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PubMedDate not supplied

Dietary fiber, phytoestrogens, and breast cancer.

The hypothesis that diet exerts an influence on breast cancer risk has emphasized a role for fat, and current dietary intervention trials to reduce that risk are designed specifically to decrease fat consumption to 15-20% of total calories. There is, however, mounting evidence that dietary fiber has a protective effect and may favorably modify the enhanced breast cancer risk associated with the typical American high-fat low-fiber diet. These data come largely from epidemiological studies, but a few experiments with animal models have also been performed. The mechanisms concerned probably involve estrogen metabolism and bioactivity, both by effects on the enterohepatic circulation of estrogens and the actions of fiber-associated phytoestrogens. More studies are essential to determine the specific types of dietary fiber that are likely to affect the risk of breast cancer, and an appropriate modification in fiber intake should then be added to dietary fat reduction in any future clinical intervention trials designed to demonstrate a favorable influence on breast cancer incidence.

Animals↗

PubMed1998

Clinical trial designs for demonstrating disease-course-altering effects in dementia.

Advances in our understanding of the pathogenesis of Alzheimer disease (AD) and vascular dementia (VaD) now permit responsible discussion of therapies that may go beyond relief of cognitive and behavioral symptoms and actually slow progression of disease. The mechanisms of neuronal death and the pathologic role of glia are being elucidated, and epidemiologic studies have suggested potential protective value for anti-inflammatory drugs, estrogen, and free-radical scavengers. However, demonstrating disease-modifying drug effects for progressive conditions such as dementia can be a daunting task, fraught with clinical, statistical, and ethical dilemmas. To evaluate trial designs for demonstrating such effects, the International Working Group on Harmonization of Dementia Drug Guidelines (IWG) conducted a symposium at the Sixth International Congress on Alzheimer's Disease and Related Disorders, held July 1998 in Amsterdam. The presentations at the IWG symposium covered the two basic designs currently being used in clinical trials, survival analysis and staggered-start/withdrawal, in addition to clinical data generated from the National Institute on Aging Alzheimer's Disease Cooperative Study vitamin E/selegiline trial in patients with AD and the phase III clinical studies of propentofylline in patients with AD and VaD. It is hoped that this article will open a dialogue among investigators and regulatory authorities regarding appropriate trial designs to support a regulatory claim for disease-modifying effects.

Aged↗

PubMed1979

Interaction of drugs, hormones, and nutrition in the causes of cancer.

Hormones may act as promoters in the carcinogenic process, and occasionally their metabolites may act as antihormones or have new physiologic effects. Drugs can interact with the endocrine system in many ways. They can promote secretion of a hormone, alter its rate of removal from plasma, change plasma protein-binding characteristics, or modify routes of metabolism. Estrogens have a preparative effect on the uterine endometrium. There are biologic, clinical and epidemiologic reasons for believing that estrogen administration to postmenopausal women increases the risk for endometrial cancer. Although there are similar biologic reasons to associate prolonged estrogenic stimulation with breast cancerr, evidence for such an association is weak. Oral contraceptive use has been associated with a variety of hepatocellular tumors. Although estrogens, per se, can effect several hepatic functions, it seems likely that the 17 alpha-alkyl and 17 alpha-ethinyl functions of the progestins and estrogens are involved in this process. The role of estrogen use during pregnancy in the causation of vaginal cancer in female offspring and the role of androgens in prostate cancer have been discussed.

Anovulation↗

PubMed2003

Directory of clinical databases: improving and promoting their use.

BACKGROUND: The controversy surrounding the actual and potential use of clinical databases partly reflects the huge variation in their content and quality. In addition, use of existing clinical databases is severely limited by a lack of knowledge of their availability. OBJECTIVES: To develop and test a standardised method for assessing the quality (completeness and accuracy) of clinical databases and to establish a web based directory of databases in the UK. METHODS: An expert group was set up (1). to establish the criteria for inclusion of databases; (2). to develop a quality assessment instrument with high content validity, based on epidemiological theory; (3). to test empirically, modify, and retest the acceptability to database custodians, face validity and floor/ceiling effects; and (4). to design a website. RESULTS: Criteria for inclusion of databases were the provision of individual level data; inclusion in the database defined by a common circumstance (e.g. condition, treatment), an administrative arrangement, or an adverse outcome; and inclusion of data from more than one provider. A quality assessment instrument consisting of 10 items (four on coverage, six on reliability and validity) was developed and shown to have good face and content validity, no floor/ceiling effects, and to be acceptable to database custodians. A website (www.docdat.org) was developed. Indications over the first 18 months (number of visitors to the site) are that it is increasingly popular. By November 2002 there were around 3500 hits a month. CONCLUSIONS: A website now exists where visitors can identify clinical databases in the UK that may be suitable to meet their aims. It is planned both to develop a local version for use within a hospital and to encourage similar national systems in other countries.

