Letters to the Editor
see this bias across all diagnostic subgroups" (1, p. 129). We are unaware of any basis for such a presumption, and the authors do not cite any references to support this statement. Intuitively, it seems quite possible that the emotional effects of children's malignancies on parents may vary with the type of malignancy and its course, response to treatment, complications, and other such factors. Considering the foregoing and the fact that this paper ultimately fails to demonstrate compelling statistically significant results, this study can hardly be properly characterized as supporting an association, let alone a causal relation, between parental smoking and risk of childhood cancer. The mechanisms suggested by the authors, as well as the "risk estimate" that they make, are thus highly speculative, premature, and inappropriate. REFERENCES
1. John EM, Savitz DA, Sandier DP. Prenatal exposure to parents' smoking and childhood cancer. Am J Epidemiol 1991 ;133:123-32. 2. Feinstein AR. Para-analysis, faute de mieux, and the perils ofridingon a data barge. J Gin Epidemiol 1989;42:929-35. 3. Alexander FE, Ricketts TJ, McKjnney PA, et al. Community lifestyle characteristics and risk of acute lymphoblastic leukemia in children. Lancet 199O;336:1461-5.
Philip Witorsch Center for Environmental Health and Human Toxicology The George Washington University Medical Center Washington, DC 20037 Joseph M. Wu Department of Biochemistry and Molecular Biology New York Medical College Valhalla, NY 10595 Maurice E. LeVois Environmental Health Services P.O. Box 301 Tiburon, CA 94920
In their paper on parental smoking and childhood cancer, John et al. (1) say that they consider their results "suggestive of a possible influence of parents' smoking on childhood cancer" (1, p. 123), and they estimate that "6 percent of all childhood cancers and 17 percent of acute lymphocytic leukemias might be attributable to this exposure" (1, p. 131). While the words "suggestive," "possible," and "might" imply uncertainty,
Downloaded from https://academic.oup.com/aje/article-abstract/135/6/713/80106 by guest on 25 October 2019
John et al. (I) recently reported an association between parental smoking and risk of childhood cancer, and they implied that this was a causal relation. With regard to their report, the following points should be noted: 1. The study was not designed to address the possible health effects of parental smoking on children, and the findings, being the result of post hoc examination of data ("data dredging" or "para-analysis"), may be biased (2). 2. Control fathers were significantly better educated than case fathers, which suggests that socioeconomic status might differ between cases and controls. Socioeconomic status is related to the risk of childhood leukemia (3), and there may have been uncontrolled confounding for this endpoint. More importantly, when adjustments were made for father's education, odds ratios were reduced across all categories of childhood cancer, and the lower limits of the 95 percent confidence intervals included 1.0 in all cases. A similar result was obtained when one parent's smoking was controlled for the other parent's smoking. 3. There was no demonstrable dose-response relation between the father's smoking and cancer risk, either for all cancers or for acute lymphocytic leukemia. Similar analysis based on the mother's smoking, which compared only two levels of maternal smoking and involved small numbers of subjects, demonstrated only slight increases in odds ratios with increasing dose. 4. The odds ratios for associations with smoking by both parents were not significantly different from the odds ratios associated with maternal smoking alone, whether or not there was adjustment for father's education. To the extent that smoking by both parents represents greater exposure than smoking by the mother alone, there is inconsistency in dose response. 5. The authors seem to apply a different standard to the interpretation of data that they perceive as supporting their presumption of a parental smoking effect than to data that are inconsistent with that view. For example, data in table 2 (1, p. 127) on all cancers and maternal smoking during the first trimester of pregnancy, showing odds ratios of 1.3 associated with 1-10 cigarettes per day and 1.7 associated with >1 i cigarettes per day, are characterized as "suggesting a dose-response gradient" (1, p. 126). Data in table 3 on all cancers and paternal smoking, showing odds ratios of 1.9, 1.3, and 1.0 with I10, 11-20, and >21 cigarettes per day, respectively, are characterized as follows: "[T]he associations with father's smoking actually decreased slightly [emphasis added] with an increasing number of cigarettes smoked" (1, p. 127). 6. The authors dismiss the possible role of reporting bias by contending that "if case mothers were more likely to overreport or underreport smoking during pregnancy, one would expect to
713
714
Letters to the Editor
REFERENCES
1. John EM, Savitz DA, Sandier DP. Prenatal exposure to parents' smoking and childhood cancer. Am J Epidemiol 1991;133:123-32. 2. Doll R. The epidemiology of childhood leukemia. J R Stat Soc [Part 3] 1989; 152:341-51. 3. International Agency for Research on Cancer. Tobacco smoking. IARC Monogr Eval Carcinog Risk Chem Hum 1986;38:305-8.
