Occupational exposure assessment in case-control studies: opportunities for improvement

Community based case-control studies are an efficient means to study disease aetiologies, and may be the only practical means to investigate rare diseases. However, exposure assessment remains problematic. We review the literature on the validity and reliability of common case-control exposure assessment methods: occupational histories, job-exposure matrices (JEMs), self reported exposures, and expert assessments. Given the variable quality of current exposure assessment techniques, we suggest methods to improve assessments, including the incorporation of hygiene measurements: using data from administrative exposure databases; using results of studies identifying determinants of exposure to develop questionnaires; and where reasonable given latency and biological half life considerations, directly measuring exposures of study subjects.     

Pooled exposure assessment for matched case-control studies

Exposure assessment using biologic specimens is important for epidemiology but may become impracticable if assays are expensive, specimen volumes are marginally adequate, or analyte levels fall below the limit of detection. Pooled exposure assessment can provide an effective remedy for these problems in unmatched case-control studies. We extend pooled exposure strategies to handle specimens collected in a matched case-control study. We show that if a logistic model applies to individuals, then a logistic model also applies to an analysis using pooled exposures. Consequently, the individual-level odds ratio can be estimated while conserving both cost and specimen. We discuss appropriate pooling strategies for a single exposure, with adjustment for multiple, possibly continuous, covariates (confounders) and assessment of effect modification by a categorical variable. We assess the performance of the approach via simulations and conclude that pooled strategies can markedly improve efficiency for matched as well as unmatched case-control studies.     

Determining exposure underreporting in pharmacoepidemiologic case-control studies: methods and example

Many pharmacoepidemiologic case-control studies have to rely on what their subjects relate about the drugs to which they have been exposed and the durations of exposure. There is often good reason to suppose that not all exposures are actually reported and to suspect reporting rates may differ between cases and controls. We introduce two procedures designed to determine the extent of underreporting of exposures. These procedures make use of data from the case-control study itself, as well as sales, demographic and market research data for a reference population to which study subjects belong. We apply these procedures to data from the International Primary Pulmonary Hypertension Study (IPPHS) linking anorexigens with PPH. We show that exposures to the anorectic agent dexfenfluramine beginning in or before 1989 were highly significantly underrepresented in the data for IPPHS controls, relative to exposures beginning after 1989 (P < 0.01); there is no corresponding evidence for relative underrepresentation of early exposure for IPPHS cases. However, data on control exposures from 1990 to 1992 are consistent with the hypothesis that these exposures were not underreported to the IPPHS. Subject to certain key modeling assumptions and the availability of some supplemental data, it is possible to investigate the extent of underreporting of exposure in a pharmacoepidemiologic case-control study and in particular to determine if study results are likely to have been affected by recall bias.     

Indoor radon exposure and lung cancer risk: a review of case-control studies

BACKGROUND: Radon is a radioactive gas that tends to accumulate in indoor environment. A causal relationship between lung cancer and radon exposure has been demonstrated in epidemiologic studies of miners. The objective of this paper is to present the results of case-control studies of lung cancer risk associated with indoor radon exposure. METHODS: Case-control studies published since 1990 are included in this review. This type of protocol is particularly well suited for studying the relationship between indoor radon exposure and lung cancer risk, taking into account possible confounding factors such as tobacco smoking. The characteristics and results of these studies are summarized. The limitations associated with each of these studies are also discussed. RESULTS: The results of available studies are relatively concordant and suggest a positive association between lung cancer risk and indoor radon exposure with an estimated excess relative risk of about 6 to 9% per 100Bq/m3 increase in the observed time-weighted average radon concentration. The order of magnitude of this estimation agrees with extrapolations from miners but some studies may suffer from inadequate statistical power. CONCLUSION: At present, efforts are underway to pool together the data from the existing studies of indoor radon. This pooling analysis with thousands of cases and controls will provide a more precise estimate of the lung cancer risk from indoor radon exposure and explore the effect of modifying factors, such as smoking.     

