Grant Number:	5R01CA034493-22 Interpret this number
Primary Investigator:	Koutsky, Laura
Organization:	University Of Washington
Project Title:	Etiology and Natural History of Cervical Neoplasia
Fiscal Year:	2007

DESCRIPTION (provided by applicant): Our long-term goal is to develop sensitive, specific, and inexpensive approaches to cervical cancer screening. In our previous proposal, we performed the first U.S.-based study of the accuracy and cost effectiveness of primary screening by traditional Pap and cervical HPV DNA testing. We found that testing for HPV was considerably more sensitive but less specific than Pap testing for detection of cervical intraepithelial neoplasia grade 3 (CIN3). While the role of high sensitivity in detecting disease cannot be disputed, when the trade-offs low specificity there are substantial cost implications, especially for a screening test that is repeated at regular intervals. Preliminary results from our group suggest that testing for the cyclin-dependant kinase inhibitor, p16INK4a, may provide a more accurate indication of disease status than either Pap or HPV DNA testing. Since p16INK4a is protein, there is potential for developing a low cost ELISA assay. Furthermore, our pilot data suggest that p16INK4a is associated with infection by variants of HPV16 that are most strongly linked with CIN3 and cancer. In HPV-associated tumors, levels of p16INK4a increase due to inactivation of Rb by HPV E7. Lastly, our preliminary data suggest that a self-collected vaginal swab for HPV DNA testing may be a viable screening option for women who avoid, or who do not have access to, pelvic examinations. In the proposed project, we plan to define the accuracy and relative cost-effectiveness of p16INK4a testing of a clinician collected sample and HPV DNA testing of a self-collected vaginal swab sample. In addition, we will explore the hypothesis that variation in levels of E7 gene expression defines differences in the oncogenic potential of HPV16 variants. While Pap test screening of healthy women has substantially reduced cervical cancer deaths over the last 50 years, false negative and false positive screening test results have also deprived women of their sense of well-being, initiated potentially harmful diagnostic testing and treatment, and wasted health-care resources. Clear public health benefits will accrue from development of more accurate and less costly screening tests.




Inverse association between methylation of human papillomavirus type 16 DNA and risk of cervical intraepithelial neoplasia grades 2 or 3.
Authors: Xi L.F. , Jiang M. , Shen Z. , Hulbert A. , Zhou X.H. , Lin Y.Y. , Kiviat N.B. , Koutsky L.A. .
Source: Plos One, 2011; 6(8), p. e23897.
PMID: 21887341
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Accuracy and cost-effectiveness of cervical cancer screening by high-risk human papillomavirus DNA testing of self-collected vaginal samples.
Authors: Balasubramanian A. , Kulasingam S.L. , Baer A. , Hughes J.P. , Myers E.R. , Mao C. , Kiviat N.B. , Koutsky L.A. .
Source: Journal Of Lower Genital Tract Disease, 2010 Jul; 14(3), p. 185-95.
PMID: 20592553
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Evaluation Of An Elisa For P16ink4a As A Screening Test For Cervical Cancer
Authors: Balasubramanian,A. , Hughes,J. , Mao,C. , Ridder,R. , Herkert,M. , Kiviat,N.B. , Koutsky,L.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 Nov; 18(11), p. 3008-17.
PMID: 19843667
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Depot-medroxyprogesterone acetate and combined oral contraceptive use and cervical neoplasia among women with oncogenic human papillomavirus infection.
Authors: Harris T.G. , Miller L. , Kulasingam S.L. , Feng Q. , Kiviat N.B. , Schwartz S.M. , Koutsky L.A. .
Source: American Journal Of Obstetrics And Gynecology, 2009 May; 200(5), p. 489.e1-8.
PMID: 19375566
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Sequence variation of human papillomavirus type 16 and measurement of viral integration by quantitative PCR.
Authors: Jiang M. , Baseman J.G. , Koutsky L.A. , Feng Q. , Mao C. , Kiviat N.B. , Xi L.F. .
Source: Journal Of Clinical Microbiology, 2009 Mar; 47(3), p. 521-6.
PMID: 19116350
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Development and evaluation of a liquid bead microarray assay for genotyping genital human papillomaviruses.
