Ann. occup. Hyg., Vol. 47, No. 1, pp. 37-47, 2003
© 2003 British Occupational Hygiene Society
Published by Oxford University Press
Retrospective Exposure Assessment and Quality Control in an International Multi-centre Case–Control Study
1 Department of Occupational and Environmental Medicine, Lund University Hospital, SE-221 85 Lund, Sweden; 2 Finnish Institute of Occupational Health, Helsinki, Finland; 3 Instituto Nacional de Seguridad e Higiene en el Trabajo, Barcelona, Spain; 4 Dipartimento di Medicina del Lavoro, Clinica del Lavoro ‘L. Devoto’, Milan, Italy; 5 Department of Occupational Medicine, Telemark Central Hospital, Skien, Norway; 6 National Institute of Occupational Health, Copenhagen, Denmark; 7 Institute of Public Health, University of Copenhagen, Copenhagen, Denmark; 8 Department of Environmental Epidemiology, Istituto Nazionale per la Recerca sul Cancro, Genova, Italy
Received 1 July 2002; in final form 19 September 2002
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The paper presents the exposure assessment method and quality control procedure used in an international, multi-centre case–control study within a joint Nordic and Italian cohort. This study was conducted to evaluate whether occupational exposure to carcinogens influenced the predictivity of high frequency of chromosomal aberrations (CA) in peripheral lymphocytes for increased cancer risk. Occupational hygienists assessed exposures in each participating country: Denmark, Finland, Italy, Norway and Sweden. The exposure status to a carcinogen or a clastogen was coded in the cohort according to the original CA studies at the time of CA testing, but not for the whole work life. An independent occupational hygienist coordinated harmonization of the assessment criteria and the quality control procedure. The reliability of the exposure assessments was calculated as deviation from the majority of the assessors, as Cohen’s
and as overall proportion of the agreements. The reassessment of the exposures changed the exposure statuses significantly, when compared with the original cohort. Harmonization of the exposure criteria increased the conformity of the assessments. The prevalence of exposure was higher among the original assessors (the assessor from the same country as the subject) than the average prevalence assessed by the other four in the quality control round. The original assessors classified more job situations as exposed than the others. Several reasons for this are plausible: real country-specific differences, differences in information available to the home assessor and the others and misunderstandings or difficulties in translation of information. To ensure the consistency of exposure assessments in international retrospective case–control studies it is important to have a well-planned study protocol. Due to country-specific environments a hygienist from each participating country is necessary. A quality control study is recommended, to be performed as described, combined with round-table meetings to minimize information bias between the assessors.
Keywords: case–control; exposure assessment; international; reliability; retrospective
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In occupational epidemiology one of the most crucial tasks is to assess exposure retrospectively (Kauppinen, 1996). To increase the credibility of retrospective case–control studies, thorough presentation of the exposure assessment procedure and measures of intra- and inter-rater reliability is recommended (Stewart and Stewart, 1994). Reliability has been evaluated in some studies (Goldberg et al., 1986; De Cock et al., 1996; Siemiatycki et al., 1997; Benke et al., 1997, 2001; Tinnerberg et al., 2001), but such data are, to our knowledge, sparse when the exposure assessment has been performed in more than one country.
An international epidemiological study aiming to answer the question of whether occupational exposure to carcinogens modified the association between chromosomal aberrations (CA) in peripheral lymphocytes (PBL) and cancer gave the opportunity to evaluate methods for exposure assessment. It had earlier been shown that a high frequency of CA in healthy subjects predicts an increased cancer risk (Hagmar et al., 1994; Bonassi et al., 1995). The results from a European collaborative study [The European Study Group on Cytogenetic Biomarkers and Health (ESCH)] convincingly supported the earlier studies and also showed that the cancer predictivity of CA was not modified by either country, gender, age at cytogenetic testing or time since testing (Hagmar et al., 1998). However, whether the predictivity of CA for cancer was dependent or independent of exposure to carcinogens remained to be evaluated. To clarify this a nested case–control study was conducted within the ESCH cohort (Bonassi et al., 2000). The results from that study showed that neither exposure to occupational carcinogens nor smoking modified the risk predicted by CA.
