Bias in Studies of Parental Self-reported Occupational Exposure and Childhood Cancer
Joachim Schüz1 ,
Logan G. Spector2 and
Julie A. Ross2
1 Institute for Medical Biostatistics, Epidemiology, and Informatics (IMBEI), University of Mainz, Mainz, Germany.
2 Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Received for publication November 7, 2002; accepted for publication April 9, 2003.
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ABSTRACT
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Several case-control studies have demonstrated positive associations between parental occupational exposures and childhood cancer. However, an overestimation of risk estimates due to recall bias is of concern. The magnitude and nature of this bias were explored using data from a German case-control study on childhood leukemia conducted between 1992 and 1997. A moderate overreporting of occupational exposures by fathers was observed, particularly for the prenatal period. Overreporting was most apparent when the time between exposure and interview was short. It was also found that job titles were no satisfactory substitute for information on specific occupational exposures. The results of this analysis emphasize the need for more sophisticated exposure assessment methods in epidemiologic studies of childhood cancer. However, because future case-control studies will at least partially rely on questionnaire data, improvements including probing questions, better interview techniques, and validation studies are indicated.
bias (epidemiology); case-control studies; child; leukemia; mental recall; occupational exposure
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INTRODUCTION
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The most common childhood malignancies diagnosed in developed countries include leukemia, brain tumors, neuroblastoma, lymphomas, and Wilms tumor (1). Although the etiology of most childhood cancers is largely unknown, several case-control studies have demonstrated positive associations between either specific parental job titles or occupational exposures and childhood cancer (2). Occupational exposures to specific mutagens could be etiologically important preconceptionally (through creation of germline mutations that could potentially be passed on to the child), during pregnancy (through transplacental crossover), and postnatally (through direct transmission of exposure residues). As in all case-control studies, however, recall bias is a concern. For example, parents of cases may think more about past exposures and either overreport an experience or recall trivial events, whereas a parent of a healthy child may simply not remember or may believe an exposure to be unimportant.
In a recent case-control study of self-reported parental exposures, slightly elevated risk estimates for most of the occupational exposures explored were found (3). Interestingly, many parents reported that occupational exposures occurred during the prenatal period but not during the postnatal period. Although this was plausible for mothers, who may have more often stayed at home with their infants, such a pattern was found for fathers as well. This same pattern also held for most exposure groups. Reports of similar findings in a similarly conducted study elsewhere add to the concern (4) of underlying bias. In this paper, we analyze the data further to describe this potential bias and to offer potential solutions.
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MATERIALS AND METHODS
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Details of this comprehensive case-control study have been published elsewhere (5). Briefly, the study comprised three case-control studies including the following: 1) a study of childhood cancer in Lower Saxony, the northwestern part of Germany; 2) a study of childhood leukemia and lymphoma embedded in an ecologic study in the vicinity of all German nuclear installations and selected control regions; and 3) a study of childhood cancer covering the entire region of West Germany, the former Federal Republic of Germany. All studies included childhood cancer cases diagnosed before the age of 15 years who were registered with the German Childhood Cancer Registry at the University of Mainz. Diagnostic groups involved in all three studies were acute leukemia and non-Hodgkins lymphoma. Children with a brain tumor, neuroblastoma, nephroblastoma, rhabdomyosarcoma, or bone tumor were enrolled only in Lower Saxony and West Germany. The malignancy was diagnosed between July 1988 and June 1993 for Lower Saxony, between January 1980 and September 1994 for the vicinity of all German nuclear installations and selected control regions, and between October 1992 and September 1994 for West Germany, respectively. All controls were drawn from population registration files; registration of residency for people of all ages is compulsory in Germany. For the vicinity of all German nuclear installations and selected control regions and for West Germany, one control was sampled for each case from the community where the case lived at the date of diagnosis. Matching criteria were gender and date of birth within 1 year. For Lower Saxony, two controls were sampled for each child with leukemia, again matched for gender and age. One control was recruited from the same community as the case. The second control was drawn from a randomly selected community of Lower Saxony by a population-weighted sampling procedure. No Lower Saxony controls were drawn for children with solid tumors.
The studies were carried out simultaneously during 1992 and 1997. There was some overlap among the three studies; for example, leukemia cases that were diagnosed between October 1992 and July 1993 and lived in the vicinity of a nuclear power plant within the boundaries of Lower Saxony were eligible for all three study parts. For the three studies combined, the response rates were approximately 79 percent among leukemia cases, 78 percent among cases with solid tumors, and 67 percent among controls. Each case, however, was included only once in the analyses presented here. Details on nonparticipation have been published elsewhere (6).
