A modified Latent Class Model assessment of human papillomavirus-based screening tests for cervical lesions in women with atypical glandular cells: a Gynecologic Oncology Group study
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In the absence of gold standard diagnoses, we estimate age-specific false-positive and false-negative prediction rates of HPV-, cytology-, and histology-based tests for significant cervical lesions (SCL) in US women with AGC-NOS Pap smear diagnoses.
Modified Latent Class Model (LCM) analyses, with prevalence of SCL modeled as a function of age, were applied to GOG-0171 study data (n = 122). The accuracies of several HPV-based tests, including Hybrid Capture II high-risk HPV (HC2 H-HPV); carbonic anhydrase IX (CA-IX); and invasive histological diagnosis, were compared. 1-PPV and 1-NPV were written as functions of sensitivity, specificity, and prevalence to obtain age-specific false-positive and false-negative rates.
The histology-based test was nearly perfect (sensitivity = 1.00, CI = 0.98–1.00; specificity = 0.99, CI = 0.96–1.00). Otherwise, HC2 H-HPV performed best (sensitivity = 1.00, CI = 1.00–1.00; specificity = 0.87, CI = 0.79–0.94). The false-positive detection rates (1-PPV) for HC2 H-HPV were high (>17 %) at each age, while those of the histological diagnoses were low (<5 % at ages ≤60 and <17 % overall ages). False-negative prediction rates (1-NPV) for HC2 H-HPV were <0.11 % at each age and were uniformly lower than those of other tests, including the histology-based test (<0.25 %). CA-IX together with HC2 H-HPV did not improve performance.
Women with negative HC2 H-HPV can safely forego invasive treatment (i.e., cone or LEEP biopsy, hysterectomy) in favor of observational follow-up. Additional biomarkers must be found for use in combination with HC2 H-HPV to reduce false-positive rates. This novel application of a modified LCM exemplifies methods for potential use in future cancer screening studies when gold standard diagnoses are not available.
KeywordsHuman papillomavirus Carbonic anhydrase IX Atypical glandular cells GOG HPV
The following member institutions participated in this study: Abington Memorial Hospital, Walter Reed Army Medical Center, University of Mississippi Medical Center, University of California at Los Angeles, University of Pennsylvania Cancer Center, University of Cincinnati, University of Texas Southwestern Medical Center at Dallas, Wake Forest University School of Medicine, University of California Medical Center at Irvine, Tufts-New England Medical Center, The Cleveland Clinic Foundation, SUNY at Stony Brook, Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer Council, Fox Chase Cancer Center, Women’s Cancer Center—University of Nevada, University of Oklahoma, Tacoma General Hospital, Tampa Bay Cancer Consortium, Gynecologic Oncology Network/Brody School of Medicine, Ellis Fischel Cancer Center, Fletcher Allen Health Care, University of Wisconsin Hospital, University of Texas-Galveston. This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469) and the Gynecologic Oncology Group Statistical and Data Center (CA 37517).
Conflict of interest
The authors wish to report that there are no conflicts of interest.
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