Authors: Feng Q. , Cherne S. , Winer R.L. , Balasubramanian A. , Lee S.K. , Hawes S.E. , Kiviat N.B. , Koutsky L.A. .
Source: Journal Of Clinical Microbiology, 2009 Mar; 47(3), p. 547-53.
PMID: 19144800
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Evaluation Of A New P16(ink4a) Elisa Test And A High-risk Hpv Dna Test For Cervical Cancer Screening: Results From Proof-of-concept Study
Authors: Mao,C. , Balasubramanian,A. , Yu,M. , Kiviat,N. , Ridder,R. , Reichert,A. , Herkert,M. , von Knebel Doeberitz,M. , Koutsky,L.A. .
Source: International Journal Of Cancer. Journal International Du Cancer, 2007-06-01 00:00:00.0; 120(11), p. 2435-8.
PMID: 17294450
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Should Liquid-based Cytology Be Repeated At The Time Of Colposcopy?
Authors: Mao,C. , Balasubramanian,A. , Koutsky,L.A. .
Source: Journal Of Lower Genital Tract Disease, 2005 Apr; 9(2), p. 82-8.
PMID: 15870528
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Cigarette smoking, oncogenic human papillomavirus, Ki-67 antigen, and cervical intraepithelial neoplasia.
Authors: Harris T.G. , Kulasingam S.L. , Kiviat N.B. , Mao C. , Agoff S.N. , Feng Q. , Koutsky L.A. .
Source: American Journal Of Epidemiology, 2004-05-01 00:00:00.0; 159(9), p. 834-42.
PMID: 15105176
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p16(INK4a) expression correlates with degree of cervical neoplasia: a comparison with Ki-67 expression and detection of high-risk HPV types.
Authors: Agoff S.N. , Lin P. , Morihara J. , Mao C. , Kiviat N.B. , Koutsky L.A. .
Source: Modern Pathology : An Official Journal Of The United States And Canadian Academy Of Pathology, Inc, 2003 Jul; 16(7), p. 665-73.
PMID: 12861062
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The theoretical population-level impact of a prophylactic human papilloma virus vaccine.
Authors: Hughes J.P. , Garnett G.P. , Koutsky L. .
Source: Epidemiology (cambridge, Mass.), 2002 Nov; 13(6), p. 631-9.
PMID: 12410003
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The Effect Of Vaginal Speculum Lubrication On The Rate Of Unsatisfactory Cervical Cytology Diagnosis
Authors: Amies A.M. , Miller L. , Lee S.K. , Koutsky L. .
Source: Obstetrics And Gynecology, 2002 Nov; 100(5 Pt 1), p. 889-92.
PMID: 12423848
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Do condoms prevent genital HPV infection, external genital warts, or cervical neoplasia? A meta-analysis.
Authors: Manhart L.E. , Koutsky L.A. .
Source: Sexually Transmitted Diseases, 2002 Nov; 29(11), p. 725-35.
PMID: 12438912
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Evaluation Of Human Papillomavirus Testing In Primary Screening For Cervical Abnormalities: Comparison Of Sensitivity, Specificity, And Frequency Of Referral
Authors: Kulasingam S.L. , Hughes J.P. , Kiviat N.B. , Mao C. , Weiss N.S. , Kuypers J.M. , Koutsky L.A. .
Source: Jama, 2002-10-09 00:00:00.0; 288(14), p. 1749-57.
PMID: 12365959
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Determinants of cervical cancer rates in developing countries.
Authors: Drain P.K. , Holmes K.K. , Hughes J.P. , Koutsky L.A. .
Source: International Journal Of Cancer, 2002-07-10 00:00:00.0; 100(2), p. 199-205.
PMID: 12115570
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Liquid-based Papanicolaou smears without a transformation zone component: should clinicians worry?
Authors: Baer A. , Kiviat N.B. , Kulasingam S. , Mao C. , Kuypers J. , Koutsky L.A. .
Source: Obstetrics And Gynecology, 2002 Jun; 99(6), p. 1053-9.