Occupational case-control studies: II. Recommendations for exposure assessment

Obtaining valid and reliable quantitative exposure estimates is a significant challenge in community-based case-control studies in part, because industrial hygiene monitoring data are usually not available and detailed information on the job and work environment is usually not systematically obtained or assessed. To improve the quality and credibility of disease risk information obtained from occupational case-control studies, we recommend that standardized exposure assessment methods be used to derive quantitative exposure estimates. We identify sources of variation inherent to the assessment process, including: the quality of the information reported on the job, industry, activities, and materials; the industrial hygienist's familiarity with the reported job/industry; the probability that the job/industry was exposed, which depends on plant preferences for particular substances, on process technology, and on customer specifications; and variability in workplace characteristics. To improve the reliability of estimating job-related exposures both within and between studies, we recommend that the epidemiologic analyses be conducted with and without data rated to be of poor quality; that contact be made with experts when the study industrial hygienist is unfamiliar with the manufacturing process in question; that existing data bases be used to estimate the probability of exposure; that a data base be developed that describes manufacturing processes; and that explicit criteria based on industrial hygiene principles be used to evaluate workplace characteristics. In addition, a procedure is described for deriving quantitative exposure estimates by using a reference scale of frequently monitored jobs with their associated mean exposure levels. Areas of research are identified to improve exposure assessment in community-based case-control studies.     

Assessment of skewed exposure in case-control studies with pooling

Pooling-based strategies that combine samples from multiple participants for laboratory assays have been proposed for epidemiologic investigations of biomarkers to address issues including cost, efficiency, detection, and when minimal sample volume is available. A modification of the standard logistic regression model has been previously described to allow use with pooled data; however, this model makes assumptions regarding exposure distribution and logit-linearity of risk (i.e., constant odds ratio) that can be violated in practice. We were motivated by a nested case-control study of miscarriage and inflammatory factors with highly skewed distributions to develop a more flexible model for analysis of pooled data. Using characteristics of the gamma distribution and the relation between models of binary outcome conditional on exposure and of exposure conditional on outcome, we use a modified logistic regression to accommodate nonlinearity because of unequal shape parameters in gamma distributed exposure for cases and controls. Using simulations, we compare our approach with existing methods for logistic regression for pooled data considering: (1) constant and dose-dependent effects; (2) gamma and log-normal distributed exposure; (3) effect size; and (4) the proportions of biospecimens pooled. We show that our approach allows estimation of odds ratios that vary with exposure level, yet has minimal loss of efficiency compared with existing approaches when exposure effects are dose-invariant. Our model performed similarly to a maximum likelihood estimation approach in terms of bias and efficiency, and provides an easily implemented approach for estimation with pooled biomarker data when effects may not be constant across exposure. Copyright ? 2012 John Wiley & Sons, Ltd.     

Full-likelihood approaches to misclassification of a binary exposure in matched case-control studies

We consider analysis of matched case-control studies where a binary exposure is potentially misclassified, and there may be a variety of matching ratios. The parameter of interest is the ratio of odds of case exposure to control exposure. By extending the conditional model for perfectly classified data via a random effects or Bayesian formulation, we obtain estimates and confidence intervals for the misclassified case which reduce back to standard analytic forms as the error probabilities reduce to zero. Several examples are given, highlighting different analytic phenomena. In a simulation study, using mixed matching ratios, the coverage of the intervals are found to be good, although point estimates are slightly biased on the log scale. Extensions of the basic model are given allowing for uncertainty in the knowledge of misclassification rates, and the inclusion of prior information about the parameter of interest.     

An estimating equation approach for the analysis of case-control studies with exposure measured at several levels

Liang gave an extension of the Mantel-Haenszel estimating procedure for a common odds ratio to logistic regression models. It is applicable to case-control studies with multiple exposure levels, which yield K 2 x J tables. This paper provides variance and covariance estimators, which are consistent in both sparse-data and large-strata, for Liang's estimating functions in the K 2 x J tables case, and proposes an approximate confidence interval method for the common odds ratios.     