The subjects in the Nordic and Italian cohorts (Hagmar et al., 1998) were originally selected to participate in cross-sectional cytogenetic studies because of their potential occupational exposure to clastogens or carcinogens or because they were unexposed. CA in PBL have been used as a biomarker in order to survey genotoxic or carcinogenic exposures in workplaces since the 1960s. The exposure information for the cohort members was limited to the period of CA testing in the original studies. The nested case–control study provided the opportunity to collect information on lifetime occupational histories and other relevant factors.
The aim of this paper is to describe the exposure assessment method used in an international multi-centre case–control study and to evaluate the quality control procedure performed.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The exposure assessment procedure
Five occupational hygienists assessed exposures in each participating country: Denmark, Finland, Italy, Norway and Sweden. There was also an independent occupational hygienist team (Spain) to verify the reliability of the exposure assessment procedure. The exercise was divided into six steps: (i) a review of the literature from the original cytogenetic studies, selection of relevant exposure indices (agents or activities) and establishment of the criteria for exposure classification; (ii) identification of subjects; (iii) data collection for the exposures (occupational exposure, smoking status, cytostatics, radiotherapy) for all cases and controls; (iv) harmonization of assessment criteria among occupational hygienists; (v) individual exposure assessments; (vi) analysis of the reliability of the assessments. During the procedure the whole group of occupational hygienists met five times. Moreover, some of the group met several times and there was also frequent use of e-mail to facilitate the work.
The ethical aspects of the study protocol were approved by the local Ethics Committees or legal authorities in all the participating countries.
Selection of exposure indices
Scientific publications on chromosomal aberrations originating from the original cytogenetic studies comprising the basis for the pooled cohort (Hagmar et al., 1994; Bonassi et al., 1995) were compiled and carefully scrutinized. Relevant exposure agents or occupational activities, which were the reason for the original cytogenetic testing, were identified and listed. The main criteria in the selection of exposures with a potential impact on the association between CA and cancer risk were clear evidence or a strong suspicion of their carcinogenic or clastogenic properties.
A matrix with 23 categorized occupational exposure indices was constructed (Table 1). Some subjects had not only been exposed to the agents included in the original cytogenetic studies, but also to others classified as class I carcinogens by the International Agency for Research on Cancer. A further category was created summarizing exposure for these agents.
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Exposure assessments were performed semi-quantitatively at four levels (none, low, medium and high) for 18 of the agents, at three levels (none, low and high) for two agents and qualitatively for the remaining four agents. Cut-off limits between the different exposure levels were carefully defined and set in three different ways. For two agents they were based on absorbed dose and for a further 12 they were based on 8 h time-weighted average (TWA) air concentrations, expressed as either absolute values or as a percentage of the corresponding threshold limit value (TLV) [American Conference of Governmental Industrial Hygienists (ACGIH, 1997)]. For the remaining six agents the limits were based on either the frequency of exposure or the type of activity. An even distribution of the subjects in each exposure level category was taken into account to set quantitative cut-off values. Background exposures were defined for seven ubiquitous agents to which the general population can be exposed at low levels (Table 1).
Study population
The cohort of subjects examined as adults for CA in PBL between 1965 and 1988 comprised 3541 subjects (1968 from 10 laboratories in the Nordic countries and 1573 from 10 laboratories in Italy). In total, the Nordic cohorts comprised 93 incident cancer cases and the Italian cohort comprised 62 deceased cancer cases during a follow-up period that ended between 1993 and 1996 for the participating countries. For the nested case–control study, the 155 cases and their corresponding controls gave 582 subjects (Bonassi et al., 2000), which was the population in the present study.
Of the 582 subjects, 159 had been classified as unexposed in the original cytogenetic studies, 401 as exposed to one of the 17 original exposures also assessed in this study and 22 were classified as exposed in the original studies but not to one of the exposure categories assessed in this study (Table 2).
