Occupational Case-Control Studies

Transcription

1 Epktemiologlc Reviews Copyright O 1994 by The Johns HopWns University School of Hygiene and Public Health Ail rights reserved VoL 16, No. 1 Printed In U.SA. Occupational Case-Control Studies Harvey Checkoway 1 and Paul A. Demers 2 INTRODUCTION The case-control design has become an important strategy for identifying occupational risk factors, primarily for rare diseases and diseases with long induction times. There are three principal types of case-control studies in occupational epidemiology: 1) case-control studies that are nested within defined occupational cohorts; 2) community- or registry-based casecontrol studies conducted among the population at large; and 3) record linkage studies in which cases and controls are identified from vital records or disease registry data and occupational information is retrieved from the same source or by linkage with census data or other existing data sets. All three of these types of case-control studies share the common goals of attempting to identify occupational risk factors and to quantify their effects. However, these types of studies differ with regard to the specificity of information available and hence the confidence with which etiologic inferences can be drawn from their findings. This paper summarizes the design features of the three main categories of occupational casecontrol studies. Emphasis is placed on newer developments in application of the case-control design. Received for publication June 30, 1993, and in final form December 17, Abbreviation: JEM, job exposure matrix. 1 Department of Environmental Health, School of Public Health and Community Medicine, University of Washington, Seattle, WA. 2 Occupational Hygiene Program, University of British Columbia, Vancouver, British Columbia, Canada. Reprint requests to Dr. Harvey Checkoway, Department of Environmental Health, SC-34, School of Public Health and Community Medicine, University of Washington, Seattle, WA NESTED CASE-CONTROL STUDIES Indications for performing nested case-control studies The reason for performing a nested casecontrol study rather than a full cohort analysis is that data concerning potentially confounding factors, exposure(s) of interest, or disease diagnosis are not readily available and it is not cost- and/or time-efficient to collect the information for the entire cohort. Cost-efficiency is ordinarily viewed in terms of the reduced study size of the nested case-control study, relative to a full cohort analysis. Savings in resources may be realized in nested case-control studies as a result of reductions in data collection, processing, and editing. However, improvements in cost- and time-efficiency may not be as great as one would anticipate when exposure assessment requirements are not diminished in proportion to the reduced study size of a nested case-control study. The most common indication for conducting a nested case-control study is the situation where there is an opportunity to obtain data on potentially confounding factors, such as smoking or family history of disease, that ordinarily would not be available in work history records. This information may be obtained from study subjects by means of postal or telephone questionnaires. In case-control studies nested within cohort mortality studies, information on confounders may only be available from proxy respondents, such as next of kin. Identifying and contacting suitable proxy respondents can pose forbidding logistic problems, and data derived from these sources may suffer from incompleteness and poor quality (1). The most desirable characteristics of a proxy 151

2 152 Checkoway and Demers respondent are accessibility and prolonged and close contact with the study subject during adult life. Most occupational studies that collect data tend to rely on spouses as proxy respondents for these reasons (2). There is also some empirical evidence indicating that reasonably reliable data on smoking and other lifestyle factors can be obtained from interviews of adult offspring (3), although offspring have been contacted infrequently in occupational case-control studies. Traditionally, many occupational cohort studies focus on fatal diseases occurring over long time periods; consequently, there typically will be a larger proportion of deceased persons among cases than among controls. Differences in vital status between cases and controls can create imbalances in the accuracy and detail of confounder data when data collection involves either inperson or telephone interviews or postal questionnaire surveys. When this situation occurs, confounding can be examined separately within strata defined by the source of data, subject or proxy (1), although vital status differences between cases and controls may remain problematic. An alternative approach is to select proxy respondents for all subjects, irrespective of vital status, and compare evaluations of confounding based on subject-derived and proxy-derived data (4). Of course, this strategy will add subjects and hence expense to the study, and may not be feasible for common practice. Collecting data on potential confounders or their surrogates may be impossible for cases and controls who have long since left the industry under study. This situation may require indirect methods of controlling confounding that involve adjustments to observed effect estimates under varying assumptions of the strengths of the relations between the confounder, exposure, and disease risk (5, 6). Indirect adjustments for confounding have been evaluated mainly in the context of controlling for the effects of smoking, but they could also be applied for other unmeasured risk factors, such as previous or subsequent employment in other hazardous occupations. If the quality of questionnaire