Comparative exposure ratios: A non-parametric,multifactor technique for case-control studies

The odds ratio in a two-by-two table is widely used in case-control studies to measure association between disease and a binary risk factor. In this article we propose a more general measure of association, the comparative exposure ratio (CER), which is the ratio of the number of case-control pairs where the case has greater exposure divided by the number where the control has greater exposure. In simple cases, the CER is an odds ratio or a weighted combination of odds ratios. In more general cases a CER continues to measure association even when an odds ratio computation is not feasible. Moreover, CERs improve on odds ratios in several ways: they do not require binary risk factors, or a choice of the scale of measurement of continuous risk factors; they make it possible to investigate multiple risk factors simultaneously, without multivariate parametric assumptions; they also can be used to detect patterns that might indicate possible causal pathways. We illustrate how various choices of the definition of ‘greater exposure’ make the CER a powerful and flexible tool. We give expressions for confidence intervals for CERs, and verify in a pilot simulation that they are valid. Finally, we illustrate with a case-control study of cervical dysplasia how exploratory inference using CERs can be carried out. (This research was partially supported by grants from the National Cancer Institute, CA 41108 and CA 25702).     

The exposure odds ratio in nested case-control studies with competing risks

A nested case-control study, also known as an ambidirectional study, is a case-control study within a cohort study. Although distortion by competing risks is well-recognized in follow-up studies, the problem has not been as widely appreciated in nested case-control studies. This paper extends previous work concerning the bias associated with competing risks for nested case-control studies. Specifically, the distorting effect of competing risks is illustrated for three methods of control selection. Assuming the proportional hazards model, the authors derived formulas for the bias of the odds ratio when competing risks cannot be ignored. Examples illustrate the magnitude of bias that occurs when the exposure of interest is associated with competing causes of death or withdrawal.     

Effects of systematic exposure assessment errors in partially ecologic case-control studies

BACKGROUND: In ecologic studies, group-level rather than individual-level exposure data are used. When using group-level exposure data, established by sufficiently large samples of individual exposure assessments, the bias of the effect estimate due to sampling errors or random assessment errors at the individual-level is generally negligible. In contrast, systematic assessment errors may produce more pronounced errors in the group-level exposure measures, leading to bias in ecologic analyses. METHODS: We focus on effects of systematic exposure assessment errors in partially ecologic case-control studies. Individual-level information on disease status, group membership, and covariates is obtained from registries, whereas the exposure is a group-level measure obtained from an established exposure database. Effects on bias and coverage of 95% CI in various error situations are investigated under the linear risk model, using both simulated and empirical ecologic data on exposures that are binary at the individual level. RESULTS: Our simulations suggest that the bias produced by systematic exposure assessment errors under the linear risk model is generally approximately equal to the ratio of the slope bias and the intercept bias in ordinary linear regression with measurement errors in the independent variable. Consequently, bias in either direction can occur. Exposure assessment errors that systematically distort the group-level exposure measures have more pronounced effects on bias and coverage than errors producing random fluctuations of the group-level measures, which imply bias towards the null. CONCLUSIONS: The results indicate the need for careful consideration of potential effects of systematic distortions of the group-level exposure measures when constructing and applying group-level exposure databases, such as probabilistic job exposure matrices.     

Models for retrospective quantification of indoor radon exposure in case-control studies

In epidemiologic studies on lung cancer risk due to indoor radon the quantification of individual radon exposure over a long time period is one of the main issues. Therefore, radon measurements in one or more dwellings, which in total have been inhabited by the participants for a sufficient time-period, are necessary as well as consideration of changes of building characteristics and ventilation habits, which influence radon concentration. Given data on 1-y alpha-track measurements and personal information from 6,000 participants of case-control studies in West and East Germany, an improved method is developed to assess individual radon exposure histories. Times spent in different rooms of the dwelling, which are known from a personal questionnaire, are taken into account. The time spent outside the house (average fraction 45%) varies substantially among the participants. Therefore, assuming a substantially lower radon exposure outside the dwelling, the residence time constitutes an important aspect of total radon exposure. By means of an analysis of variance, important determinants of indoor radon are identified, namely constant conditions such as type of house (one family house or multiple dwelling), type of construction (half-timbered, massive construction, lightweight construction), year of construction, floor and type of basement, and changeable conditions such as heating system, window insulation, and airing habits. A correction of measurements in former dwellings by factors derived from the analysis is applied if current living conditions differ from those of the participants at the time when they were living in the particular dwellings. In rare cases the adjustment for changes leads to a correction of the measurements with a factor of about 1.4, but a reduction of 5% on average only. Exposure assessment can be improved by considering time at home and changes of building and ventilation conditions that affect radon concentration. The major concern that changes in ventilation habits and building conditions lead to substantial errors in exposure (and therefore risk) assessment cannot be confirmed in the data analyzed.     