PMID: 12052599
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Acquisition And Natural History Of Human Papillomavirus Type 16 Variant Infection Among A Cohort Of Female University Students
Authors: Xi L.F. , Carter J.J. , Galloway D.A. , Kuypers J. , Hughes J.P. , Lee S.K. , Adam D.E. , Kiviat N.B. , Koutsky L.A. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2002 Apr; 11(4), p. 343-51.
PMID: 11927494
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Papanicolaou Test Screening And Prevalence Of Genital Human Papillomavirus Among Women Who Have Sex With Women
Authors: Marrazzo J.M. , Koutsky L.A. , Kiviat N.B. , Kuypers J.M. , Stine K. .
Source: American Journal Of Public Health, 2001 Jun; 91(6), p. 947-52.
PMID: 11392939
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Comparison Of Variant-specific Hybridization And Single-strand Conformational Polymorphism Methods For Detection Of Mixed Human Papillomavirus Type 16 Variant Infections
Authors: Emeny R.T. , Herron J.R. , Xi L.F. , Koutsky L.A. , Kiviat N.B. , Wheeler C.M. .
Source: Journal Of Clinical Microbiology, 1999 Nov; 37(11), p. 3627-33.
PMID: 10523565
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Genital Human Papillomavirus Infection In Women Who Have Sex With Women
Authors: Marrazzo J.M. , Koutsky L.A. , Stine K.L. , Kuypers J.M. , Grubert T.A. , Galloway D.A. , Kiviat N.B. , Handsfield H.H. .
Source: The Journal Of Infectious Diseases, 1998 Dec; 178(6), p. 1604-9.
PMID: 9815211
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Hydrogen Peroxide-producing Lactobacilli And Acquisition Of Vaginal Infections
Authors: Hawes S.E. , Hillier S.L. , Benedetti J. , Stevens C.E. , Koutsky L.A. , Wolner-Hanssen P. , Holmes K.K. .
Source: The Journal Of Infectious Diseases, 1996 Nov; 174(5), p. 1058-63.
PMID: 8896509
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The inflammatory Papanicolaou smear: what does it mean?
Authors: Eckert L.O. , Koutsky L.A. , Kiviat N.B. , Krone M.R. , Stevens C.E. , Eschenbach D.A. .
Source: Obstetrics And Gynecology, 1995 Sep; 86(3), p. 360-6.
PMID: 7651643
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Analysis Of Human Papillomavirus Type 16 Variants Indicates Establishment Of Persistent Infection
Authors: Xi L.F. , Demers G.W. , Koutsky L.A. , Kiviat N.B. , Kuypers J. , Watts D.H. , Holmes K.K. , Galloway D.A. .
Source: The Journal Of Infectious Diseases, 1995 Sep; 172(3), p. 747-55.
PMID: 7658068
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Determinants Of Cervical Ectopia And Of Cervicitis: Age, Oral Contraception, Specific Cervical Infection, Smoking, And Douching
Authors: Critchlow C.W. , Wölner-Hanssen P. , Eschenbach D.A. , Kiviat N.B. , Koutsky L.A. , Stevens C.E. , Holmes K.K. .
Source: American Journal Of Obstetrics And Gynecology, 1995 Aug; 173(2), p. 534-43.
PMID: 7645632
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A Cohort Study Of The Risk Of Cervical Intraepithelial Neoplasia Grade 2 Or 3 In Relation To Papillomavirus Infection
Authors: Koutsky L.A. , Holmes K.K. , Critchlow C.W. , Stevens C.E. , Paavonen J. , Beckmann A.M. , DeRouen T.A. , Galloway D.A. , Vernon D. , Kiviat N.B. .
Source: The New England Journal Of Medicine, 1992-10-29 00:00:00.0; 327(18), p. 1272-8.
PMID: 1328880
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Prevalence And Cytologic Manifestations Of Human Papilloma Virus (hpv) Types 6, 11, 16, 18, 31, 33, 35, 42, 43, 44, 45, 51, 52, And 56 Among 500 Consecutive Women
Authors: Kiviat N.B. , Koutsky L.A. , Critchlow C.W. , Lorincz A.T. , Cullen A.P. , Brockway J. , Holmes K.K. .
Source: International Journal Of Gynecological Pathology : Official Journal Of The International Society Of Gynecological Pathologists, 1992 Jul; 11(3), p. 197-203.
