KHANNA, N.*,†,‡; MISHRA, S. I.†,§,‖; TIAN, G.¶; TAN, M. T.¶; ARNOLD, S.*; LEE, C.†,#; RAMACHANDRAN, S.**; BELL, L.**; BAQUET, C. R.†,‡,§,‖,#,††; LORINCZ, A.**
*Department of Family Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
†School of Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
‡Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
§Department of Epidemiology and Prevention Medicine, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
‖Office of Research Policy and Planning, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
¶Information Technology and Biostatistics Division, Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland
#Department of Internal Medicine, University of Maryland, Baltimore, Maryland
**Research and Development, Digene Corporation, Gaithersburg, Maryl
††Department of Medicine, University of Maryland, Baltimore, Maryland
Address correspondence and reprint requests to: Niharika Khanna, MD, University of Maryland School of Medicine, 29 South Paca Street, Baltimore, MD 21201, USA. Email: firstname.lastname@example.org
Prior presentations: The results were presented in part at the annual conference of the European Research Organization on Genital Infection and Neoplasm (EUROGIN), April 13–16, 2003, Paris, France, and at the annual conference of the North American Primary Care Research Group, October 25–28, 2003, Banff, Canada.
Accepted for publication October 5, 2006
Human papillomavirus (HPV) DNA typing is a triage alternative for Papanicolaou smears classified as atypical squamous cells of undetermined significance (ASCUS)(1–6). In the United States, Behavioral Risk Factor Surveillance System data reported in 2004 that 85.9% of American women aged 18 years or older had been screened for cervical cancer using a Pap test within the past 3 years(7). Research indicates that precancerous conditions and invasive cervical cancer are more likely to be found in women who have never been screened or who have not been screened within the last 5 years(8).
HPV detection is an integral part of cervical cancer screening, and a wide range of specimen collection procedures are now being tested(9). Several methods of collection of vaginal specimens have been explored, such as use of tampons, cervical brushes, cervicovaginal lavage, and cotton or Dacron swabs(10–12). Preliminary studies using self-collection of vaginal specimens indicate that women are willing to provide such specimens for HPV DNA testing; in fact, the majority of women prefer this method to speculum-assisted sampling (ie, clinician-collected specimens) of the cervix(13–19). In addition to being more acceptable to women, self-collection of vaginal specimens for HPV DNA testing may decrease the cost of the HPV DNA test(20,21).
A few studies have explored ethnic and sociocultural factors influencing self-collection and the acceptance of vaginal specimens for HPV DNA testing(13,22,23). The purpose of the current study is twofold: first, to explore the social and behavioral predictors of acceptance of self-collection of vaginal specimens among patients recruited from an urban, university-based family medicine ambulatory clinic(24) and, second, to assess the concordance in detection of HPV between self-collected vaginal specimens and clinician-collected cervical specimens, to allow for vaginal testing as evidence of HPV infection in future.
Materials and methods
A total of 502 (64.9%) women aged 18–69 years met inclusion criteria. Four hundred and ninety-nine cervical specimens and 398 vaginal specimens were analyzed for HPV DNA using Hybrid Capture 2 (hc2, Digene Corporation, Gaithersburg, MD). The study was conducted using cross-sectional consecutive sampling procedures, self-administered questionnaires, and patient-collected vaginal and clinician-collected cervical specimens for HPV DNA testing using hc2.
Study design and procedures
After the study protocol and consent forms were approved by the University of Maryland Institutional Review Board, the study participants provided written informed consent and were assigned a unique identifier number. This report focuses on results related to detection of HPV DNA in cervical and vaginal specimens using hc2.
The study, conducted between December 2001 and November 2002, used a cross-sectional design with consecutive sampling procedures. The study setting was an urban, university-affiliated family medicine clinic where 41,000 patient visits occur annually. Women were recruited when they presented for routine gynecological care at the Family Health Center. The study procedures included selection and recruitment of eligible participants, informed consent, completion of a self-administered questionnaire, and collection of specimens by both patients and clinicians. A health educator with special training in human sexuality implemented all study procedures.