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Data collection
The responsible occupational hygienist in each country gathered data on occupational exposures, smoking, radiotherapy and cytostatic treatments. The subjects were approached with a postal questionnaire and asked to provide a lifelong working history by listing the name and location of company for each job held, main job tasks, smoking habit and the year of receiving cytostatics or radiotherapy. The inquiry was sent to cases and controls or, if deceased, to next of kin (only widows or widowers, children, parents or siblings were accepted). Together with the questionnaire, an explanatory covering letter was sent. When the questionnaire had been returned, the occupational hygienist performed a partly structured telephone interview with the responder, in which more specific questions about working activities were asked (e.g. what did the company produce, which was the subject’s main work task, did the subject use any specific chemicals or materials, specific questions about the work environment, were there any important other activities in the same premises where the subject had worked). Further questions about names of co-workers or company employees were added if needed. If subjects did not spontaneously return the questionnaire, a reminder was sent and finally a telephone interview was performed. Exposure data from the original cytogenetic studies (exposure measurements, exposure assessments or interviews with the subjects about working activities) and other exposure measurements performed at the companies were also used. Several of the companies involved in the original cytogenetic studies were also visited or contacted by an occupational hygienist. Past and present work activities, working conditions and exposure levels were thereby clarified. Other information sources included contacts with other companies where the subjects had been employed, former co-workers, company records and medical records. When the medical or company records were reliable and covered the whole occupational history, the subjects were not interviewed. Information on the completeness and type of information compiled for the exposure assessment for each subject was registered and is shown in Fig. 1.
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Availability of information and best fit procedures varied between countries. In Italy, for all but one subject there was earlier information available mainly from medical records from the time of cytogenetic analysis. In most medical records the occupational histories were extensively described. The main drawback was that the information mainly covered only the time prior to the CA test. Medical records were used when available in the Nordic countries, but were not available to the same extent as in Italy. In Denmark, all subjects came from a study of stainless steel welders for which a questionnaire follow-up was made on the total cohort and supplemented with information from telephone interviews and registries. In Norway, much information was gained from two companies, from which subjects exposed to nickel and vinyl chloride and subjects considered as unexposed were recruited. In Finland, a lot of information was gained from the original studies; the nuclear radiation centre assessed exposure to ionizing radiation. In Sweden, a large proportion of the subjects were recruited as comparison subjects because they were considered as not occupationally exposed to carcinogens or clastogens. For these subjects there was no earlier information available and telephone interviews were the only information source.
Harmonization of assessment criteria
In order to harmonize the occupational exposure assessments, a round to test the agreement was performed. Based on short descriptions of jobs and available data on exposures translated into English by every occupational hygienist, the independent occupational hygienist team selected 27 subjects (5%). The selection was done in order to cover as many agents as possible at various exposure levels. All ascertained exposure information for these 27 subjects was translated into English and sent to the five participating occupational hygienists, for independent exposure assessments.
Inconsistencies found were presented and discussed at a meeting with all the hygienists. This review and discussion resulted in better definitions of exposure categories and cut-off limits. Borderline exposures in particular were discussed using the experience from all the participating countries. Agreements on how to rate specific jobs and activities not described in the original papers were also reached. Inconsistencies in the way the subjects had been coded were highlighted, resulting in improved coding instructions. At the end, consensus on all assessments was reached and necessary corrections in the exposure matrix were adopted.
Exposure assessments
The occupational exposure for each subject was assessed without knowing the case–control status, from the year of finishing school (or age 15 years) until year of cancer diagnosis, year of cancer death or end of follow-up period, whichever occured first. For the matched controls, end of follow-up was considered identical to that of the case. Exposure to a certain agent was defined as a job period of at least 1 year.
For periods for which data on the occupational history or exposures were missing two additional codes were defined, certain exposure but to an uncertain level and uncertain exposure status.
Quality control
Final assessments were submitted to a quality control procedure with a similar structure to the harmonization step. The independent hygienist randomly selected 55 subjects (9%), the work histories of which were translated into English by the original assessor and sent to the four occupational hygienists in the other countries.
The reliability of the exposure assessments was calculated as a deviation from the majority of the assessors, as Cohen’s and as overall proportion of agreement. In all calculations of reliability, the periods coded for a certain exposure but to an uncertain level were reclassified as a low exposure and the periods coded as uncertain exposure were reclassified as unexposed. The number of exposure periods for each specific exposure index was calculated and defined as one time window when none of the raters changed the assessed exposure level. If one assessor changed the exposure level a new period started. This meant that for a particular exposure agent a subject classified as unexposed for the entire period contributed to one comparison, whereas a subject for whom the exposure status changed once during the assessment period contributed to two periods. All five assessors assessed a total of 1642 exposure periods.
