Publications by authors named "Brian Befano"

26 Publications

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Deep Metric Learning for Cervical Image Classification.

IEEE Access 2021 29;9:53266-53275. Epub 2021 Mar 29.

National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Cervical cancer is caused by the persistent infection of certain types of the Human Papillomavirus (HPV) and is a leading cause of female mortality particularly in low and middle-income countries (LMIC). Visual inspection of the cervix with acetic acid (VIA) is a commonly used technique in cervical screening. While this technique is inexpensive, clinical assessment is highly subjective, and relatively poor reproducibility has been reported. A deep learning-based algorithm for automatic visual evaluation (AVE) of aceto-whitened cervical images was shown to be effective in detecting confirmed precancer (i.e. direct precursor to invasive cervical cancer). The images were selected from a large longitudinal study conducted by the National Cancer Institute in the Guanacaste province of Costa Rica. The training of AVE used annotation for cervix boundary, and the data scarcity challenge was dealt with manually optimized data augmentation. In contrast, we present a novel approach for cervical precancer detection using a deep metric learning-based (DML) framework which does not incorporate any effort for cervix boundary marking. The DML is an advanced learning strategy that can deal with data scarcity and bias training due to class imbalance data in a better way. Three different widely-used state-of-the-art DML techniques are evaluated- (a) Contrastive loss minimization, (b) N-pair embedding loss minimization, and, (c) Batch-hard loss minimization. Three popular Deep Convolutional Neural Networks (ResNet-50, MobileNet, NasNet) are configured for training with DML to produce class-separated (i.e. linearly separable) image feature descriptors. Finally, a K-Nearest Neighbor (KNN) classifier is trained with the extracted deep features. Both the feature quality and classification performance are quantitatively evaluated on the same data set as used in AVE. It shows that, unlike AVE, without using any data augmentation, the best model produced from our research improves specificity in disease detection without compromising sensitivity. The present research thus paves the way for new research directions for the related field.
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http://dx.doi.org/10.1109/access.2021.3069346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224396PMC
March 2021

Network Visualization and Pyramidal Feature Comparison for Ablative Treatability Classification Using Digitized Cervix Images.

J Clin Med 2021 Mar 1;10(5). Epub 2021 Mar 1.

Communications Engineering Branch, Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.

Uterine cervical cancer is a leading cause of women's mortality worldwide. Cervical tissue ablation is an effective surgical excision of high grade lesions that are determined to be precancerous. Our prior work on the Automated Visual Examination (AVE) method demonstrated a highly effective technique to analyze digital images of the cervix for identifying precancer. Next step would be to determine if she is treatable using ablation. However, not all women are eligible for the therapy due to cervical characteristics. We present a machine learning algorithm that uses a deep learning object detection architecture to determine if a cervix is eligible for ablative treatment based on visual characteristics presented in the image. The algorithm builds on the well-known RetinaNet architecture to derive a simpler and novel architecture in which the last convolutional layer is constructed by upsampling and concatenating specific RetinaNet pretrained layers, followed by an output module consisting of a Global Average Pooling (GAP) layer and a fully connected layer. To explain the recommendation of the deep learning algorithm and determine if it is consistent with lesion presentation on the cervical anatomy, we visualize classification results using two techniques: our (i) Class-selective Relevance Map (CRM), which has been reported earlier, and (ii) Class Activation Map (CAM). The class prediction heatmaps are evaluated by a gynecologic oncologist with more than 20 years of experience. Based on our observation and the expert's opinion, the customized architecture not only outperforms the baseline RetinaNet network in treatability classification, but also provides insights about the features and regions considered significant by the network toward explaining reasons for treatment recommendation. Furthermore, by investigating the heatmaps on Gaussian-blurred images that serve as surrogates for out-of-focus cervical pictures we demonstrate the effect of image quality degradation on cervical treatability classification and underscoring the need for using images with good visual quality.
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http://dx.doi.org/10.3390/jcm10050953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957626PMC
March 2021

The relationship of human papillomavirus and cytology co-testing results with endometrial and ovarian cancer diagnoses.

Gynecol Oncol 2021 Apr 14;161(1):297-303. Epub 2021 Jan 14.

Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA, USA.

Background: To investigate whether routine cervical screening using human papillomavirus (HPV) and cytology co-testing effectively identifies women with endometrial (EC) or ovarian (OvC) cancer.

Methods: In 2003, Kaiser Permanente Northern California implemented triennial co-testing in women aged ≥30 years. Index screening results (n = 2,385,729) were linked to subsequent EC (n = 3434) and OvC (n = 1113) diagnoses from January 1, 2003 to December 31, 2017. EC were categorized as type 1 or 2, and, selectively, EC and OvC diagnoses were stratified on whether symptoms were present at the time of the co-test. Fractions and absolute risks of EC or OvC of each co-testing result were calculated.

Results: Most EC (82.18%) and OvC (88.68%) were preceded by a negative HPV and negative cytology co-test. More EC were preceded by atypical squamous cells of undetermined significance (ASC-US) or more severe (ASC-US+) cytology and negative HPV test (n = 290) (8.44% of EC) compared to a negative cytology and a positive HPV test (n = 31) (0.89% of EC) (p < 0.001). The absolute risk of any EC diagnosis following ASC-US+ and negative HPV test was 0.48%. Atypical glandular cells (AGC) cytology and a negative HPV result preceded 6.92% of any EC diagnosis, with an absolute risk of 4.02%, but preceded only 1.13% of type 2 EC cases, with an absolute risk of 0.24%, in asymptomatic women. AGC cytology and a negative HPV result preceded 1.44% of OvC, with an absolute risk of 0.28%.

Conclusions: Abnormal cervical screening tests, even AGC cytology, rarely precedes and poorly predict women with EC or OvC.
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http://dx.doi.org/10.1016/j.ygyno.2021.01.005DOI Listing
April 2021

A study of type-specific HPV natural history and implications for contemporary cervical cancer screening programs.

EClinicalMedicine 2020 May 25;22:100293. Epub 2020 Apr 25.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Background: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found.