data does not represent an improvement over indirect methods, then a nested-case control study may not be indicated. Another indication for conducting a nested case-control study is the situation where work history or exposure information for an entire cohort is either difficult or too expensive to collect. Such a situation can arise when the outcome of interest is rare and, consequently, the numbers of cases and controls needed are very small in relation to the size of the full cohort, or when the cohort consists of workers employed at many different workplaces. If one anticipated conducting nested case-control studies, a twophase data collection process could be used. Only the basic data needed to identify cases and to select controls (personal identifiers, demographic variables, dates of hire and termination) would be abstracted from personnel records in the first phase, and complete work history and exposure data would be abstracted for cases and controls in the second phase. Sometimes the personnel records of a company must be reviewed thoroughly in order to enumerate a cohort properly, and it may be possible to collect detailed work history records at the same time at relatively little extra expense. In addition, cost requirements for exposure assessment, which often represents a substantial effort, will not be reduced appreciably when the cases' and controls' collective work experience includes most jobs (and time periods) of the cohort. However, a nested case-control study can be a much more efficient use of resources when a cohort can be compiled using a simple or inexpensive source, such as computerized lists of company or plant employees or membership rosters from a union, but detailed work history or exposure information is more difficult to retrieve. For example, in a study of chemical exposures and respiratory cancers in the Finnish wood products industry (7), the cohort consisted of 3,805 workers employed for at least 1 year at one of 19 plants that were identified for each of the participating companies. Using a nested case-

3 Occupational Case-Control Studies 153 control design, work histories only needed to be collected for 57 respiratory cancer cases and 171 controls, approximately 6 percent of the full cohort. In recent years, there has been a growing trend of disease and injury surveillance within industries, particularly in large plants that have relatively stable workforces. Surveillance can be regarded as a special type of the cohort study design that, unlike most traditional occupational cohort studies, focuses on the occurrence of and risk factors for nonfatal health outcomes. Surveillance programs typically generate data on secular patterns of disease incidence and prevalence, and may be used to compare risks among various sectors of the workforce. Disease incidence may be ascertained by "passive" surveillance approaches that rely on case reports to company medical departments or are based on insurance claims. Where available, disease registries and hospital and insurance records serve as sources of disease incidence data, although the completeness of coverage for an entire cohort may be difficult to determine. Alternatively, surveillance can take a more active form of screening for disease and injury or for preclinical markers of disease (e.g., chest radiographic abnormalities) among worker subgroups thought to be at greatest risk. Nested case-control studies increasingly have become a prominent feature of industry-based surveillance programs oriented toward determining causal factors. Noteworthy advantages of the case-control design for surveillance purposes include the potential to ensure high levels of disease diagnostic validity and the ability to collect data on potentially relevant confounders directly from study participants. Design aspects The principal elements of a nested casecontrol study are inclusion of all identified cases of the index disease(s) and selection of a comparison group which represents a sampling of the cohort, or study base, that generated the cases (8-10). In situations where disease ascertainment may not be complete for the entire cohort, controls should have an opportunity for diagnosis that is similar to that of the cases. The validity of findings from a nested case-control study, relative to a full cohort analysis, depends on appropriate selection of controls. Thus, the case-control study should, to the extent possible, reflect the same time-dependent relations between exposure, age, follow-up time, and disease incidence as would be observed in a cohort study. Therefore, the appropriate control sampling strategy is to select controls from among cohort members who were free of the disease of interest at the times when the cases were diagnosed, or at the times when their deaths occurred in a mortality study (10). This sampling scheme, also known as "incidence density sampling," has been shown to obviate the need for the rare disease assumption (11,12), thus permitting valid case-control studies of rare and common diseases (including mortality from all causes combined) characterized by either acute or prolonged induction intervals. Issues relating to matching, validity, and statistical efficiency in nested case-control studies are in theory identical to those that arise in any case-control study. Date and age of first exposure, duration of follow-up, and time since first employment are frequently important determinants of disease risk (13); thus, there may be some desire to match subjects with regard to these factors in a nested case-control study. Individual matching of cases to controls offers some advantages, primarily ensuring similar or overlapping distributions of suspected confounders (matching factors). However, there can be decided disadvantages, such as the difficulty of matching on factors that vary over time and the potential loss of cases for analysis when matches cannot be identified (14). In occupational studies, the optimal general strategy is to adjust for differences in the distributions of suspected confounders in the analysis rather than to match. The justification for this viewpoint is that the nested case-control study should mimic the cohort design as closely as possible (9,10). Matching may be useful for a small number of

