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PubMedDate not supplied

Methodologic issues in hospital epidemiology. IV. Risk ratios, confounding, effect modification, and the analysis of multiple variables.

Most information in hospital epidemiology comes from observational studies of hospitalized patients, not from planned experiments. Data from observational studies have frequently been used to investigate the effect of exposure to a single factor as a cause or determinant of a discrete outcome, such as infection or death. In such observational studies, the characteristics of study patients may vary widely even within a single hospital. In these investigations, extraneous variables such as differing severity of underlying illness, acting in concert with the exposure variable being studied, may distort the apparent effect of the exposure on the outcome through confounding or may modify the effect of the exposure on the outcome without distorting the relation between them. The data from six published studies are reanalyzed through the use of stratification by severity of underlying illness in order to demonstrate the impact of confounding and effect modification by a third, extraneous variable. Simple methods for dealing with confounding and effect modification in data from hospital epidemiology are presented.

Analysis of Variance↗
PubMed2004

Age effects of coronary artery bypass graft on cognitive status change among elderly male twins.

BACKGROUND: Research regarding long-term cognitive outcome following coronary artery bypass graft (CABG) is inconsistent, which may be due in part to differential genetic and environmental influences within most study samples. METHODS: The authors examined the effect of CABG on cognitive status change scores in members of the National Academy of Sciences-National Research Council Twins Registry of World War II veterans. Subjects were administered the modified Telephone Interview for Cognitive Status (TICS-m) at approximately 3-year intervals between 1990 and 2002 as part of an epidemiologic study of dementia. RESULTS: Based on co-twin control analyses using a repeated-measures analysis of variance matching twins discordant for CABG within the pair (n = 464 individuals) across three age categories (63 to 70, 71 to 73, 74 to 83), the authors found at follow-up that men who had CABG between ages 63 and 70 showed an increase in TICS-m scores and performed better than their co-twin who did not have the procedure. No significant differences were found within twin pairs for the older two age groups following CABG surgery. This age effect was replicated when comparing individuals positive for CABG surgery with nonfamilial, age- and education-matched controls who were negative for CABG. CONCLUSIONS: In this study of twin pairs who share many genetic and environmental risks for cerebrovascular problems, the results suggest that timing of the CABG procedure may be important to predicting positive cognitive outcomes.

Age Factors↗
PubMed2006

Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis.

Epidemiological and biochemical data suggest a link between the cholesterol metabolism, the amyloid precursor protein (APP) processing and the increased cerebral beta-amyloid (Abeta) deposition in Alzheimer's disease (AD). The individual and combined effects of a high-cholesterol (HC) diet and the overexpression of the human apoB-100 gene were therefore examined on the cerebral expression and processing of APP in homozygous apoB-100 transgenic mice [Tg (apoB(+/+))], a validated model of atherosclerosis. When fed with 2% cholesterol for 17 weeks, only the wild-type mice exhibited significantly increased APP695 (123%) and APP770 (138%) mRNA levels in the cortex. The HC diet-induced hypercholesterolemia significantly increased the APP isoform levels in the membrane-bound fraction, not only in the wild-type animals (114%), but also in the Tg apoB(+/+) group (171%). The overexpression of human apoB-100 gene by the liver alone reduced the brain APP isoform levels in the membrane-bound fraction (78%), whereas the levels were increased by the combined effect of HC and the overexpression of the human apoB-100 gene (134%). The protein kinase C and beta-secretase protein levels were not altered by the individual or combined effects of these two factors. Our data indicate that the two atherogenic factors, the HC diet and the overexpression of the human apoB-100 gene by the liver, could exert different effects on the processing and expression of APP in the mice brain.

Amyloid Precursor Protein Secretases↗
PubMed1992

Theoretical and methodological aspects of BCG vaccine from the discovery of Calmette and Guérin to molecular biology. A review.

The BCG vaccine has been used to prevent tuberculosis since 1921 and applied for immunostimulation in neoplasia since the 1960s. Both the preventive and immunostimulation effects have been evaluated and communicated with contradictory, positive and negative conclusions. For an objective evaluation and interpretation of the protective efficacy, effectiveness and efficiency of the BCG vaccination it must be considered that: (1) several BCG substrains have been developed in manufacturing laboratories that differ in the residual virulence which determines immunogenicity and reactogenicity; (2) various liquid and freeze-dried BCG vaccine production methods are used, resulting in different BCG viable units per dose; (3) quantitative bioassay methods are not yet being used for statistical quality control of the vaccine; (4) BCG products are applied in various demographical, epidemiological and socioeconomic conditions with different vaccination policies; (5) inadequate biostatistical models are often used to analyse efficacy, effectiveness and adverse reactions. The same conditions influence the precise evaluation of BCG immunostimulation in neoplasia. Recombinant DNA technology will modify production methods, and explain at the molecular level the mechanism of the protective effects BCG confers in tuberculosis and immunostimulation in neoplasia. High level laboratory techniques and biostatistical methods, based on probability logic and inductive inference, ensure appropriate experimental designs and the exact analysis of laboratory data and the results of vaccination policies. They will lead to the evaluation of the protective effect of BCG in order to reduce the BCG contradictions.