Databases, Factual↗

PubMed2000

[Categorizing variables in the statistical analysis of data: consequences for interpreting the results].

Frequently during the process of data analysis in epidemiological studies, the scale of one or more continuous variables is changed. The objective of this paper was to assess the consequences of categorizing variables during data analysis. We studied three situations with different scenarios for statistical analysis with regression models. The results show that dichotomizing continuous variables can substantially modify the relationships between dependent and independent variables. Thus, for example, in epidemiological studies trying to evaluate the effect of an exposure on a response, the magnitude and/or the direction of this effect can be biased by dichotomizing a variable. We therefore recommend avoiding, as much as possible, the categorization of variables when doing analyses.

Analysis of Variance↗

PubMed2003

'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?

Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.

Animals↗

PubMed1993

Measurement issues in environmental epidemiology.

This paper deals with the area of environmental epidemiology involving measurement of exposure and dose, health outcomes, and important confounding and modifying variables (including genotype and psychosocial factors). Using examples, we illustrate strategies for increasing the accuracy of exposure and dose measurement that include dosimetry algorithms, pharmacokinetic models, biologic markers, and use of multiple measures. Some limitations of these methods are described and suggestions are made about where formal evaluation might be helpful. We go on to discuss methods for assessing the inaccuracies in exposure or dose measurements, including sensitivity analysis and validation studies. In relation to measurement of health outcomes, we discuss some definitional issues and cover, among other topics, biologic effect markers and other early indicators of disease. Because measurement error in covariates is also important, we consider the problems in measurement of common confounders and effect modifiers. Finally, we cite some general methodologic research needs.

Biomarkers↗

PubMed1990

High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein.

Oxidatively modified low-density lipoprotein (LDL), generated as a result of incubation of LDL with specific cells (e.g., endothelial cells, EC) or redox metals like copper, has been suggested to be an atherogenic form of LDL. Epidemiological evidence suggests that higher concentrations of plasma high-density lipoprotein (HDL) are protective against the disease. The effect of HDL on the generation of the oxidatively modified LDL is described in the current study. Incubation of HDL with endothelial cells, or with copper, produced much lower amounts of thiobarbituric acid-reactive products (TBARS) as compared to incubations that contained LDL at equal protein concentrations. Such incubations also did not result in an enhanced degradation of the incubated HDL by macrophages in contrast to similarly incubated LDL. On the other hand, inclusion of HDL in the incubations that contained labeled LDL had a profound inhibitory effect on the subsequent degradation of the incubated LDL by the macrophages while having no effect on the generation of TBARS or the formation of conjugated dienes. This inhibition was not due to the modification of HDL as suggested by the following findings. (A) There was no enhanced macrophage degradation of the HDL incubated with EC or copper alone, together with LDL, despite an increased generation of TBARS. (B) HDL with the lysine groups blocked (acetyl HDL, malondialdehyde (MDA) HDL) was still able to prevent the modification of LDL and (C) acetyl HDL and MDA-HDL competed poorly for the degradation of oxidatively modified LDL. It is suggested that HDL may play a protective role in atherogenesis by preventing the generation of an oxidatively modified LDL. The mechanism of action of HDL may involve exchange of lipid peroxidation products between the lipoproteins.

Animals↗

PubMed1991

Hypotheses to explain the association between vigorous physical activity and amyotrophic lateral sclerosis.

Many epidemiologic studies indicate a relation between vigorous physical activity and amyotrophic lateral sclerosis. Physical activity itself is unlikely to cause amyotrophic lateral sclerosis, but could it modify the effects of other etiologic factors such as neurotoxins? Vigorous physical activity could potentiate the effect of a toxin to motor neurons by any of several mechanisms, especially if the toxin's effects were mediated through excitation. Exercise could alter the extent of exposure or could influence the distribution, metabolism or potency of an excitotoxin. Future epidemiologic studies of amyotrophic lateral sclerosis should include sufficient detail about vigorous physical exercise to explore this relationship further.

Amyotrophic Lateral Sclerosis↗

PubMed2003

Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk.