4 154 Checkoway and Demers variables, such as sex and date of birth, to minimize confounding from these clearly extraneous variables. Proportionate mortality (or incidence) studies compare the distribution of disease incidence in an occupational cohort with an expected distribution based on proportions of disease incidence in an external reference population. This design, which is often used as a relatively quick and inexpensive substitute for a cohort study, has been shown to be a special form of case-control study using an external reference population (15). The control group represents deaths or cases of diseases other than the one under evaluation. Exposure is defined as membership in a particular industry or occupation, whereas cases or deceased persons from the reference population are considered nonexposed. In some instances, it may be possible to identify as the control group persons with a single disease or disease grouping thought to be unrelated to the exposure(s) of interest, although this may be difficult to determine when prior evidence is scant (16). Exposure assessment The procedures used for estimating occupational exposure in nested-case control studies are identical to those commonly used in cohort studies. While some exposure information may be collected using questionnaires, the approach most commonly used is to link work history information, generally contained in employment personnel records, with information on the locations and amounts of specific agents or substances in the workplace (7). The term "work history," as it is typically used in occupational cohort studies, refers to the job titles, department or work area names, and relevant dates of employment in the industry being studied. Exposure classification in an industry-based study can be as crude as the mere fact of ever being employed in that industry or, at the other extreme, may involve detailed dosimetric quantities that span workers' entire employment periods. Ideally, industrial hygiene monitoring data for persons employed in particular jobs or work areas are the principal source of detailed exposure information for chemicals, dusts, and physical agents such as noise or radiation. Dose surrogates of intermediate informativeness include duration of employment in the industry at large, duration of employment in specific work areas or jobs, and duration of employment in jobs ranked on an ordinal exposure scale (17). Qualitative or semiquantitative estimates of exposure may be based on ancillary data from interviews with occupational health and safety personnel or senior workers familiar with the industry, and from records pertaining to usage of raw materials and changes in industrial processes. This information may be essential in assessing exposures, especially those that occurred many years in the past. The specificity and accuracy of exposure assessment, and hence the ability to investigate dose-response relations, in either an occupational cohort or nested case-control study are dependent on the amount and quality of available work history and exposure data. Unfortunately, extensive exposure monitoring is performed within relatively few industries, and it is more common for records to be incomplete or unavailable for the exposures of interest, especially for earlier time periods that are of primary concern for diseases with long induction periods. Thus, many occupational studies suffer from a lack of detailed and quantitative exposure information. Nonetheless, localization of high-risk jobs, tasks, or work areas can be valuable for focusing exposure remediation efforts or for identifying previously unrecognized hazards. The assistance of industrial hygienists or other persons familiar with the nature of exposure in the occupation or industry of interest is an essential element of valid exposure assessment. Examples of nested case-control studies A study of ischemic heart disease among aluminum production workers (18) exemplifies some of the design features and particular advantages of nested case-control studies. The cases were 306 men whose first

5 Occupational Case-Control Studies 155 episodes of ischemic heart disease occurred between 1975 and The source cohort included over 6,000 workers. Cases were identified from absenteeism lists or death certificates, and diagnoses were confirmed through review of medical records by a cardiologist, medical indications of disease progression over time, or electrocardiographic and/or angiographic evidence of ischemic heart disease. A control series was selected comprising male workers who were alive as of the cases' diagnosis dates and were free of cardiac disease as determined by review of company medical records. In addition, controls were matched to cases with regard to birth date, hire date, and length of employment. Data on weight, height, blood pressure, medical history, smoking, and pulmonary function were extracted from the medical records. Medical history and confounder data were supplemented by information from a self-administered questionnaire sent to each case and control. Work history data were abstracted from company work history records. Industrial hygiene data were available for some of the many workplace chemicals, and were used to classify jobs on a relative exposure scale. Table 1 shows relative risk