Methods: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30-65 yielding 14,158 type-specific infections.

Findings: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks <5%). In the absence of progression, HPV clearance rates were similar by type, with 80% of infections no longer detected within three years; persistence to seven years without progression was uncommon. The predictive value of abnormal cytology was most evident for prevalent CIN3+, but less evident in follow-up. A woman's age did not modify risk; rather it was the duration of persistence that was important.

Interpretation: HPV type and persistence are the major predictors of progression to CIN3+; at a minimum, distinguishing HPV16 is clinically important. Dividing the other HPV types into three risk-groups is worth considering.
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http://dx.doi.org/10.1016/j.eclinm.2020.100293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264956PMC
May 2020

Association of HPV35 with cervical carcinogenesis among women of African ancestry: Evidence of viral-host interaction with implications for disease intervention.

Int J Cancer 2020 11 16;147(10):2677-2686. Epub 2020 May 16.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.

HPV35 has been found in only ∼2% of invasive cervical cancers (ICC) worldwide but up to 10% in Sub-Saharan Africa, warranting further investigation and consideration of impact on preventive strategies. We studied HPV35 and ethnicity, in relation to the known steps in cervical carcinogenesis, using multiple large epidemiologic studies in the U.S. and internationally. Combining five U.S. studies, we measured HPV35 positivity and, in Northern California, observed HPV35 type-specific population prevalence and estimated 5-year risk of developing precancer when HPV35-positive. HPV35 genetic variation was examined for differences in carcinogenicity in 1053 HPV35+ cervical specimens from a U.S. cohort and an international collection. African-American women had more HPV35 (12.1% vs 5.1%, P < .001) and more HPV35-associated precancers (7.4% vs 2.1%, P < .001) compared to other ethnicities. Precancer risks after HPV35 infection did not vary by ethnicity (global P = .52). The HPV35 A2 sublineage showed an increased association with precancer/cancer in African-Americans (OR = 5.6 vs A1, 95% CI = 1.3-24.8) and A2 was more prevalent among ICC in Africa than other world regions (41.9% vs 10.4%, P < .01). Our analyses support a strong link between HPV35 and cervical carcinogenesis in women of African ancestry. Current HPV vaccines cover the majority of cervical precancer/cancer across all ethnic groups; additional analyses are required to determine whether the addition of HPV35 to the already highly effective nine-valent HPV vaccine would provide better protection for women in Africa or of African ancestry.
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http://dx.doi.org/10.1002/ijc.33033DOI Listing
November 2020

A demonstration of automated visual evaluation of cervical images taken with a smartphone camera.

Int J Cancer 2020 11 19;147(9):2416-2423. Epub 2020 May 19.

Lister Hill National Center for Biomedical Communications, National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.

We examined whether automated visual evaluation (AVE), a deep learning computer application for cervical cancer screening, can be used on cervix images taken by a contemporary smartphone camera. A large number of cervix images acquired by the commercial MobileODT EVA system were filtered for acceptable visual quality and then 7587 filtered images from 3221 women were annotated by a group of gynecologic oncologists (so the gold standard is an expert impression, not histopathology). We tested and analyzed on multiple random splits of the images using two deep learning, object detection networks. For all the receiver operating characteristics curves, the area under the curve values for the discrimination of the most likely precancer cases from least likely cases (most likely controls) were above 0.90. These results showed that AVE can classify cervix images with confidence scores that are strongly associated with expert evaluations of severity for the same images. The results on a small subset of images that have histopathologic diagnoses further supported the capability of AVE for predicting cervical precancer. We examined the associations of AVE severity score with gynecologic oncologist impression at all regions where we had a sufficient number of cases and controls, and the influence of a woman's age. The method was found generally resilient to regional variation in the appearance of the cervix. This work suggests that using AVE on smartphones could be a useful adjunct to health-worker visual assessment with acetic acid, a cervical cancer screening method commonly used in low- and middle-resource settings.
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http://dx.doi.org/10.1002/ijc.33029DOI Listing
November 2020

A Study of Partial Human Papillomavirus Genotyping in Support of the 2019 ASCCP Risk-Based Management Consensus Guidelines.

J Low Genit Tract Dis 2020 Apr;24(2):144-147

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Introduction: The 2019 ASCCP Risk-Based Management Consensus Guidelines include recommendations for partial human papillomavirus (HPV) genotyping in management of abnormal cervical cancer screening results. The guidelines are based on matching estimates of cervical intraepithelial neoplasia (CIN) 3+ risk to consensus clinical action thresholds. In support of the guidelines, this analysis addresses the risks predicted by individual identification of HPV 16 and HPV 18.

Methods: Risk estimates were drawn from a subset of women in the Kaiser Permanente Northern California screening program, whose residual cervical specimens were HPV typed as part of the HPV Persistence and Progression study. We calculated risk of CIN 3+ to assess how identification of HPV 16, HPV 18, or 12 other "high-risk" HPV types would influence recommended clinical management of new abnormal screening results, taking into account current cytologic results and recent screening history. Immediate and/or 5-year risks of CIN 3+ were matched to clinical actions identified in the guidelines.

Results: Identification of HPV 16 at the first visit including HPV testing elevated immediate risk of diagnosing CIN 3+ sufficiently to mandate colposcopic referral even when cytology was Negative for Intraepithelial Lesions or Malignancy and to support a preference for treatment of cytologic high-grade squamous intraepithelial lesion. HPV 18 less clearly elevated CIN 3+ risk.

Conclusions: Identification of HPV 16 clearly mandated consideration in clinical management of new abnormal screening results. HPV 18 positivity must be considered as a special situation because of established disproportionate risk of invasive cancer. More detailed genotyping and use beyond initial management will be considered in guideline updates.
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http://dx.doi.org/10.1097/LGT.0000000000000530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141756PMC
April 2020

Risk Estimates Supporting the 2019 ASCCP Risk-Based Management Consensus Guidelines.

