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A common assumption made In modeling system life from series and parallel systems is that the component lives are independent. This study investigates the magnitude of the errors one may incur by erroneously asuming the component lifetimes have independent exponential distributions when in fact the lifetimes follow the bivariate exponential distribution of Marshall & Olkin (series or parallel systems) or that of Freund (parallel systems).

We evaluated calcium glucarate (CGT) and N-(4-hydroxyphenyl)retinamide (HPR) for their effectiveness as anti-tumor agents. For this evaluation, we tested the effects of CGT and HPR given alone or combined in the diet on the growth of established 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors. When given alone, optimal doses of CGT (128.0 mmol/kg in the diet) or HPR (2.0 mmol/kg in the diet) administered daily for 25 days reduced mammary tumor sizes by approximately 15% or 20%, respectively. Suboptimal doses of CGT (64.0 mmol/kg) or HPR (0.75 mmol/kg) administered daily for 25 days only slightly inhibited tumor growth; over the 25-day period, the tumor sizes in rats on the CGT diet and in rats on the HPR diet increased by 55% and 70%, respectively, compared with a 98% increase in tumor sizes in the rats on the control diet. In contrast, the combination of suboptimal doses of CGT (64.0 mmol/kg) and HPR (0.75 mmol/kg) administered daily for 25 days decreased tumor sizes by 33%. These results are statistically significant. They show that CGT and HPR act synergistically. Consequently, lower concentrations of these agents can be used to inhibit mammary tumor development and growth.

In this first article of a series on controlled clinical trials in emergency medicine, an overview of the structure of such studies and the relevant issues related to study design, data generation, statistical analysis, and reporting are presented. The importance of precise patient selection, randomization and stratification, blinding, and equivalent therapeutic intervention in study design has been discussed. In addition, precise outcome and measurement criteria, assessor qualifications, deficiencies in data, appropriate sample-size selection, and reporting are also presented. Although an idealized framework for the conduct and analysis of a controlled clinical trial is provided, it should be appreciated that design and analytical compromises may at times be difficult to avoid in clinical research. Future articles in this series will discuss randomization in clinical trials, alternatives to randomization, beta error and sample-size determination, the statistical and analytical issues related to imperfections in the execution of a trial, and issues related to the reporting of clinical trials.

In an attempt to reduce the confusion regarding reported effects of age upon maximal exercise heart rate (HR max), a comprehensive review of the English literature was conducted to obtain descriptive statistical data representing over 23,000 independent subjects from 5 to 81 years old. The data were split randomly into two data sets for independent regression analyses. HR max was the dependent variable while independent variables include: age, age2, age3, age4, sex, level of fitness, type of ergometer, exercise protocol, continent of residence, and race. After cross validation the data were pooled and reanalyzed. Additional validation was accomplished on identifiable subsets of the data, e.g., cross sectional, longitudinal, training, comparative ergometry, and comparative sex studies. Results identified negative linear and non-linear age factors, an ergometry factor, a fitness factor and a continent factor. Age accounted for about 70–75% of the variability. Generalized equations were proposed. Ev...

Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoquinone] diacetate (3b) and 2,2'-ethylenebis[6-(bromomethyl)-p-benzoquinone] (3c), were studied in vivo and in vitro using an established epithelial/Burkitt lymphoma hybrid cell line (D98/HR1) previously shown to induce carcinomas in nude mice. Inactivity of both test compounds in vitro, the relative resistance of these cells to test drugs in vitro, and the selective antitumor properties of the bis(bromomethyl) analogue in vivo lead to the proposal that this compound undergoes bioreduction to an alkylating species in the hypoxic core of the tumor, thereby exerting its action.