estimates (odds ratios) for employment in various jobs and work areas. Excess risk of ischemic heart disease appeared to occur in the re- TABLE 1. Ischemic heart disease risks In relation to specific aluminum production jobs* Work area Maintenance installation Chemicals Casting Rod mills Reduction Sodertoerg pot room Prebake Pot lining Electrode plant cases controls ORt Adapted from Theriault QP, et al. (18), Am J Ind Mad 1988; t OR, odds ratio. Adjusted for age, smoking, obesity, blood pressure, and serum liptds. duction areas of the plant; however, further analyses with respect to specific agents, including carbon monoxide, noise, and thermal stress, did not reveal any remarkable etiologic relations. This study illustrates the advantages of the nested case-control study for obtaining data on important risk factors that could confound observed occupational associations and for minimizing diagnostic misclassification. The same objectives could have been met by performing subcohort analyses of the entire workforce, but at a substantially increased cost. A Scandinavian study of adverse reproductive outcomes in relation to exposures experienced by women in the dry cleaning industry (19) provides a good example of a situation where identification of cases and controls was more convenient than enumeration and follow-up of an entire cohort. Cohorts of laundry and dry cleaning workers were constructed from plant records in Sweden, Finland, and Denmark, and birth outcomes were determined by means of linkage with centralized medical birth registers and hospital registers. Cohort membership required employment in the industry for at least 1 month during the period Case mothers were women who had either experienced a spontaneous abortion or delivered a baby with a low birth weight or congenital malformation. Controls were women who had given birth to healthy babies within 2 years of the case mothers (i.e., an approximation to density matching). Exposures during pregnancy were estimated from industrial hygiene monitoring data and, for the Swedish and Danish women, from self-reports of specific job duties obtained by means of standardized interviews and postal questionnaires. Data on smoking and alcohol use were also obtained from interviews and questionnaires. Spontaneous abortion risk was greatest at the highest exposures for Danish and Finnish workers, although no association was detected among the Swedish workers (table 2). An example of a nested case-control study within a screening cohort is provided by Acquavella et al.'s (20) study of adenoma-

6 156 Checkoway and Demers TABLE 2. Spontaneous abortion and tetrachloroethylene exposure in the dry cleaning Industry In Sweden, Denmark, and Finland* Country and exposure level Sweden None Low High Denmark None Low High Finland None Low High cases controls ORt Adapted from Olsen J, et al. (19), ScandJ Work Environ Health 1990; t OR, odds ratio. Adjusted for parity, smoking, and alcohol use. tous polyps of the colon among polypropylene manufacturing workers at a chemical plant. The medical screening program had been prompted by an apparent cluster of colorectal cancers among workers engaged in this manufacturing process. Workers in the polypropylene unit were offered colorectal screening that consisted of a test for occult blood in the stool, sigmoidoscopy, and barium enema. Among screening participants, one case of colon cancer and 23 cases of adenomatous polyps were detected. For each case, three controls were selected from among screened workers who were free of colorectal lesions. Exposures to particular chemicals in the polypropylene unit were assessed by occupational hygienists' ratings; this information was linked with cases' and controls' work history records to estimate cumulative exposures. Moderate to strong associations with adenomatous polyps were detected for two complex chemical mixtures, base plant polymer and finishing additives, and for asbestos (table 3). COMMUNITY-BASED CASE-CONTROL STUDIES Investigations of occupational risk factors can be accomplished by comparing occu- TABLE 3. Nested case-control study of adenomatous polyps of the colon and exposures In a polypropylene manufacturing unit at a chemical plant* Exposure Finishing polymer Base plant polymer Finishing additives Asbestos exposedt cases exposedt controls ORt Adapted from Acquavella JF, et al. (20), Am J Epidemiol 1991; 133: t Above the median exposure score of cases and controls, respectively, allowing for a 10-year latency interval. % OR, odds ratio. pational exposures among cases and controls identified from community sources, such as hospitals or disease registers. Such studies do not require enumeration and follow-up of occupational cohorts. There are several reasons for conducting communitybased, rather than nested, case-control studies: 1) cohorts for some occupations may be difficult or impossible to enumerate (e.g., farmers); 2) available occupational cohorts may not be sufficiently large to study some rare diseases that can be identified more readily from disease registers; and 3) associations with a broad spectrum of occupational exposures can be explored in the context of case-control studies with other emphases at a minimal additional cost. Community-based case-control studies can also permit estimation of population attributable risks to the extent that controls' exposures are representative of the exposures in the source population. Design aspects In general, the design aspects of community-based case-control studies that examine the risk of disease associated with occupational exposures are the same as those whose primary purpose is to examine other risk factors. Cases in community-based studies are typically identified from hospitals, disease registers, or vital statistics registers, such as those kept for birth and death certificates. Controls should be selected from the same study base as the cases (21), although in practice the study base may not be clearly