Eligibility criteria for the selection of study participants were as follows: (a) voluntary participation of adult women (18 years and older); (b) no presenting symptoms; (c) no abnormal Pap test results, genital cancer, cervical surgery, or immune treatment of the cervix within 1 year; (d) fluency in English; and (e) not currently pregnant. Study personnel invited 773 women to participate in the study, of whom 561 women agreed to participate and 212 women refused before their eligibility could be determined. Of the 561 women who agreed to participate, 59 did not meet the eligibility criteria, as they were pregnant, had a hysterectomy, were HIV positive, had recent cervical surgery, and/or used immunotherapy or chemical applications on the cervix. Clinician-collected cervical specimens were obtained from all 502 participants who met the inclusion criteria and who completed the self-administered questionnaire. Self-collected vaginal specimens were provided by 401 participants (80.3%). Three specimens were discarded due to technical reasons, leaving 398 specimens. Three hundred and ninety-eight of the 499 (79.8%) women preferred self-collection to the clinician-collected method. The primary reason given by the 101 participants who did not provide self-collected vaginal specimens was (a) unfamiliarity with how to obtain the specimen, despite detailed explanation of the specimen collection procedure and use of graphics (see Fig. 1); (b) lack of time; or (c) perceived discomfort with obtaining a self-collected vaginal specimen. All cervical and vaginal specimens were collected into Digene specimen transport medium using a Christmas tree cervical sampling brush (Digene Corporation).
Women were divided into two groups based on age <30 and >30 years, based on the natural history of HPV in women and the higher chance of persistent HPV with resulting cervical disease in women >30 years of age. In addition, to identify patterns of acceptance of self-collected vaginal tests based on level of education, we divided women into those with fewer than 13 years of education and those with at least 13 years of education.
Eligible participants completed a baseline questionnaire that included sociodemographic measures: age; race/ethnicity (white non-Hispanic [WNH], African American [AA], and other including Native American, Pacific Islander, Asian, and Hispanic); marital status; educational level; number of pregnancies, living children, and abortions or miscarriages; health status (ie, ever had abnormal Pap tests, history of pelvic and genitourinary infections, hysterectomy, and/or removal of the ovaries); and lifestyle and behavioral variables such as tobacco use (current smoker, past smoker, or never smoked), current consumption of alcohol (never consumed alcohol, ever consumed, or currently consume alcohol), current use of birth control method (none, barrier method, oral, implanted, or injectable hormonal method, tubal ligation, or vasectomy), number of years of oral contraceptive pill use (if applicable), current use of a condom, and number of lifetime sexual partners. The health educator explained the contents of the questionnaire and was available to answer questions. The questionnaire took approximately 20 min to complete.
Collection of biologic samples
The health educator explained the procedures for self-collection of vaginal samples to eligible and consented study participants and provided a diagram outlining the procedure (Fig. 1). The participants were directed to the examination room for self-collection of vaginal specimens for HPV DNA testing using the Digene cervical sampling brush. Specimens were collected consistently in the following order from each patient: (a) self-collected vaginal specimen, (b) clinician-collected cervical cytologic specimen, and (c) clinician-collected cervical HPV specimen using the Digene cervical sampling brush. Specimens for cytology were sent to the University of Maryland Pathology laboratory. Specimens for HPV tests collected in specimen transport medium using the Digene brush were stored at room temperature for transport biweekly to the laboratory at Digene Corporation for analysis. Liquid-based cervical cytology was performed using standard procedures (Cytyc Corporation, Marlborough, MA, and TriPath Imaging, Inc., Burlington, NC) and referenced Bethesda 2001 classification in cytologic reports (Fig. 2). HPV typing was done using the Digene hc2 assay(25–29).
Analysis of biologic samples
The hc2 test was performed on all vaginal and cervical samples in a blinded fashion to eliminate bias using the Probe B cocktail consisting of high-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. All HPV results referenced in this article refer to high-risk HPV(29). The assay was performed according to standard protocol in the laboratory of one of the authors (A.L.). hc2 is a second-generation Hybrid Capture® assay using specific RNA probes, hybridization, antibody capture, and signal amplification to allow rapid standardized testing of the genetic material of infectious agents in the laboratory setting. It is a signal amplification assay that uses a technique combining antibody capture and chemiluminescent signal detection. Only Probe B for high-risk types of HPV was utilized. (The hc2 HPV assay also provides a Probe A to detect low-risk HPV types.) The basic steps of the hc2 assay are described in published literature(29).
Statistical analysis methods
Data were entered into an SPSS 10.0 database using dual data entry, and over 10% of the database was further audited to ensure accuracy and completeness. Each participant was assigned a unique study identifier number to ensure confidentiality, and the database with names was kept in a locked room to which only selected study staff had access. Data were analyzed using SAS (Release 8.2, SAS Institute Inc., Cary, NC) and S-PLUS (Academic Site Edition Version 6.2.1, Insightful Corporation, Seattle, WA)(30).