BCG Vaccine↗
PubMed1995

Survival time and season-of-treatment initiation in children with acute lymphoblastic leukemia.

We examined survival in childhood acute lymphoblastic leukemia (ALL) as a function of season-of-treatment initiation. Survival for 1797 children aged 15 and under from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, diagnosed and treated from 1973-1986 was obtained. There was no significant seasonal pattern for survival by season-of-treatment initiation. Neither age, gender, nor treatment type served as effect modifiers or confounders in this relationship. Female gender, age between one and ten years, and certain broad categories of treatment type were significant predictors of survival in separate univariate analyses, however. The nonsignificance of the results do not support the concept that season-of-treatment initiation is a prognostic factor in survival from ALL in children.

Adolescent↗
PubMed1989

[Perspectives in the development of health care in Czechoslovakia].

The finding that the health status of the population is shaped in particular by social and cultural conditions is accepted not only by health workers but also by political and executive authorities of the State. For the further development health care of the people is of revolutionary importance. If society will find adequate political will to take the appropriate measures, we may expect radical changes in all spheres of national economy, social life, science and culture. The basic demand is that health workers must acquire new sociomedical thinking which supplements and at the same time replaces the out-dated biomedical pattern. Structural changes will pertain in particular to mechanisms and organizational measures which will ensure the implementation of the health policy beyond the framework of the health services. In the system of health services we may anticipate that the centre of gravity in health care will shift from the traditional hospital to out-patient facilities with emphasis on the newly conceived function of primary health care. Training of health workers will have to be modified to the effect that graduates will be better prepared to meet actual needs of health care focused on prevention, economy, effectiveness and quality. It will be necessary to create favourable conditions for the development of socio-ecological, epidemiological and operational research. The democratization of health care will call for greater interest and initiative on the part of the public as regards collective and individual health. Our partial health projects should be re-arranged into a single comprehensive nation-wide programme which will include all spheres of health care in the sense of the WHO programme in its modification for Europe.

Czechoslovakia↗
PubMed1998

The case-time-control design: further assumptions and conditions.

The case-time-control design is a strategy that was developed to tackle the problem of confounding by indication in the nonexperimental assessment of intended or known effects of drugs. By using subjects as their own controls, the case-time-control design, under an explicitly defined model, eliminates the biasing effect of unmeasured confounding factors in the situation where exposure varies over time. The correct application of this design is based on a specific model that contains inherent assumptions and imposes certain conditions for the approach to be valid. In a recent article, Greenland questioned the validity of the case-time-control design by presenting several "counterexamples." In this paper, we review the assumptions inherent to the validity of the case-time-control model. We show that the presumed counterexamples are not what they are claimed to be, simply because they do not conform to the logistic model explicitly underlying the case-time-control approach. These examples are shown to arise from an alternative model that includes a confounder by period interaction, a term expressly avoided in the case-time-control model. When the data from these examples are modified to satisfy the correct model, the resulting case-time-control estimates of the treatment odds ratio are exactly 2, the true treatment effect. We clarify the necessity of this assumption in the context of matching in epidemiology. We also discuss briefly the assumptions of conditional independence and carryover effects.

Bias↗
PubMed1999

Causal diagrams for epidemiologic research.

Causal diagrams have a long history of informal use and, more recently, have undergone formal development for applications in expert systems and robotics. We provide an introduction to these developments and their use in epidemiologic research. Causal diagrams can provide a starting point for identifying variables that must be measured and controlled to obtain unconfounded effect estimates. They also provide a method for critical evaluation of traditional epidemiologic criteria for confounding. In particular, they reveal certain heretofore unnoticed shortcomings of those criteria when used in considering multiple potential confounders. We show how to modify the traditional criteria to correct those shortcomings.

Epidemiologic Methods↗
PubMed2000

Estimating the mortality impacts of particulate matter: what can be learned from between-study variability?