7 Occupational Case-Control Studies 157 delineated. Thus, for example, a casecontrol study in which cases are selected from hospitals may use other hospitalized patients as controls under the assumption that both groups derive from the same source, the hospital catchment area. In studies where cases are identified from population-based disease registers, control selection is frequently carried out using population sampling procedures, such as random digit dialing (22) or variants of that method (23). In registry-based studies, other registered noncase events are selected as the source for controls. For example, in a study of congenital malformations, controls may be normal births that occurred during the same time periods as the cases. Irrespective of the selection method or source of controls, the principles of density matching to balance the case-control design with the cohort design also apply to community-based case-control studies. The comparability of geographic residence between the cases and controls is also an important consideration, because the distribution of occupations and industries may be closely related to the proximity of available workplaces. Exposure assessment The primary sources of occupational exposure information in community-based studies are questionnaires involving inperson or telephone interviews or postal surveys. The type and level of detail obtained from such questionnaires will depend on the goals of the study. At the most basic level, studies whose primary goal is to examine nonoccupational risk factors may limit their collection of occupational data to lifetime employment history, consisting of job titles, industries, and dates of employment. The investigators may not include questions on exposure to specific workplace agents, in order to avoid collection of large amounts of uninformative data, as can result from low exposure prevalences or subjects' inability to recall specific details of exposure. The basic employment information can be used to estimate relative risks for ever versus never employment in various industries or occupations, or to estimate risks according to duration of employment. In addition, linkage of employment history data with an existing job exposure matrix permits exploration of numerous possible associations with particular workplace agents. Subsequent investigations can then focus in greater depth on the broad occupational associations detected in preliminary investigations. However, for studies where occupational exposures are a primary focus, a detailed questionnaire should include questions that can generally be classified into three major categories: 1) general questions on work history; 2) questions specific to particular occupations; and 3) questions specific to particular exposures (24). In addition to the information obtained from the general work history, data regarding job tasks, materials handled, use of protective equipment, and the subjects' own assessments of exposure should also be sought. The occupational and exposure-specific questions should be designed with the assistance of someone knowledgeable of the particular exposure circumstances in order to gather detailed information that can then be combined with knowledge of exposure levels in various industries to construct quantitative or semiquantitative dose estimates (25). In all cases where interviews are used, it is beneficial to familiarize interviewers with the level of detail desired or the particular types of occupational and exposure information needed in order to avoid the collection of useless data. Computer-assisted interviews have been proposed as an effective means of providing context-specific probes to interviewers (26). An example of one of the most comprehensive community-based studies yet carried out is the large case-control study conducted by Siemiatycki (27) among hospitalized cancer patients in Montreal, Quebec, Canada. In-depth interviews eliciting details on occupational history were conducted among nearly 4,000 cancer patients whose disease was diagnosed in 19 Montreal hospitals during the period The interview included detailed questions regarding each previously held job,

8 158 Checkoway and Demers and interviewers were encouraged to probe for as much detailed information as possible. The job histories were then evaluated by a specially trained team of chemists and industrial hygienists as to exposures to approximately 275 common occupational agents. Table 4 summarizes findings from a subset of these analyses concerning occupational dust exposures and nonadenocarcinoma of the lung (28). The semiquantitative exposure classifications suggested potential dose-response relations with both silica and excavation dust. This study has been used to examine literally hundreds of associations between occupational exposure and cancer; some observed associations have confirmed associations previously demonstrated from industry-based studies (e.g., silica and lung cancer (29)), whereas others may stimulate further inquiry. The method used in the Montreal casecontrol study to conduct detailed occupational history interviews and to determine types of exposure is very time-consuming and labor-intensive (25). An intermediate approach for exposure assessment in community-based studies is to classify jobs by exposure type and level using a job exposure matrix (JEM). JEMs may be constructed solely on the basis of expert opinion, such as that devised by Hoar et al. (30), or may be based on observations made during systematic surveys of industry, such as the National Occupational Hazard Survey conducted by TABLE 4. Results of a hospital-based