Cell frequency, percentages, and odds ratios were calculated by exact procedures available in SAS. All P values were computed by Chi-square test for large samples and by Fisher exact test for small samples.
McNemar test was used to assess if the HPV detection rates in vaginal and cervical specimens would be equal; the corresponding P value was calculated with S-PLUS. The 0.05 level was used for statistical significance. Factors that may influence the acceptance of self-administered vaginal samples included age >30 or <30 years based on HPV natural history and education <13 or >13 years based on the observation that women who completed with at least a high school education are more likely to be positive for HPV. Agreement to provide self-collected vaginal specimens for HPV DNA testing, HPV DNA positivity in self-collected vaginal and clinician-collected cervical specimens, and Pap test cytologic exam were also studied. Number of sexual partners was divided into 1, 2–6, and >7, based on previous studies estimating risk for HPV infection linked to number of sexual partners(31,32). Analysis on oral contraceptive use could not be conducted due to missing values. No virgins were included in the analysis.
Self-collection of vaginal specimens
The majority of eligible women (398/499 [79.8%]) self-obtained vaginal specimens for HPV DNA analysis and preferred this method to clinician-collected cervical specimens. In our study, 76.6% (216/282) AA, 88.1% (156/176) WNH women, and 63.4% (26/41) women of other races (P < 0.0001) agreed to self-collect vaginal specimens (analysis not shown). Table 1 presents the distribution of demographics and lifestyle and behavioral factors for the 499 eligible women. Mean age of the participants was 32 years, including 253 women aged <30 years and 244 women aged >30 years. Only 80.2% of women <30 years of age and 78.8% of women >30 years of age obtained self-collected vaginal specimens for HPV detection. Only 76.6% of 282 AA women agreed to collect a vaginal specimen compared with 88.1% of 176 non-Hispanic Caucasian women who agreed to collect a vaginal specimen. This difference is statistically significant. All together, 79.8% (398/499) women agreed and preferred to self-collect vaginal specimens and 20.2% refused. The reasons for refusal to self-collect specimens included unfamiliarity with obtaining self-collected specimens, lack of time, and no desire to touch their own genitalia. Women with no more than high school education were less likely to obtain self-collected specimens, 77% compared with 82.7% of women with college education. However, this difference was not statistically significant. No differences were observed between married (78.8%) and single women (79.9%) who agreed to self-collect specimens. There was no statistical difference in collection of vaginal specimens in women who had ever smoked (79.4%) vs women who had never smoked (81%). Similarly, no differences were observed in condom users (77.9%) vs those who had never used condoms (80.8%). Among women who self-collected vaginal specimens, 83.0% (329/396) had normal Pap smears, 10.8% (43/396) had ASCUS Pap smears, 5.5% (22/396) had LSIL (low-grade squamous intraepithelial lesion) Pap smears, and 0.05% (2/396) had HSIL (high-grade squamous intraepithelial lesion) Pap smears.
Further analysis using multivariable logistic regression to study the variation with sociodemographic factors revealed that willingness to self-collect a specimen was present among women across a spectrum of levels of education; marital status; numbers of sexual partners, pregnancies, and abortions; tobacco, alcohol, contraceptive pill, and condom use; and cytology results (analysis not shown).
Detection of HPV DNA in vaginal and cervical specimens
HPV DNA detection was concordant or positive in both cervical and vaginal specimens in 13.4% (53/398) women. Cervical specimen tests were positive for HPV in 16.0% (80/499), and vaginal specimen tests were positive in 26.1% (104/398) of women tested (P < 0.001). Hence, McNemar test showed statistically significant differences in detection of HPV in vaginal and cervical specimens. Twelve women (3.0%) were positive for cervical HPV but negative for vaginal HPV, and 51 women (12.8%) were negative for cervical HPV but positive for vaginal HPV. No virgins were included in this study.
