Research Article| Volume 20, ISSUE 2, P345-367, June 2000

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Statistical Issues in Human Papillomavirus Testing and Screening

  • Eduardo L. Franco
    Address reprint requests to: Eduardo L. Franco, PhD, Division of Epidemiology, Department of Oncology, McGill University, 546 Pine Avenue West, Montreal, Québec, Canada H2W 1S6
    From the Departments of Oncology, Epidemiology and Biostatistics, McGill University, Montreal, Québec, Canada
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      Much progress has been made in the past 10 years concerning laboratory detection and measurement of human papillomavirus (HPV) infection by amplified and nonamplified DNA hybridization techniques. The advances in laboratory testing for HPV have helped to elucidate the etiologic role that this virus has in cervical carcinogenesis, which has spawned new epidemiologic research on the natural history and prevention of cervical cancer. Regardless of the research purpose, etiology or prevention, there are critical statistical and study design issues related to measurement of HPV infection status and its cervical lesion outcomes that may affect the validity of epidemiologic and screening efficacy studies. Meticulous attention to study conduct and laboratory detection helps to minimize the influence of measurement errors and detection biases. Simple statistical analysis techniques are also available to correct or to control for some of the problems.
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        • Cox J.T.
        • Lorincz A.T.
        • Schiffman M.H.
        • et al.
        Human papillomavirus testing by hybrid capture appears to be useful in triaging women with a cytologic diagnosis of atypical squamous cells of undetermined significance.
        Am J Obstet Gynecol. 1995; 172: 946
        • Cox J.T.
        • Schiffman M.H.
        • Winzelberg A.J.
        • et al.
        An evaluation of human papillomavirus testing as part of referral to colposcopy clinics.
        Obstet Gynecol. 1992; 80: 389
        • Duffy S.W.
        • Rohan T.E.
        • McLaughlin J.R.
        Design and analysis considerations in a cohort study involving repeated measurement of both exposure and outcome: The association between genital papillomavirus infection and risk of cervical intraepithelial neoplasia.
        Stat Med. 1994; 13: 379
        • Ferenczy A.
        • Franco E.
        • Arseneau J.
        • et al.
        Diagnostic performance of hybrid capture human papillomavirus deoxyribonucleic acid assay combined with liquid-based cytologic study.
        Am J Obstet Gynecol. 1996; 175: 651
        • Franco E.L.
        Cancer causes revisited: Human papillomavirus and cervical neoplasia.
        J Natl Cancer Inst. 1995; 87: 779
        • Franco E.L.
        Measurement errors in epidemiological studies of human papillomavirus and cervical cancer.
        in: Munoz N. Bosch F.X. Shah K.V. The Epidemiology of Human Papillomavirus and Cervical Cancer. Oxford University Press, Oxford1992: 181
        • Franco E.L.
        The sexually transmitted disease model for cervical cancer: Incoherent epidemiologic findings and the role of misclassification of human papillomavirus infection.
        Epidemiology. 1991; 2: 98
        • Franco E.L.
        Statistical issues in studies of human papillomavirus infection and cervical cancer.
        in: Franco E.L. Monsonego J. New Developments in Cervical Cancer Screening and Prevention. Blackwell, London1997: 39
        • Franco E.L.
        • Ferenczy A.
        Assessing gains in diagnostic utility when human papillomavirus testing is used as a Pap smear adjunct for triaging women with cervical cytological abnormalities.
        Am J Obstet Gynecol. 1999; 181: 382
        • Franco E.L.
        • Rohan T.E.
        • Villa L.L.
        Epidemiologic evidence and human papillomavirus infection as a necessary cause of cervical cancer.
        J Natl Cancer Inst. 1999; 91: 506
        • Hakama M.
        Screening for cervical cancer.
        in: Miller A.B. Advances in Cancer Screening. Kluwer Academic Publishers, Boston1996: 41
        • Hatch K.D.
        • Schneider A.
        • Abdel-Nour M.W.
        An evaluation of human papillomavirus testing for intermediate-and high-risk types as triage before colposcopy.
        Am J Obstet Gynecol. 1995; 172: 1150
        • Ho G.Y.F.
        • Burk R.D.
        • Klein S.
        • et al.
        Persistent genital human papillomavirus infection as a risk factor for persistent cervical dyplasia.
        J Natl Cancer Inst. 1995; 87: 1365
      1. I ARC Working Group: Human Papillomaviruses. I ARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 64. Lyon, International Agency for Research on Cancer, 1995

