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Biomedical subjects

L S Freedman

Publications and source records attributed to L S Freedman.

At least 55 records · Page 3Linked to original sources
PubMed1995

System delay in breast cancer in whites and blacks.

Survival differences have been noted between black women and white women with breast cancer. It is hypothesized that a prolonged interval between initial medical consultation and establishment of a diagnosis (system delay), resulting in a more advanced stage of disease at diagnosis, might explain part of this survival difference. This study was performed to determine whether system delay differs between black and white breast cancer patients, and to examine predictors of delay in blacks and whites. The study population consisted of 996 female breast cancer patients from the National Cancer Institute's Black/White Cancer Survival Study, a cohort study carried out in 1985-1986 in the metropolitan areas of Atlanta, Georgia, New Orleans, Louisiana, and San Francisco/Oakland, California. The median system delay was slightly longer for blacks than for whites--2.7 weeks versus 2.1 weeks--but this difference was not statistically significant. Having a palpable lump at diagnosis was associated with reduced system delay in both races, while use of a public clinic increased system delay for blacks. Older women were less likely to be subject to longer system delay than younger women, and this effect was somewhat more pronounced in whites. Survival differences between blacks and whites are probably not due to differences in system delay. However, many women had delays of at least 3 months. Given that younger age and the absence of a palpable lump were the factors most predictive of significant system delay, interventions should be targeted specifically toward reducing system delay in younger women who present without the classical painless lump.

Adult↗
PubMed1995

Interplay between design and analysis for behavioral intervention trials with community as the unit of randomization.

This paper outlines an approach for the design and analysis of randomized controlled trials investigating community-based interventions for behavioral change aimed at health promotion. The approach is illustrated using the Community Intervention Trial for Smoking Cessation (COMMIT), conducted from 1988 to 1993, involving 11 pairs of communities in North America, matched on geographic location, size, and sociodemographic factors. The situation discussed is when assignment to intervention is done at the community level; for COMMIT, the very nature of the intervention required this. The number of communities as a key determinant of the statistical power of the trial. The use of matched pairs of communities can achieve a gain in statistical efficiency. Randomization is used to obtain an unbiased assessment of the intervention effect; randomization also provides the basis for statistical analysis. Permutation tests (and corresponding test-based confidence intervals), using community as the unit of analysis, follow directly from the randomization distribution. Within this framework, individual-level covariates can be used for imputation of missing values and for adjusting analyses of intervention effect.

Health Behavior↗
PubMed1995

What does it mean to be a cancer gene carrier? Problems in establishing causality from the molecular genetics of cancer.

This article addresses the following question: What does it mean to be a cancer gene carrier? The existence of families prone to cancer has prompted an intense search for predisposing heritable gene mutations. Genes that impart susceptibility to colorectal, breast, and ovarian cancers have been recently identified. It is doubtful, however, that the action of a single mutant gene totally accounts for the development of malignant disease. The mutant gene likely causes cancer in these family members only in conjunction with other genes, environmental factors, or both. Furthermore, although an individual carrier of a mutant gene within a cancer-prone family has an increased risk of malignancy, nutritional, pharmacologic, or other interventions may still confer protection. Extrapolations from cancer-prone families to the general population are even more problematic. The excess risk of malignancy among carriers of mutant genes who are not members of cancer-prone families is unknown. Large-scale epidemiologic studies are needed to determine the magnitude (or even the existence) of such excess risk.

Environmental Exposure↗
PubMed1995

Potential impact of genetic testing on cancer prevention trials, using breast cancer as an example.

Using breast cancer as an example, we explored the potential impact that a highly predictive genetic test could have on the design and analysis of cancer prevention trials. We discuss three situations in this article: 1) trials that are in progress when the genetic test first becomes available as a research tool but is not available for general use, 2) trials in progress when the genetic test becomes generally available to the public, and 3) trials that begin after the test becomes generally available. We have concluded that the availability of a highly predictive genetic test will provide impediments to prevention trials in the form of increased noncompliance and also will provide opportunities in the form of new trials that include only persons at very high risk of developing cancer. Such trial designs could, under favorable circumstances, substantially reduce the size, duration, and cost of cancer prevention trials. The availability of a highly predictive genetic test will make the discovery of effective interventions even more urgent, and the randomized trial will still provide the most reliable method of evaluating prevention strategies.

Adult↗
PubMed1995

Adjusting for time trends when estimating the relationship between dietary intake obtained from a food frequency questionnaire and true average intake.

