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

Abstract

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.

Figure 1.

Receiver-operator curves for the 4 human papillomavirus tests and the clinical center pathology-read cytology for detection of cervical precancer over the 2-year duration of ALTS, 1997–2001. Four definitions were used for precancer: □, a CIN-2 diagnosis or more severe on either pathology review (endpoint 1); Δ, a CIN-2 diagnosis or more severe on both pathology reviews (consensus CIN 2+) (endpoint 2); ○, a CIN-3 diagnosis or more severe on either pathology review (endpoint 3); +, a diagnosis of CIN 3 on one pathology review and CIN 2 or more severe on the other pathology review (endpoint 4); and ▪, a CIN-3 diagnosis or more severe on both pathology reviews (endpoint 5) (consensus CIN 3). ALTS, Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study; AMP, AMPLICOR (Roche Molecular Systems, Inc., Pleasanton, California); CIN 2 and CIN 3, cervical intraepithelial neoplasia grades 2 and 3, respectively; Cytology, clinical center pathology interpretation of enrollment ThinPrep cytology (Cytyc Corporation, Marlborough, Massachusetts (now Hologic)), with atypical squamous cells of undetermined significance or worse considered as positive; hc2, Hybrid Capture 2 (Qiagen Corporation, Gaithersburg, Maryland); LA, linear array; LBA, line blot assay.