case-control study of occupational exposures and cancer In Montreal, Quebec, Canada: silica exposure, excavation dust, and nonadenocarclnoma of the lung* Exposure group Short and low Short and high Long and low Long and high All exposures combined Silica cases ORt Excavation dust ORt Adapted from StemiatycH J, et al. (28), Am J Ind Mod 1989;16: t OR, odds ratio. Adjusted for age, ethnic group, sodoeconomlc status, smoking, and asbestos exposure. the US National Institute for Occupational Safety and Health (31). A JEM may be constructed for a particular study and then used in other investigations, or it may be devised with the intention of general application (30, 32). Use of an existing JEM has the advantage of convenience and may be helpful in revealing new etiologic insights, although the potential for exposure misclassification can be a severe constraint on causal inference in studies that rely on this method (33). On the other hand, the circumstances of exposure can vary considerably between different geographic regions. Consequently, JEMs constructed for a particular study by persons familiar with local conditions and changes in exposure types and levels over time may be much more accurate than a general purpose JEM. There is convincing empirical evidence from the Montreal study that the detailed interview and exposure assessment method reduces exposure misclassification and thus offers much greater statistical power for detecting associations than application of a JEM (34). Surrogate respondents may be required to provide information on the case's occupational history in studies of rapidly fatal diseases or conditions that impair cognition. There have been attempts to evaluate the validity of surrogate responses, using the worker's answer or an objective source of data (e.g., the employment history record) as the standard (35 37). The patterns that emerge are that spouses, offspring, and siblings tend to underreport the total number of jobs held, and predictably, specificity greatly exceeds sensitivity for both employment in particular industries and exposures to individual agents. It is perhaps noteworthy that workers tend to underreport their own exposures to specific agents (38-40), and the reliability of responses varies greatly by agent (41). Exposure assessments in communitybased case-control studies typically are less detailed than those achievable in studies nested within defined occupational cohorts. This occurs because data abstracted from detailed records of workplace assignments

9 Occupational Case-Control Studies 159 and associated exposure levels that can permit dose-response estimation in nested casecontrol studies are not available in community-based studies unless special efforts are made to retrieve this information. VITAL RECORD AND DISEASE REGISTRY LINKAGE STUDIES An increasingly popular design, which may also be considered a variant of the community-based study, uses data from population-based registries of deaths, births, or diseases to identify cases and controls, which then are compared with respect to routinely recorded occupational information, such as data contained in national census records. This design may also be considered a proportionate mortality or incidence study if all deaths, births, or persons with recorded diseases other than the one under study are included as controls. This approach has the obvious advantages of minimal data collection requirements and large study sizes in comparison with casecontrol studies nested within occupational cohorts or community-based case-control studies requiring the interview of all study participants. Exposure assessment may be as simple as determining industries or occupations recorded in vital records, or it may involve classifying this information according to specific exposures using a JEM or by rating jobs according to the likelihood of exposure to an agent of interest. A study that examined the association between nasal and nasopharyngeal cancer and formaldehyde in Denmark provides a good example of this approach. Olsen et al. (42) combined cancer site and histologic information from the Danish Cancer Registry with occupational history information from the Supplementary Pension Fund and Central Population Registry. The data were linked using the 10-digit Danish personal identification number. The work histories for 525 sinonasal and 314 nasopharyngeal cancer cases and 2,465 controls (persons with colon, rectum, prostate, or breast cancer) were assessed for exposures to formaldehyde and other suspected causal agents by three industrial hygienists blinded as to case/control status. Linkage of large databases of census information and populationbased disease registry data can also be a cost-efficient means of constructing occupational cohorts, which in turn can generate nested case-control studies. Thus, it is possible to combine the methods and data sources of nested industry-based and community-based case-control studies. An even simpler and less expensive design involves the use of records from a single source. For example, in a study of occupation and lung cancer, Zahm et al. (43) compared occupational histories of lung cancer cases of various histologic types with those of a control group comprising patients with other cancers. Information regarding cancer site, occupation and industry, and tobacco use were all collected from the computerized records of the Missouri Cancer Registry. Vital record studies provide a relatively efficient means of screening for potential etiologic relations with broadly defined industries and occupations, and may be adequate for detecting strong associations. However, exposure assessments in these studies are generally far less detailed and specific than in other occupational casecontrol studies. The primary reason for this limitation is that vital and disease registry records do not customarily depict lifetime occupational history (except in instances where an individual has held only one job) and may be inaccurate (44, 45). Moreover, recording practices for industries and occupations vary greatly by region and may not be complete, which can complicate the planning of large-scale studies and interpretation of data. DISCUSSION The case-control design has become a widely used and accepted approach for studying occupational hazards. The validity of findings from nested case-control studies, relative to findings from analyses of full cohorts, has been demonstrated empirically and theoretically (46). The principal differ-