In measuring food intake, three common methods are used: 24-hour recalls, food frequency questionnaires and food records. Food records or 24-hour recalls are often thought to be the most reliable, but they are difficult and expensive to obtain. The question of interest to us is to use the food records or 24-hour recalls to examine possible systematic biases in questionnaires as a measure of usual food intake. In Freedman, et al. (1991), this problem is addressed through a linear errors in variables analysis. Their model assumes that all measurements on a given individual have the same mean and variance. However, such assumptions may be violated in at least two circumstances, as in for example the Women's Health Trial Vanguard Study and in the Finnish Smokers' Study. First, some studies occur over a period of years, and diets may change over the course of the study. Second, measurements might be taken at different times of the year, and it is known that diets differ on the basis of seasonal factors. In this paper, we will suggest new models incorporating mean and variance offsets, i.e., changes in the population mean and variance for observations taken at different time points. The parameters in the model are estimated by simple methods, and the theory of unbiased estimating equations (M-estimates) is used to derive asymptotic covariance matrix estimates. The methods are illustrated with data from the Women's Health Trial Vanguard Study.

Analysis of Variance↗
PubMed1994

Can energy adjustment separate the effects of energy from those of specific macronutrients?

Energy adjustment is used in nutritional epidemiology in an attempt to separate specific effects of macronutrients (carbohydrate, fat, and protein) from one another and from the generic effect of the total quantity of energy consumed. However, models in which the risk of disease is allowed to depend simultaneously on daily total energy consumption and separate components of energy that sum to the total are not identifiable: the specific effects of individual macronutrients and the generic effect of energy cannot be disentangled by multivariate analysis. The standard, residual, and partition methods exclude one or more macronutrients from consideration, thereby allowing estimation, but the parameters that are estimated no longer represent specific macronutrient or generic energy effects. Therefore, an interpretation of a regression coefficient from these methods as a specific effect of a macronutrient or as the generic effect of energy requires additional, almost always questionable, assumptions. For example, a conclusion based on data alone that there is a specific fat effect upon the development of breast cancer but no specific effects of other macronutrients and no generic energy effect is not possible. Notwithstanding these serious problems, some useful etiologic inference still can be made.

Energy Metabolism↗
PubMed1994

A unified method for monitoring and analysing controlled trials.

Group sequential methods are becoming increasingly popular for monitoring and analysing large controlled trials, especially clinical trials. They not only allow trialists to monitor the data as it accumulates, but also reduce the expected sample size. Such methods are traditionally based on preserving the overall type I error by increasing the conservatism of the hypothesis tests performed at any single analysis. Using methods which are based on hypothesis testing in this way makes point estimation and the calculation of confidence intervals difficult and controversial. We describe a class of group sequential procedures based on a single parameter which reflects initial scepticism towards unexpectedly large effects. These procedures have good expected and maximum sample sizes, and lead to natural point and interval estimates of the treatment difference. Hypothesis tests, point estimates and interval estimates calculated using this procedure are consistent with each other, and tests and estimates made at the end of the trial are consistent with interim tests and estimates. This class of sequential tests can be considered in both a traditional group sequential manner or as a Bayesian solution to the problem.

Bayes Theorem↗
PubMed1994

Energy adjustment methods for nutritional epidemiology: the effect of categorization.

The authors discuss the interpretation of four alternative energy adjustment methods (Residual, Standard, Partition, and Nutrient Density) that have been proposed for the analysis of nutritional epidemiology studies. These methods have so far been compared under circumstances where intake of the nutrient of interest is measured as a continuous variable. Because it is common practice to categorize nutrient intakes in the analysis, the authors investigate the effect of such categorization on the interpretation of results from the four methods with the use of computer simulations and statistical theory. They consider four cases: where the nutrient intake is either divided into quartiles or ordered so as to investigate trend over the quartile groups, combined with using an adjusting variable that is either continuous or categorized. The results show: 1) the Residual, Standard, and Partition methods are no longer equivalent as they are in the continuous case; 2) compared with the Standard method, the Residual method appears to be more powerful for detecting trends in relative odds, is more robust to residual confounding when the adjustment variable is categorized, and provides more meaningful odds ratios; and 3) the Residual and Nutrient Density methods give closely similar results.

Bias↗
PubMed1993

Nine-year mean follow-up of one-stage anteroposterior excision of hemivertebrae in the lumbosacral spine.

Six patients with lumbosacral hemivertebrae were treated by one-stage anterior and posterior excision of the hemivertebrae. Long-term follow-up is reported. Overall, correction of the lumbosacral curve was 46%, including one case of pseudarthrosis and subsequent loss of correction. More importantly, truncal imbalance was restored unless other congenital thoracic anomalies were present. New methods of calculating rib cage shift on the pelvis as well as vertebral column displacement from the sagittal plane are presented.