OBJECTIVES We hypothesized that plasma factors important for the development of atherosclerosis play a major role in the occurrence of cardiac allograft vasculopathy (CAV). BACKGROUND Cardiac allograft vasculopathy is a major cause of death among heart transplant recipients, has a poorly understood pathogenesis and has similarities to atherosclerotic coronary disease. METHODS The study population consisted of 93 postcardiac transplant recipients. Thirty-one patients with congestive heart failure (CHF) and 18 healthy individuals served as control subjects. Posttransplant coronary anatomy was evaluated by angiography and intravascular ultrasound. Laboratory analyses of lipids, homocysteine, vitamin B 12 and folate, fibrinogen, vonWillebrand factor antigen (vWFAg) and renin were obtained on all participants. RESULTS Posttransplant patients were found to have elevated serum triglycerides, total cholesterol/high-density lipoprotein cholesterol ratio, lipoprotein (a), homocysteine, vWFAg, fibrinogen and renin and lower high-density lipoprotein cholesterol. Most of these laboratory atherogenic factors were also elevated to a similar degree in the CHF control population. Although most atherogenic markers were elevated, there was little correlation with CAV severity. Cardiac allograft vasculopathy severity varied with time after transplantation, 3-hydroxy-methyl-glutaryl-coenzyme A reductase inhibitor use and prior cytomegalovirus infection. Even within the normal range, lower RBC folate levels were associated with increased severity of CAV. CONCLUSIONS The posttransplant course is associated with increased clinical and laboratory atherogenic factors, some of which likely contribute to the severity of coronary vasculopathy. Compared with normal control subjects, many of these markers are already increased in pretransplant CHF patients with or without occlusive coronary artery disease.

In this second article of a series that explores design and analysis issues in controlled clinical trials in emergency medicine, we have discussed the case for randomization, reviewed the methods involved in simple randomization, highlighted some of the practical problems involved with randomization, and presented some modified randomization schemes intended to remedy these problems.

The overall objective of this proposal is to investigate the robustness to departures from independence of methods currently in use in reliability studies when competing failure modes or competing causes of failure associated with a single mode are present in a series system. The first specific aim is to examine the error one makes in modeling a series system by a model which assumes statistically independent component lifetimes when in fact the component lifetimes follow some multivariate distribution. The second specific aim is to assess the effects of the independence assumption error in estimating component parameters from life tests on series systems. In both cases, estimates of such errors will be determined via mathematical analysis and computer simulations for several prominent multivariate distributions. A graphical display of the errors for representative distributions will be made available to researchers who wish to assess the possible erroneous assumption of independent competing risks. A third aim is to tighten the bounds on estimates of component reliability when the risks belong to a general dependence class of distributions (for example, positive quadrant dependence, positive regression dependence, etc.). Major decisions involving reliability studies, based on competing risk methodology, have been made in the past and will continue to be made in the future. This study will provide the user of such techniques with a clearer understanding of the robustness of the analyses to departures from independent risks, an assumption commonly made by the methods currently in use.

One hundred fifty-six hospitalized adult patients treated with ticarcillin, piperacillin, mezlocillin, or cefotaxime (control) were prospectively observed for determination of frequencies of platelet dysfunction and bleeding. Increases in bleeding times (greater than or equal to 5 min above pretreatment values) occurred in 73% of patients receiving ticarcillin, 43% receiving piperacillin, 25% receiving mezlocillin, and 17% receiving cefotaxime (P less than .0001); chemotherapy, thrombocytopenia, age of greater than or equal to 60 years, dose of greater than or equal to 12 g per day, and duration of treatment of six or more days were significant covariables. Significant bleeding occurred in 34% of patients treated with ticarcillin, 17% with piperacillin, 2% with mezlocillin, and 5% with cefotaxime (P = .0005); chemotherapy, thrombocytopenia, primary marrow disorders affecting platelet function, prolonged prothrombin time, and azotemia were significant covariables. Bleeding was associated with an elevated pretreatment bleeding time, an increase in bleeding time during treatment, and the maximal observed bleeding time during treatment (P less than .0001).