J Low Genit Tract Dis 2020 Apr;24(2):132-143

Division of Gynecologic Oncology, Kaiser Permanente Medical Care Program, Oakland, CA (contributed before retirement).

The 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines for the management of cervical cancer screening abnormalities recommend 1 of 6 clinical actions (treatment, optional treatment or colposcopy/biopsy, colposcopy/biopsy, 1-year surveillance, 3-year surveillance, 5-year return to regular screening) based on the risk of cervical intraepithelial neoplasia grade 3, adenocarcinoma in situ, or cancer (CIN 3+) for the many different combinations of current and recent past screening results. This article supports the main guidelines presentation by presenting and explaining the risk estimates that supported the guidelines.

Methods: From 2003 to 2017 at Kaiser Permanente Northern California (KPNC), 1.5 million individuals aged 25 to 65 years were screened with human papillomavirus (HPV) and cytology cotesting scheduled every 3 years. We estimated immediate and 5-year risks of CIN 3+ for combinations of current test results paired with history of screening test and colposcopy/biopsy results.

Results: Risk tables are presented for different clinical scenarios. Examples of important results are highlighted; for example, the risk posed by most current abnormalities is greatly reduced if the prior screening round was HPV-negative. The immediate and 5-year risks of CIN 3+ used to decide clinical management are shown.

Conclusions: The new risk-based guidelines present recommendations for the management of abnormal screening test and histology results; the key risk estimates supporting guidelines are presented in this article. Comprehensive risk estimates are freely available online at https://CervixCa.nlm.nih.gov/RiskTables.
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http://dx.doi.org/10.1097/LGT.0000000000000529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147417PMC
April 2020

A study of the risks of CIN3+ detection after multiple rounds of HPV testing: Results of the 15-year cervical cancer screening experience at Kaiser Permanente Northern California.

Int J Cancer 2020 09 26;147(6):1612-1620. Epub 2020 Mar 26.

Division of Cancer Epidemiology and Genetics, Clinical Genetics Branch, National Cancer Institute, Bethesda, MD, USA.

Many countries are transitioning to HPV testing for cervical cancer screening, despite a lack of long-term experience. To anticipate multi-round screening performance, we analyzed 15-year HPV testing results at Kaiser Permanente Northern California (KPNC). We evaluated HPV test result patterns among women aged 30-64 undergoing triennial HPV/cytology cotesting at KPNC during 2003-2018. We calculated incidence rates and proportion of CIN3+ diagnoses associated with the most frequent HPV testing patterns overall and stratified by age. From 2003 to 2018, a total of 1,361,581 women had a valid HPV test result, and 7,087 were diagnosed with CIN3+. Incidence rates of CIN3+ after HPV positivity were lowest when HPV detection was new and highest in women with prevalent infections (770 vs. 13,910/100,000 person-years). Repeat test negativity reduced subsequent incidence rates of CIN3+ to extremely low levels (18/100,000 person-years following four consecutive negative results). For mixed patterns of positivity/negativity, the recency and frequency of positive tests were associated with increased rates of CIN3+ diagnosis. Most CIN3+ cases (76%) were diagnosed in women who were positive at baseline (the first known positive HPV result); 16% were attributed to apparent newly detected infections and 3% to possible reappearing infections. These results corroborate previous findings that current HPV positivity, particularly when prevalent rather than new, is associated with the highest rates of CIN3+. In a screening program implementing HPV testing, most CIN3+ is detected at the first HPV positive test.
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http://dx.doi.org/10.1002/ijc.32950DOI Listing
September 2020

An Observational Study of Deep Learning and Automated Evaluation of Cervical Images for Cancer Screening.

J Natl Cancer Inst 2019 09;111(9):923-932

Background: Human papillomavirus vaccination and cervical screening are lacking in most lower resource settings, where approximately 80% of more than 500 000 cancer cases occur annually. Visual inspection of the cervix following acetic acid application is practical but not reproducible or accurate. The objective of this study was to develop a "deep learning"-based visual evaluation algorithm that automatically recognizes cervical precancer/cancer.

Methods: A population-based longitudinal cohort of 9406 women ages 18-94 years in Guanacaste, Costa Rica was followed for 7 years (1993-2000), incorporating multiple cervical screening methods and histopathologic confirmation of precancers. Tumor registry linkage identified cancers up to 18 years. Archived, digitized cervical images from screening, taken with a fixed-focus camera ("cervicography"), were used for training/validation of the deep learning-based algorithm. The resultant image prediction score (0-1) could be categorized to balance sensitivity and specificity for detection of precancer/cancer. All statistical tests were two-sided.

Results: Automated visual evaluation of enrollment cervigrams identified cumulative precancer/cancer cases with greater accuracy (area under the curve [AUC] = 0.91, 95% confidence interval [CI] = 0.89 to 0.93) than original cervigram interpretation (AUC = 0.69, 95% CI = 0.63 to 0.74; P < .001) or conventional cytology (AUC = 0.71, 95% CI = 0.65 to 0.77; P < .001). A single visual screening round restricted to women at the prime screening ages of 25-49 years could identify 127 (55.7%) of 228 precancers (cervical intraepithelial neoplasia 2/cervical intraepithelial neoplasia 3/adenocarcinoma in situ [AIS]) diagnosed cumulatively in the entire adult population (ages 18-94 years) while referring 11.0% for management.

Conclusions: The results support consideration of automated visual evaluation of cervical images from contemporary digital cameras. If achieved, this might permit dissemination of effective point-of-care cervical screening.
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http://dx.doi.org/10.1093/jnci/djy225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748814PMC
September 2019

Automated Cervical Screening and Triage, Based on HPV Testing and Computer-Interpreted Cytology.

J Natl Cancer Inst 2018 11;110(11):1222-1228

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD.

Background: State-of-the-art cervical cancer prevention includes human papillomavirus (HPV) vaccination among adolescents and screening/treatment of cervical precancer (CIN3/AIS and, less strictly, CIN2) among adults. HPV testing provides sensitive detection of precancer but, to reduce overtreatment, secondary "triage" is needed to predict women at highest risk. Those with the highest-risk HPV types or abnormal cytology are commonly referred to colposcopy; however, expert cytology services are critically lacking in many regions.