Epidemiologic studies of the link between particulate matter (PM) concentrations and mortality rates have yielded a range of estimates, leading to disagreement about the magnitude of the relationship and the strength of the causal connection. Previous meta-analyses of this literature have provided pooled effect estimates, but have not addressed between-study variability that may be associated with analytical models, pollution patterns, and exposed populations. To determine whether study-specific factors can explain some of the variability in the time-series studies on mortality from particulate matter [less than/equal to] 10 microm in aerodynamic diameter (PM(10)), we applied an empirical Bayes meta-analysis. We estimate that mortality rates increase on average by 0.7% per 10 microg/m(3) increase in PM(10) concentrations, with greater effects at sites with higher ratios of particulate matter [less than/equal to] 2.5 microm in aerodynamic diameter (PM(2.5))/PM(10). This finding did not change with the inclusion of a number of potential confounders and effect modifiers, although there is some evidence that PM effects are influenced by climate, housing characteristics, demographics, and the presence of sulfur dioxide and ozone. Although further analysis would be needed to determine which factors causally influence the relationship between PM(10) and mortality, these findings can help guide future epidemiologic investigations and policy decisions.

Air Pollution↗
PubMed1992

The Malaria Vaccine Epidemiology and Evaluation Project of Papua New Guinea: rationale and baseline studies.

The range of possible malaria vaccines, against different species of Plasmodium and various stages in the life cycle of the parasite in both human host and mosquito vector, is reviewed. The importance, in a malaria-endemic area, of protection by a malaria vaccine against disease rather than infection is emphasized, and the ways by which disease prevention may be achieved are discussed. Mechanisms of production and presentation of vaccines are considered, including the importance of appropriate and more effective adjuvants. The variety of immune responses to malaria is set out and linked to both human and plasmodial genetic factors. Host genetics may also modify susceptibility to malaria through mechanisms which are not immunological. There is a need for entomological studies of the Anopheles vectors, especially but not only in preparation for transmission-blocking vaccines. This overall complexity justifies a multidimensional approach to epidemiology and field-site preparation. An iterative procedure is proposed for initial field evaluation, through adult male volunteers to community studies in immune adults and then to semi-immune school children, before evaluation in the principal target population of nonimmune young children. The outcome variables for epidemiological evaluation are specified. After this brief review of malaria vaccines, the baseline studies being undertaken by the Malaria Vaccine Epidemiology and Evaluation Project of the Papua New Guinea Institute of Medical Research in the Wosera area of East Sepik Province are discussed in some detail, and their rationale linked to the range and complexity of the malaria vaccines that have been reviewed. These studies are described under the headings of their principal components of epidemiology, parasitology, immunology, genetics and entomology.

Animals↗
PubMed2001

The cost-effectiveness of fluorodeoxyglucose 18-F positron emission tomography in the N0 neck.

BACKGROUND: Although surgery and radiation are effective treatments of regional lymphatics for classification N0 head and neck squamous cell carcinoma (HNSCC) patients, both have morbidities that could be avoided in approximately 70% of patients without lymph node disease with better diagnostic information. 18-F fluoro-2-deoxyglucose positron emission tomography (FDG-PET) has shown promise in detecting subclinical lymph node disease, but its cost and availability have limited its use. Here, we sought to determine whether the use of FDG-PET was cost-effective as part of a treatment strategy for classification N0 HNSCC patients. METHODS: The cost-effectiveness of proceeding from classification of N0 by computed tomography to a PET scan was estimated using standard methods of economic evaluation. Costs were for a large, Midwestern university medical center. Probabilities were computed from a review of the literature. Utilities were obtained by a time-tradeoff method, and life expectancy was estimated using the Surveillance, Epidemiology, and End Results database. Outcomes measures were cost per year of life saved and cost per quality-adjusted life-year. RESULTS: Modified radical neck dissection was associated with the lowest morbidity (utility [u] = 0.93), and radical neck dissection plus radiation was associated with the highest (u = 0.68). Life expectancy was estimated to be 5.9 and 11.5 years for patients with and without lymph node disease, respectively. The incremental cost-effectiveness ratio for the PET strategy was $8718 per year of life saved, or $2505 per quality-adjusted life-year. CONCLUSIONS: A diagnostic and treatment strategy that proceeds from classification of N0 to a PET scan is cost-effective. Prospective studies that evaluate this strategy are important to assure that these simulation results are realized in clinical practice.

Adult↗
PubMed2001

Radiation risk estimates in the beginning of the 21st century.

