Impact of improved classification on the association of human papillomavirus with cervical precancer

Philip E. Castle, Mark Schiffman, Cosette M. Wheeler, Nicolas Wentzensen, Patti E. Gravitt

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Misclassification of exposure and surrogate endpoints of disease can obscure causal relations. Using data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS, 1997-2001), the authors explored the impact of exposure (human papillomavirus (HPV) detection) and endpoint (histologic cervical precancer) classification on their mutual association. Women referred into this study with an atypical squamous cells of undetermined significance Papanicolaou test with satisfactory results for all 4 HPV tests were included in this analysis (n = 3,215; 92.2%). HPV testing results were related to different definitions of cervical precancer, based on paired, worst 2-year histologic diagnoses, by calculating clinical sensitivity, specificity, and odds ratios. The authors found that HPV test sensitivity increased and specificity decreased with increasing certainty of cervical precancer, with HPV testing having the highest sensitivity (92%-98%) and lowest specificity (46%-54%) for consensus cervical intraepithelial neoplasia grade 3 (CIN 3). The overall accuracy of each HPV test, as measured by odds ratios, was greatest for consensus CIN-3 diagnoses, from 2- to 4-fold greater than for a less stringent precancer definition of any diagnosis of CIN 2 or more severe. In summary, there was convergence of greater certainty of carcinogenic HPV with greater certainty of a precancerous diagnosis, such that all 4 HPV tests almost always tested positive in women most likely to have cervical precancer. Finding increasingly strong associations when both test and diagnostic misclassification are reduced is a useful sign of "true association" in molecular epidemiology.

Original languageEnglish (US)
Pages (from-to)155-163
Number of pages9
JournalAmerican journal of epidemiology
Issue number2
StatePublished - Jan 2010
Externally publishedYes


  • Cervical intraepithelial neoplasia
  • Misclassification
  • Papillomavirus infections
  • Uterine cervical neoplasms

ASJC Scopus subject areas

  • Epidemiology


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