BACKGROUND: Polymorphisms in the fibrinogen and factor XIII genes are associated with atherothrombotic risk, but clinical studies have produced inconsistent results and laboratory studies have not explained these findings. We aimed to investigate interactions between polymorphisms in the factor XIII and fibrinogen genes, fibrinogen concentrations, and other cardiovascular risk factors in relation to fibrin structure and function. METHODS: We used permeation analysis and electron microscopy to investigate interactions between fibrin structure, factor XIII Val34Leu, fibrinogen Aalpha Thr312Ala, fibrinogen Bbeta Arg448Lys, and fibrinogen concentrations in plasma and purified systems. FINDINGS: Increased fibrinogen concentrations were associated with decreases in permeability, with tighter clot structures in the presence of factor XIII 34Val alleles compared with those in the presence of 34Leu alleles. Findings were confirmed by scanning electron microscopy of fibrin. Similar changes in permeability were noted for Aalpha fibrinogen 312Ala compared with that for 312Thr. INTERPRETATION: Our results show interactions between coding polymorphisms in fibrinogen and factor XIII and fibrinogen concentrations that modify fibrin and explain the apparent paradox between epidemiological studies of factor XIII 34Leu and reported in-vitro effects on fibrin structure and function. We suggest a potential complexity of gene-gene and gene-environment interactions in determining cardiovascular risk.

Aged↗

PubMedDate not supplied

Recent dietary guidelines to prevent and treat cardiovascular disease, diabetes, and obesity.

Nutrition guidelines are emphasizing dietary patterns as primary and secondary prevention trials provide increasing evidence of the importance of lifestyle changes to prevent/control cardiovascular disease (CVD) risk factors such as diabetes and hypertension. Despite the increasing evidence that weight loss and modified dietary patterns are effective, there is considerable debate about the level of carbohydrate that will be most beneficial. Epidemiologic studies indicate that certain ethnic and racial minority groups have increased CVD risk with higher rates of obesity, hypertension, diabetes, and stroke. Immigrant and Native American populations have had a dramatic rise in obesity, diabetes, and ultimately CVD with acculturation, accompanied by a higher fat intake and decreased physical activity. Culturally tailored intervention approaches are being used to reduce risk. The lack of third-party payment still limits the availability of nutrition services. However, medical nutrition therapy is covered by Medicare for diabetes and pending legislation will extend coverage to CVD. Medical education researchers have developed tools such as the WAVE (Weight, Activity, Variety and Excess) pocket guide as a quick method to facilitate addressing referral for medical nutrition therapy that can be readily incorporated into practice settings.

Cardiovascular Diseases↗

PubMed1986

A rapid challenge protocol for determination of non-specific bronchial responsiveness.

A rapid method for determination of non-specific bronchial hyperreactivity was developed. Resistance to breathing was determined by a modified expiratory airway interrupter technique and combined with a dosimeter-controlled nebulizer which made continuous determination of response possible during challenge. The patients inhaled histamine chloride 8 mg/ml at every eighth breath until resistance to breathing (Rt) was increased by 60%. The number of inhalations (NI) or the provocative concentration (PC60-Rt) of histamine increasing Rt by 60% were determined in 68 patients. The new method correlated well to a non-cumulative standard protocol and could be terminated either within 10 min or within 20 inhalations. The results of this new challenge procedure enables us to predict the responsiveness to inhaled histamine precisely enough to separate patients into hyperreactive or normal reactive patients. Furthermore, the repeatability of the new method is comparable or superior to that of standard methods. The 95% confidence interval for the difference between replicates was the observed value +/- 2.4 NI. Thus this new method will be suited for studies of drug modifying effect on bronchial hyperreactivity since individual dose titration is easily performed, and the method could be valuable in epidemiological and occupational surveys as well.

Adolescent↗

PubMed1979

Epidemiological opportunities in alcohol-related cancer.

Alcohol combined with tobacco smoking is an established risk factor for cancers of the oropharynx, esophagus, and larynx. It should be possible to clarify further the role of alcohol itself, the modifying effects of tobacco, dose-response relationships, and nutritional cofactors. Studies are also needed to delineate the steps by which alcohol consumption leads to liver cancer and to resolve the suggestion that certain beverages may predispose to other cancers including those of the pancreas and rectum. Epidemiological investigations should be combined with experimental work to identify hazardous fractions in alcoholic beverages and to delineate the mechanisms by which alcohol promotes carcinogenesis. Epidemiologists and biometricians may also contribute toward the development of programs aimed at primary prevention and early detection of cancers related to alcohol and tobacco. Incorporation of research questions into data collection systems deserves serious questions into data collection systems deserves serious consideration as a means of obtaining additional valuable information for etiological studies.

Alcoholism↗

PubMed1989

Ecological bias, confounding, and effect modification.

