Invited commentary: Human papillomavirus infection and risk of cervical precancer--using the right methods to answer the right questions

Abstract

Epidemiologists are well aware of the negative consequences of measurement error in exposure and outcome variables to their ability to detect putative causal associations. However, empirical proof that remedying the misclassification problem improves estimates of epidemiologic effect is seldom examined in detail. Of all areas in cancer epidemiology, perhaps the best example of the consequences of misclassification and of the steps taken to circumvent them was the pursuit, beginning in the mid-1980s, of the human papillomavirus (HPV) infection-cervical cancer association. The stakes were high: Had the wrong conclusions been reached epidemiologists would have been led astray in the search for competing hypotheses for the sexually transmissible agent causing cervical cancer or in ascribing to HPV infection a mere ancillary role among many lifestyle, hormonal, and environmental factors. The article by Castle et al. in this issue of the Journal (Am J Epidemiol. 2010;171(2):155-163) provides a detailed account of the joint influences of improved HPV and cervical precancer measurements in gradually unveiling the strong magnitude of the underlying association between viral exposure and cervical lesion risk. In this commentary, the authors extend the findings of Castle et al. by providing additional empirical evidence in support of their arguments.

Figure 1.

Simplified etiologic model for cervical cancer showing the role of distal (sexual activity) and intermediate (HPV infection) variables and the ancillary role of cofactors. HPV, human papillomavirus.

Figure 2.

Odds ratios and 95% confidence intervals for the association between human papillomavirus (HPV) infection (via HPV DNA detection) and invasive cervical cancer risk in successive molecular epidemiologic studies (mostly case-control) (from top to bottom, references 10–21). CI, confidence interval; NAH, nonamplified hybridization; PCR, polymerase chain reaction.

Figure 3.

Kaplan-Meier plots of the cumulative incidence of any-grade squamous intraepithelial lesions (SILs) on Papanicolaou cytology results (n = 887) according to human papillomavirus (HPV) DNA positivity at enrollment received up to August 1997 in the Ludwig-McGill cohort study. Solid line, HPV negative; broken line, HPV positive. Top graph: analysis based on Papanicolaou diagnoses from the local cytology laboratory. Bottom graph: analysis based on review Papanicolaou diagnoses. Adapted with permission from the Pan American Health Organization (PAHO) (23).