Methods: To permit completely automatable cervical screening/triage, we designed and validated a novel triage method, a cytologic risk score algorithm based on computer-scanned liquid-based slide features (FocalPoint, BD, Burlington, NC). We compared it with abnormal cytology in predicting precancer among 1839 women testing HPV positive (HC2, Qiagen, Germantown, MD) in 2010 at Kaiser Permanente Northern California (KPNC). Precancer outcomes were ascertained by record linkage. As additional validation, we compared the algorithm prospectively with cytology results among 243 807 women screened at KPNC (2016-2017). All statistical tests were two-sided.

Results: Among HPV-positive women, the algorithm matched the triage performance of abnormal cytology. Combined with HPV16/18/45 typing (Onclarity, BD, Sparks, MD), the automatable strategy referred 91.7% of HPV-positive CIN3/AIS cases to immediate colposcopy while deferring 38.4% of all HPV-positive women to one-year retesting (compared with 89.1% and 37.4%, respectively, for typing and cytology triage). In the 2016-2017 validation, the predicted risk scores strongly correlated with cytology (P < .001).

Conclusions: High-quality cervical screening and triage performance is achievable using this completely automated approach. Automated technology could permit extension of high-quality cervical screening/triage coverage to currently underserved regions.
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http://dx.doi.org/10.1093/jnci/djy044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454428PMC
November 2018

Low Risk of Cervical Cancer/Precancer Among Most Women Under Surveillance Postcolposcopy.

J Low Genit Tract Dis 2018 Apr;22(2):97-103

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

Objective: To inform impending postcolposcopy guidelines, this analysis examined the subsequent risk of CIN 3+ among women with a grade lower than CIN 2 (< CIN 2) colposcopy results, taking into account the referring results that brought them to colposcopy and cotest results postcolposcopy.

Methods: We analyzed 107,005 women from 25 to 65 years old, recommended for colposcopy at Kaiser Permanente Northern California. We estimated absolute risks of CIN 3+ among women: (1) recommended for colposcopy (precolposcopy), (2) following colposcopy and with histology results < CIN 2 (postcolposcopy), and (3) with cotest results 12 months after a < CIN 2 colposcopy (return cotest).

Results: After colposcopy showing < CIN 2 (n = 69,790; 87% of the women at colposcopy), the 1-year risk of CIN 3+ was 1.2%, compared with 6.3% at the time of colposcopy recommendation. Negative cotest results 1 year after colposcopy identified a large group (37.1%) of women whose risk of CIN 3+ (i.e., <0.2% at 3 years after postcolposcopy cotest) was comparable with women with normal cytology in the screening population. These risks are consistent with current guidelines recommending repeat cotesting 12 months after colposcopy < CIN 2 and a 3-year return for women with a negative postcolposcopy cotest.

Conclusions: Most women are at low risk of subsequent CIN 3+ after a colposcopy showing < CIN 2, especially those who are human papillomavirus-negative postcolposcopy, consistent with current management guidelines for repeat testing intervals. Before the finalizing the upcoming guidelines, we will consider additional rounds of postcolposcopy cotesting.
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http://dx.doi.org/10.1097/LGT.0000000000000382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895141PMC
April 2018

Validation of a Human Papillomavirus (HPV) DNA Cervical Screening Test That Provides Expanded HPV Typing.

J Clin Microbiol 2018 05 25;56(5). Epub 2018 Apr 25.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

As cervical cancer screening shifts from cytology to human papillomavirus (HPV) testing, a major question is the clinical value of identifying individual HPV types. We aimed to validate Onclarity (Becton Dickinson Diagnostics, Sparks, MD), a nine-channel HPV test recently approved by the FDA, by assessing (i) the association of Onclarity types/channels with precancer/cancer; (ii) HPV type/channel agreement between the results of Onclarity and cobas (Roche Molecular Systems, Pleasanton, CA), another FDA-approved test; and (iii) Onclarity typing for all types/channels compared to typing results from a research assay (linear array [LA]; Roche). We compared Onclarity to histopathology, cobas, and LA. We tested a stratified random sample ( = 9,701) of discarded routine clinical specimens that had tested positive by Hybrid Capture 2 (HC2; Qiagen, Germantown, MD). A subset had already been tested by cobas and LA ( = 1,965). Cervical histopathology was ascertained from electronic health records. Hierarchical Onclarity channels showed a significant linear association with histological severity. Onclarity and cobas had excellent agreement on partial typing of HPV16, HPV18, and the other 12 types as a pool (sample-weighted kappa value of 0.83); cobas was slightly more sensitive for HPV18 and slightly less sensitive for the pooled high-risk types. Typing by Onclarity showed excellent agreement with types and groups of types identified by LA (kappa values from 0.80 for HPV39/68/35 to 0.97 for HPV16). Onclarity typing results corresponded well to histopathology and to an already validated HPV DNA test and could provide additional clinical typing if such discrimination is determined to be clinically desirable.
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http://dx.doi.org/10.1128/JCM.01910-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925726PMC
May 2018

Epidemiologic Evidence That Excess Body Weight Increases Risk of Cervical Cancer by Decreased Detection of Precancer.

J Clin Oncol 2018 04 22;36(12):1184-1191. Epub 2018 Jan 22.

Megan A. Clarke, Li C. Cheung, Nicolas Wentzensen, Julia C. Gage, Hormuzd A. Katki, Maria Demarco, and Mark Schiffman, National Cancer Institute, Bethesda; Brian Befano and John Schussler, Information Management Services, Calverton, MD; Barbara Fetterman, Walter K. Kinney, Thomas S. Lorey, and Nancy E. Poitras, Kaiser Permanente Medical Group, Berkeley, CA; Tina R. Raine-Bennett, Kaiser Permanente Northern California, Oakland, CA; and Philip E. Castle, Albert Einstein College of Medicine, Bronx, NY.

