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Definition, sources, magnitude, effect modifiers, and strategies of reduction of the healthy worker effect.

This article summarizes, compares, and contrasts the definition, sources, magnitude, effect modifiers, and strategies of reduction of the healthy worker effect (HWE), based on the opinion expressed in the papers of nine contributors who responded to the request of the Industrial Disease Standards Panel (IDSP), Ontario, Canada. It provides an insight into the complex issues relating to the HWE. In addition, the catalog of 15 strategies to reduce the HWE is deemed to be useful for investigators in occupational epidemiology.

Age Factors↗

Methodologic issues in hospital epidemiology. III. Investigating the modifying effects of time and severity of underlying illness on estimates of cost of nosocomial infection.

Published estimates of extra cost and prolongation of hospital stay attributed to nosocomial infection obtained from epidemiologic comparisons are almost twice as large as judgements in studies based on subjective impressions. It is possible that this disparity may result from confounding by time and severity of underlying illness. Whether the effects of time and secondary disease diagnoses modified the results of an epidemiologic comparison of infected patients and comparison subjects matched on primary diagnosis and operation have been investigated. Whereas the average prolongation of hospital stay in a prevalence series of patients with nosocomial infection was 13.3 days, the average prolongation for the corresponding incidence series of infections from the same study population was only 7.3 days, or about one-half as long. No substantive changes resulted from adjusting for duration of exposure to hospital prior to infection. Five selected secondary diagnoses had the potential for substantial confounding effects on epidemiologic comparisons but had little overall effect on the estimates in this study. The large size of our estimates in both prevalence and incidence series is not the result of residual confounding by the effects of time or secondary disease diagnoses. Results from prevalence and incidence series must be clearly distinguished because the same events will be perceived differently in the two types of series.

Adult↗

Divergent biases in ecologic and individual-level studies.

Several authors have shown that ecologic estimates can be biased by effect modification and misclassification in a different fashion from individual-level estimates. This paper reviews and discusses ecologic biases induced by model misspecification; confounding; non-additivity of exposure and covariate effects (effect modification); exposure misclassification; and non-comparable standardization. Ecologic estimates can be more sensitive to these sources of bias than individual-level estimates, primarily because ecologic estimates are based on extrapolations to an unobserved conditional (individual-level) distribution. Because of this sensitivity, one should not rely on a single regression model for an ecologic analysis. Valid ecologic estimates are most feasible when one can obtain accurate estimates of exposure and covariate means in regions with internal exposure homogeneity and mutual covariate comparability; thus, investigators should seek out such regions in the design and analysis of ecologic studies.

Bias↗

[Nocebo effect: the other side of placebo].

Administration of drugs is often followed by beneficial (placebo effects) and harmful (nocebo effects) effects that are not always related to their mechanism of action. Nocebo effects are rather unknown even when may be the source of many adverse reactions which could be erroneously attributed to drug therapy. Some mechanisms have been postulated which might be associated with the development of nocebo effects. Expectancy, learning and classical conditioning are probably important in the psychological domain. The neuropharmacological substrate is much less known yet an opioid peptide-cholecystokinin interaction has been suggested. At the clinical setting, a nocebo effect should be suspected in those patients who present common unspecific symptoms after drug administration and have a tendency to somatize. An early detection of these patients may contribute to the prevention of the nocebo effect.

Clinical Trials as Topic↗

Adjusting for screening history in epidemiologic studies of cancer: why, when, and how to do it.

In epidemiologic studies of cancer, differences between exposed and nonexposed persons with regard to a history of cancer screening during the time the malignancy (or an antecedent lesion) typically is present prior to diagnosis can be a source of confounding if one of the following conditions is present: (1) the screening modality identifies premalignant changes whose treatment has the potential to prevent the cancer from developing; or (2) the number of cases included in the study would have been smaller but for the presence of screening. These situations occur commonly, arguing that consideration be given to screening history in the design (with attention to distinguishing true screening tests from those administered to persons with signs or symptoms of cancer) and analysis of epidemiologic studies of those cancers for which screening modalities are in use in the study population.

Bias↗

A review of the effects of random measurement error on relative risk estimates in epidemiological studies.

