Bayesian dual threshold design with Dirichlet distribution: An alternative way to frequentist multi-stage phase II designs in oncology

Many phase II clinical studies in oncology use two-stage frequentist design such as Simon's optimal design. However, they have a common logistical problem regarding the patient accrual at the interim. Strictly speaking, patient accrual at the end of the first stage may have to be suspended until all patients have events, success or failure. For example, when the study endpoint is six-month progression free survival, patient accrual has to be stopped until all outcomes from stage I is observed. However, study investigators may have concern when accrual is suspended after the first stage due to the loss of accrual momentum during this hiatus. We propose a two-stage phase II design that resolves the patient accrual problem due to an interim analysis, and it can be used as an alternative way to frequentist two-stage phase II studies in oncology. ^

A STUDY OF ZINC CONCENTRATION IN HAIR AS AN INDICATION OF ZINC IMBALANCES

Trace metal imbalances have been implicated in several disease and nutritional states. There is mounting concern to identify the nutritional balance of the trace metals needed for growth, mental acuity and physical functioning. These two factors, diseases in which trace metals show involvement and nutritional balance, have made it necessary to be able to accurately describe the trace metal balances of an individual. Although several investigators have measured the concentration of trace metals in the hair and related those observed concentrations to various disease and nutritional states, no one has satisfactorily answered the questions of whether hair is useful to determine trace metal imbalances, whether the concentrations found in hair reflect tissue or serum concentrations of the trace metals, or whether any tissue accurately reflects body status of the trace metals.^ Male mice were used to examine several tissues, heart, liver, kidney, spleen, intestine, brain, bone, hair and serum for copper and zinc concentrations. The environment and dietary intake of the animals were carefully controlled, so that environmental and physical variables were minimized. Dietary intake of zinc was varied while copper intake was held constant. Each experimental diet group was matched with a pair fed control group.^ Of the tissues examined, only the serum was indicative of an early state of zinc imbalance. Neither hair nor the other tissues examined for copper and zinc concentrations were indicative of an acute zinc imbalance in a normal mature mouse. Zinc deficiencies or excesses may manifest themself differently in the chronic imbalance state or in the weanling, aged or traumatized mouse. The tissue response to zinc imbalance may vary in these cases. ^

Factors contributing to the attrition of women in the African-American Nutrition for Life study

Background. There is currently a push to increase the number of minorities in cancer clinical trials in an effort to reduce cancer health disparities. Overcoming barriers to clinical trial research for minorities is necessary if we are to achieve the goals of Healthy People 2010. To understand the unexpectedly high rate of attrition in the A NULIFE study, the research team examined the perceived barriers to participation among minority women. The purpose of this study was to determine if either personal or study-related factors influenced healthy pre-menopausal women aged 25-45 years to terminate their participation in the A NULIFE Study. We hypothesized that personal factors were the driving forces for attrition rates in the prevention trial.^ Methods. The target population consisted of eligible women who consented to the A NULIFE study but withdrew prior to being randomized (N= 46), as well as eligible women who completed the informed consent process for the A NULIFE study and withdrew after randomization (N= 42). Examination of attrition rates in this study occurred at a time point when 10 out of 12 participant groups had completed the A NULIFE study. Data involving the 2 groups that were actively engaged in study activities were not used in this analysis. A survey instrument was designed to query the personal and study-related factors that were believed to have contributed to the decision to terminate participation in the A NULIFE study.^ Results. Overall, the highest ranked personal reason that influenced withdrawal from the study was being “too busy” with other obligations. The second highest ranked factor for withdrawal was work obligations. Whereas, more than half of all participants agreed that they were well-informed about the study and considered the study personnel to be approachable, 54% of participants would have been inclined to remain in the study if it were located at a local community center.^ Conclusions. Time commitment was likely a major factor for withdrawal from the A NULIFE study. Future investigators should implement trials within participant communities where possible. Also, focus group settings may provide detailed insight into factors that contribute to the attrition of minorities in cancer clinical trials.^

A nested case-control study of radiation exposure and brain cancer incidence in the United States Air Force