Purpose Obesity has been inconsistently linked to increased cervical cancer incidence and mortality; however, the effect of obesity on cervical screening has not been explored. We investigated the hypothesis that increased body mass might decrease detection of cervical precancer and increase risk of cervical cancer even in women undergoing state-of-the-art screening. Methods We conducted a retrospective cohort study of 944,227 women age 30 to 64 years who underwent cytology and human papillomavirus DNA testing (ie, cotesting) at Kaiser Permanente Northern California (January 2003 to December 2015). Body mass index was categorized as normal/underweight (< 25 kg/m), overweight (25 to < 30 kg/m), or obese (≥ 30 kg/m). We estimated 5-year cumulative risks of cervical precancer and cancer by category of body mass index using logistic Weibull survival models. Results We observed lower risk of cervical precancer (n = 4,489) and higher risk of cervical cancer (n = 490) with increasing body mass index. Specifically, obese women had the lowest 5-year risk of precancer (0.51%; 95% CI, 0.48% to 0.54% v 0.73%; 95% CI, 0.70% to 0.76% in normal/underweight women; P trend < .001). In contrast, obese women had the highest 5-year risk of cancer (0.083%; 95% CI, 0.072% to 0.096% v 0.056%; 95% CI, 0.048% to 0.066% in normal/underweight women; P trend < .001). Results were consistent in subgroups defined by age (30 to 49 v 50 to 64 years), human papillomavirus status (positive v negative), and histologic subtype (glandular v squamous). Approximately 20% of cervical cancers could be attributed to overweight or obesity in the women in our study who underwent routine cervical screening. Conclusion In this large, screened population, overweight and obese women had an increased risk of cervical cancer, likely because of underdiagnosis of cervical precancer. Improvements in equipment and/or technique to assure adequate sampling and visualization of women with elevated body mass might reduce cervical cancer incidence.
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http://dx.doi.org/10.1200/JCO.2017.75.3442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908221PMC
April 2018

Relative Performance of HPV and Cytology Components of Cotesting in Cervical Screening.

J Natl Cancer Inst 2018 05;110(5):501-508

Albert Einstein College of Medicine, Bronx, NY.

Background: The main goal of cervical screening programs is to detect and treat precancer before cancer develops. Human papillomavirus (HPV) testing is more sensitive than cytology for detecting precancer. However, reports of rare HPV-negative, cytology-positive cancers are motivating continued use of both tests (cotesting) despite increased testing costs.

Methods: We quantified the detection of cervical precancer and cancer by cotesting compared with HPV testing alone at Kaiser Permanente Northern California (KPNC), where 1 208 710 women age 30 years and older have undergone triennial cervical cotesting since 2003. Screening histories preceding cervical cancers (n = 623) and precancers (n = 5369) were examined to assess the relative contribution of the cytology and HPV test components in identifying cases. The performances of HPV testing and cytology were compared using contingency table methods, general estimating equation models, and nonparametric statistics; all statistical tests were two-sided.

Results: HPV testing identified more women subsequently diagnosed with cancer (P < .001) and precancer (P < .001) than cytology. HPV testing was statistically significantly more likely to be positive for cancer at any time point (P < .001), except within 12 months (P = .10). HPV-negative/cytology-positive results preceded only small fractions of cases of precancer (3.5%) and cancer (5.9%); these cancers were more likely to be regional or distant stage with squamous histopathology than other cases. Given the rarity of cancers among screened women, the contribution of cytology to screening translated to earlier detection of at most five cases per million women per year. Two-thirds (67.9%) of women found to have cancer during 10 years of follow-up at KPNC were detected by the first cotest performed.

Conclusions: The added sensitivity of cotesting vs HPV alone for detection of treatable cancer affected extremely few women.
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http://dx.doi.org/10.1093/jnci/djx225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279277PMC
May 2018

Risks of CIN 2+, CIN 3+, and Cancer by Cytology and Human Papillomavirus Status: The Foundation of Risk-Based Cervical Screening Guidelines.

J Low Genit Tract Dis 2017 Oct;21(4):261-267

1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD; 2Regional Laboratory, Kaiser Permanente Northern California, Berkeley, CA; 3Magee-Womens Hospital of UPMC, Gynecology Specialties, Pittsburgh, PA; 4Kaiser Permanente Northern California, Berkeley, CA; 5Information Management Services Inc, Calverton, MD; and 6Albert Einstein College of Medicine, Bronx, NY.

Objectives: The next round of the American Society for Colposcopy and Cervical Pathology (ASCCP)-sponsored cervical cancer screening and management guidelines will recommend clinical actions based on risk, rather than test-based algorithms. This article gives preliminary risk estimates for the screening setting, showing combinations of the 2 most important predictors, human papillomavirus (HPV) status and cytology result.

Materials And Methods: Among 1,262,713 women aged 25 to 77 years co-tested with HC2 (Qiagen) and cytology at Kaiser Permanente Northern California, we estimated 0-5-year cumulative risk of cervical intraepithelial neoplasia (CIN) 2+, CIN 3+, and cancer for combinations of cytology (negative for intraepithelial lesion or malignancy [NILM], atypical squamous cells of undetermined significance [ASC-US], low-grade squamous intraepithelial lesion [LSIL], atypical squamous cells cannot exclude HSIL [ASC-H], high-grade squamous intraepithelial lesion [HSIL], atypical glandular cells [AGC]) and HPV status.

Results: Ninety percent of screened women had HPV-negative NILM and an extremely low risk of subsequent cancer. Five-year risks of CIN 3+ were lower after HPV negativity (0.12%) than after NILM (0.25%). Among HPV-negative women, 5-year risks for CIN 3+ were 0.10% for NILM, 0.44% for ASC-US, 1.8% for LSIL, 3.0% for ASC-H, 1.2% for AGC, and 29% for HSIL+ cytology (which was very rare). Among HPV-positive women, 5-year risks were 4.0% for NILM, 6.8% for ASC-US, 6.1% for LSIL, 28% for ASC-H, 30% for AGC, and 50% for HSIL+ cytology.