The methods of exposure assessment were identical in all three studies and were performed by the same personnel. Exposure was assessed by a self-administered questionnaire and a subsequent telephone interview with both parents. The questionnaire was based on a structured questionnaire developed by the former US Childrens Cancer Group (4, 7). The questionnaire asked parents to list all of their occupations (job title, branch of industry, and dates when they started and stopped working in this particular job). This job list was verified during the telephone interview; at that time, the specific activities or duties in each job were also assessed. Furthermore, the self-administered questionnaire included a list of 11 substance groups that were regarded as possibly hazardous to health including (ordered as on the questionnaire) the following: 1) solvents; 2) paints or lacquers; 3) oil products; 4) pesticides (including herbicides and insecticides); 5) chemicals other than those in groups 14; 6) plastic or resin fumes; 7) industrial dusts; 8) metal melting; 9) ionizing radiation; 10) gases; and 11) other substances. For all these substance groups, parents were requested to specify whether they were occupationally exposed to one or more of these substance groups during the year before conception, during pregnancy, or after the childs birth (but before diagnosis) or whether they were never exposed to any of these substances. The questionnaire consisted of six checkboxes for every substance group (one per period for each parent) and two checkboxes for no exposure at all (one for each parent). If no ticks were made for any checkbox, data were coded as missing. For each category, there was also an entry field where the parents could name the specific substance they used; few parents used this field. For two exposure categories (radiation and pesticides), there was an additional section with more detailed questions probed during the telephone interview. Parents who were exposed to ionizing radiation were asked if they had worked under dosimetric surveillance (if so, the investigators tried to obtain the cumulative preconceptional radiation dose) or if they had worked in a nuclear power plant. All parents were asked if they had used insecticides in the home, if they had used pesticides in the garden, or if they were farmers or had been working the land on a part-time basis and, at any time, had had contact with pesticides.
Statistical analysis
The risk analyses on parental occupational exposures have been published in a previous paper (3). For this methodological approach, we pooled all study components in order to achieve the largest possible study population. Odds ratios were calculated with unconditional logistic regression analysis stratified for sex, age (age groups of 1 year), and year of birth and additionally adjusted for socioeconomic status and degree of urbanization (8). This frequency-matched design was also the preferred statistical model in previous papers.
We also retained the original individual matching and calculated all odds ratios by applying a conditional logistic regression model (3). Because of the smaller sample size, the confidence intervals became wider; however, there was no substantial difference between the individually matched and the frequency-matched models that cannot be explained by random variation (data not shown). We also evaluated the individual contributions of the three single studies to the overall results. There were no material differences. The reason for this, however, might be that the nationwide study involved 70.2 percent of the combined study population (71.0 percent of cases and 69.0 percent of controls) and therefore greatly influenced the overall direction of the study. Adjustment for study origin did not alter the results (data not shown).
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RESULTS
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Of 66 analyses of childhood leukemia and parental occupational exposures (11 substance groups, three time periods, two parents), only 12 risk estimates (18 percent) were below unity and 51 were above unity (77 percent) (table 1); the remaining three odds ratios were 1.00. Although nine of these odds ratios were statistically significantly increased (two-sided p values < 0.05), no odds ratio was significantly decreased. Regarding the three time periods, three odds ratios (14 percent) were below unity for exposure in the year before conception, one odds ratio (5 percent) was below unity for exposure during pregnancy, and eight odds ratios (36 percent) were below unity for exposure between birth and the date of diagnosis (or pseudodiagnosis date among controls). This pattern was also seen for other diagnostic groups. Of 110 analyses of childhood solid tumors and parental occupational exposures during pregnancy (11 substance groups, five tumor groups, two parents), 26 odds ratios (26 percent) were below unity and 78 (71 percent) were greater than unity.
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TABLE 1. Distribution of odds ratios for childhood leukemia and parental occupational exposures, Germany, 19921997
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Table 2 shows the prevalences of self-reported paternal occupational exposures for fathers of leukemia cases and of controls. Among cases, the prevalence for each of the nine specific substance groups was consistently higher during the preconceptional period than during pregnancy, and it often decreased again in the postnatal period. Among controls, the prevalence was also always highest during the preconceptional period, but it was usually lowest during pregnancy. When the analysis was restricted to fathers who maintained the same job during the whole period of interest, the observed pattern remained almost the same (table 2). The definition of fathers without a job change was quite strict: Only fathers who gave no change in job title, company, or activities were included.