Defining a new term

Organizations are using extranets to engage in electronic commerce with trading partners. But the definitions of what constitute an extranet vary widely.     

Control-informant agreement on exposure history in case-control studies of Alzheimer's disease.

Data on control-informant agreement from four published case-control studies of Alzheimer's disease are compared, using both the kappa statistic and proportion of agreement for the presence and absence of exposures. Agreement was best for exposures involving lifestyle, medical interventions or disorders of more recent origin, and worst for exposures which involved judgements by the respondent. Agreement levels are similar across studies, and are commensurate with levels of specificity and sensitivity to be expected in this type of enquiry. We discuss the problems and implications associated with the interpretation of data from such studies of the elderly.     

Methodologic issues in exposure assessment for case-control studies of cancer and herbicides

Epidemiologic studies of cancer and exposure to herbicides have shown puzzling inconsistencies. Exposure-response gradients have been reported for non-Hodgkin's lymphoma in Sweden and Kansas, but no significant associations were seen in New Zealand or Washington State. Subjects in these studies were categorized by exposure using information obtained primarily by interview. A number of questions can be raised regarding the reliability and validity of such an exposure assessment. We examined procedures used to assess pesticide exposures in case-control studies of cancer to evaluate their limitations and their probable effects on risk estimates. Except for case recall bias, problems of misclassification in these studies would tend to bias risk estimates toward the null and dilute exposure-response gradients. These problems are, therefore, unlikely explanations for the positive associations between cancer and herbicide use noted in some investigations. A tendency for false-negative findings, however, is not reassuring, and improvements in exposure assessment are needed if epidemiologic investigations are to continue to provide reliable information on the relationships of cancer and pesticide exposure.     

Respiratory diseases and pesticide exposure: a case-control study in Lebanon

STUDY OBJECTIVE: To evaluate the odds of being exposed to pesticides in asthmatic adults. DESIGN: A case-control study was performed in Lebanon. SETTING: People were approached when consulting physicians as outpatients. PATIENTS: Asthmatic patients and non-asthmatic controls in several Lebanese hospitals were interviewed. MAIN RESULTS: The study included 407 subjects from 10 medical centres. Any exposure to pesticides was associated to asthma (OR = 2.11 (1.47 to 3.02); p<10(-4)). Occupational use presented the highest association (OR = 4.98 (1.07 to 23.28); p = 0.02), followed by regional exposure (OR 3.51 (2.11 to 5.85); p<10(-4)). Results were confirmed by multivariate analysis, particularly for regional exposure (OR(a) = 2.78; p = 0.02) and house exposure (OR(a) = 2.17; p = 0.001). CONCLUSIONS: Results are comparable to those found in other studies; especially for occupational exposure. Pesticides toxicological effects may explain chronic respiratory symptoms and asthma associations found with all exposure types. Pesticide exposure was associated with asthma in Lebanese adults.     

Occupational lead exposure and strabismus in offspring: a case-control study

The authors conducted a population-based case-control study to investigate the association between strabismus and parental occupational lead exposure. Cases were children diagnosed with nonrestrictive strabismus between 1985 and 1986 at Baltimore, Maryland-area pediatric ophthalmology practices and clinics (n = 377). Controls were matched for age and hospital of birth (n = 377). Jobs held by parents were assessed for lead exposure by industrial hygienists. The time window for lead exposure was defined as the period from conception through age 9 months. The unadjusted odds ratio for maternal lead exposure and the esotropic form of strabismus was 2.6 (95% confidence interval (CI) 0.4-27). Unadjusted odds ratios for paternal occupational lead exposure and esotropia were 1.0 (95% CI 0.5-2.1) for low exposure, 2.1 (95% CI 0.9-5.3) for moderate exposure, and 1.2 (95% CI 0.4-3.3) for high exposure. The study results suggest the possibility of a weak association between paternal lead exposure and strabismus in offspring.     

Latency and time-dependent exposure in a case-control study

Detailed historical data are elicited often from subjects in retrospective studies, yielding time-dependent measures of exposures. Investigation of a hypothesized period of latency can be made by examining disease/exposure relationships in multiple time windows, either along the age or time-before diagnosis axes. We suggest splitting the data into many time intervals and separately fitting regression models to the available data in each interval. Covariances between estimated coefficients from different intervals are empirically estimated, and used for assessing variability of specified functions of the time-specific coefficients. Alternative methods of interval formation and their consequences are discussed. We apply these methods to a French case-control study of oral contraceptive use and cervical cancer incidence, and compare the results to those of standard analyses.     