Ecological bias is sometimes attributed to confounding by the group variable (ie the variable used to define the ecological groups), or to risk factors associated with the group variable. We show that the group variable need not be a confounder (in the strict epidemiological sense) for ecological bias to occur: effect modification can lead to profound ecological bias, whether or not the group variable or the effect modifier are independent risk factors. Furthermore, an extraneous risk factor need not be associated with the study variable at the individual level in order to produce ecological bias. Thus the conditions for the production of ecological bias by a covariate are much broader than the conditions for the production of individual-level confounding by a covariate. We also show that standardization or ecological control of variables responsible for ecological bias are generally insufficient to remove such bias.

Data Interpretation, Statistical↗

PubMed1992

Biomarkers in occupational cancer epidemiology: considerations in study design.

Epidemiologic studies of occupational groups have been central to the identification of human carcinogens. The incorporation of a biochemical component into occupational studies of cancer can expand the possibilities for identifying human carcinogens and for understanding the disease process. Two epidemiologic studies of occupation and cancer which include evaluation of biomarkers are described. The association of acetylator phenotype with bladder cancer risk was studied in benzidine-exposed workers. The association of benzene-related leukopenia with leukemia is being studied in benzene-exposed workers. These investigations illustrate issues in the use of biomarkers in epidemiologic studies of cancer risk. Such studies require the identification and characterization of the population at risk. Disease susceptibility factors are amenable for inclusion in these studies and can be statistically modeled as exposure-effect modifiers. Biomarkers of exposure are mainly of importance in short-term longitudinal and cross-sectional studies of exposure and intermediate outcomes and for validation of other data sources. Several sources of error can affect the results of molecular epidemiologic studies. Aside from minimizing laboratory error, consideration must be given in the design and execution of these studies to potential problems in subject selection and field collection of biologic samples and other relevant data.

Benzene↗

PubMed1988

Measurement technique influences the response of transfer factor (TICO) to salbutamol in patients with airflow limitation.

Single-breath transfer factor obtained using a multibreath estimate of alveolar volume (TI) was measured before and after salbutamol in twenty patients with reversible airflow limitation. The effective breathholding time was calculated by four methods due respectively to Ogilvie and colleagues as modified by the American Thoracic Society (ATS), ATS Epidemiological Standardization Project (ESP), Jones and Meade in which allowance was made for the time of sample collection and a simplified method in which the allowance for sampling was in terms of volume, not time. Two patients could perform the test procedure only after salbutamol. Amongst the remainder the transfer factor calculated using a single-breath estimate of alveolar volume (TI') was on average 12% less than TI. Carbon monoxide transfer coefficient (KCO), TI and TI' were highest by the ESP method and lowest by the Ogilvie method. Inhalation of salbutamol (200 gamma) did not affect TI' by any method or TI and KCO by the Jones and Meade method but results by the other methods were reduced; in the case of the modified Ogilvie method the reduction was 3.9%. This error was due to overestimation of effective breathholding time by neglecting the reduction of 39% which occurred in the time of sample collection. The time of inspiration was unchanged whilst the time of deadspace washout was reduced by 16%. After bronchodilatation the absence of a change in TI' was due to the overestimation of effective breathholding time being offset by an increase in the proportion of alveolar volume measured by the single-breath procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Biological markers: their use in quantitative assessments.

Biological markers can be conceptualized in terms of categories of markers that form a continuum representing a sequence of events from exposure to disease. These categories include markers of internal dose, biologically effective dose, early response, and disease. Outside of this sequence are susceptibility factors that can act at any point along the way to modify the effects of external exposures on disease outcomes. Examples of the use of these different types of markers in epidemiologic research are provided. There are many factors that one must consider when selecting a biological marker for use in an epidemiologic study. These factors include: the objectives of the study, the availability and specificity of potential markers, the feasibility of measuring the markers in various biological media, the invasiveness of the techniques necessary to measure the markers, the amount of biological specimen needed for analysis, the time to appearance of the markers in the biological media, the persistence of the markers in biological media, the variability of marker levels within and between individuals, the stability of markers in storage, as well as the cost, sensitivity, specificity, and reliability of the assays used to measure the markers. Each of these characteristics is discussed. The usefulness of biological markers in an epidemiologic study depends on the objectives of the study and whether the properties of the markers fulfill the objectives of the study in a feasible and cost-effective manner.

Biomarkers↗

PubMed1994

Familial risk of breast cancer and abortion.

We found that the risk of breast cancer associated with a family history of breast cancer increased with the number of abortions (induced as well as spontaneous) in a study of 495 breast cancer cases and 785 controls aged 20 to 56 years. For the women who had undergone at least two abortions, the risk associated with a family history did not seem to depend on the type of abortion. This finding suggests that the effect of a family history on the risk of breast cancer is modified by event(s) resulting from abortions. Further epidemiological studies should be conducted to verify the existence of this interaction.

Abortion, Induced↗