Commentary: Smoking and human papillomavirus infection: the pursuit of credibility for an epidemiologic association

As the most important among the modifiable risk factors for many cancer types tobacco smoking is dutifully treated as a potent confounder when epide- miologists explore new candidate relations. The role for smoking changes from 'confounder' to 'con- founded' variable in anogenital cancers. Among the latter, cervical cancer is a case in point. Smoking was first suspected as a risk factor for cervical cancer in the mid 60s but although most studies have replicated the finding1 the association was always seen with suspicion because of confounding by sexual activity.2 Number of sexual partners and age at first intercourse are unequivocal key determinants of risk, which has long suggested that an infectious sexually-transmitted agent plays an aetiological role. Controlling for these two measures of sexual behaviour tended to dampen the associations with smoking in cervical cancer studies but in many of them it remained statistically detectable. Concerns about residual confounding by unmeasured sexual behaviours or insufficient control of confounding due to misclassification of sexual activity information led the International Agency for Research on Cancer (IARC) to defer judgment about a carcinogenic role for smoking in cervical cancer in its first monograph focusing on tobacco products in 1986.3 This intractable situation was nicely captured in 1994 in an insightful article in the Journal which demonstrated that, as long as the putative sexually- transmitted aetiologic agent remained unmeasured and uncontrolled for in an epidemiological study, the association with smoking would continue to be hope- lessly confounded, despite best efforts at adjusting for sexual activity variables.4 It did not help when the first molecular epidemiologic studies in the late 80s heeded this advice by placing the human papillomavirus (HPV) at centre stage for the