Defining and investigating occupational asthma: a consensus approach

Background

At present there is no internationally agreed definition of occupational asthma and there is a lack of guidance regarding the resources that should be readily available to physicians running specialist occupational asthma services.

Aims

To agree a working definition of occupational asthma and to develop a framework of resources necessary to run a specialist occupational asthma clinic.

Method

A modified RAND appropriateness method was used to gain a consensus of opinion from an expert panel of clinicians running specialist occupational asthma clinics in the UK.

Results

Consensus was reached over 10 terms defining occupational asthma including: occupational asthma is defined as asthma induced by exposure in the working environment to airborne dusts vapours or fumes, with or without pre‐existing asthma; occupational asthma encompasses the terms “sensitiser‐induced asthma” and “acute irritant‐induced asthma” (reactive airways dysfunction syndrome (RADS)); acute irritant‐induced asthma is a type of occupational asthma where there is no latency and no immunological sensitisation and should only be used when a single high exposure has occurred; and the term “work‐related asthma” can be used to include occupational asthma, acute irritant‐induced asthma (RADS) and aggravation of pre‐existing asthma. Disagreement arose on whether low dose irritant‐induced asthma existed, but the panel agreed that if it did exist they would include it in the definition of “work‐related asthma”. The panel agreed on a set of 18 resources which should be available to a specialist occupational asthma service. These included pre‐bronchodilator FEV₁ and FVC (% predicted); peak flow monitoring (and plotting of results, OASYS II analysis); non‐specific provocation challenge in the laboratory and specific IgE to a wide variety of occupational agents.

Conclusion

It is hoped that the outcome of this process will improve uniformity of definition and investigation of occupational asthma across the UK.Occupational asthma is the most common form of occupational lung disease in industrialised nations and causes significant morbidity and disability. Meta‐analysis of studies estimating the proportion of cases of asthma in adults of working age to which occupational factors have contributed, have shown an attributable risk of between 9% and 15%.¹ At present there is no internationally agreed definition of occupational asthma. More importantly perhaps, in the UK there is no standard approach to investigating or managing these patients.All definitions of occupational asthma specify that the causal agent should be specific to the workplace^{2,3,4,5,6,7,8} and early definitions also stipulated that there should also be a sensitising mechanism.^5,6,7 However, evidence of sensitisation is only found in a minority of cases and occupational exposures can cause asthma without immune sensitisation (reactive airways dysfunction syndrome). An alternative, more pragmatic approach has been taken, with two types of occupational asthma being proposed, distinguishable by whether or not there is a latent period between exposure and symptoms.⁹ The first type (also termed “allergic”) appears following a latency period and the allergic mechanisms responsible may or may not yet be fully characterised. The second type (“non‐allergic”) encompasses irritant induced asthma or reactive airways dysfunction syndrome (RADS).⁹ Recently published evidence‐based guidelines for the identification, management and prevention of occupational asthma¹ also proposes two types of occupational asthma and avoids implying a specific immunological mechanism. The authors define occupational asthma as being either “hypersensitivity induced occupational asthma” (characterised by a latency period and non‐irritant mechanism) or “irritant induced occupational asthma” (due to an irritant mechanism and not requiring a latent interval). Increases in asthma symptoms, or re‐activation of quiescent asthma in individuals with pre‐existing asthma due to workplace exposure are normally excluded by definitions of occupational asthma. A variety of terms are used to define this concept, such as “work aggravated asthma”.¹⁰Consensus techniques have helped to improve the diagnosis and management of asthma in recent years¹¹ and are particularly useful in situations where the evidence base is sparse or undecided.^12,13,14 These techniques focus on exploring consensus among a group of experts by synthesising opinions in combination with available evidence. Consensus techniques are also becoming an increasingly important mechanism for developing quality tools.¹⁵The aim of this study was to use a consensus technique in an attempt to agree a working definition for occupational asthma in the UK and to develop indicators of good practice in the investigation of patients with suspected occupational asthma.