In the early years of the 21st century, results from a number of epidemiologic studies of populations with specific ionizing radiation exposures will become available. These include populations with accidental exposures in the former Soviet Union and elsewhere and populations with occupational exposures from routine operations of nuclear power plants. The strengths and limitations of these studies are reviewed together with the radiation protection questions they may answer. Many of these studies will provide specific information to complement the atomic-bomb survivor studies, particularly the effects of dose-rate and exposure protraction, modifiers of radiation risks (both environmental and host factors), and different types of radiation. These studies will therefore be important as a test of the adequacy of the current scientific bases for the radiation protection of workers and the general public. An example is thyroid cancer risk in young children following the Chernobyl accident, which has brought attention to a very high sensitivity of very young children that was difficult to assess on the basis of atomic-bomb data alone. Radiation protection will also benefit from formal comparisons and combined analyses of data from populations with different exposure patterns and exposures. Finally, future epidemiological studies will be most valuable if they are well focused, designed specifically to answer outstanding radiation protection questions. An integrated approach based on epidemiology and mechanistic studies, in which epidemiologic studies are designed to test specific mechanistic hypotheses and realistic mechanistic models are used for the analysis of epidemiological data, will probably be the most fruitful for radiation protection.

Accidents, Occupational↗
PubMed2001

Dietary trial in prostate cancer: Early experience and implications for clinical trial design.

Much epidemiologic and case-controlled evidence suggests that diet may be a modifier of prostate cancer risk. However, the role of dietary modification in men known to have prostate cancer is a matter of some debate. To elucidate the effect of diet and comprehensive lifestyle changes on cancer risk, we are conducting a randomized, prospective clinical trial on men with clinically localized prostate cancer who have selected "watchful waiting" as primary therapy. Since its inception in April 1997, 93 men have been randomized to control (n = 47) or dietary and lifestyle intervention (n = 46). Patients in the intervention group are asked to eat a low-fat, soy-supplemented vegan diet and take part in stress management, psychosocial group support, and exercise programs. After 1 year, adherence to all four interventions was greater than 80%, and no deaths or adverse outcomes have occurred. To date, we have collected prostate-specific antigen and endorectal magnetic resonance imaging and spectroscopy data on 63 patients (34 control and 29 intervention). This study demonstrates that a randomized, prospective dietary trial for men with localized prostate cancer is safe and feasible. The methodologies used provide insights into practical aspects of diet design and compliance assessment that may be useful templates for future dietary trials.

Diet, Vegetarian↗
PubMed2000

Calcium, vitamin D, sunshine exposure, dairy products and colon cancer risk (United States).

OBJECTIVE: Epidemiologic studies on calcium, vitamin D and colon cancer are inconsistent, whereas experimental studies more regularly show a protective effect. To evaluate potential sources of inconsistencies, data from a large case-control study were analyzed, stratifying on potential effect modifiers. METHODS: Data were collected by certified interviewers in Northern California, Utah and Minnesota. Analyses included 1993 incident colon cancer cases and 2410 population-based controls. Multivariate logistic regression models included age, sex, BMI, family history, physical activity, intake of energy, dietary fiber, aspirin and NSAIDs. RESULTS: Dietary calcium was inversely associated with colon cancer risk in men (OR highest vs lowest quintile = 0.6, 95% CI = 0.5-0.9) and women (OR = 0.6, 95% CI = 0.4-0.9). No statistically significant associations were observed for dietary vitamin D or sunshine exposure. Consumption of total low-fat dairy products was associated with a statistically significantly decreased risk in men and women (ORs highest vs lowest category of intake = 0.8 and 0.7 respectively). Calcium supplement use was inversely associated with risk in both sexes (ORs use vs non-use = 0.8). Vitamin D supplements were inversely associated with risk in men (OR = 0.5) and women (OR = 0.6) but confidence limits included 1.0. CONCLUSIONS: These data provide additional support of an inverse association between high levels of calcium intake and colon cancer risk.

Aged↗
PubMed2006

Powerful multilocus tests of genetic association in the presence of gene-gene and gene-environment interactions.

In modern genetic epidemiology studies, the association between the disease and a genomic region, such as a candidate gene, is often investigated using multiple SNPs. We propose a multilocus test of genetic association that can account for genetic effects that might be modified by variants in other genes or by environmental factors. We consider use of the venerable and parsimonious Tukey's 1-degree-of-freedom model of interaction, which is natural when individual SNPs within a gene are associated with disease through a common biological mechanism; in contrast, many standard regression models are designed as if each SNP has unique functional significance. On the basis of Tukey's model, we propose a novel but computationally simple generalized test of association that can simultaneously capture both the main effects of the variants within a genomic region and their interactions with the variants in another region or with an environmental exposure. We compared performance of our method with that of two standard tests of association, one ignoring gene-gene/gene-environment interactions and the other based on a saturated model of interactions. We demonstrate major power advantages of our method both in analysis of data from a case-control study of the association between colorectal adenoma and DNA variants in the NAT2 genomic region, which are well known to be related to a common biological phenotype, and under different models of gene-gene interactions with use of simulated data.

