Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3.

BACKGROUND: Persistent infections with carcinogenic human papillomavirus (HPV) types are the necessary cause of cervical cancer. We recently demonstrated that the HPV16 genome is strongly methylated in cervical precancer compared with transient infections. However, the extent of methylation in other HPV types and its role in progression to cancer is poorly understood. METHODS: We analyzed whole-genome methylation patterns of the three next most carcinogenic HPV genotypes: HPV31 (closely related to HPV16), and two other closely related types, HPV18 and HPV45. DNA was extracted from cervical cytology specimens from 92 women with precancer and 96 women infected with HPV31, HPV18, or HPV45, but who had no cytological or histological abnormalities. After bisulfite modification, genome-wide pyrosequencing was performed covering 80-106 sites. We calculated differences in median methylation, odds ratios, areas under the curve, and Spearman rank correlation coefficients for methylation levels between different sites. All statistical tests were two-sided. RESULTS: For all three HPV types, we observed strongly elevated methylation levels at multiple CpG sites in the E2, L2, and L1 regions among women with cervical intraepithelial neoplasia grade 3 compared with women with transient infections. We observed high correlation of methylation patterns between phylogenetically related types. The highest areas under the curve were 0.81 for HPV31, 0.85 for HPV18, and 0.98 for HPV45. Differential methylation patterns in cervical intraepithelial neoplasia grade 3 patients with multiple infections suggest that methylation can clarify which of the infections is causal. CONCLUSIONS: Carcinogenic HPV DNA methylation indicates transforming HPV infections. Our findings show that methylation of carcinogenic HPV types is a general phenomenon that warrants development of diagnostic assays.

Use of electronic health records can improve the health care industry's environmental footprint.

Electronic health records have the potential to improve the environmental footprint of the health care industry. We estimate that Kaiser Permanente's electronic health record system, which covers 8.7 million beneficiaries, eliminated 1,000 tons of paper records and 68 tons of x-ray film, and that it has lowered gasoline consumption among patients who otherwise would have made trips to the doctor by at least three million gallons per year. However, the use of personal computers resulted in higher energy consumption and generated an additional 250 tons of waste. We conclude that electronic health records have a positive net effect on the environment, and that our model for evaluating their impact can be used to determine whether their use can improve communities' health.

Human papillomavirus (HPV) genotypes in women with cervical precancer and cancer at Kaiser Permanente Northern California.

BACKGROUND: The human papillomavirus (HPV) Persistence and Progression Cohort is a natural history study of carcinogenic HPV positive women. Here, we present the HPV genotypes found in first ∼500 cases of cervical intraepithelial neoplasia grade 3 (CIN3) or more severe disease (CIN3+) diagnosed at the study baseline. METHODS: Women aged 30 and older were screened for cervical cancer using Pap smears and tested for carcinogenic HPV using Hybrid Capture 2 (HC2; Qiagen). We randomly selected women who tested HPV positive and were diagnosed with CIN3+ (n = 448) or without CIN3+ (

Variable risk of cervical precancer and cancer after a human papillomavirus-positive test.

OBJECTIVE: To explore the effect of screening history on the risk of cervical precancer and cancer after an human papillomavirus (HPV)-positive test. METHODS: A large health maintenance organization introduced cytology and HPV cotesting into routine clinical practice in 2003. We selected women aged 30 and older who tested HPV positive, cytology negative between January 2006 and December 2008 who had any clinical follow-up documented before January 2010 (n=26,799). The 1-year and 4-year cumulative incidence rates and rate ratios for cervical intraepithelial neoplasia grade 2 or higher (CIN 2+) with 95% confidence intervals (95% CIs) were calculated as estimates of absolute risk and relative risk, respectively. Results were stratified on immediate past HPV test and Pap results. RESULTS: Without consideration of past screening round, the 1-year and 4-year cumulative incidence rates for CIN 2+ after an HPV-positive, Pap-negative result were 2.83 (95% CI 2.55-3.12) and 7.89 (95% CI 7.00-8.78). However, risks varied substantially by past screening result. For example, the 4-year risk of CIN2+ was greater for women who had a past HPV-positive, Pap-negative result (cumulative incidence rate=11.79, 95% CI 10.22-13.36) compared with those who had HPV-negative, Pap-negative result (cumulative incidence rate=4.56, 95% CI 3.43-5.69; cumulative incidence rate ratio=2.59, 95% CI 2.30-2.87). CONCLUSION: Because cervical precancer is associated with persistent HPV infection, the risk associated with an HPV-positive test can vary significantly depending on the immediate past screening round. Optimizing screening programs will require knowledge of screening history.