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TABLE 2. Prevalences, expressed as percentage, of paternal occupational exposures to potential health hazards, Germany, 19921997
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A material difference between cases and controls was seen when the proportions of prenatally occupationally exposed fathers were analyzed separately for different time intervals between the childs birth date and the date of the interview. As illustrated for paints or lacquers and for plastic or resin fumes in figure 1, among case fathers, there was a sharp decline in exposure prevalences with increasing time between birth and interview. This decline was not observed for controls. This pattern was similar for all 11 substance groups and had a considerable impact on the risk estimates. The odds ratios, calculated separately for the three time intervals, are shown in table 3. Except for industrial dusts, the odds ratios were always highest if the time period between birth and interview date was short. For maternal prenatal exposures, there was no trend in the risk estimates with time between birth and interview (table 3). In addition, no consistent pattern emerged by looking at the different exposure prevalences.

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FIGURE 1. Fraction of fathers occupationally exposed to paints or lacquers (solid curve) or occupationally exposed to plastic or resin fumes (dashed curve), presented separately for case (filled circles) and control (filled squares) fathers and for the different time lags between the date of birth and the date of the interview, Germany, 19921997.
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TABLE 3. Odds ratios for prenatal parental occupational exposures by time period between the date of birth and the date of the interview, Germany, 19921997
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Table 4 presents a comparison between self-reported occupational exposures and job titles. Because exposures occur in many different occupations, only the five most frequent job titles are listed per substance group. These five most frequent job titles, however, often accounted for less then half of all exposed subjects. As can be seen in table 4, high proportions of exposed parents within a job category were rather exceptions, such as painters and varnishers reporting an exposure to paints or lacquers (94 percent). In many occupations, in which an exposure seemed to be very likely from the job title, for example, farmers or gardeners and exposure to pesticides, fewer proportions of parents than expected reported an occupational exposure. There were some job titles for which a relevant fraction of parents reported an occupational exposure that is not typically associated with that job title (e.g., painters and varnishers who reported an exposure to pesticides). Finally, there were some unlikely occupational exposures reported with specific job titles (e.g., pesticides and ionizing radiation among office workers).
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TABLE 4. Selected parental self-reported occupational exposures and job title (in the year before conception), Germany, 19921997
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DISCUSSION
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In a recent German population-based case-control study on childhood cancer, most of the risk estimates for childhood cancer with parental occupational exposures were at least slightly elevated. Furthermore, many parents reported occupational exposures only for the prenatal but not postnatal period of the index child. We examined the data in more detail to explore if there was some kind of systematic bias. This brought up the following questions: 1) If there was bias, what was its nature? Was it a more general type of bias, or was it specific for particular substance groups, for a particular time period, or for one of the parents? 2) If there was bias, was it a differential bias, that is, different in magnitude for cases and controls, and thus had the potential to inflate the risk estimates? If so, what was the strength of the bias? 3) If there was bias, could this bias be avoided by cross-checking the self-reported occupational exposures with other items from the questionnaire, that is, the parental occupational history?
Addressing question 1, it seems to be that the risk analysis for parental occupational exposures was affected by bias. The most peculiar finding of our analysis was that fathers especially reported more exposures during the prenatal period of their child than during the postnatal period, even though the postnatal period was mostly a longer time window (while the prenatal period was usually 1 year and 9 months, the postnatal period from birth to diagnosis ranged from a few months up to 14 years). Since this pattern was seen also for fathers who maintained the same job during the whole observation period, the prevalence differences between the periods were likely due to bias rather than to some real effect. The pattern emerged for case fathers as well as for control fathers; however, it was more pronounced for case fathers. A possible explanation is that, at the time the parents filled in the questionnaire, their focus was on the prenatal period because they thought that this time period was more important and, thus, they overvalued rather minor exposures. In the instructions for the self-administered questionnaire, it was emphasized that the questions had to be answered by both father and mother; however, since the majority of the questions was related to maternal topics, it is conceivable that a number of questionnaires were filled in only by the mother. This kind of surrogate response could lead to overreporting by the mothers regarding whether the father was occupationally exposed or not. Because odds ratios were at least slightly elevated for all substance groups and because the exposure prevalence patterns were similar for all substance groups, it was a general kind of bias.
As response rates were 79 percent among cases and 67 percent among controls, nonresponse bias needs to be discussed as a possible cause of the observed bias. One argument against a material impact of nonresponse bias is that the same sort of bias was seen for all substance groups and, consequently, also for a variety of different occupations. Thus, exposures were linked to socioeconomic status in different ways. Participation among controls, on the other hand, was clearly related to a higher socioeconomic status (6) and, if response bias had a strong impact, one would expect this to be dissimilar for different substance groups. In conclusion, the observed bias is likely to be due to recall, but it is difficult to determine whether it was caused mainly by surrogate responses, by selective recall, or just by memory errors.
