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Use of the confidence interval function.

Graphics displaying all confidence intervals around a point estimate have been referred to as P-value functions and consonance intervals. We recommend use of the term confidence interval function (CI function) rather than P-value function. The CI function is useful because it simultaneously depicts point estimation, variability, and the relation of these two factors to the null value. The usefulness of the CI function in demonstrating the concepts of effect modification and confounding, in meta-analysis, and in the comparison of various confidence interval procedures is evaluated. Software packages that produce CI functions are described.

Confidence Intervals↗

Identifiability and exchangeability for direct and indirect effects.

We consider the problem of separating the direct effects of an exposure from effects relayed through an intermediate variable (indirect effects). We show that adjustment for the intermediate variable, which is the most common method of estimating direct effects, can be biased. We also show that even in a randomized crossover trial of exposure, direct and indirect effects cannot be separated without special assumptions; in other words, direct and indirect effects are not separately identifiable when only exposure is randomized. If the exposure and intermediate never interact to cause disease and if intermediate effects can be controlled, that is, blocked by a suitable intervention, then a trial randomizing both exposure and the intervention can separate direct from indirect effects. Nonetheless, the estimation must be carried out using the G-computation algorithm. Conventional adjustment methods remain biased. When exposure and the intermediate interact to cause disease, direct and indirect effects will not be separable even in a trial in which both the exposure and the intervention blocking intermediate effects are randomly assigned. Nonetheless, in such a trial, one can still estimate the fraction of exposure-induced disease that could be prevented by control of the intermediate. Even in the absence of an intervention blocking the intermediate effect, the fraction of exposure-induced disease that could be prevented by control of the intermediate can be estimated with the G-computation algorithm if data are obtained on additional confounding variables.

Algorithms↗

Parents' and teachers' ratings of problem behaviours in children: genetic and contrast effects.

We obtained ratings on the Conners' scales from teachers (CTRS-28) and parents (CPRS-48) for 61 monozygotic and 64 dizygotic twin pairs, aged between 7 and 11 years. Model-fitting analyses were carried out to estimate the extent of genetic and environmental influences on problem behaviours, and to explore possible contrast effects in ratings by parents and teachers. Confirming previous findings with other measures, there was evidence of moderate to strong genetic effects on a range of problem behaviours. Parents' ratings on the Anxiety, Impulsive-Hyperactive and Learning Problem sub-scales showed significant evidence of contrast effects. There was no evidence of such rater bias or competitive sibling interaction effects in ratings by teachers, or in parents' ratings on the Conduct Problem and Psychosomatic sub-scales.

Analysis of Variance↗

Residential magnetic fields and childhood leukemia: a meta-analysis.

OBJECTIVES: This article uses meta-analysis methodology to examine the statistical consistency and importance of random variation among results of epidemiologic studies of residential magnetic field exposure and childhood leukemia. METHODS: A variety of meta-analytic statistical methods were applied to all available studies combined and on sub-groups of studies chosen by exposure characteristics. Sample sizes and fail-safe n's were calculated to determine the robustness of results and the potential role of publication bias. RESULTS: Most studies show elevated but not statistically significant odds ratios. Results for exposures assessed by wire codes, distance, and/or historically reconstructed fields are relatively consistent, homogeneous, and positive, while those for direct magnetic field measurements are consistent, homogeneous, and marginally protective. Several unpublished studies, or a single unpublished study with several hundred subjects, would be needed to nullify the observed data. CONCLUSIONS: The observed results identify a consistent risk that cannot be explained by random variation. The data supporting magnetic fields as the principal risk factor are suggestive but inconsistent. Additional studies using innovative designs that focus on highly exposed children offer the most hope of untangling this issue.

Bias↗

Prolonged breastfeeding and malnutrition: confounding and effect modification in a Brazilian cohort study.

We examined the association between prolonged breastfeeding and anthropometric status in a population-based cohort study of 5,914 liveborns from the city of Pelotas in Southern Brazil. When children from all socioeconomic groups were studied, there was no important association between current breastfeeding and anthropometric status at age 12 months. Children who were still breastfed at age 20 months--and, to a lesser extent, at 43 months--presented with poorer anthropometric status than their nonbreastfed counterparts. We did not find the same pattern in all socioeconomic groups, however. Children from low-income families who were breastfed tended to present better anthropometric status than those who were not, whereas the reverse was observed for children of middle- and high-income families. After controlling for confounding variables, the nutritional advantage of breastfeeding among low-income families was no longer clear, while the superiority of nonbreastfed infants amongst middle- and high-income children persisted. These findings indicate that some of the controversy regarding the nutritional effects of prolonged breastfeeding may have been caused by confounding and effect modification. Any decisions on whether or not breastfeeding should be encouraged after the first year of life should take into account the characteristics of the population as well as the anti-infective and birth-spacing properties of breastfeeding.

Anthropometry↗

Sources of variation in spirometric measurements. Identifying the signal and dealing with noise.

Variation in spirometric lung function measurements can be ascribed to technical and biological sources and is conveniently classified as within- or between-subject and within- or between-population. A necessary first step is to identify which sources of variation constitute "noise" and which "signal" in the various applications in occupational medicine. This chapter proposes strategies to enhance signal and deal with noise, and it delineates areas in which additional research to strengthen existing information would maximize the usefulness of spirometric measurements.

Artifacts↗

Measurement of nonspecific bronchial responsiveness in epidemiologic studies: methacholine challenge testing in the field.

Methacholine challenge testing is the most commonly used method for detecting and quantifying nonspecific bronchial hyperresponsiveness and has been used primarily in the clinical investigation of occupational asthma. This chapter reviews the rationale, methodology, and interpretation of this test which are relevant to conducting methacholine challenge testing outside the clinic ("in the field"). It also reviews the issues surrounding the methodology of methacholine challenge testing in general and, in particular, its use in epidemiologic studies.

Asthma↗

How to design an effective research study.

The previous paper in this series (March 13) examined three methodological issues: sample selection, treatment and/or intervention and observation and measurement. Here, aspects of research design and procedures will be considered. Research design is important in helping to ensure that the results can be correctly interpreted and that observed changes can be attributed to the planned intervention rather than to other intervening factors. The description of the procedure explains how the selected methods were combined and describes the practical details of how the study was carried out.

Confounding Factors, Epidemiologic↗

A potential pitfall in control of covariates in epidemiologic studies.

Control of covariates is essential in nonexperimental epidemiologic studies. Important covariates, such as smoking or alcohol consumption, often are crudely categorized in epidemiologic analyses. In this paper, I illustrate by both hypothetical and empirical examples that control of crudely categorized covariates can yield strongly misleading results. In particular, I show that, under certain conditions, control for crudely classified covariates can even be worse than not controlling for such covariates at all. I conclude that covariate specification is an issue that requires much more care than it commonly receives in epidemiologic analyses.

Case-Control Studies↗

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↗