Risk of cervical precancer and cancer in women aged 30 years and older with an HPV-negative low-grade squamous intraepithelial lesion screening result.

OBJECTIVE: To characterize the 6- and 18-month cumulative risk of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) in women aged 30 years and older after a low-grade squamous intraepithelial lesion (LSIL) cytology and high-risk human papillomavirus (HPV)-negative screening result in routine clinical practice. MATERIALS AND METHODS: Comprehensive quality assurance databases of screening test and biopsy results from the Regional Laboratory of the Kaiser Permanente Northern California Health Plan were reviewed. All women aged 30 years and older with LSIL cytology were sorted by high-risk HPV status. Associated biopsy results were tabulated, and the corresponding risks of CIN 2+ and CIN 3+ diagnosed within 18 months after LSIL cytology were calculated overall and by decade of age. RESULTS: During the 6-year period, from 2003 to 2008, 4,113 LSIL cases were interpreted in women aged 30 years and older for which corresponding high-risk HPV and biopsy results were available. The proportion of women with LSIL testing positive for HPV declined with age, from 89% in the group aged 30 to 39 years to 76% in women older than 50 years (p < .001). Of 622 women with HPV-negative LSIL cytology, there was no case of cancer detected at colposcopy occurring within 6 months of the screening test. The 18-month risks of CIN 2+ and CIN 3+ were 3.5% and 1.4%, respectively. CONCLUSIONS: The risk of CIN 3+ is sufficiently low in women aged 30 years and older with high-risk HPV-negative LSIL that 1 year follow-up rather than immediate colposcopy should be considered when it occurs in routine clinical practice.

Patients' perspectives on nonadherence to statin therapy: a focus-group study.

CONTEXT: Nonadherence to statin therapy is associated with poor cardiovascular outcomes. OBJECTIVE: We explored factors and perceptions that contribute to statin therapy nonadherence. DESIGN: We conducted a qualitative study that was based on three patient focus groups using a structured discussion guide to explore factors related to statin therapy nonadherence, information sources, perceptions of statins and cardiovascular risks factors, and suggestions for improving adherence. PARTICIPANTS: We enrolled 18 adult patients of an integrated delivery system who had been newly prescribed a statin between November 2006 and August 2007, with a subsequent one- to six-month gap in drug supply as documented by automated pharmacy data. MEASURES: We performed content analysis of verbatim focus-group transcripts to assess themes within each domain. RESULTS: Study participants identified many factors that contributed to their statin therapy nonadherence, including concerns or experiences with adverse effects, uncertainty about the benefits or importance of statins for their overall health, and lack of convenience. Concerns about the adverse effects of statins were a dominant theme. Although most participants believed that having a high cholesterol level is unsafe, many were unsure about their personal need for statins if they were making other lifestyle changes or had only borderline high cholesterol levels. Participants suggested that systematic follow-up, as well as greater information about the risks and benefits of statins and the merits of alternative approaches for lowering cholesterol, could have improved their adherence to therapy. CONCLUSIONS: Many patients reduced statin use because of concerns about adverse effects and desire for more information about statins. Effective interventions that address patients' underlying concerns and perceptions are needed to improve statin therapy adherence.

The age-specific relationships of abnormal cytology and human papillomavirus DNA results to the risk of cervical precancer and cancer.

