the standard "weighted" approach, especially when the counter-matching variable is rare and in such scenarios the efficiency gains exceeds 80%. Moreover, we consider all possible conceptual violations of the required assumptions and show that moderate departures from the above-mentioned requirements lead to negligible levels of bias; numerical values for the bias under common scenarios are provided. The method is illustrated via an analysis of BRCA1/2 deleterious mutations in the radiation treatment counter-matched WECARE study of second breast cancer.

Prevalence and predictors of recent skin examination in a population-based twin cohort.

BACKGROUND: The incidence of melanoma is increasing worldwide. Guidelines for clinical skin exam for improving early diagnosis of melanoma remain inconsistent, and current data on factors associated with regular skin screening on a population basis are limited. METHODS: We used self-reported data from 50,044 members of the California Twin Program, a population-based cohort of twins born in California between 1908 and 1982, to identify prevalence and determinants of recent clinical screening for skin cancer. RESULTS: Prevalence of skin examination was higher than national estimates, with 32% of respondents of all ages reporting ever having skin examination. Sociodemographic and constitutional risk factors including white race, educational attainment, marital status, and number of large moles were strongly associated with recent screening, as were individual and family history of skin cancer. Lower socioeconomic status, racial/ethnic minority status, and paradoxically, frequent UV-related risk behaviors in adulthood were associated with a lower likelihood of recent screening. CONCLUSIONS: As the evidence concerning the efficacy of skin examination continues to evolve, attention should be paid to motivators and barriers of screening, particularly in high-risk subgroups where lack of screening may contribute to disparate rates of thicker melanomas and lower survival. IMPACT: Our results demonstrate the need for prevention strategies targeted to specific at-risk groups to increase earlier detection leading to improved outcomes.

Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival.

BACKGROUND: Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown. METHODS: We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided. RESULTS: Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes. CONCLUSIONS: History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.

IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients.

Positive detection of minimal residual disease (MRD) by multichannel flow cytometry (MFC) prior to hematopoietic cell transplantation (HCT) of patients with acute lymphoblastic leukemia (ALL) identifies patients at high risk for relapse, but many pre-HCT MFC-MRD negative patients also relapse, and the predictive power MFC-MRD early post-HCT is poor. To test whether the increased sensitivity of next-generation sequencing (NGS)-MRD better identifies pre- and post-HCT relapse risk, we performed immunoglobulin heavy chain (IgH) variable, diversity, and joining (V[D]J) DNA sequences J NGS-MRD on 56 patients with B-cell ALL enrolled in Children's Oncology Group trial ASCT0431. NGS-MRD predicted relapse and survival more accurately than MFC-MRD (P < .0001), especially in the MRD negative cohort (relapse, 0% vs 16%; P = .02; 2-year overall survival, 96% vs 77%; P = .003). Post-HCT NGS-MRD detection was better at predicting relapse than MFC-MRD (P < .0001), especially early after HCT (day 30 MFC-MRD positive relapse rate, 35%; NGS-MRD positive relapse rate, 67%; P = .004). Any post-HCT NGS positivity resulted in an increase in relapse risk by multivariate analysis (hazard ratio, 7.7; P = .05). Absence of detectable IgH-V(D)J NGS-MRD pre-HCT defines good-risk patients potentially eligible for less intense treatment approaches. Post-HCT NGS-MRD is highly predictive of relapse and survival, suggesting a role for this technique in defining patients early who would be eligible for post-HCT interventions. The trial was registered at www.clinicaltrials.gov as #NCT00382109.

TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521).

Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.

The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial.

Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.

Children's Oncology Group's 2013 blueprint for research: stem cell transplantation.

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.

Regression models for the effects of exposure rate and cumulative exposure.

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.

Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan.

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.

Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children's Oncology Group study.

The Children's Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.

Background stratified Poisson regression analysis of cohort data.

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.