Peter N. Lee P. N. Lee Statistics and Computing Ltd. Hamilton House 17 Cedar Road Sutton, Surrey SM2 5DA, England
THE A UTHORS REPLY We thank Kilpatrick (1), Witorsch et al. (2), and Lee (3) for their comments on our paper (4).
Kilpatrick (1) and Witorsch et al. (2) question our use of data collected for another purpose (5) to evaluate the potential cancer risk associated with parents' smoking. While it was not the primary hypothesis motivating the study, parents' smoking was of sufficient interest at the outset that considerable effort was devoted to obtaining complete parental smoking histories. Our paper results directly from that a priori interest. In our opinion, the relevant question is not whether the study was funded for this purpose but whether the data on parental smoking are unbiased and of sufficient quality to address the question. In designing the study of electromagnetic fields and childhood cancer, Savitz et al. (5) made no design decisions that adversely affected our ability to study parental smoking. Kilpatrick's (1) concern about our use of the term "exposure" may reflect, in part, a misinterpretation of our intentions. It is true that fathers who smoke might not smoke at home, but there is no reason to believe that the resulting misclassification would differ for cases and controls. The use of father's smoking as a proxy measure of smoking at home will bias results regarding passive smoking toward the null. On the other hand, people may breathe passive smoke constituents even when the smoker is no longer in the room, because of deposition of particles in room dust (6). The father's smoking does, however, provide an accurate measure of preconception exposure that might affect genetic material. As we ourselves noted (4), our results may be due to confounding by unmeasured risk factors. It should be noted, however, that there are few well-accepted risk factors that account for substantial numbers of childhood cancers. Genetic diseases, as cited by Lee (3), are rare and are not likely to be present. Other factors, such as pesticides and parents' occupation, may be more important, and we were only able to address these to the extent that they correlated with father's education. "Ill health and poor nutrition," factors cited by Kilpatrick (1), could easily result from smoke exposure, and thus they cannot be considered true confounding factors. We don't agree with Kilpatrick (1) that sophisticated statistical models always provide the best results. We examined risks associated with several sources of smoke exposure at different time periods. Many of the measures were correlated with each other, and we felt that separate analyses gave more readily interpretable results. Unlike many models, our approach required no assumptions about relations among exposure variables. Within this framework, we did adjust individually for many potentially confounding variables. With the exception of father's education, none affected the odds ratios. We agree with Witorsch et al. (2) and Lee (3) that our results may raise more questions than
Downloaded from https://academic.oup.com/aje/article-abstract/135/6/713/80106 by guest on 25 October 2019
one wonders whether such speculation is justified, in view of the extreme weakness of the authors' case and the tendency for the media to present mere possibilities as facts. In interpreting their findings, one should note inter alia the following: 1. None of the seven odds ratios cited in their abstract was statistically significant, even though these odds ratios were selected from a longer list, others being weaker and even, in some cases, nonsignificantly negative. 2. The association might have been due, or partly due, to a tendency for smokers to be underrepresented among the controls, because of the method of control selection, which led to a nonresponse proportion of 21.4 percent and a subsequent refusal rate of 19.8 percent (which was much higher than that (8.7 percent) for the cases). 3. The list of confounding factors considered seems inadequate. Doll (2), in his review of the epidemiology of childhood leukemia (which, incidentally, did not even mention parental smoking as a possible cause!), referred to a number of factors not considered by John et al. (1), including genetic causes (Down's syndrome and various hereditary causes), ionizing radiation, parental occupation, and viral infection. Doll's review makes it plain that the etiology of leukemia is poorly understood and that there may be other important risk factors, conceivably correlated with smoking, that await discovery. In 1986, the International Agency for Research on Cancer reviewed the available data on childhood cancers and parental cigarette smoking, concluding that the data "do not provide clear evidence as to whether or not there is a clear association" (3, p. 308). The study by John et al. (1) (and other studies they cite that have been published since then) does nothing to affect this conclusion.
