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.

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.

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

Unlabelled: 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 < .

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.

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).

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.

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.

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.

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.

Lagging exposure information in cumulative exposure-response analyses.

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.

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.

Dactinomycin and vincristine toxicity in the treatment of childhood cancer: a retrospective study from the Children's Oncology Group.

Background: Dactinomycin (AMD) and vincristine (VCR) have been used for the treatment of childhood cancer over the past 40 years but evidence-based dosing guidance is lacking.

Methods: Patient AMD and VCR dose and drug-related adverse event (AE) information from four rhabdomyosarcoma (RMS) and two Wilms tumor (WT) studies were assembled. Statistical modeling was used to account for differences in AE data collection across studies, develop rate models for grade 3/4 CTCAE v3 hepatic- (AMD) and neuro- (VCR) toxicity, assess variation in toxicity rates over age and other factors, and predict toxicity risk under current dosing guidelines.

Hierarchical latency models for dose-time-response associations.

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.

Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.

Background: Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women.

Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer.

Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutations in BRCA1 and BRCA2, it is critical to determine the effectiveness of standard adjuvant therapies in preventing CBC in mutation carriers. The WECARE study is a matched, case-control study of 708 women with CBC as cases and 1,399 women with unilateral breast cancer (UBC) as controls, including 181 BRCA1/BRCA2 mutation carriers. Interviews and medical record reviews provided detailed information on risk factors and breast cancer therapy.