Journal Article

Modeling the Time Dependence of the Association between Human Papillomavirus Infection and Cervical Cancer Precursor Lesions

Nicolas F. Schlecht, Robert W. Platt, Abdissa Negassa, Eliane Duarte-Franco, Thomas E. Rohan, Alex Ferenczy, Luisa L. Villa and Eduardo L. Franco

in American Journal of Epidemiology

Published on behalf of Johns Hopkins Bloomberg School of Public Health

Volume 158, issue 9, pages 878-886
Published in print November 2003 | ISSN: 0002-9262
Published online November 2003 | e-ISSN: 1476-6256 | DOI:
Modeling the Time Dependence of the Association between Human Papillomavirus Infection and Cervical Cancer Precursor Lesions

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The authors studied the time-dependent association between human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) among women enrolled in a cohort study in Brazil (1993–2002), using repeated Papanicolaou cytologic examination and HPV testing by polymerase chain reaction. Through simulation with conceivable alternative cohort designs, they investigated different regression modeling approaches using time-varying covariates, time-varying hazard ratio functions, and repeated events to assess the effect of delay in lesion detection. Associations between HPV and early SIL were of high magnitude. The age-adjusted hazard ratios for the association between HPV at enrollment and low-grade SIL decreased gradually with time until 72 months for both oncogenic types of HPV (hazard ratio = 3.96, 95% confidence interval (CI): 2.5, 6.4) and nononcogenic types (hazard ratio = 2.37, 95% CI: 1.3, 4.3). The hazard ratio for incident high-grade SIL remained constant, ranging from 7.15 (95% CI: 2.0, 25.1) at 12 months to 6.26 (95% CI: 2.7, 14.5) at 72 months for oncogenic types of HPV. With oncogenic HPV as the time-dependent predictor variable, the hazard ratios for incident SIL and high-grade SIL events were 14.2 (95% CI: 8.7, 23.1) and 32.7 (95% CI: 8.4, 127.3), respectively. Investigators may underestimate the prognostic value of HPV detection using designs that rely on HPV ascertainment at a single time point. The waning in hazard ratios should be considered in the implementation of HPV testing-based screening programs.

Keywords: cervix neoplasms; longitudinal studies; papillomavirus, human; precancerous conditions; statistics; survival analysis; Abbreviations: CI, confidence interval; HPV, human papillomavirus; SIL, squamous intraepithelial lesion.

Journal Article.  6900 words.  Illustrated.

Subjects: Public Health and Epidemiology

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