Chemical investigations leading to the construction of bis(bioreductive) alkylating agents having both conformationally restricted and mobile spacer regions are described. Two targets having the conformationally mobile ethylene spacer group, namely, 2,2'-ethylenebis[6-(hydroxymethyl)-p-benzoquinone] diacetate (3b) and 2,2'-ethylenebis[6-(bromomethyl)-p-benzoquinone] (3c), were studied in vivo and in vitro using an established epithelial/Burkitt lymphoma hybrid cell line (D98/HR1) previously shown to induce carcinomas in nude mice. Inactivity of both test compounds in vitro, the relative resistance of these cells to test drugs in vitro, and the selective antitumor properties of the bis(bromomethyl) analogue in vivo lead to the proposal that this compound undergoes bioreduction to an alkylating species in the hypoxic core of the tumor, thereby exerting its action.

This study was designed to determine prognostic risk indicators of nonischemic dilated cardiomyopathy (DC). Sixty-nine patients were studied. Each patient underwent physical examination (including a history), electrocardiography, echocardiography, cardiac catheterization, 24-hour monitoring and endomyocardial biopsy. The mortality rate at 1 year was 35% (24 deaths). Univariate analysis revealed that the most powerful predictor of prognosis was the left intraventricular conduction delay (p = 0.003). The pulmonary capillary wedge pressure was also predictive of mortality (p = 0.005). Other significant factors, in order of importance, were ventricular arrhythmias (p = 0.007), mean right atrial pressure (p = 0.008), angiographic ejection fraction (p = 0.03), atrial fibrillation or flutter (p = 0.01) and the presence of an S3 gallop (p = 0.05). Factors such as duration of symptoms, presence of mitral regurgitation, end-diastolic diameter, myocardial cell size and percent fibrosis in the biopsy and treatment with vasodilators, antiarrhythmic and anticoagulant drugs were not significant predictors. Multivariate analysis was used to determine which combination of factors could most accurately predict survival and death. The most important factors were left conduction delay, ventricular arrhythmias and mean right atrial pressure. An equation was derived that can be applied to the prognosis of patients with DC. Thus, the clinical assessment of patients with DC can accurately predict the probability of surviving or dying in 1 year.

This study investigates economic differentials in cancer survival using more adequate measures of economic status and controlling for confounding variables more systematically than earlier studies. For 1180 white males, a variant of the Cox regression model is employed to estimate the direct and interaction effects of economic status on survivorship, controlling for age at diagnosis, stage, severity of disease, and initial course of treatment. The results do not show a strong relationship. Estimates of direct or main economic effects rarely reach even borderline statistical significance; they are highly sensitive to model specification and the measurement of the economic variable. An equally weak interaction effect between economic status and stage is detected in several cases, but the parameter estimates are unstable. Such measurement and specification errors have probably exaggerated the importance of economic factors in cancer survival in earlier investigations.

SURVIVAL MEASUREMENTS AND CONCEPTS. Survival Data. Measures of Mortality and Morbidity. Ratios, Proportions, and Means. Survival Distributions. MORTALITY EXPERIENCES AND LIFE TABLES. Life Tables: Fundamentals and Construction. Complete Mortality Data. Estimation of Survival Function. Incomplete Mortality Data: Follow-Up Studies. Fitting Parametric Survival Distributions. Comparison of Mortality Experiences. MULTIPLE TYPES OF FAILURE. Theory of Competing Causes: Probabilistic Approach. Multiple Decrement Life Tables. Single Decrement Life Tables Associated with Multiple Decrement Life Tables: Their Interpretation and Meaning. Estimation and Testing Hypotheses in Competing Risk Analysis. SOME MORE ADVANCED TOPICS. Concomitant Variables in Lifetime Distributions Models. Age of Onset Distributions. Models of Aging and Chronic Diseases. Indexes.

Bounds on the marginal survival function based on data from a competing-risks experiment are obtained. These bounds require an investigator to specify a range of possible concordances for the times to occurrences of the competing risks. These bounds are tighter than those of Peterson (1976, Proceedings of the National Academy of Sciences 73, 11-13).

When there is extreme censoring on the right, the Kaplan-Meier product-limit estimator is known to be a biased estimator of the survival function. Several modifications of the Kaplan-Meier estimator are examined and compared with respect to bias and mean squared error.