Addressing question 2 and assuming that there was in fact recall bias, this bias was likely to be differential. This is supported by the observation that for case fathers there was a decline in exposure prevalences with increasing time between the childs birth date and the date of the interview, a decline that was not seen for fathers of control children. Other support may come from the observations that, among housewives, case mothers consistently reported more exposures than did control mothers, irrespective of the substance group (data not shown), and that for all substance groups, among case parents the difference between the prevalence of prenatal exposures and the prevalence of postnatal exposures was greater than for control parents. Consequently, it is possible that the risk estimates for parental occupational exposures were inflated. Since most risk estimates were between 1.1 and 1.2 in magnitude, however, it is unlikely that recall bias can entirely explain associations in the order of 1.52.
A very popular example of differential recall bias in retrospective studies is bias due to underreporting by control subjects, which means that, while cases reflect about potential causes of their disease and therefore may recall former events quite well, controls tend to forget former exposures, particularly when the exposure was a long time ago (9, 10). In our study, underreporting by controls was not likely, because the prevalence of exposure among control parents was not related to the time between the childs birth and the date of the interview. On the other hand, there was a correlation between time and prevalence of exposure among cases, with substantially higher exposure prevalences for shorter time intervals between the relevant exposure period and the interview date. This could indicate a special type of over-reporting by cases: Case parents may tend to recall insignificant or once-in-a-lifetime exposures or events (e.g., a 1-day spraying against insects), which they are less likely to remember if the time interval between this event and the interview is longer.
Addressing question 3, our data show material differences between exposure classifications based on parental self-reported exposures or job titles. In contrast to self-reported parental occupational exposure, for which we found evidence of differential exposure misclassification caused by differential recall bias (question 2), misclassification of exposure based on job titles is likely to be the same for cases and controls, thus being nondifferential and likely to lead to an underestimation of associations. While this is an improvement over the apparent differential misclassification of self-reported exposure, it is a concern that much lower proportions of respondents report exposure to substances than their job titles would warrant. Misclassification of exposure based on job title, while nondifferential, may be substantial. Hence, job title is not a satisfactory substitute for self-reported exposures.
In summary, it is doubtful that new childhood cancer studies based solely on either of these two crude measures of parental occupational exposures will provide any new insight into possible relations between health hazards at the workplace and childhood cancer. Nevertheless, studies have observed associations among childhood cancer and paternal exposures to paints, solvents, and pesticides. In particular, associations among childhood leukemia, non-Hodgkins lymphoma, and parental occupational exposure to pesticides are stronger than associations that could be attributed to recall bias (11, 12). The data derived from this evaluation suggest a very modest magnitude of recall bias in such studies, while associations with risk estimates of 1.5 or higher merit further investigations.
Because future case-control studies will at least partially have to rely on questionnaire data, probing questions on the numbers of exposure events, durations of exposures, specific substances, purposes of the use of specific substances, and doses of substances are essential to help discriminate between relevant and irrelevant exposures (13, 14). Such probing questions are not only invaluable in identifying relevant exposures, but they also provide some limited quantitative assessment. At the very least, probing questions lead both cases and controls to reflect more fully on any exposure opportunities than does a simple yes/no question. Another general tool for facilitating recall is the use of life events to stimulate the respondents memory, even if its usefulness would have been limited in this particular study. Probing questions should be accompanied by a clear definition of "exposure" so that different respondents have the same understanding of it, something that is easier to incorporate in face-to-face interviews compared with self-administered questionnaires.
However, even those improved methods will be limited by an individuals ability to correctly recall past events, since probing does not necessarily ensure better information on exposure. Other potential avenues could include the development of direct and indirect environmental monitoring tools. Sophisticated exposure assessment methods have been utilized for some exposures, including dosimeters and electromagnetic fields (15), and it will be important to explore alternate methods to assess occupational exposures (16). One area for future development could include collection of blood samples from parents (and possibly, children) to explore associations between reported exposures and biologic measures of dose and effect (e.g., DNA adducts, glycophorin A mutations, and so on) (17, 18).
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ACKNOWLEDGMENTS
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The German case-control study was funded by the German Federal Ministry for the Environment, Nuclear Safety, and Nature Preservation. This work was supported in part by Childrens Cancer Research Fund grant T32 CA09607.
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NOTES
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Correspondence to Dr. Joachim Schüz, IMBEI, University of Mainz, Obere Zahlbacher Str. 69, D-55101 Mainz, Germany (e-mail: schuez{at}imbei.uni-mainz.de). 
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