Deviations from the majority
In the calculations of deviations from the majority of assessors only the exposure status (non-exposed/exposed) was taken into account. The deviations are presented in three ways: (i) for each specific exposure; (ii) for all exposures by an assessor; (iii) for the main classification used in the epidemiological study.
For each specific exposure
All assessed periods were divided into four groups: (i) all assessors agreed on non-exposed status; (ii) one assessor had a deviating opinion on the exposure status (exposed/non-exposed); (iii) two assessors had deviating opinions on the exposure status; (iv) all five assessors agreed on exposure. The expected numbers of deviations on own assessments were calculated as the total numbers of deviating assessments divided by the number of raters (5). Thus, for example, for organic solvents the number is (17 + 2 x 19)/5 (Table 4). The observed number of deviations on own assessments was compared with the expected number. The assessments performed by the assessor from the same country as the subject were defined as own assessments.
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For all exposures for each assessor
For the subjects from the five different countries, the number of periods classified as exposed by at least one rater were calculated. The sum of these periods is the same as the total number of periods from categories (ii), (iii) and (iv) above. The expected numbers of deviations in exposed periods for each country were calculated as if the deviating periods were evenly distributed over the countries; number of exposed periods for the country multiplied by total deviations (114 + 2 x 78; from Table 4) divided by total number of exposed periods. The expected number of deviations on own assessments was calculated by dividing by the number of raters (5). The expected number of deviations was compared with the observed deviating periods from own assessments for each country.
Main classification used in the epidemiological study
In the epidemiological study the exposures were collapsed into three groups: (i) medium or high exposures to agents evaluated in the original cytogenetic studies and classified by the IARC as human carcinogens (class 1); (ii) all other agents in the matrix; (iii) non-exposed. In our calculations of the deviations from the majority of the assessors we used the time window from 5 years before the time of CA test until the test.
Cohen’s
The reliability of the period assessments was calculated as values in 4 x 4 matrices (no, low, medium or high exposure). Since five countries were involved, 10 pair-wise values were calculated for each specific agent if the prevalence for each assessor was >3%. Furthermore, for multiple ratings according to Fleiss (1981) for the 4 x 4 matrix and for a 2 x 2 matrix (non-exposed/exposed) and prevalence were calculated. The overall proportion of agreement (Fleiss, 1981) was calculated when the 10 pairwise matrices were summed up to one matrix.
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RESULTS |
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Data collection
The information sources used in the five different countries are shown in Fig. 1. For eight subjects (1.4%) there was no information available and for another seven (1.2%) the data were so scarce that the exposure status remained uncertain. For 142 subjects (24%) there was only one source of information and for 210 (36%) there were at least three different sources of information.
The total number of person-years under observation was 24 176. Data were missing for 1131 person-years (4.7%) and for 384 person-years (1.6%) data were so scarce that only uncertain assessments could be performed.
Prevalence of exposure
The distribution of the exposure prevalences is displayed in Table 1. The highest exposure prevalences were found for agents such as organic solvents that have been widely used. High exposure prevalences were also seen for agents that were common in the original studies. Among the 73 subjects that were classified as exposed to other IARC class 1 chemicals the most common exposures were silica (45%), wood dust (11%), mineral oil (11%) and working in a shoe factory (10%).
The exposure statuses of the subjects in the case–control study according to the original cytogenetic studies on the cohort are presented in Table 2. As a result of the present study only 99 of the 159 subjects considered as unexposed in the original cytogenetic studies were classified as unexposed during their whole work history. Work histories were missing for five subjects and 55 were assessed as exposed for at least one time period. Of these 55 subjects, 25 were also coded as exposed at the time of CA testing. Organic solvents and polycyclic aromatic hydrocarbons (PAH) were the most common exposures among this group. Of the 423 subjects that had been classified as exposed in the original cytogenetic studies, 23 were reclassified as unexposed by the five raters, data were missing for 10 and 390 subjects were assessed as exposed. At the time of CA testing the hygienists assessed that 281 of these 390 subjects were exposed for the original exposure and 22 for another exposure.
Quality control
The exposure prevalences for the 55 subjects assessed by the original assessors from the five different countries were compared with the prevalences assessed by the other occupational hygienists (Table 3). For all five countries, the prevalences assessed by the original assessor were higher than the average prevalence assessed by the other four. For three of the five countries the prevalence assessed by the original assessor was the highest assessed prevalence for that country.