10 160 Checkoway and Demers ence is the greater statistical precision attainable with a full cohort analysis of the data. The decision as to whether to perform an analysis of disease risk in relation to exposure history for an entire cohort or to conduct a nested case-control study should be guided by cost considerations and the anticipated potential gains in validity that might be realized by collection of data on confounding factors in a nested case-control study. The savings in time and effort of a nested case-control study are, in fact, seldom great if the only objective is to reduce the amount of data to be handled, i.e., no additional data collection. In particular, the exposure assessment effort, which frequently is the most labor-intensive component of an occupational study, may not diminish appreciably when a sample of the cohort is selected. Thus, the main advantages of the nested case-control study relate to collection of data on confounders and, in some instances, additional clinical information that may improve disease classification. In recent years, there has been increasing emphasis placed on hazard and disease surveillance within industries. The case-control design should prove to be valuable for determining risk factors for diseases and injuries that are identified prospectively, such as from disease screening programs. Occupational health surveillance within the population at large may exploit case-control methods by examining changes in etiology for diseases with and without known occupational risk factors. For instance, a community-based case-control study of occupation and breast cancer, which is not ordinarily regarded as a work-related condition, may reveal newly emerging occupational hazards. Inclusion of at least rudimentary questions on occupational history has often been a standard aspect of community-based studies. At times, occupational history data are collected without any particular research objectives, other than to describe the study population in terms of socioeconomic characteristics. Even when occupational risk factors are not the primary emphasis of a study, thorough collection of occupational history information may ultimately be productive after the study's original hypotheses have been examined. An example is a recent analysis of occupational history data which demonstrated associations between potential exposure to electromagnetic fields and male breast cancer in a study that was originally designed for other purposes (47). In theory, community-based case-control studies have tremendous potential for investigating occupational exposures as disease risk factors. This potential will be realized if sufficiently detailed occupational data are collected and efforts are made to determine which reported agents and exposure levels actually existed in the assessed industries and workplaces. Inclusion of detailed historical data on workplace exposures in a community-based case-control study has been demonstrated successfully in a study of childhood leukemia and paternal radiation exposures at the Sellafield, England, nuclear facility (48). The ideal situation for achieving the most comprehensive and highest quality data on diseases and exposures would be linkage of incidence data from population-based disease registries with exposure monitoring data collected in workplaces. If this were to occur, the distinction between industrybased and community-based studies would no longer be necessary. Instead, an occupational case-control study would, in theory, be capable of examining dose-response relations within a particular industry, and would allow estimation of the contribution of occupational exposures to the community burden of specific diseases. The requisite technology for accomplishing this objective exists in many countries and could be developed in others. The major limiting factors are the extent to which occupational exposures are recognized as health hazards in the population at large and the appropriation of adequate resources. REFERENCES 1. Nelson LM, Longstreth WT Jr, Koepsell TD, et al. Proxy respondents in epidemiologic research.

11 Occupational Case-Control Studies 161 Epidemiol Rev 1990;12:71-«6. 2. Marsh GM, Sachs DPL, Callahan C, et al. Direct methods of obtaining information on cigarette smoking in occupational studies. Am J Ind Med 1988;13: Sandier DP, Shore DL. Quality of data on parents' smoking and drinking provided by adult offspring. Am J Epidemiol 1986;124: Nelson LM, Longstreth WT, Koepsell TD, et al. Completeness and accuracy of interview data from proxy respondents: demographic, medical and lifestyle factors. Epidemiology 1994 (in press). 