BACKGROUND: To estimate the relationship of human papillomavirus (HPV) detection and abnormal cytology with histologic diagnoses of cervical precancer and cancer. METHODS: From 2003 to 2008 we examined the HPV, cytology, and diagnostic results from almost one million cervical cancer screenings done on women aged 30 and older who were members in Kaiser Permanente Northern California, a large health maintenance organization that introduced cotesting in 2003. Women were screened using conventional Pap tests and a DNA test for a pool of 13 high-risk HPV genotypes. Women with HPV-positive atypical squamous cells of undetermined significance and other abnormal cervical cytology, independent of their HPV results, routinely underwent colposcopy. Results were stratified by 5-year age groups from 30 to 64. RESULTS: High-grade squamous intraepithelial lesions (HSIL), atypical squamous cells, cannot exclude HSIL (ASC-H), and atypical glandular cells were more strongly associated with cervical intraepithelial neoplasia grade 3 while low-grade squamous intraepithelial lesions (LSIL) and HPV-positive atypical squamous cells of undetermined significance were more strongly associated with cervical intraepithelial neoplasia grade 2 (CIN2). Cervical cancer was most commonly found in women with HSIL and atypical glandular cells cytology. Human papillomavirus-negative women with ASC-H cytology were at a reduced but significant risk of CIN2 or more severe (CIN2+) (10.6%) compared with HPV-positive women with ASC-H cytology. Human papillomavirus-negative women with LSIL were at a 4.0% risk of CIN2+, and among women 50 and older, at a 0.5% risk of CIN2+ with no cancers were diagnosed. CONCLUSION: Human papillomavirus testing may be useful for triage for colposcopic referral for LSIL cytology in older women but not for ASC-H cytology at any age. LEVEL OF EVIDENCE: II.

Relationship of atypical glandular cell cytology, age, and human papillomavirus detection to cervical and endometrial cancer risks.

OBJECTIVE: To quantify the age-specific and reproductive organ-specific cancer risk after an atypical glandular cell (AGC) cytologic interpretation in large clinic-based sample in which routine high-risk human papillomavirus (HPV) testing is conducted. METHODS: : To estimate the absolute risk of cervical precancer, cervical cancer, and endometrial cancer in women with AGC cytology, we conducted a cross-sectional study of women with AGC cytology (n=1,422) in a large health maintenance organization that introduced high-risk HPV DNA testing into cervical cancer screening in 2003. Risks and binomial exact 95% confidence intervals (CIs) of cervical intraepithelial neoplasia grade 2 or more severe (CIN 2 or worse) and endometrial cancer were calculated. RESULTS: A total of 238 women with AGC cytology (16.7%, 95% CI 14.8-18.8%) were diagnosed with CIN 2 or worse, endometrial cancer, or other cancers. Among women aged 50 years or older, 420 high-risk HPV-negative women were at a 10.5% (95% CI 7.7-13.8%) risk of endometrial cancer, and 77 high-risk HPV-positive women were at a 10.4% (95% CI 4.6-19.4%) risk of cervical cancer and 0% (95% CI 0.0-4.7%) risk of endometrial cancer. CONCLUSION: High-risk HPV testing may distinguish between risk of endometrial cancer and cervical cancer in women with AGC cervical cytology, particularly in women aged 50 years or older. LEVEL OF EVIDENCE: III.

Pregnancy outcomes by pregnancy intention in a managed care setting.

OBJECTIVES: Published studies show poor pregnancy outcomes associated with unintended pregnancies are disproportionately higher than in planned pregnancies and place a burden on the health care system. This study was designed to compare pregnancy intention rates, compare sociodemographic characteristics of women by pregnancy intention and compare pregnancy outcomes in a managed care setting. METHODS: A large managed health care organization in California conducted a retrospective medical record review of 1,784 women seeking prenatal care in 2002 to learn how women self-reported their pregnancy intention, compare pregnancy intention rates between this health plan to the national data, and to compare antecedents and pregnancy outcomes based on pregnancy intention. RESULTS: Overall, 62.1% of pregnancies were self-reported as intended with 26.4% mistimed and 11.4% unwanted. Being young, single, having lower educational attainment, having other living children, consuming alcohol and being a woman of color were the greatest predictors of having an unintended pregnancy. Despite these predictors, birth outcomes for unintended pregnancies in this setting showed no statistical difference from planned pregnancies. CONCLUSION: Awareness of pregnancy intention of the women who are at greatest risk may be an important contributor to improving birth outcomes and health plan decisions about reproductive care services. Early entry to prenatal care and integrated services that decrease substance abuse and support high-risk pregnancy management are important contributors to reducing poor pregnancy outcomes.

Five-year experience of human papillomavirus DNA and Papanicolaou test cotesting.