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The distribution of deviating assessments for each exposure index is displayed in Table 4. The numbers of deviating periods for an agent are strongly correlated with the total numbers of periods for that agent (Spearman’s
= 0.89, P < 0.01). The proportion of full agreement on the exposure status for the 1642 periods was 88%, the majority (84%) of the periods being coded unexposed. Thus, one or two raters disagreed on the exposure status for 12% of the periods. The number of observed deviations on own assessments was higher than or equal to the expected deviations on own assessments for all agents except four: organic solvents, benzene, styrene and ionizing radiation. The total number of observed deviations on own assessments was higher than expected (60 versus 53). Of the 192 deviating periods, the minority of assessors regarded 132 (69%) of them as exposed. For the 60 deviations on own assessments as many as 56 (93%) belonged to the assessments that were in a minority (Table 4). The numbers of expected and observed deviating periods on own assessments for all periods are displayed in Table 5 with respect to the five assessors. For four of five assessors the numbers of observed deviating periods are higher or equal to the expected ones.
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When considering the classification of exposure applied in the epidemiological study 34 of the 55 subjects were classified in the same exposure category independently of the assessor. All three levels of exposure were assigned to only two subjects. Regarding the remaining 19 subjects, one or two assessors’ classification differed from the majority and nine of these were on own assessments.
The calculated values, range and overall proportion of agreement are presented in Table 6. Strong negative correlations were seen between the prevalences and reliability of exposure assessment, expressed as values (4 x 4 matrix, Spearman’s = –0.76, P < 0.01; 2 x 2 matrix, Spearman’s = –0.71, P < 0.01) and as overall proportion of agreement (4 x 4 matrix, Spearman’s = –0.91, P < 0.01; 2 x 2 matrix, Spearman’s = –0.67, P < 0.01). Considering the observed negative correlation between the exposure prevalences and the values, the value for the exposure index for other IARC class 1 agents was substantially lower than expected from its prevalence.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To increase the credibility of occupational epidemiology studies the importance of explicit descriptions of the methods of exposure assessment used are increasingly stressed (Stewart et al., 1996). The present cohort nested case–control study has an unusual design. In many occupational cohort studies the subjects have an occupation or an exposure in common. In this cohort, the common factor was analysis of CA in PBL. Similar study designs can be expected in the future in molecular epidemiology, where biomarkers of exposure, early effect and genetic susceptibility are used.
All the subjects from the original cytogenetic studies had been exposed to potential carcinogenic or clastogenic agents or they had been selected as unexposed comparison subjects. The exposure assessment in the original studies mainly considered one exposure agent, disregarding other possible carcinogenic or clastogenic exposures. If the classification of exposure performed for the original cytogenetic studies had been used in the present study it would have resulted in a high degree of misclassification, presuming that the reassessments were regarded as a gold standard for the true values. For example, 16% of the original unexposed comparison subjects were reassessed as exposed at the time of the cytogenetic test.
When evaluating the quality of a retrospective exposure assessment there is often no true or gold standard to compare with. The common way to analyse the quality has been to calculate the reliability within or between assessors (Goldberg et al., 1986; De Cock et al., 1996; Benke et al., 1997, 2001; Siemiatycki et al., 1997; Tinnerberg et al., 2001) and present the results as statistics. In all these studies the assessors originated from one country. To our knowledge, reliability has been assessed in only one international case–control study ('t Mannetje et al., 2001), but the procedure and results have been only briefly presented. In this study some of the differences in the assessed exposure statuses resulted from true differences in exposure profiles of the same occupations between the countries. In other, however very few, international retrospective case–control studies where occupational exposure has been assessed it has been based on self-reported exposures or occupations sometimes coupled to a job–exposure matrix (Mandel et al., 1995; Fortuny et al., 1999; Heinemann et al., 2000) or on actual measured exposure levels (Bonde et al., 1999) or performed locally and thereafter centrally reviewed (Cordier et al., 1997) or only performed centrally after using a standardized interview form (Hernberg et al., 1983).
The reliability of the assessments is not easy to interpret as values. The value depends on the size of the matrix, on the prevalence of exposure and also on the balance in the marginal (Feinstein and Cicchetti, 1990). The larger the matrix the lower the expected values and the higher the prevalences the lower the values. In this study, in addition to the values we present the overall proportion of agreements and also deviations from the majority of the assessors.