Many articles in the recent epidemiological literature have discussed the effects of random error and misclassification on effect estimation, but many of these have been unclear and hard to follow. This paper reviews and interprets many of these and summarizes the use of the correlation coefficient in assessing the likely effect of measurement error on relative risk estimates for variables that are either continuous or ordered. A table of expected values of relative risks (RRs) calculated in different ways for different levels of random error is presented and the typically large expected attenuation in RR values is shown. The recommendation of taking repeated or multiple measurements whenever possible is endorsed.

Confounding Factors, Epidemiologic↗

The risk of epithelial ovarian cancer in short-term users of oral contraceptives.

Short-term use (less than 1 year) or oral contraceptives has been associated with increased to slightly decreased risks of epithelial ovarian cancer in several studies. To determine what might account for a statistically significant 40% reduction in risk associated with as little as 3 to 6 months of use, a finding previously reported from the Cancer and Steroid Hormone Study, and to consider the implications for mechanisms of pathogenesis, the authors compared numerous characteristics of short-term users of oral contraceptives (41 cases, 412 controls) with those of never users (242 cases, 1,517 controls). The reduced risk among short-term users was consistently restricted to women who stopped using oral contraceptives for medical reasons, which were essentially side effects; there was little evidence of a protective effect among women who stopped for nonmedical reasons. Factors such as age, parity, family history of ovarian cancer, estrogen dose, history of sterilization, and latency (interval from first use) could not account for the finding. These analyses suggest that short-term use of oral contraceptives has little to no effect per se on reducing the risk of epithelial ovarian cancer and that side effects resulting in cessation of oral contraceptive use shortly after it was begun may be indicative of factors that are protective against the disease.

Adult↗

Causal inference based on counterfactuals.

BACKGROUND: The counterfactual or potential outcome model has become increasingly standard for causal inference in epidemiological and medical studies. DISCUSSION: This paper provides an overview on the counterfactual and related approaches. A variety of conceptual as well as practical issues when estimating causal effects are reviewed. These include causal interactions, imperfect experiments, adjustment for confounding, time-varying exposures, competing risks and the probability of causation. It is argued that the counterfactual model of causal effects captures the main aspects of causality in health sciences and relates to many statistical procedures. SUMMARY: Counterfactuals are the basis of causal inference in medicine and epidemiology. Nevertheless, the estimation of counterfactual differences pose several difficulties, primarily in observational studies. These problems, however, reflect fundamental barriers only when learning from observations, and this does not invalidate the counterfactual concept.

Causality↗

The role of cigarette smoking in the association between periodontal disease and coronary heart disease.

BACKGROUND: Cigarette smoking is a significant risk factor for both coronary heart disease and periodontal disease. The goal of this study was to better understand the role of smoking in the relationship between periodontal disease and heart attack history. METHODS: The study population consisted of 5,285 participants in the Third National Health and Nutrition Examination Survey (NHANES) during 1988-1994 and who were age 40 years or older when examined. The data analysis employed logistic regression models and accounted for the complex sampling design used in NHANES. RESULTS: After adjustment for potential confounders, we only found significant associations between periodontal loss of attachment (LOA) and heart attack history for smokers, with odds ratios and 95% confidence interval (CI) of 2.64 (1.48 to 4.71), 3.84 (1.22 to 12.10) and 5.87 (1.91 to 18.00) for those with 2.0 to 2.99, 3.0 to 3.99, and 4 mm or more mean LOA, respectively. When the analysis was stratified by smoking status and tertile of age at heart attack, the statistically significant associations were limited to smokers who had a heart attack between the ages of 25 and 50 years, with odds ratios and 95% Cl associated with increasing mean LOA for this group of 3.29 (1.35 to 8.04), 7.32 (1.60 to 33.51), and 8.04 (1.91 to 18.00), respectively. CONCLUSIONS: These results suggest that cigarette smoking is a necessary cofactor in the relationship between periodontal disease and coronary heart disease, and the increase in risk appears to be age dependent. However, the key role played by smoking in the etiology of both periodontal and heart diseases makes it difficult to determine how much of the observed association resulted from periodontal disease.

Adult↗

Effects of gender of subjects and experimenter on susceptibility to motion sickness.