see this bias across all diagnostic subgroups" (1, p. 129). We are unaware of any basis for such a presumption, and the authors do not cite any references to support this statement. Intuitively, it seems quite possible that the emotional effects of children's malignancies on parents may vary with the type of malignancy and its course, response to treatment, complications, and other such factors. Considering the foregoing and the fact that this paper ultimately fails to demonstrate compelling statistically significant results, this study can hardly be properly characterized as supporting an association, let alone a causal relation, between parental smoking and risk of childhood cancer. The mechanisms suggested by the authors, as well as the "risk estimate" that they make, are thus highly speculative, premature, and inappropriate. REFERENCES
1. John EM, Savitz DA, Sandier DP. Prenatal exposure to parents' smoking and childhood cancer. Am J Epidemiol 1991 ;133:123-32. 2. Feinstein AR. Para-analysis, faute de mieux, and the perils ofridingon a data barge. J Gin Epidemiol 1989;42:929-35. 3. Alexander FE, Ricketts TJ, McKjnney PA, et al. Community lifestyle characteristics and risk of acute lymphoblastic leukemia in children. Lancet 199O;336:1461-5.
Philip Witorsch Center for Environmental Health and Human Toxicology The George Washington University Medical Center Washington, DC 20037 Joseph M. Wu Department of Biochemistry and Molecular Biology New York Medical College Valhalla, NY 10595 Maurice E. LeVois Environmental Health Services P.O. Box 301 Tiburon, CA 94920
In their paper on parental smoking and childhood cancer, John et al. (1) say that they consider their results "suggestive of a possible influence of parents' smoking on childhood cancer" (1, p. 123), and they estimate that "6 percent of all childhood cancers and 17 percent of acute lymphocytic leukemias might be attributable to this exposure" (1, p. 131). While the words "suggestive," "possible," and "might" imply uncertainty,
Downloaded from https://academic.oup.com/aje/article-abstract/135/6/713/80106 by guest on 25 October 2019
John et al. (I) recently reported an association between parental smoking and risk of childhood cancer, and they implied that this was a causal relation. With regard to their report, the following points should be noted: 1. The study was not designed to address the possible health effects of parental smoking on children, and the findings, being the result of post hoc examination of data ("data dredging" or "para-analysis"), may be biased (2). 2. Control fathers were significantly better educated than case fathers, which suggests that socioeconomic status might differ between cases and controls. Socioeconomic status is related to the risk of childhood leukemia (3), and there may have been uncontrolled confounding for this endpoint. More importantly, when adjustments were made for father's education, odds ratios were reduced across all categories of childhood cancer, and the lower limits of the 95 percent confidence intervals included 1.0 in all cases. A similar result was obtained when one parent's smoking was controlled for the other parent's smoking. 3. There was no demonstrable dose-response relation between the father's smoking and cancer risk, either for all cancers or for acute lymphocytic leukemia. Similar analysis based on the mother's smoking, which compared only two levels of maternal smoking and involved small numbers of subjects, demonstrated only slight increases in odds ratios with increasing dose. 4. The odds ratios for associations with smoking by both parents were not significantly different from the odds ratios associated with maternal smoking alone, whether or not there was adjustment for father's education. To the extent that smoking by both parents represents greater exposure than smoking by the mother alone, there is inconsistency in dose response. 5. The authors seem to apply a different standard to the interpretation of data that they perceive as supporting their presumption of a parental smoking effect than to data that are inconsistent with that view. For example, data in table 2 (1, p. 127) on all cancers and maternal smoking during the first trimester of pregnancy, showing odds ratios of 1.3 associated with 1-10 cigarettes per day and 1.7 associated with >1 i cigarettes per day, are characterized as "suggesting a dose-response gradient" (1, p. 126). Data in table 3 on all cancers and paternal smoking, showing odds ratios of 1.9, 1.3, and 1.0 with I10, 11-20, and >21 cigarettes per day, respectively, are characterized as follows: "[T]he associations with father's smoking actually decreased slightly [emphasis added] with an increasing number of cigarettes smoked" (1, p. 127). 6. The authors dismiss the possible role of reporting bias by contending that "if case mothers were more likely to overreport or underreport smoking during pregnancy, one would expect to
713
714
Letters to the Editor
REFERENCES
1. John EM, Savitz DA, Sandier DP. Prenatal exposure to parents' smoking and childhood cancer. Am J Epidemiol 1991;133:123-32. 2. Doll R. The epidemiology of childhood leukemia. J R Stat Soc [Part 3] 1989; 152:341-51. 3. International Agency for Research on Cancer. Tobacco smoking. IARC Monogr Eval Carcinog Risk Chem Hum 1986;38:305-8.
Peter N. Lee P. N. Lee Statistics and Computing Ltd. Hamilton House 17 Cedar Road Sutton, Surrey SM2 5DA, England
THE A UTHORS REPLY We thank Kilpatrick (1), Witorsch et al. (2), and Lee (3) for their comments on our paper (4).
Kilpatrick (1) and Witorsch et al. (2) question our use of data collected for another purpose (5) to evaluate the potential cancer risk associated with parents' smoking. While it was not the primary hypothesis motivating the study, parents' smoking was of sufficient interest at the outset that considerable effort was devoted to obtaining complete parental smoking histories. Our paper results directly from that a priori interest. In our opinion, the relevant question is not whether the study was funded for this purpose but whether the data on parental smoking are unbiased and of sufficient quality to address the question. In designing the study of electromagnetic fields and childhood cancer, Savitz et al. (5) made no design decisions that adversely affected our ability to study parental smoking. Kilpatrick's (1) concern about our use of the term "exposure" may reflect, in part, a misinterpretation of our intentions. It is true that fathers who smoke might not smoke at home, but there is no reason to believe that the resulting misclassification would differ for cases and controls. The use of father's smoking as a proxy measure of smoking at home will bias results regarding passive smoking toward the null. On the other hand, people may breathe passive smoke constituents even when the smoker is no longer in the room, because of deposition of particles in room dust (6). The father's smoking does, however, provide an accurate measure of preconception exposure that might affect genetic material. As we ourselves noted (4), our results may be due to confounding by unmeasured risk factors. It should be noted, however, that there are few well-accepted risk factors that account for substantial numbers of childhood cancers. Genetic diseases, as cited by Lee (3), are rare and are not likely to be present. Other factors, such as pesticides and parents' occupation, may be more important, and we were only able to address these to the extent that they correlated with father's education. "Ill health and poor nutrition," factors cited by Kilpatrick (1), could easily result from smoke exposure, and thus they cannot be considered true confounding factors. We don't agree with Kilpatrick (1) that sophisticated statistical models always provide the best results. We examined risks associated with several sources of smoke exposure at different time periods. Many of the measures were correlated with each other, and we felt that separate analyses gave more readily interpretable results. Unlike many models, our approach required no assumptions about relations among exposure variables. Within this framework, we did adjust individually for many potentially confounding variables. With the exception of father's education, none affected the odds ratios. We agree with Witorsch et al. (2) and Lee (3) that our results may raise more questions than
Downloaded from https://academic.oup.com/aje/article-abstract/135/6/713/80106 by guest on 25 October 2019
one wonders whether such speculation is justified, in view of the extreme weakness of the authors' case and the tendency for the media to present mere possibilities as facts. In interpreting their findings, one should note inter alia the following: 1. None of the seven odds ratios cited in their abstract was statistically significant, even though these odds ratios were selected from a longer list, others being weaker and even, in some cases, nonsignificantly negative. 2. The association might have been due, or partly due, to a tendency for smokers to be underrepresented among the controls, because of the method of control selection, which led to a nonresponse proportion of 21.4 percent and a subsequent refusal rate of 19.8 percent (which was much higher than that (8.7 percent) for the cases). 3. The list of confounding factors considered seems inadequate. Doll (2), in his review of the epidemiology of childhood leukemia (which, incidentally, did not even mention parental smoking as a possible cause!), referred to a number of factors not considered by John et al. (1), including genetic causes (Down's syndrome and various hereditary causes), ionizing radiation, parental occupation, and viral infection. Doll's review makes it plain that the etiology of leukemia is poorly understood and that there may be other important risk factors, conceivably correlated with smoking, that await discovery. In 1986, the International Agency for Research on Cancer reviewed the available data on childhood cancers and parental cigarette smoking, concluding that the data "do not provide clear evidence as to whether or not there is a clear association" (3, p. 308). The study by John et al. (1) (and other studies they cite that have been published since then) does nothing to affect this conclusion.