Overall agreements were high; the same exposure class, as defined in the epidemiological study, was assigned by all the assessors for 34 of 55 (62%) subjects. The ranges of the pair-wise calculated values were from poor to excellent (Table 6). The for multiple raters for both the 4 x 4 and 2 x 2 matrices were from fair to excellent. A similar pattern was seen between the overall proportion of agreement and . The lowest agreements, when also taking into account the correlation between the prevalence and the overall proportion of agreement, were seen for other IARC class 1 agents, asbestos and benzene. Similar results were also seen for the calculations of deviations (Table 4). It is interesting that two of these three agents are not included in Table 2, in which the main original exposures are presented. Further, the observed deviations on own assessments were also among the highest for asbestos and other IARC class 1 agents and also for another agent not in the original studies, man-made mineral fibres. These exposures were little considered during our harmonization meeting as they were thought to be rare. Furthermore, it was not possible to discuss the other IARC class 1 agents in detail, as this ‘exposure’ in fact consisted of several. During harmonization frequent exposures were more thoroughly discussed than rare ones. If all exposures had been discussed to the same extent a higher conformity would probably have also been seen for these rare exposures.
The prevalence of exposure, stratified by assessor for the 55 subjects in the quality control round, was higher among the original raters than the average prevalence among the other assessors (Table 3). Further, four of five assessors had an equal or higher observed number of deviating periods on own assessments than expected (Table 5) and 93% of deviations on own assessments were in a minority. These results indicate that the home assessors classified more job situations as exposed than the others, especially for agents that had not been thoroughly discussed in the harmonization phase of the assessment procedure.
One reason for this discrepancy could be that there are real differences with respect to occupational exposures between the countries. Such differences were also found during harmonization in the present study and have been discussed by 't Mannetje et al. (2001). Another reason could be differences in the level of information between the home assessor and the others, due to personal knowledge about the specific environments and misunderstandings or difficulties in translation of the information. The effect of such differences in information when industrial hygienists assess exposure has been evaluated (Stewart et al., 2000); it was found that with a limited amount of information the hygienists could not produce assessments as more in-depth evaluations. Although Stewart’s study and this study are not fully comparable, they still both indicate that the home assessors estimated the exposures better than the others, as they probably had more in-depth knowledge of the exposure situations. Thus, for the previously mentioned reasons, misclassification of the exposures of cases and referents was probably lower than the results of the quality control round indicate.
Another problem was how we performed the quality control. The exercise was performed using only written information. For several subjects there were misunderstandings of the translated text, as none of the assessors were native English speakers. To increase the quality of the quality control it is essential to work towards the goal that all assessors have the same information as in the assessment procedure. A possible way to solve this would have been to have one or two round-table meetings at which the information for each subject in the quality control round was presented orally. With such round-table meetings misunderstandings could have been immediately ruled out.
We do not think that this has had an important influence on interpretation of the epidemiological study as all subjects were matched on country and possible misclassification of the above kinds would be non-differential.
When performing an international retrospective case–control study it is important to have participating assessors from the countries involved in the study, as they have country-specific knowledge. To ensure consistency of the exposure assessments it is important to have a well-planned study protocol and to give the assessors the possibility of meeting and discussing the procedure and assessment criteria. Performing one or several harmonization steps probably increases the conformity of the assessments. The quality of the quality control could probably be increased if the procedure were combined with round-table meetings. To organize a quality control round in international studies is more complicated than in national studies.
Acknowledgements—We are indebted to Marina Buratti, Carita Lindholm, Per Sundell and Jan Rosemberg for their valuable assistance in the exposure assessments and to Zoli Mikoczy and Joaquín Pérez-Nicolás for their epidemiological assistance. This study was supported by the European Union Biomed 2 Program (Contract no. BMH4-CT96-0874), the Swedish Medical Research Council, the Swedish Cancer Society, the Swedish Council for Work Life Research, the Academy of Finland, the Danish Occupational Environment Fund, the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Italian Ministry of Health and the Italian Ministry of the University and of Scientific and Technological Research.
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FOOTNOTES |
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* Author to whom correspondence should be addressed. Fax: +46 46143702; e-mail: hakan.tinnerberg{at}ymed.lu.se
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