BACKGROUND: It has been reported that females are more susceptible to motion sickness than males, but these reports have failed to take into account the possible effects of the gender of the experimenter and the subjective nature of reports of symptoms of motion sickness. To deal with the first possible confound, we used male and female experimenters. To deal with the second issue, we recorded gastric myoelectric activity so as to be able to quantify gastric tachyarrhythmia, an objective measure that has been shown previously to correlate highly with severity of symptoms. METHOD: There were 34 male and 34 female participants were assigned to either a male or female experimenter. Symptoms of motion sickness were induced by placing participants in an optokinetic drum for an 8-min baseline period followed by a 16-min rotation period. Electrogastrograms (EGGs) were continuously recorded, and reports of symptoms were obtained from the participants every 3 min during rotation. RESULTS: Comparison of male and female subjects' symptom scores revealed that females had higher symptom scores than males; however, no significant main effects for gender of the subject or experimenter were found. However, on a post-session questionnaire, females reported experiencing significantly more GI symptoms than males. Gender comparisons of the change in gastric tachyarrhythmia power from baseline to rotation yielded no significant differences. CONCLUSIONS: Females report more overall symptoms of motion sickness and significantly more GI symptoms than males, but do not show greater increases in gastric tachyarrhythmia during exposure to a rotating drum.

Adolescent↗

A 'sufficient cause' model for dental caries.

BACKGROUND: It is generally believed that dental caries is an infectious disease. The occurrence of dental caries is affected by a variety of determinants. In order to estimate the precise extent of the relation between specific determinants and the outcome phenomenon (i.e. the occurrence of dental caries), a coherent disease model is required. This model should also permit multivariate analysis to control for confounders and interactions. Only with such a disease model will it be possible to investigate the relation between the occurrence of a determinant and dental caries, and to estimate the extent of this relation. The known causal models for the explanation of dental caries do not fully meet these requirements. METHOD: Rothman's 'sufficient cause' model has been used as a starting point for the development of a new coherent disease model, to explain the occurrence of dental caries and allow multivariate analysis. RESULTS: The sufficient cause for dental caries comprises three component causes: sufficient microorganisms with cariogenic potential, easily fermentable carbohydrates and teeth. Whether dental caries actually occurs also depends on the influence of independent risk factors that interact with the component causes in a protective, as well as in a risk-increasing manner. These independent risk factors are saliva, fluoride, oral hygiene and diet. CONCLUSIONS: The 'sufficient cause' model for dental caries is a biological model in which distinction between protective and risk-increasing factors has been made, and interaction between factors has been described. With this model, it will now be possible to assess the extent of the relationship between a determinant and dental caries (the outcome phenomenon) using multivariate techniques.

Confounding Factors, Epidemiologic↗

Characteristics of the healthy worker effect.

The healthy worker effect (HWE), which can mask mortality excesses resulting from occupational exposures, poses a methodological problem for those who study occupational cohorts. This problem is further complicated by the fact that the strength of the HWE may vary from one occupational cohort to another. Understanding the HWE is particularly important for investigators of nuclear worker cohorts, because screening associated with the security clearance process may amplify the HWE among certain subpopulations of nuclear workers. This review suggests that the HWE is modified by a number of factors, including gender, race, age at hire, occupational class, length of employment, monitored status, length of follow-up, and cause of death. In general, these factors operate similarly in nuclear and other occupational cohorts. Given that many of these factors may be highly correlated with exposure, or proxy measurements for exposure, it is important for investigators to understand how these factors relate independently with mortality. Continuing to document the HWE and its changes over time is essential to the proper interpretation of exposure effects in occupational cohorts in general, and in nuclear cohorts in particular.

Effect Modifier, Epidemiologic↗

Influence of confounding factors on designs for dose-effect relationship estimates.

Three types of designs can be used to estimate the drug dose-effect relationship during phase II clinical trials: parallel-dose designs (parallel); cross-over designs (X), and dose-escalation designs ([symbol: see text]). Despite the use of non-linear mixed effect models, the potential influence of confounding factors on [symbol: see text] designs has not been previously fully elucidated; we undertook simulations to investigate this for all three experimental designs. We found that: (i) monotonic spontaneous evolution of the effect (EV) did not affect the maximum effect estimation (Emax) and the dose giving 50 per cent of this (ED50); (ii) EV similar to a regression to the mean gave rise to biases for [symbol: see text] designs; (iii) the introduction of a pharmacodynamic carry-over generates important biases and imprecision for [symbol: see text] designs, even when the carry-over is adjusted for; (iv) the introduction of non-responders resulted in bias and imprecision for both Emax and ED50 in all three designs.

Antihypertensive Agents↗