Conclusions: As a foundation for the next guidelines revision, we confirmed with additional precision the risk estimates previously reported for combinations of HPV and cytology. Future analyses will estimate risks for women being followed in colposcopy clinic and posttreatment and will consider the role of risk modifiers such as age, HPV vaccine status, HPV type, and screening and treatment history.
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http://dx.doi.org/10.1097/LGT.0000000000000343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625966PMC
October 2017

Why does cervical cancer occur in a state-of-the-art screening program?

Gynecol Oncol 2017 09 10;146(3):546-553. Epub 2017 Jun 10.

Division of Cancer Epidemiology and Genetics, NCI, Bethesda, MD, USA.

Background: The goal of cervical screening is to detect and treat precancers before some become cancer. We wanted to understand why, despite state-of-the-art methods, cervical cancers occured in relationship to programmatic performance at Kaiser Permanente Northern California (KPNC), where >1,000,000 women aged ≥30years have undergone cervical cancer screening by triennial HPV and cytology cotesting since 2003.

Methods: We reviewed clinical histories preceding cervical cancer diagnoses to assign "causes" of cancer. We calculated surrogate measures of programmatic effectiveness (precancers/(precancers and cancers)) and diagnostic yield (precancers and cancers per 1000 cotests), overall and by age at cotest (30-39, 40-49, and ≥50years).

Results: Cancer was rare and found mainly in a localized (treatable) stage. Of 623 cervical cancers with at least one preceding or concurrent cotest, 360 (57.8%) were judged to be prevalent (diagnosed at a localized stage within one year or regional/distant stage within two years of the first cotest). Non-compliance with recommended screening and management preceded 9.0% of all cancers. False-negative cotests/sampling errors (HPV and cytology negative), false-negative histologic diagnoses, and treatment failures preceded 11.2%, 9.0%, and 4.3%, respectively, of all cancers. There was significant heterogeneity in the causes of cancer by histologic category (p<0.001 for all; p=0.002 excluding prevalent cases). Programmatic effectiveness (95.3%) and diagnostic yield were greater for squamous cell versus adenocarcinoma histology (p<0.0001) and both decreased with older ages (p<0.0001).

Conclusions: A state-of-the-art intensive screening program results in very few cervical cancers, most of which are detected early by screening. Screening may become less efficient at older ages.
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http://dx.doi.org/10.1016/j.ygyno.2017.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743197PMC
September 2017

Assessment of a New Lower-Cost Real-Time PCR Assay for Detection of High-Risk Human Papillomavirus: Useful for Cervical Screening in Limited-Resource Settings?

J Clin Microbiol 2017 08 17;55(8):2348-2355. Epub 2017 May 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Inexpensive and easy-to-perform human papillomavirus (HPV) tests are needed for primary cervical cancer screening in lower-resource regions. In a convenience sample of 516 residual exfoliative cervical specimens from the Kaiser Permanente Northern California and U.S. National Cancer Institute Persistence and Progression Study, we assessed the agreement and clinical performance of a simple, inexpensive real-time PCR assay for the detection of 13 carcinogenic HPV types (the H13 assay; Hybribio, Hong Kong) that is marketed in limited-resource settings compared to previous testing by the Hybrid Capture 2 assay (HC2; Qiagen, Germantown, MD) and the Onclarity assay (BD Diagnostics, Sparks, MD). The test set was chosen to include many HPV-positive specimens. The reference standard was a combination of HC2 and Onclarity results for HPV detection and histologic diagnosis of controls (less than cervical intraepithelial neoplasia grade 2 [
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http://dx.doi.org/10.1128/JCM.00492-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527412PMC
August 2017

A cohort study of cervical screening using partial HPV typing and cytology triage.

Int J Cancer 2016 Dec 26;139(11):2606-15. Epub 2016 Aug 26.

National Cancer Institute Division of Cancer Epidemiology and Genetics, Rockville, MD.

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification ("triage") of HPV-positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed ∼9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups ("high-grade," ASC-US/LSIL, NILM). For the resultant 15 HPV group-cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established "benchmark" risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV "clearance"; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology.
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http://dx.doi.org/10.1002/ijc.30375DOI Listing
December 2016

Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections.

J Infect Dis 2016 Mar 30;213(6):939-47. Epub 2015 Oct 30.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville.

Background: Results from the Costa Rica Vaccine Trial (CVT) demonstrated partial cross-protection by the bivalent human papillomavirus (HPV) vaccine, which targets HPV-16 and HPV-18, against HPV-31, -33, and -45 infection and an increased incidence of HPV-51 infection.

Methods: A study nested within the CVT intention-to-treat cohort was designed to assess high-risk HPV variant lineage-specific vaccine efficacy (VE). The 2 main end points were (1) long-term incident infections persisting for ≥2 years and/or progression to high-grade squamous intraepithelial lesions (ie, cervical intraepithelial neoplasia grade 2/3 [CIN 2/3]) and (2) incident transient infections lasting for <2 years. For efficiency, incident infections due to HPV-16, -18, -31, -33, -35, -45, and -51 resulting in persistent infection and/or CIN 2/3 were matched (ratio, 1:2) to the more-frequent transient viral infections, by HPV type. Variant lineages were determined by sequencing the upstream regulatory region and/or E6 region.

Results: VEs against persistent or transient infections with HPV-16, -18, -33, -35, -45, and -51 did not differ significantly by variant lineage. As the possible exception, VEs against persistent infection and/or CIN 2/3 due to HPV-31 A/B and HPV-31C variants were -7.1% (95% confidence interval [CI], -33.9% to 0%) and 86.4% (95% CI, 65.1%-97.1%), respectively (P = .02 for test of equal VE). No difference in VE was observed by variant among transient HPV-31 infections (P = .68).

Conclusions: Overall, sequence variation at the variant level does not appear to explain partial cross-protection by the bivalent HPV vaccine.
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http://dx.doi.org/10.1093/infdis/jiv519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760417PMC
March 2016

Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial.