Child↗
PubMed1993

Interpretation of energy adjustment models for nutritional epidemiology.

The authors discuss the interpretation of three alternative energy adjustment models for nutritional epidemiology. It is shown that four different effects are addressed by these models: 1) adding nutrient N, 2) substituting nutrient N for "other" nutrients, 3) adding "other" nutrients, and 4) adding both N and "other" nutrients in a specific ratio. Each of these effects may be estimated from any of the three models. The relative standard errors for the four estimated effects are also provided.

Diet↗
PubMed1993

The design of observer agreement studies with binary assessments.

We discuss the design of observer agreement studies with binary assessments, with particular emphasis on the need for adequate sample size and the use of replicate observations. First, we present a method and tables for determining the sample size required for ensuring a desired precision for the estimate of the probability of disagreement between two observers. Second, for studies including replicate observations, we present a statistical model that allows estimation of the magnitude of within- and between-observer variation. We then derive sample sizes guaranteeing a specified precision for these estimates, present tables of these sample sizes and give examples of their use.

Confidence Intervals↗
PubMed1993

Intraepithelial and postinvasive neoplasia as a stochastic continuum of clonal evolution, and its relationship to mechanisms of chemopreventive drug action.

The progression of intraepithelial and postinvasive neoplasia depends on the occurrence of clonal evolution, defined as the continuous development of mutations and selective clonal expansions in the neoplastic cell population. The two continuously repeating events of clonal evolution, mutation and clonal expansion, occur at unpredictable times and locations. Therefore the neoplastic process is best characterized as a stochastic, i.e., probabilistic, continuum. The rate of intraepithelial neoplastic progression is continuously driven by the dosage level of exposure to mutagens and mitogens. For example, in chronic smokers the length of time before development of lung cancer depends on the number of cigarettes smoked per day. A commonly held misconception is that human carcinogenesis develops after an initial short period of mutation followed by a long period of stimulated proliferation (the multistage model). This incorrect idea derives from the sequential nature of the consecutive two- or three-step operational protocols imposed on experimental animal models by the experimenter. In reality, human carcinogenesis develops as the result of simultaneous and continuous exposure to mutagens and mitogens over the entire period of tumor development. A recent example is the finding that the intraepithelial neoplasia of colorectal adenomas continuously progresses through serial waves of mutation and clonal expansion. The rational design of chemopreventive agents should be based on blocking the two parameters which continuously drive neoplasia: mutagenesis and mitogenesis. In addition to blocking exposure, chemopreventive agents may act at many points during activation and DNA adduction of mutagens, or during stimulation of the proliferation signal pathway by mitogens. Based on the chemopreventive strategy of blocking mutagenesis and mitogenesis, chemopreventive agents are classed as either antimutagenic or antimitogenic. A third class, the antioxidants, are both antimutagenic and antimitogenic, and operate by the common mechanism of breaking free radical chain reactions initiated by reactive oxygen species. In the program of the Chemoprevention Investigational Studies Branch, Division of Cancer Prevention and Control, National Cancer Institute, preclinical development of antimutagens, antimitogens, and antioxidants is well under way, and some of these agents are highlighted here.

Antioxidants↗
PubMed1993

Applying Bayesian ideas in drug development and clinical trials.

The Bayesian paradigm emphasizes that studies are not performed in isolation, and that external evidence can be used formally in the design, monitoring and reporting of clinical trials. A variety of tools for assessing the current evidence for treatment efficacy are presented, making use of graphical display to provide insight into ethical and efficiency issues in starting and stopping trials--these are illustrated with a trial in osteosarcoma that is currently taking place. Finally we recommend that an additional 'interpretation' section is placed in clinical reports to provide a bridge between 'results' and 'discussion'--it is this section that would contain the Bayesian perspective.

Bayes Theorem↗
PubMed1993

Pathology review in cancer research.

Pathology observer agreement studies are clearly important in the development of new pathology assessments and in the quality control of those assessments in common use. Setting up such studies, and reporting and interpreting their results requires careful thought and statistical expertise. Investigators are advised to seek collaboration with a statistician before embarking on these studies. Pathology reference panel reviews in multicentre studies are useful for checking eligibility when there is a high level of disagreement on the eligibility criterion between local pathologists and the reference panel members, but good agreement between members of the panel. However, such situations are uncommon.

Animals↗