Detection of HPV DNA in cervical samples in each cytologic category
Pap test results were normal in 84.1% (418/497) of women in this study (Table 2). Seventy-nine women (15.9%) had abnormal Pap test results: 10.3% (51/497) ASCUS, 5.2% (26/497) LSIL, and 0.04% (2/497) HSIL. For clinician-obtained cervical specimens, the HPV test result was positive in 10.8% (45/418) of women with normal Pap tests, 31.4% (16/51) of women with ASCUS, 73.1% (19/26) of women with LSIL, and 100% (2/2) of women with HSIL. For patient-collected vaginal specimens, the HPV assay was positive in 21.6% (71/329) of women with normal Pap tests, 39.5% (17/43) of women with ASCUS, 59.1% (13/22) of women with LSIL, and 100% (2/2) of women with HSIL (Table 2). Among the 12 women HPV positive in cervical specimens and negative in vaginal specimens, there were 83% (10/12) normal Pap smears and 17% (2/12) with LSIL Pap smears. There was a statistically significant difference in detection of vaginal HPV (21.6%) vs cervical HPV (10.8%) in women with normal Pap smears (P≤ 0.0001). The number of women with LSIL and HSIL smears was small, and hence, those results are difficult to interpret.
Our study was conducted in an urban, Baltimore, university-affiliated family medicine clinic, and we included all women presenting to the clinic for routine gynecological examination to ensure that a diverse and representative sample was recruited. The participant group was selected from women who were likely to value health promotion and disease prevention and who had used preventive and cancer screening services in the past. The goal of this study was to assess the agreeability of women to obtain self-collected specimens for HPV typing, and we also assessed the concordance in detection rates of HPV between self-collected vaginal specimens and clinician-collected cervical specimens. We found that self-collected vaginal sampling was acceptable to 398/499 (79.8%) women of all ages and races, with some variation in acceptance of self-collection of vaginal specimen as follows: 216/282 (76.6%) in the AA group, 156/176 (88.1%) in WNH group, and 25/40 (62.5%) among women in our “other race” group comprising Asian, Pacific Islander, Native American, and mixed race. Further study of other sociodemographic factors found that willingness to self-collect a specimen was present among women with multiple other variables. This observation is similar to those of other studies that have explored acceptability of self-collection of vaginal specimens for HPV(13–19). We observed that women with prior pregnancies were slightly less likely to self-collect a vaginal specimen, possibly because women with children were less likely to want to spend additional time on the study.
The test for HPV used in this study was hc2. A Christmas tree–shaped brush was used both for self-collection and for clinician-collected specimens. The hc2 test was selected due to its commercial availability and its robust features that allow specimen storage and transport at room temperature. The Christmas tree–shaped brush was an efficient method of specimen collection; 499 specimens were analyzable of the 502 collected. The hc2 HPV test used in the study does not determine HPV type but allows detection of 13 common high-risk HPV types as a group(29). A future study with the use of a HPV genotyping test would allow us to precisely identify HPV types in this population and to obtain information of value in developing clinical applications of the self-collection of vaginal specimens for HPV typing.
Overall in our study, the detection of HPV was consistently higher in vaginal specimens than in cervical specimens. Interestingly, women with either normal or ASCUS Pap smears had a higher number of vaginal specimens positive for HPV compared to cervical specimens. However, because the number of women with LSIL and HSIL Pap smears was small, we were unable to draw any conclusions from this finding regarding HPV detection and the link to cytology. In our study, we found that women with seven or more partners were more likely to be simultaneously positive for HPV in both cervical and vaginal specimens. We postulated that women with seven or more partners may be infected with multiple HPV types, thus leading to this observation. Prior research studies have noted higher detection of HPV in self-collected vaginal samples compared to clinician-collected samples, and some variation in HPV detection related to number of sexual partners has been reported(33–37).
Prior studies have found that self-sampling for high-risk HPV showed a 91% concordance with clinician sampling for HPV DNA(8). Another study found that more high-risk HPV was found in self-sampling than clinician sampling(10). For detecting high-grade cervical intraepithelial neoplasia and cancers, Wright et al. (17) found that self-sampling of the vagina was as sensitive as the conventional Pap smear (66.1% and 67.9%, respectively) but not as sensitive as HPV DNA testing on clinician-obtained cervical specimens (83.9%). The self-sampling approach was less specific than the Pap smear, showing a false-positive rate for HPV DNA of 17.1% compared to the Pap smear rate of 12.3%(17). Other studies have suggested similar findings(38,39). In our study, 13.4% (53/398) women were concordantly positive in vaginal and cervical specimens, and 3.0% (12/398) women were negative for self-collected vaginal specimens but positive for clinician-collected cervical specimens. We did not study the association of HPV detection and cytology, due to the low number of abnormal Pap smears in our data.