BMJ 2015 Sep 7;351:h4358. Epub 2015 Sep 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

Objective: To examine the effect of the bivalent human papillomavirus (HPV) vaccine on miscarriage.

Design: Observational long term follow-up of a randomized, double blinded trial combined with an independent unvaccinated population based cohort.

Setting: Single center study in Costa Rica.

Participants: 7466 women in the trial and 2836 women in the unvaccinated cohort enrolled at the end of the randomized trial and in parallel with the observational trial component.

Intervention: Women in the trial were assigned to receive three doses of bivalent HPV vaccine (n=3727) or the control hepatitis A vaccine (n=3739). Crossover bivalent HPV vaccination occurred in the hepatitis A vaccine arm at the end of the trial. Women in the unvaccinated cohort received (n=2836) no vaccination.

Main Outcome Measure: Risk of miscarriage, defined by the US Centers for Disease Control and Prevention as fetal loss within 20 weeks of gestation, in pregnancies exposed to bivalent HPV vaccination in less than 90 days and any time from vaccination compared with pregnancies exposed to hepatitis A vaccine and pregnancies in the unvaccinated cohort.

Results: Of 3394 pregnancies conceived at any time since bivalent HPV vaccination, 381 pregnancies were conceived less than 90 days from vaccination. Unexposed pregnancies comprised 2507 pregnancies conceived after hepatitis A vaccination and 720 conceived in the unvaccinated cohort. Miscarriages occurred in 451 (13.3%) of all exposed pregnancies, in 50 (13.1%) of the pregnancies conceived less than 90 days from bivalent HPV vaccination, and in 414 (12.8%) of the unexposed pregnancies, of which 316 (12.6%) were in the hepatitis A vaccine group and 98 (13.6%) in the unvaccinated cohort. The relative risk of miscarriage for pregnancies conceived less than 90 days from vaccination compared with all unexposed pregnancies was 1.02 (95% confidence interval 0.78 to 1.34, one sided P=0.436) in unadjusted analyses. Results were similar after adjusting for age at vaccination (relative risk 1.15, one sided P=0.17), age at conception (1.03, P=0.422), and calendar year (1.06, P=0.358), and in stratified analyses. Among pregnancies conceived at any time from bivalent HPV vaccination, exposure was not associated with an increased risk of miscarriage overall or in subgroups, except for miscarriages at weeks 13-20 of gestation (relative risk 1.35, 95% confidence interval 1.02 to 1.77, one sided P=0.017).

Conclusions: There is no evidence that bivalent HPV vaccination affects the risk of miscarriage for pregnancies conceived less than 90 days from vaccination. The increased risk estimate for miscarriages in a subgroup of pregnancies conceived any time after vaccination may be an artifact of a thorough set of sensitivity analyses, but since a genuine association cannot totally be ruled out, this signal should nevertheless be explored further in existing and future studies.Trial registration Clinicaltrials.gov NCT00128661 and NCT01086709.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561367PMC
http://dx.doi.org/10.1136/bmj.h4358DOI Listing
September 2015

A study of HPV typing for the management of HPV-positive ASC-US cervical cytologic results.

Gynecol Oncol 2015 Sep 4;138(3):573-8. Epub 2015 Jul 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA.

Background: In US cervical screening, immediate colposcopy is recommended for women with HPV-positive ASC-US (equivocal) cytology. We evaluated whether partial typing by Onclarity™ (BD) might identify HPV-positive women with low enough CIN3+ risk to permit 1-year follow-up instead.

Methods: The NCI-Kaiser Permanente Northern California Persistence and Progression cohort includes a subset of 13,890 women aged 21+ with HC2 (Qiagen)-positive ASC-US at enrollment; current median follow-up is 3.0years. Using stratified random sampling, we typed 2079 archived enrollment specimens including 329 women subsequently diagnosed with CIN3+, 563 with CIN2, and 1187 with
Results: The 3-year CIN3+ risk for all HC2-positive women with ASC-US was 5.2%; this establishes the "benchmark" risk for colposcopic referral. Hierarchically, 3-year cumulative risks for each typing channel were 16.0% for HPV16, 7.4% for HPV18, 7.0% for HPV31, 7.1% for grouped HPV33/58, 4.3% for HPV52, 3.9% for HPV45, 2.7% for HPV51, 1.6% for HPV39/68/35, and 1.3% for HPV59/56/66.

Discussion: ASC-US linked to HPV16, HPV18, HPV31, or HPV33/58 warrants immediate colposcopy. Optimal management of women with HPV52 or HPV45 is uncertain. Risk of women with only HPV51, HPV39/68/35, or HPV59/56/66 might be low enough to recommend 1-year retesting permitting viral clearance. This strategy would defer colposcopy for 40% of women with HPV-positive ASC-US, half of whom would be cotest-negative at 1-year return. Approximately 10% of those with CIN3 diagnosable at enrollment would be delayed 1year instead. Cost-effectiveness analyses are needed.
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http://dx.doi.org/10.1016/j.ygyno.2015.06.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556538PMC
September 2015

The Role of Human Papillomavirus Genotyping in Cervical Cancer Screening: A Large-Scale Evaluation of the cobas HPV Test.

Cancer Epidemiol Biomarkers Prev 2015 Sep 18;24(9):1304-10. Epub 2015 Jun 18.

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, The Bronx, New York. Global Coalition Against Cervical Cancer, Arlington, Virginia.

Background: The cobas HPV Test ("cobas"; Roche Molecular Systems) detects HPV16 and HPV18 individually, and a pool of 12 other high-risk (HR) HPV types. The test is approved for (i) atypical squamous cells of undetermined significance (ASC-US) triage to determine need for colposcopy, (ii) combined screening with cytology ("cotesting"), and (iii) primary HPV screening.

