Affiliations of authors: European Network for Cervical Cancer Screening, Co-ordinator Evaluation of New Technologies and Unit of Cancer Screening, Scientific Institute of Public Health, Brussels, Belgium (MA); Department of Medical Microbiology, Lund University, Malmö University Hospital, Malmö, Sweden (JD); Department of Clinical and Epidemiological Virology, University of Leuven, Leuven, Belgium (MVR); Centre for Evidence-Based Medicine, Belgian Branch of the Cochrane Collaboration, Department of General Practice, University of Leuven, Leuven, Belgium, and University of Maastricht, Maastricht, The Netherlands (FB); Central Lancashire Teaching Hospitals, Preston, U.K. (PM-H); Department of Obstetrics and Gynaecology, University Hospital of Ioannina, Ioannina, Greece (EP)
Correspondence to: Marc Arbyn, Scientific Institute of Public Health, J. Wytsmanstreet 14, B1050 Brussels, Belgium (e-mail: marc.arbyn{at}iph.fgov.be)
In their recent editorial, Solomon and Schiffman (1) commented on our meta-analysis of the accuracy of the human papillomavirus (HPV) DNA testing as an alternative to a repeat Pap smear to triage women with equivocal cervical cytology (2). In general, they agreed with our conclusion that detection of high-risk HPV DNA using the Hybrid Capture 2 (HC2) assay (Digene, Gaithersburg, MD) predicts the presence or absence of cervical intraepithelial neoplasia of grade 2 or worse disease (CIN2+) more accurately than repetition of the Pap test. The pooled sensitivity and specificity of the HC2 assay were 95% (95% confidence interval [CI] = 92.7% to 96.9%) and 67% (95% CI = 58.2% to 76.4%), respectively. The sensitivity of the HC2 assay was 16% higher (ratio of HC2 assay to repeat cytology = 1.16, 95% CI = 1.04 to 1.29) than that of repeat cytology using atypical squamous cells of undetermined significance (ASCUS) or worse as the cut point, whereas the relative specificity did not differ significantly from unity (ratio = 1.05, 95% CI = 0.96 to 1.15).
Solomon and Schiffman (1) also had some criticisms. First, they questioned the inclusion criterion, presence of an index smear showing ASCUS, which is poorly reproducible. Second, they stated that, with rapidly evolving technologies, meta-analyses are quickly outdated. These issues have already been addressed in our discussion (2). Then, they queried whether our meta-analysis considered issues of test quality. We did consider the influence of quality issues and refer readers to the pooled analysis by subgroups presented in table 6 (2) and to the multivariable meta-regression and SROC (Summary Receiver Operator Characteristic) regression presented elsewhere (3). We would like to emphasize that a meta-analysis is not merely pooling data of homogenous datasets with the sole purpose of increasing power. In diagnostic research, absence of heterogeneity is rare, and one purpose of a meta-analysis is to explore sources of the heterogeneity by using formal statistical methods. By doing so, we were able to point out that the accuracy of older HPV DNA detection systems was lower than that of the HC2 assay and that our conclusions were robust over a wide range of clinical situations.
We agree with the remark made by Solomon and Schiffman that CIN3 or worse (CIN3+) is also a relevant outcome to evaluate triage methods. Therefore, we performed a pooled analysis of four studies that present data on the accuracy of HC2 for CIN3+ (47). The sensitivity of HC2 varied from 93.3% to 100%, with a pooled estimate of 96.4% (95% CI = 93.5% to 99.9%) (Table 1). The specificity of HC2 varied from 45.8% to 69.7%, with a pooled estimate of 56.5% (95% CI = 45.5% to 67.5%). Only the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS) (5) documented the accuracy of repeat cytology for CIN3+, in which the sensitivity and specificity at a cutoff of ASCUS or worse were 85.3% (95% CI = 78.4% to 90.3%) and 42.7% (95% CI = 40.7% to 44.8%), respectively. The sensitivity at higher cytologic thresholds was substantially lower. The sensitivity of HC2 was 13% higher than that of repeat cytology at a cutoff of ASCUS or worse (ratio of 1.13, 95% CI = 1.05 to 1.22). Even the specificity of HC2 was 7% higher than that of repeat cytology at the ASCUS-or-worse cut point, and this difference in specificity was marginally statistically significant (95% CI = 1.00 to 1.14). Thus, we can conclude that high-risk HPV DNA detection using the HC2 assay is also more accurate than repeat cytology for predicting CIN3+ in women with a previous equivocal cervical smear.
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NOTES
We have no interests in the diagnostic systems described in this paper.
We acknowledge the administration of the Europe Against Cancer program of the European Commission (Directorate of SANCO, Luxembourg) and the DWTC/SSTC (Federal Services for Scientific, Cultural and Technical Affairs of the Federal Government, Brussels, Belgium) for funding this study.
REFERENCES
1 Solomon D, Schiffman M. Have we resolved how to triage equivocal cervical cytology? J Natl Cancer Inst 2004;96:2501.
2 Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J. Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 2004;96:28093.
3 Arbyn M, Buntinx F, Van Ranst M, Cortinas Abrahantes J. Triage of women with atypical or low-grade cytological abnormalities of the cervix by HPV testing: systematic review and meta-analysis. Available at http://www.iph.fgov.be/epidemio/epien/cervixen/pr01_019.pdf. [Last accessed: August 11, 2004.]
4 Lin CT, Tseng CJ, Lai CH, Hsueh S, Huang HJ, Law KS. High-risk HPV DNA detection by Hybrid Capture II. An adjunctive test for mildly abnormal cytologic smears in women > or = 50 years of age. J Reprod Med 2000;45:34550.[ISI][Medline]
5 Solomon D, Schiffman M, Tarone B. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance (ASCUS): baseline results from a randomized trial. J Natl Cancer Inst 2001;93:2939.
6 Zielinski GD, Snijders PJ, Rozendaal L, Voorhorst FJ, Runsink AP, De Schipper FA, et al. High-risk HPV testing in women with borderline and mild dyskaryosis: long-term follow-up data and clinical relevance. J Pathol 2001;195:3006.[CrossRef][ISI][Medline]
7 Lonky NM, Felix JC, Naidu YM, Wolde Tsadik G. Triage of atypical squamous cells of undetermined significance with hybrid capture II: colposcopy and histologic human papillomavirus correlation. Obstet Gynecol 2003;101:4819.
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