5. Axelson O, Steenland K. Indirect methods of assessing the effects of tobacco use in occupational studies. Am J Ind Med 1988;13: Gail MH, Wacholder S, Lubin JH. Indirect corrections for confounders under multiplicative and additive risk models. Am J Ind Med 1988; 13: Kauppinen T, Partanen T. Use of plant- and period-specific job exposure matrices in studies of occupational cancer. Scand J Work Environ Health 1988;14: Miettinen OS. Design options in epidemiologic research: an update. Scand J Work Environ Health 1982;8(suppl 1): Axelson O. The case-referent study some comments on its structure, merits and limitations. Scand J Work Environ Health 1985;ll: Pearce NE, Checkoway H, Dement JM. The design and conduct of occupational epidemiology studies. III. The design of case-control studies. Am J Ind Med 1989; 15: Miettinen OS. Estimability and estimation in case-referent studies. Am J Epidemiol 1976; 103: Lubin JH, Gail MH. Biased selection of controls for case-control analyses of cohort studies. Biometrics 1984;40: Pearce NE, Checkoway H, Shy C. Time-related factors as potential confounders and effect modifiers in studies based on an occupational cohort. Scand J Work Environ Health 1986;12: Wacholder S, Silverman DT, McLaughlin JK, et al. Selection of controls in case-control studies. III. Design options. Am J Epidemiol 1992;135: Miettinen OS, Wang J-D. An alternative to the proportionate mortality ratio. Am J Epidemiol 1981; 114: Pearce N, Checkoway H. Case-control studies using other diseases as controls: problems of excluding exposure-related diseases. Am J Epidemiol 1988;127: Checkoway H. Methods of treatment of exposure data in occupational epidemiology. Med Lav 1986;77: Theriault GP, Trembtay CGH, Armstrong BG. Risk of ischemic heart disease among primary aluminum production workers. Am J Ind Med 1988;13: Olsen J, Hemminki K, Ahlborg G, et al. Low birthweight, congenital malformations, and spontaneous abortions among dry-cleaning workers in Scandinavia. Scand J Work Environ Health 1990;16: Acquavella JF, Owen CV, Bird MG, et al. An adenomatous polyp case-control study to assess occupational risk factors following a workplace colorectal cancer cluster. Am J Epidemiol 1991; 133: Wacholder S, McLaughlin JK, Silverman DT, et al. Selection of controls in case-control studies. I. Principles. Am J Epidemiol 1992;135: Waksberg J. Sampling methods for random digit dialing. J Am Stat Assoc 1978;73:4O Harlow BL, Davis S. Two one-step methods for household screening and interviewing using random digit dialing. Am J Epidemiol 1988;127: Gerin M, Siemiatycki J. The occupational questionnaire in retrospective epidemiological studies: recent approaches in community-based studies. Appl Occup Environ Hyg 1991 ;6: Gerin M, Siemiatycki J, Kemper H, et al. Obtaining occupational exposure histories in epidemiologic case-control studies. J Occup Med 1985;27:42O Stewart P. Assessing occupational exposures in epidemiologic studies. Keynote address to the 24th Congress of the International Commission on Occupational Health, Nice, France, September Siemiatycki J. Risk factors for cancer in the workplace. Boca Raton, FL: CRC Press, Siemiatycki J, Dewar R, Lakhani R, et al. Cancer risks associated with 10 inorganic dusts: results from a case-control study in Montreal. Am J Ind Med 1989;16: International Agency for Research on Cancer. Evaluation of carcinogenic risks to humans: an updating of IARC Monographs 1 to 42 (supplement 7). Lyon, France: International Agency for Research on Cancer, 1987: Hoar SK, Morrison AS, Cole P, et al. An occupational exposure and linkage system for the study of occupational carcinogens. J Occup Med 1980;22: Seiber WK, Sundin DS, Frazier TM, et al. Development, use, and availability of a job exposure matrix based on National Occupational Hazard Survey data. Am J Ind Med 1991;20: Pannett B, Coggon D, Acheson ED. A job-exposure matrix for use in population based studies in England and Wales. Br J Ind Med 1985;42: Plato N, Steineck G. Methodology and utility of a job-exposure matrix. Am J Ind Med 1993;23: Dewar R, Siemiatycki J, Gerin M. Loss of statistical power associated with the use of a jobexposure matrix in occupational case-control studies. Appl Occup Environ Hyg 1991 ;6: Pershagen G, Axelson O. A validation of questionnaire information on occupational exposure and smoking. Scand J Work Environ Health 1982;8: Lerchen ML, Samet JM. An assessment of the validity of questionnaire responses provided by a surviving spouse. Am J Epidemiol 1986;123: Miligi L, Masala G. Methods of exposure assessment for community-based studies: aspects in-

12 162 Checkoway and Demers herent to the validation of questionnaires. Appl Occup Environ Hyg 1991;6: Bond GG, Bodner KM, Sobel W, et al. Validation of work histories obtained from interviews. Am J Epidemiol 1988;128: Brisson C, Vezina M, Bernard PM, et al. Validity of occupational histories obtained by interviews with female workers. Am J Ind Med 1991;19: Joffe M. Validity of exposure data derived from a structured questionnaire. Am J Epidemiol 1992;135: van der Gulden JWJ, Jansen IW, Verbeek ALM, et al. Repeatability of self-reported data on occupational exposure to particular compounds. Int J Epidemiol 1993;22: Olsen JH, Jensen SP, Hinks M, et al. Occupational formaldehyde exposure and increased nasal cancer risk in man. Int J Cancer 1984;34: Zahm SH, Brownson RC, Chang JC, et al. Study of lung cancer histologic types, occupation, and smoking in Missouri. Am J Ind Med 1989;15: Steenland K, Beaumont J. The accuracy of occupation and industry data on death certificates. J Occup Med 1984;26: Selikoflf I. Death certificates in occupational studies, including occupational hazards: inaccuracies in occupational categories. Am J Ind Med 1992;22: Pearce NE, Checkoway H, Dement JM. The design and conduct of occupational epidemiology studies. IV. Analysis of case-control studies. Am J Ind Med 1989;15: Demers PA, Thomas DB, Rosenblatt KA, et al. Occupational exposure to electromagnetic fields and breast cancer in men. Am J Epidemiol 1991; 134: Gardner MJ, Snee MP, Hall AJ, et al. Results of case-control study of leukaemia and lymphoma among young people near the Sellafield nuclear plant in West Cumbria. Br Med J 1990;300: