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. 1998 Oct 10;317(7164):1017. doi: 10.1136/bmj.317.7164.1017a

Smoking and risk of myocardial infarction

Statistical and biological interactions should not be confused

Thomas V Perneger 1
PMCID: PMC1114030  PMID: 9765186

Editor—Prescott et al report that smoking increases the risk of myocardial infarction significantly more in women (relative risk 2.24) than in men (relative risk 1.43).1 Interactions between components of smoke and hormonal factors were suspected.

Readers may conclude from this study that men and women do not differ at all. On the basis of data on the prevalence of smoking (table 2 in Prescott et al’s paper) and from reported relative risks, we can calculate that in women the risk of developing myocardial infarction during follow up is 5.88% (380/6461) in smokers and 2.63% (132/5011) in non-smokers; in men, the risk is 10.62% (902/8490) in smokers and 7.38% (349/4701) in non-smokers. These are best estimates based on published data; the figures would change slightly if former smokers were removed from the group of non-smokers. The difference that is attributable to smoking was therefore 3.25% in women and 3.24% in men. Over 12 years, smoking caused an additional myocardial infarction in one person out of 31—equally distributed between men and women.

This shows that statistical interaction should not be confused with biological interaction. Statistical interaction concerns the modelling of combined effects of two or more risk factors for a disease in populations, and biological interaction refers to biochemical reactions in an individual. Whether statistical interaction exists or not depends on the specification of the model that is applied to data—“interaction” means that a model that simply adds the effects of two risk factors (in this case sex and smoking) does not accurately describe their joint effect (the risk of myocardial infarction in men who smoke).

Prescott et al used a multiplicative model and found a significant interaction; I used an additive model and found none. It is not uncommon to find a positive interaction on the additive scale and a negative interaction on the multiplicative scale. Models of absolute and relative risk have their respective merits and disadvantages, neither is wrong or right, and neither has anything to say about the biology of the phenomenon under study. Prescott et al may be right in their hypothesis that components of smoke interact with hormones in causing myocardial infarction, but their data do not show that this is happening.

References

  • 1.Prescott E, Hippe M, Schnohr P, Hein HO, Vestbo J. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316:1043–1047. doi: 10.1136/bmj.316.7137.1043. . (4 April.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 1998 Oct 10;317(7164):1017.

Studying relative risk is not enough

Jin-Ling Tang 1, James A Dickinson 1

Editor—Prescott et al show that women who smoke have a high relative risk of myocardial infarction, which is highest in those aged under 55 and decreases with age.1-1 These age specific relative risks are higher than those for men at the same age. Prescott et al hypothesise that tobacco may be more harmful to women because of antioestrogenic effects. The greater risks in women and young people could, however, have alternative explanations.

As in all other populations studied, the absolute risk is much less in women than in men and in young than in old people, as Prescott et al show in their figure 1.1-1 The additional absolute risk caused by smoking is small among young women and relatively high only because of the low baseline level. Should Prescott et al rather suggest that smoking is less harmful in women?

Relative risk measures the effect of a risk factor for a disease compared with the total effects of all other risk factors for the same disease in a population. A greater relative risk may simply be a result of studying a population that has few other risk factors for the disease.1-2 It is a misinterpretation of heterogeneity of relative risk to consider a greater relative risk to be more harmful when its absolute clinical and public health impact is small and more appropriately measured by attributable risk.1-3 The relative risk due to smoking, for example, is much higher for lung cancer than heart disease—lung cancer has few other causes, but smoking kills more people through heart disease because this disease is much more common, so the additional absolute risk (the attributable risk) of heart disease is much greater. Epidemiological studies show that the relative risk of raised blood pressure and raised blood cholesterol concentrations is much greater in young people than in middle aged or elderly ones. Does this mean that these factors are more harmful in young people? Clinical and preventive measures have generally been targeted at older people as the benefits from intervention in young people are too small to be worth while.

The greater relative risk that Prescott et al observe in women is due only to the fact that women before the menopause have much fewer or lower levels of risk factors than men of the same age. To postulate a new effect is not warranted on the basis of these data.

References

  • 1-1.Prescott E, Hippe M, Schnohr P, Hein HO, Vestbo J. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316:1043–1046. doi: 10.1136/bmj.316.7137.1043. . (4 April.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Rothman K, Poole C. A strengthening programme for weak associations. Int J Epidemiol. 1968;17(suppl):955–959. doi: 10.1093/ije/17.4.955. [DOI] [PubMed] [Google Scholar]
  • 1-3.Greenland S, Rothman KJ. Concepts of interaction. In: Rothman KJ, Greenland S, editors. Modern epidemiology. 2nd ed. Philadelphia: Lippincott-Raven; 1998. pp. 329–342. [Google Scholar]
BMJ. 1998 Oct 10;317(7164):1017.

Smoking is a feminist issue

Penella J Woll 1

Editor—Prescott et al’s finding that women who smoke are at 50% greater risk of myocardial infarction than men who smoke is important and deserves wide publicity.2-1 Cardiovascular disease is, however, not the only risk associated with smoking. There is already strong evidence that smoking is 20-70% more likely to result in lung cancer in women than in men,2-2 and the risk of oral cancer is more than doubled in women.2-3 Although lung cancer has recently overtaken breast cancer as the commonest cause of death from cancer in British women, the epidemic of smoking related deaths in women is only just beginning.

Prescott et al comment that the excess risk of death from cardiovascular disease falls rapidly when people stop smoking. The same is not true for lung cancer, where the risk falls slowly. Smoking causes clonal mutations in the respiratory epithelium that persist for years.2-4,2-5 Consistent with this, smoking in youth is more dangerous than smoking in old age.

Women know that they are more susceptible to alcohol than men. They need to learn that they are also at greater risk from smoking than men. On a visit to the United States last month I was horrified to see one brand of cigarettes advertised on billboards as “a woman thing.” The cynical marketing of cigarettes to women in developing countries will ensure that the lessons so painfully learnt here are repeated thoughout the world.

References

  • 2-1.Prescott E, Hippe M, Schnohr P, Hein HO, Vestbo J. Smoking and risk of myocardial infarction in women and men: longitudinal population study. BMJ. 1998;316:1043–1046. doi: 10.1136/bmj.316.7137.1043. . (4 April.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.Zang EA, Wynder EL. Differences in lung cancer risk between women and men: examination of the evidence. J Natl Cancer Inst. 1996;88:183–192. doi: 10.1093/jnci/88.3-4.183. [DOI] [PubMed] [Google Scholar]
  • 2-3.Muscat JE, Richie JP, Thompson S, Wynder EL. Gender differences in smoking and risk for oral cancer. Cancer Res. 1996;56:5192–5197. [PubMed] [Google Scholar]
  • 2-4.Mao L, Lee JS, Kurie JM, Fan YH, Lippman SM, Lee JJ, et al. Clonal genetic alterations in the lungs of current and former smokers. J Natl Cancer Inst. 1997;89:857–862. doi: 10.1093/jnci/89.12.857. [DOI] [PubMed] [Google Scholar]
  • 2-5.Wistuba I, Lam S, Behrens C, Virmani AK, Fong KM, LeRiche J, et al. Molecular damage in the bronchial epithelium of current and former smokers. J Natl Cancer Inst. 1997;89:1366–1373. doi: 10.1093/jnci/89.18.1366. [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 1998 Oct 10;317(7164):1017.

Authors’ reply

Eva Prescott 1, Merete Hippe 1

Editor—We do not agree with Perneger et al that statistical interaction and biological interaction are separate issues. Statistical interaction depends on specification of the model that is applied to data. Epidemiological analysis, however, usually attempts to go beyond statistical modelling,3-1 and, provided the model fits the data, statistical interaction may well have a biological interpretation.

When we found a statistical interaction between smoking and subjects’ sex we wondered whether this was a result of our fitting a multiplicative model on data that should be described in an additive model. We discussed this in our paper. We find it biologically plausible that cardiovascular risk factors should act in a multiplicative fashion. If, however, effects of risk factors are additive, relative risks from a multiplicative model will vary between men and women simply because baseline risks vary. If this was the case we would, firstly, expect to find higher relative risks in women for all of the cardiovascular risk factors studied (cholesterol concentration, blood pressure, body mass index, physical activity, etc). Relative risks for all of these risk factors were, however, similar in men and women. Secondly, we would expect the sex difference—the interaction term—to diminish with increasing age since baseline risks increase. This was also not found. From this we cautiously suggested possible differences in the mechanisms of action of tobacco in causing cardiovascular disease in men and women.

Our calculation was based on an additive model that was briefly described in the paper. We calculated the difference in risk—number of additional myocardial infarctions in smokers caused by smoking—on the basis of age specific relative risks for smoking and baseline incidence. We concluded that the difference in risk was higher in men up to age 65 and in women over age 65. The model suggested by Perneger et al cannot pass as an additive model. It ignores age, time under risk, and the fact that the female smokers in our study population were on average much younger than the female non-smokers.

Finally, it is important to recognise that from a public health point of view the relative risk associated with smoking is higher in women, since calculations of the impact of smoking on women’s health should not be based on relative risks calculated from studies of men.

References

  • 3-1.Rothman KJ. Interactions between causes. In: Rothman KJ. Modern epidemiology. Boston, MA: Little, Brown, 1986;311-26.

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