The implications of our study on clinical practice, clinical research, and public health would be the understanding that women with diverse backgrounds presenting for routine gynecological care are all likely to accept the self-collection technique. The limitations of our study are the inclusion of only women presenting to the office for routine gynecological care, thus impacting the ability to generalize from our observations. The cost of self-collection of vaginal specimen for HPV is likely to be cheaper due to the absence of costs related to physician examination. However, there is no assurance at this time that women who test positive for HPV in self-collected vaginal specimens will or will not be willing to follow up for recommended procedures. Further, management of women with HPV is evolving, and educational messages for women who are positive for HPV have not been decided upon(40). Research is ongoing to develop culturally sensitive messages that will address psychologic issues in HPV screening and detection(41). In our study, we found that AA women were less likely to self-collect a vaginal specimen, and this fact demonstrates the need for culturally appropriate educational messages.
The majority of women (79.8% [398/499]) preferred self-collection of vaginal specimens over clinician-collected cervical specimens. Our study was limited by 101/499 (20.2%) women who declined self-collection of specimens due to lack of time and perceived uneasiness with the use of the brush to collect the specimen. The reasons for refusing self-collection of vaginal samples are important in developing culturally sensitive educational messages; hence, in a future study, we plan to investigate this observation further to determine predictors of acceptance and accuracy of the self-test for HPV. Such a study will support the development of programs utilizing self-collection of specimens for HPV typing as a valuable public health tool.
Interestingly, 68/101 (67.3%) women who refused to obtain self-collected vaginal specimens also left the question unanswered concerning use of oral contraceptive pills, possibly due to lack of time. This observation will be further studied in a larger study including women who do not routinely access health promotion services.
Our study has produced unique data regarding the acceptance of self-collection of vaginal specimens as a method for the detection of HPV in women with diverse sociodemographic features. The great majority of women are willing to obtain self-collected vaginal specimens despite variations in sociodemographics. We found that non-Hispanic Caucasian women were somewhat more likely to obtain self-collected specimens for HPV tests. There is scope for developing culturally sensitive educational messages regarding HPV testing. The detection of HPV in vaginal specimens was consistently higher than in cervical specimens, and correlation with cytology was limited due to the low number of abnormal Pap smears in this study.
N.K. was the principal investigator and participated in the investigation's development and implementation. S.I.M. was the methodologist and assisted in developing the methods used for the study. G.T. and M.T.T. were the study biostatisticians. C.R.B. was the study's advisor. A.L. was the bench scientist from Digene Corporation. S.A., C.L., S.R., and L.B. were the research assistants working on the project.
This research was supported in part by grants from the Maryland Statewide Health Network (N.K.), a Small Business Innovation Research from NIAID N44-AI-85335 to Digene Corporation (A.L.), and the National Center for Minority Health and Health Disparities P60MD000532. The contents of the article are solely the responsibility of the authors and do not necessarily represent the views of the funding agencies. The authors acknowledge the editorial review by Kathy Mack and Linda Kesselring.
1 Walboomers JM, Jacobs MV, Manos MM et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol
2 Bosch FX, Lorincz A, Munoz N et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol
3 Follen M, Richards-Kortum R. Emerging technologies and cervical cancer [editorial]. J Natl Cancer Inst
4 Wright TC Jr, Schiffman M. Adding a test for human papillomavirus DNA to cervical-cancer screening. N Engl J Med
5 Smith RA, Cokkinides V, Eyre HJ. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin
6 Saslow D, Runowicz CD, Solomon D et al. American Cancer Society. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin
7 Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System Survey Data. Atlanta, Georgia: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2006. Available at: http://apps.nccd.cdc.gov/brfss
. Accessed March 9, 2006.