Acetylation↗
PubMed2002

Caffeinated clues and the promise of adenosine A(2A) antagonists in PD.

Large prospective epidemiologic studies have linked the consumption of coffee and other caffeinated beverages to a reduced risk of subsequently developing PD. Caffeine as well as more specific antagonists of the adenosine A(2A) receptor have also now been found to attenuate neurotoxicity in a mouse model of PD. The convergence of these epidemiologic and laboratory data supports the possibility that caffeine may reduce the risk of developing PD. However, a neuroprotective effect of caffeine in PD remains unproven; current evidence does not provide a rational basis for recommending caffeine consumption to modify the risk or progression of PD. In addition to possessing neuroprotective potential, caffeine and other A(2A) antagonists have long been known to acutely reverse motor deficits in a variety of PD models. This symptomatic antiparkinsonian benefit of blocking A(2A) receptors, coupled with their remarkably restricted expression in the basal ganglia, have made A(2A) antagonists attractive targets for drug development. Now, with the prospect of a neuroprotective bonus, the novel therapeutic potential of A(2A) antagonists appears all the more promising just as they are entering clinical trials for PD.

Age of Onset↗
PubMed2004

Is sleep apnea a risk factor for stroke? A critical analysis.

Stroke is the 3rd leading cause of death and a major cause of serious long-term disability in the United States. There are several well established and modifiable risk factors for the development of stroke. These include arterial hypertension, cardiac disease, dyslipidemia, diabetes mellitus and smoking among others. Sleep apnea has been found at alarmingly high rates (>50%) in patients with acute stroke as well as after neurologic recovery leading some to speculate that sleep apnea had been present prior to stroke. Sleep apnea is highly prevalent in the general population with a frequency of 2% to 4%. Sleep apnea is associated with high incidence of obesity, coronary artery disease and hypertension. There are several hematologic and hemodynamic changes in sleep apnea that can play significant roles in the pathogenesis of stroke. In this review, the author provides a critical analysis of the association between sleep apnea and stroke. There is convincing evidence to believe that sleep apnea is a modifiable risk factor for stroke, however, prospective studies are needed to establish the cause-and-effect relationship. Stroke and sleep-related breathing disorders are both common and are associated with significant morbidity and mortality. Several recent large epidemiological studies have shown a strong association between these 2 disorders independent of known risk factors for stroke. Understanding the link between obstructive sleep apnea and stroke may provide a novel preventative and therapeutic approach in the management of stroke.

Arrhythmias, Cardiac↗
PubMed2006

[The role of biological agents in the treatment of psoriatic arthritis, literature review].

INTRODUCTION: The recognition of the key pathogenetic role of TNF-alpha in psoriatic arthritis has made it possible to introduce new drugs in the treatment. TNF-alpha inhibitors available in Hungary (infliximab, etanercept, adalimumab) are potential therapies for patients who have not adequately responded to traditional disease-modifying antirheumatic drugs. OBJECTIVE: The aim of the study was to present the epidemiology and progression of psoriatic arthritis in Hungary based on national and international data, to assess the target population for biological therapy and to analyze their effectiveness, reviewing the available literature of randomized controlled trials. METHODS: The prevalence of psoriatic arthritis in Hungary was estimated using international data. Characteristics of psoriatic arthritis population were studied using the database of a rheumatology ward. A systematic literature search was performed to identify each relevant trial. A synthesis and comparison of the results from the 5 identified trials was performed and the average effect of biological agents was calculated. Both the fixed and the random effect model were used for the data synthesis; the results were probed with Mantel-Haenzel test. RESULTS: The prevalence of psoriatic arthritis is about 10.000-20.000 in Hungary. Average disease-duration was 10 years in the sample (n = 189), the most frequent was polyarticular form (51%). Regarding functional status the mean HAQ score was 1.46, with an average progression of 0.05 points/year. The trial data confirmed that biological agents are superior to placebo in improving symptoms (achieving ACR20); risk difference between biological treatments and placebo is 47% (RD = 0.47, 95% CI: 0.42-0.53). The biological treatment of 2 patients improves the status of 1 patient (NNT = 2.1 95% CI 1.9-2.4). There is no significant difference in efficacy between the three biological agents. CONCLUSIONS: TNF-alpha inhibitors are effective treatments of psoriatic arthritis and are safe under strict medical control. The principles of indications, contraindications, administration and control have been worked out by the Rheumatology and Physical Medicine Board.

Adalimumab↗