PMID: 1328077
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Underdiagnosis Of Genital Herpes By Current Clinical And Viral-isolation Procedures
Authors: Koutsky L.A. , Stevens C.E. , Holmes K.K. , Ashley R.L. , Kiviat N.B. , Critchlow C.W. , Corey L. .
Source: The New England Journal Of Medicine, 1992-06-04 00:00:00.0; 326(23), p. 1533-9.
PMID: 1315930
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Microbiological, epidemiological and clinical correlates of vaginal colonisation by Mobiluncus species.
Authors: Hillier S.L. , Critchlow C.W. , Stevens C.E. , Roberts M.C. , Wolner-Hanssen P. , Eschenbach D.A. , Holmes K.K. .
Source: Genitourinary Medicine, 1991 Feb; 67(1), p. 26-31.
PMID: 1916772
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Comparison Of Southern Transfer Hybridization And Dot Filter Hybridization For Detection Of Cervical Human Papillomavirus Infection With Types 6, 11, 16, 18, 31, 33, And 35
Authors: Kiviat N.B. , Koutsky L.A. , Critchlow C.W. , Galloway D.A. , Vernon D.A. , Peterson M.L. , McElhose P.E. , Pendras S.J. , Stevens C.E. , Holmes K.K. .
Source: American Journal Of Clinical Pathology, 1990 Nov; 94(5), p. 561-5.
PMID: 2173397
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Anal Human Papillomavirus Infection Among Human Immunodeficiency Virus-seropositive And -seronegative Men
Authors: Kiviat N. , Rompalo A. , Bowden R. , Galloway D. , Holmes K.K. , Corey L. , Roberts P.L. , Stamm W.E. .
Source: The Journal Of Infectious Diseases, 1990 Aug; 162(2), p. 358-61.
PMID: 1973695
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Association Between Vaginal Douching And Acute Pelvic Inflammatory Disease
Authors: Wølner-Hanssen P. , Eschenbach D.A. , Paavonen J. , Stevens C.E. , Kiviat N.B. , Critchlow C. , DeRouen T. , Koutsky L. , Holmes K.K. .
Source: Jama, 1990-04-11 00:00:00.0; 263(14), p. 1936-41.
PMID: 2313870
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The Frequency Of Unrecognized Type 2 Herpes Simplex Virus Infection Among Women. Implications For The Control Of Genital Herpes
Authors: Koutsky L.A. , Ashley R.L. , Holmes K.K. , Stevens C.E. , Critchlow C.W. , Kiviat N. , Lipinski C.M. , Wølner-Hanssen P. , Corey L. .
Source: Sexually Transmitted Diseases, 1990 Apr-Jun; 17(2), p. 90-4.
PMID: 2163115
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Decreased Risk Of Symptomatic Chlamydial Pelvic Inflammatory Disease Associated With Oral Contraceptive Use
Authors: Wølner-Hanssen P. , Eschenbach D.A. , Paavonen J. , Kiviat N. , Stevens C.E. , Critchlow C. , DeRouen T. , Holmes K.K. .
Source: Jama, 1990-01-05 00:00:00.0; 263(1), p. 54-9.
PMID: 2293688
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Prevalence Of Genital Papillomavirus Infection Among Women Attending A College Student Health Clinic Or A Sexually Transmitted Disease Clinic
Authors: Kiviat N.B. , Koutsky L.A. , Paavonen J.A. , Galloway D.A. , Critchlow C.W. , Beckmann A.M. , McDougall J.K. , Peterson M.L. , Stevens C.E. , Lipinski C.M. .
Source: The Journal Of Infectious Diseases, 1989 Feb; 159(2), p. 293-302.
PMID: 2536781
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Diagnosis and clinical manifestations of bacterial vaginosis.
Authors: Eschenbach D.A. , Hillier S. , Critchlow C. , Stevens C. , DeRouen T. , Holmes K.K. .
Source: American Journal Of Obstetrics And Gynecology, 1988 Apr; 158(4), p. 819-28.
PMID: 3259075
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Epidemiology of genital human papillomavirus infection.
Authors: Koutsky L.A. , Galloway D.A. , Holmes K.K. .
Source: Epidemiologic Reviews, 1988; 10, p. 122-63.
PMID: 2852116
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