A nested case-control study design was used to investigate the relationship between radiation exposure and brain cancer risk in the United States Air Force (USAF). The cohort consisted of approximately 880,000 men with at least 1 year of service between 1970 and 1989. Two hundred and thirty cases were identified from hospital discharge records with a diagnosis of primary malignant brain tumor (International Classification of Diseases, 9th revision, code 191). Four controls were exactly matched with each case on year of age and race using incidence density sampling. Potential career summary extremely low frequency (ELF) and microwave-radiofrequency (MWRF) radiation exposures were based upon the duration in each occupation and an intensity score assigned by an expert panel. Ionizing radiation (IR) exposures were obtained from personal dosimetry records.^ Relative to the unexposed, the overall age-race adjusted odds ratio (OR) for ELF exposure was 1.39, 95 percent confidence interval (CI) 1.03-1.88. A dose-response was not evident. The same was true for MWRF, although the OR = 1.59, with 95 percent CI 1.18-2.16. Excess risk was not found for IR exposure (OR = 0.66, 45 percent CI 0.26-1.72).^ Increasing socioeconomic status (SES), as identified by military pay grade, was associated with elevated brain tumor risk (officer vs. enlisted personnel age-race adjusted OR = 2.11, 95 percent CI 1.98-3.01, and senior officers vs. all others age-race adjusted OR = 3.30, 95 percent CI 2.0-5.46). SES proved to be an important confounder of the brain tumor risk associated with ELF and MWRF exposure. For ELF, the age-race-SES adjusted OR = 1.28, 95 percent CI 0.94-1.74, and for MWRF, the age-race-SES adjusted OR = 1.39, 95 percent CI 1.01-1.90.^ These results indicate that employment in Air Force occupations with potential electromagnetic field exposures is weakly, though not significantly, associated with increased risk for brain tumors. SES appeared to be the most consistent brain tumor risk factor in the USAF cohort. Other investigators have suggested that an association between brain tumor risk and SES may arise from differential access to medical care. However, in the USAF cohort health care is universally available. This study suggests that some factor other than access to medical care must underlie the association between SES and brain tumor risk. ^

A case-control study of the association between corneal arcus and death by cardiovascular disease among cornea donors

The cornea of the human eye can develop deposits of lipids in the periphery known as corneal arcus. [2, 10] For over a century, these deposits have been of interest as possible indicators of the accumulation of lipids in arterial walls of the heart and body with implications for heart disease. [2, 10, 11, 29] Heart disease is currently the leading cause of death in this country. [5, 29] There have been several publications suggesting an association between the development of atherosclerotic lesions and corneal arcus. [2, 12, 29] Investigators have differed in their interpretation of the relevance of corneal arcus to coronary heart disease or cardiovascular disease. However, there is widespread consensus that the presence of corneal arcus in patients under the age of 50 should prompt physicians to further investigate for dyslipidemia or heart disease. [2, 3, 6, 8, 19] Earlier studies have often suffered from difficulty in determining the presence or severity of atherosclerosis and from inconsistencies in evaluating corneal arcus. This study involves the review of mortality data, medical and social history and standardized slit lamp examination of corneal tissue donors to evaluate the prevalence of corneal arcus in relation to death by CHD or CVD. The prevalence of arcus, odds ratio, and logistic regression was utilized for statistical analysis.^

Frequencies and risk factors for bisphosphonate-related osteonecrosis of the jaw in cancer patients: A matched case-control study

Bisphosphonates represent a unique class of drugs that effectively treat and prevent a variety of bone-related disorders including metastatic bone disease and osteoporosis. High tolerance and high efficacy rates quickly ranked bisphosphonates as the standard of care for bone-related diseases. However, in the early 2000s, case reports began to surface that linked bisphosphonates with osteonecrosis of the jaw (ONJ). Since that time, studies conducted have corroborated the linkage. However, as with most disease states, many factors can contribute to the onset of disease. The aim of this study was to determine which comorbid factors presented an increased risk for developing ONJ in cancer patients.^ Using a case-control study design, investigators used a combination of ICD-9 codes and chart review to identify confirmed cases of ONJ at The University of Texas M. D. Anderson Cancer Center (MDACC). Each case was then matched to five controls based on age, gender, race/ethnicity, and primary cancer diagnosis. Data querying and chart review provided information on variables of interest. These variables included bisphosphonate exposure, glucocorticoids exposure, smoking history, obesity, and diabetes. Statistical analysis was conducted using PASW (Predictive Analytics Software) Statistics, Version 18 (SPSS Inc., Chicago, Illinois).^ One hundred twelve (112) cases were identified as confirmed cases of ONJ. Variables were run using univariate logistic regression to determine significance (p < .05); significant variables were included in the final conditional logistic regression model. Concurrent use of bisphosphonates and glucocorticoids (OR, 18.60; CI, 8.85 to 39.12; p < .001), current smokers (OR, 2.52; CI, 1.21 to 5.25; p = .014), and presence of diabetes (OR, 1.84; CI, 1.06 to 3.20; p = .030) were found to increase the risk for developing ONJ. Obesity was not associated significantly with ONJ development.^ In this study, cancer patients that received bisphosphonates as part of their therapeutic regimen were found to have an 18-fold increase in their risk of developing ONJ. Other factors included smoking and diabetes. More studies examining the concurrent use of glucocorticoids and bisphosphonates may be able to strengthen any correlations.^