        • Kaufman R.H.
        • Adam E.
        • Icenogle J.
        • et al.
        Human papillomavirus testing as triage for atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesions: Sensitivity, specificity, and cost-effectiveness.
        Am J Obstet Gynecol. 1997; 177: 930
        • Kjaer S.K.
        • Engholm G.
        • Teisen C.
        • et al.
        Risk factors for cervical human papillomavirus and herpes simplex virus infections in Greenland and Denmark: A population-based study.
        Am J Epidemiol. 1990; 131: 669
        • Koss L.G.
        The Papanicolaou test for cervical cancer detection: A triumph and a tragedy.
        JAMA. 1989; 261: 737
        • Koutsky L.A.
        • Holmes K.K.
        • Critchlow C.W.
        • et al.
        A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection.
        N Engl J Med. 1992; 327: 1272
        • Lörincz A.
        Hybrid Capture method for detection of human papillomavirus DNA in clinical specimens.
        Papillomavirus Rep. 1996; 7: 1
        • Manos M.M.
        • Ting Y.
        • Wright D.K.
        • et al.
        Use of polymerase chain reaction amplification for the detection of genital human papillomaviruses.
        Cancer Cells. 1989; 7: 209
        • McGoogan E.
        Advantages and limitations of automated screening systems in developing and developed countries.
        in: Franco E. Monsonego J. New Developments in Cervical Cancer Screening and Prevention. Blackwell Science, Oxford1997: 317
        • Munoz N.
        • Bosch F.X.
        • Desanjose S.
        • et al.
        The causal link between human papillomavirus and invasive cervical cancer: A population-based case-control study in Colombia and Spain.
        Int J Cancer. 1992; 52: 743
        • Parkin D.M.
        The epidemiological basis for evaluating screening policies.
        in: Franco E. Monsonego J. New Developments in Cervical Cancer Screening and Prevention. Blackwell Science, Oxford1997: 51
        • Reeves W.C.
        • Brinton L.A.
        • Garcia M.
        • et al.
        Human papillomavirus infection and cervical cancer in Latin America.
        N Engl J Med. 1989; 320: 1437
        • Schiffman M.H.
        New epidemiology of human papillomavirus infection and cervical neoplasia.
        J Natl Cancer Inst. 1995; 87: 1345
        • Schiffman M.H.
        • Bauer H.M.
        • Hoover R.N.
        • et al.
        Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia.
        J Natl Cancer Inst. 1993; 85: 958
        • Schiffman M.H.
        • Schatzkin A.
        Test reliability is critically important to molecular epidemiology: An example from studies of human papillomavirus infection and cervical neoplasia.
        Cancer Res. 1994; 54: S1944
        • Schneider A.
        • Zahm D.M.
        • Kirchmayr R.
        • et al.
        Screening for cervical intraepithelial neoplasia grade 2/3: Validity of cytologic study, cervicography, and human papillomavirus detection.
        Am J Obstet Gynecol. 1996; 174: 1534
        • VanDenBrule A.J.C.
        • Snijders P.J.F.
        • Gordijn R.L.J.
        • et al.
        General primer-mediated polymerase chain reaction permits the detection of sequenced and still unsequenced human papillomavirus genotypes in cervical scrapes and carcinomas.
        Int J Cancer. 1990; 45: 644
        • Villa L.L.
        • Franco E.L.
        Epidemiologic correlates of cervical neoplasia and risk of human papillomavirus infection in asymptomatic women in Brazil.
        J Natl Cancer Inst. 1989; 81: 332
        • Walboomers J.M.M.
        • Meijer C.J.L.M.
        Do HPV-negative cervical carcinomas exist?.
        J Pathol. 1997; 181: 253
        • Walter S.D.
        Estimation of test sensitivity and specificity when disease confirmation is limited to positive results.
        Epidemiology. 1999; 10: 67
        • Wright T.C.
        • Sun X.W.
        • Koulos J.
        Comparison of management algorithms for the evaluation of women with low-grade cytologic abnormalities.
        Obstet Gynecol. 1995; 85: 202