Methods: To assess the possible value of HPV16/18 typing, >17,000 specimens from a longitudinal cohort study of initially HPV-positive women (HC2, Qiagen) were retested with cobas. To study accuracy, cobas genotyping results were compared with those of an established method, the Linear Array HPV Genotyping Test (LA, Roche Molecular Systems). Clinical value of the typing strategy was evaluated by linking the cobas results (supplemented by other available typing results) to 3-year cumulative risks of CIN3+.

Results: Grouped hierarchically (HPV16, else HPV18, else other HR types, else negative), the κ statistic for agreement between cobas and LA was 0.86 [95% confidence interval (CI), 0.86-0.87]. In all three scenarios, HPV16-positive women were at much higher 3-year risk of CIN3+ than HPV16-negative women: women ages 21 and older with ASC-US (14.5%; 95% CI, 13.5%-15.5% vs. 3.5%; 95% CI, 3.3-3.6); women ages 30 years and older that were HPV-positive cytology-negative (10.3%; 95% CI, 9.6-11.1 vs. 2.3%; 95% CI, 2.2-2.4); and all women 25 years and older that were HPV-positive (18.5%; 95% CI, 17.8-19.2 vs. 4.3%; 95% CI, 4.2-4.4).

Conclusion: The cobas and LA results show excellent agreement. The data support HPV16 typing.

Impact: HPV16 typing is useful in the management of HPV-positive/cytology-negative women in cotesting, of all HPV-positive women in primary HPV testing, and perhaps in the management of HPV-positive women with ASC-US. Cancer Epidemiol Biomarkers Prev; 24(9); 1304-10.
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http://dx.doi.org/10.1158/1055-9965.EPI-14-1353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560647PMC
September 2015

Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica.

Vaccine 2015 Apr 18;33(18):2141-51. Epub 2015 Mar 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

The Costa Rica Vaccine Trial (CVT) was a randomized clinical trial conducted between 2004 and 2010, which randomized 7466 women aged 18 to 25 to receive the bivalent HPV-16/18 vaccine or control Hepatitis-A vaccine. Participants were followed for 4 years with cross-over vaccination at the study end. In 2010 the long term follow-up (LTFU) study was initiated to evaluate the 10-year impact of HPV-16/18 vaccination, determinants of the immune response, and HPV natural history in a vaccinated population. Herein, the rationale, design and methods of the LTFU study are described, which actively follows CVT participants in the HPV-arm 6 additional years at biennial intervals (3 additional study visits for 10 years of total follow-up), or more often if clinically indicated. According to the initial commitment, women in the Hepatitis-A arm were offered HPV vaccination at cross-over; they were followed 2 additional years and exited from the study. 92% of eligible CVT women accepted participation in LTFU. To provide underlying rates of HPV acquisition and cervical disease among unvaccinated women to compare with the HPV-arm during LTFU, a new unvaccinated control group (UCG) of women who are beyond the age generally recommended for routine vaccination was enrolled, and will be followed by cervical cancer screening over 6 years. To form the UCG, 5000 women were selected from a local census, of whom 2836 women (61% of eligible women) agreed to participate. Over 90% of participants complied with an interview, blood and cervical specimen collection. Evaluation of comparability between the original (Hepatitis-A arm of CVT) and new (UCG) control groups showed that women's characteristics, as well as their predicted future risk for cervical HPV acquisition, were similar, thus validating use of the UCG. LTFU is poised to comprehensively address many important questions related to long-term effects of prophylactic HPV vaccines.
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http://dx.doi.org/10.1016/j.vaccine.2015.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4390538PMC
April 2015

A population-based prospective study of carcinogenic human papillomavirus variant lineages, viral persistence, and cervical neoplasia.

Cancer Res 2010 Apr 30;70(8):3159-69. Epub 2010 Mar 30.

Divisions of Cancer Epidemiology and Genetics and Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20852, USA.

Human papillomavirus (HPV) types differ profoundly in cervical carcinogenicity. For the most carcinogenic type HPV16, variant lineages representing further evolutionary divergence also differ in cancer risk. Variants of the remaining 10 to 15 carcinogenic HPV types have not been well studied. In the first prospective, population-based study of HPV variants, we explored whether, on average, the oldest evolutionary branches within each carcinogenic type predicted different risks of >2-year viral persistence and/or precancer and cancer [cervical intraepithelial neoplasia grade 3+ (CIN3+)]. We examined the natural history of HPV variants in the 7-year, 10,049-woman Guanacaste Cohort Study, using a nested case-control design. Infections were assigned to a variant lineage determined by phylogenetic parsimony methods based on URR/E6 sequences. We used the Fisher's combination test to evaluate significance of the risk associations, cumulating evidence across types. Globally, for HPV types including HPV16, the P value was 0.01 for persistence and 0.07 for CIN3+. Excluding HPV16, the P values were 0.04 and 0.37, respectively. For HPV16, non-European viral variants were significantly more likely than European variants to cause persistence [odds ratio (OR), 2.6; P = 0.01] and CIN3+ (OR, 2.4; P = 0.004). HPV35 and HPV51 variant lineages also predicted CIN3+. HPV variants generally differ in risk of persistence. For some HPV types, especially HPV16, variant lineages differ in risk of CIN3+. The findings indicate that continued evolution of HPV types has led to even finer genetic discrimination linked to HPV natural history and cervical cancer risk. Larger viral genomic studies are warranted, especially to identify the genetic basis for HPV16's unique carcinogenicity.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-4179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855741PMC
April 2010

Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials.

BMJ 2010 Mar 2;340:c712. Epub 2010 Mar 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Rockville, MD 20852, USA.

Objective: To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage.

Design: Pooled analysis of two multicentre, phase three masked randomised controlled trials

Setting: Multicentre trials in several continents and in Costa Rica.

Participants: 26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis.

Interventions: Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months.

Main Outcome Measures: Miscarriage and other pregnancy outcomes.

Results: The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination.

Conclusion: There is no evidence overall for an association between HPV vaccination and risk of miscarriage.

Trial Registration: Clinical Trials NCT00128661 and NCT00122681.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831171PMC
http://dx.doi.org/10.1136/bmj.c712DOI Listing
March 2010
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