9 Iftner T, Villa LL. Human papillomavirus technologies. J Natl Cancer Inst Monogr
10 Peyton CL, Schiffman M, Lorincz A et al. Comparison of PCR- and hybrid capture-based human papillomavirus detection systems using multiple cervical specimen collection strategies. J Clin Microbiol
11 Serwadda D, Wawer MJ, Shah KV et al. Use of a hybrid capture assay of self-collected vaginal swabs in rural Uganda for detection of human papillomavirus. J Infect Dis
12 Harper DM, Hildesheim A, Cobb JL et al. Collection devices for human papillomavirus. J Fam Pract
13 Dzuba IG, Diaz EY, Allen B et al. The acceptability of self-collected samples for HPV testing vs. the Pap test as alternatives in cervical cancer screening. J Womens Health Gend Based Med
14 Sellors JW, Lorincz AT, Mahony JB et al. Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions. CMAJ
15 Moscicki AB. Comparison between methods for human papillomavirus DNA testing: a model for self-testing in young women. J Infect Dis
16 Hillemanns P, Kimmig R, Huttemann U et al. Screening for cervical neoplasia by self-assessment for human papillomavirus DNA. Lancet 1999
17 Wright TC, Denny L, Kuhn L et al. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA
18 Gravitt PE, Lacey JV Jr, Brinton LA et al. Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction. Cancer Epidemiol Biomarkers Prev
19 Flores Y, Shah K, Lazcano E et al. Design and methods of the evaluation of an HPV-based cervical cancer screening strategy in Mexico: the Morelos HPV Study. Salud Publica Mex
20 Goldie SJ, Kim JJ, Wright TC. Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol
21 Salmeron J, Lazcano-Ponce E, Lorincz A et al. Comparison of HPV-based assays with Papanicolaou smears for cervical cancer screening in Morelos State, Mexico. Cancer Causes Control
22 Raine T, Marcell AV, Rocca CH, Harper CC. The other half of the equation: serving young men in a young women's reproductive health clinic. Perspect Sex Reprod Health
23 Banikarim C, Chacko MR, Wiemann CM, Smith PB. Gonorrhea and chlamydia screening among young women: stage of change, decisional balance, and self-efficacy. J Adolesc Health
24 Khanna N, Brooks SE, Chen TT et al. Human papillomavirus absence predicts normal cervical histopathologic findings with abnormal papanicolaou smears: a study of a university-based inner city population. J Hum Virol
25 Bolick DR, Hellman DJ. Laboratory implementation and efficacy assessment of ThinPrep cervical cancer screening system. Acta Cytol
26 Obwegeser JH, Brack S. Does liquid-based technology really improve detection of cervical neoplasia? A prospective, randomized trial comparing the ThinPrep Pap Test with the conventional Pap test, including follow-up of HSIL cases. Acta Cytol
27 Clavel C, Masure M, Bory JP et al. Hybrid Capture II-based human papillomavirus detection, a sensitive test to detect in routine high-grade cervical lesions: a preliminary study on 1518 women. Br J Cancer
28 Solomon D, Davey D, Kurman R et al. Forum Group Members. Bethesda 2001 Workshop. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA
29 Lorincz A. Hybrid Capture method for detection of human papillomavirus DNA in clinical specimens: a tool for clinical management of equivocal Pap smears and for population screening. J Obstet Gynaecol Res
30 Altman DG. Practical statistics for medical research
. Boca Raton, FL: Chapman & Hall/CRC, 1991.
31 Syrjanen S, Shabalova I, Petrovichev N et al. Sexual habits and human papillomavirus infection among females in three New Independent States of the former Soviet Union. Sex Transm Dis
32 Moscicki AB, Palefsky J, Gonzales J, Schoolnik GK. Human papillomavirus infection in sexually active adolescent females: prevalence and risk factors. Pediatr Res
33 Daling JR, Madeleine MM, Johnson LG et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer
34 Berrington de Gonzalez A, Sweetland S, Green J. Comparison of risk factors for squamous cell and adenocarcinomas of the cervix: a meta-analysis. Br J Cancer
35 Au WW. Life style, environmental and genetic susceptibility to cervical cancer. Toxicology
36 Minkoff H, Feldman JG, Strickler HD et al. Relationship between smoking and human papillomavirus infections in HIV-infected and -uninfected women. J Infect Dis
37 Schiffman M, Castle PE. Human papillomavirus: epidemiology and public health. Arch Pathol Lab Med
38 Harper DM, Noll WW, Belloni DR, Cole BF. Randomized clinical trial of PCR-determined human papillomavirus detection methods: self-sampling versus clinician-directed—biologic concordance and women's preferences. Am J Obstet Gynecol
39 Franco EL. Chapter 13: Primary screening of cervical cancer with human papillomavirus tests. J Natl Cancer Inst Monogr
40 Clarke P, Ebel C, Catotti DN et al. The psychological impact of human papillomavirus infection: implications for health care providers. Int J STD AIDS
41 Anhang R, Goodman A, Goldie SJ. HPV communication: review of existing research and recommendations for patient education. CA Cancer J Clin
Copyright © 2007 Blackwell Publishing Ltd.