OBJECTIVE: To estimate the 5-year age group-specific test positives for Pap tests and human papillomavirus (HPV) testing in a large, general screening population of women 30 and older. METHODS: Using data from Kaiser Permanente Northern California, a large health maintenance organization that introduced cotesting in 2003, we evaluated the cotesting results overall and by 5-year age groups. Women (n=580,289) who opted for and underwent cotesting (n cotests=812,598) between January 2003 and April 2008 were included in the analysis. Pap tests interpreted as atypical squamous cells of undetermined significance (ASC-US) or more severe were considered to be positive. Women were tested for carcinogenic HPV using an assay approved by the U.S. Food and Drug Administration. Binomial exact 95% confidence intervals (CIs) were calculated. RESULTS: Overall, 6.27% (95% CI 6.21-6.32%) of cotests were carcinogenic HPV positive, and only 3.99% (95% CI 3.94-4.03%) cotests had normal cytology and were carcinogenic HPV positive. By comparison, 5.18% (95% CI 5.13-5.23%) of cotests had ASC-US or more severe cytology, and 2.87% (95% CI 2.84-2.91%) of cotests had ASC-US or more severe cytology and were carcinogenic HPV negative. CONCLUSION: In a general screening population, concerns about excessive HPV test positives among women aged 30 years and older are not borne out.

Risks for cervical intraepithelial neoplasia 3 among adolescents and young women with abnormal cytology.

OBJECTIVE: To estimate the risks of cervical intraepithelial neoplasia (CIN) 3 among girls and women aged 13 to 24 years who were referred for abnormal cytology while receiving care in a large health maintenance organization. METHODS: At the time of referral, patients had a colposcopic examination and biopsy if needed. Histology was sent to a centralized laboratory. Patients were interviewed for risk behaviors. Data analysis included multinomial logistic regression analysis to compare three groups: CIN 3 to CIN 1 or less, CIN 3 to CIN 2, and CIN 2 to CIN 1 or benign. RESULTS: Cervical intraepithelial neoplasia-3 was found in 6.6% (95% confidence interval [CI] 4.6-8.6%) of the 622 girls and women referred and no cancers were detected. Risk for CIN 3 compared to CIN 1 or less included human papillomavirus 16 or 18 (odds ratio [OR] 30.93, 95% CI 6.95-137.65), high-risk, non-16/18 human papillomavirus (OR 6.3, 95% CI 1.3-29.4), and time on oral contraceptives (OR 1.36 per year of use, 95% CI 1.08-1.71). CONCLUSION: Our data support conservative care for adolescents and young women with abnormal cytology since CIN 3 was rare and cervical cancer was never found. Human papillomavirus 16 or 18 was strongly associated with for CIN 3, and testing for these types may be warranted for triage of abnormal cytology in this age group. LEVEL OF EVIDENCE: II.

Changes in rates of hysterectomy and uterine conserving procedures for treatment of uterine leiomyoma.

OBJECTIVE: The purpose of this study was to investigate treatment of uterine leiomyoma by hysterectomy and uterine conserving procedures (UCPs). STUDY DESIGN: Data from Kaiser Permanente Northern California members undergoing hysterectomy, myomectomy, uterine artery embolization (UAE) and endometrial ablation (EA) for uterine leiomyoma from 1997-2003 were collected. Statistical analysis included trend tests and survival analysis. RESULTS: Hysterectomy rates for leiomyoma decreased significantly from 2.13 per 1000 to 1.91 (P < .0001). Rates for myomectomy (.4-.37) and EA (.26-.27) remained stable (P = .17 and .26, respectively), whereas rates for UAE increased significantly from < .01-.24 (P < .0001). The combined rates for hysterectomy and UCPs remained stable at 2.79 (P = .95). Rate of hysterectomy after UCP increased over time, and at 6 years reached 11.5%, 17.7%, and 7.9% for EA, UAE, and myomectomy, respectively. CONCLUSION: Whereas rate of hysterectomy for leiomyoma decreased, total rate of invasive treatment remained stable. Increase in rate of UAE had the greatest impact on treatment, possibly replacing hysterectomy.

Intrauterine contraception: evaluation of clinician practice patterns in Kaiser Permanente Northern California.

BACKGROUND: Despite the medical evidence, few women of reproductive age in the United States use intrauterine contraception (IUC) in comparison with women worldwide. To reduce cost as a barrier, Kaiser Permanente removed the cost to the patient for IUC throughout California in 2002. The goal of this study was to evaluate whether providing evidence-based information about IUC would result in changes in the knowledge, attitudes and practice patterns of clinicians and in greater IUC utilization as compared with removing cost alone. STUDY DESIGN: A comprehensive education intervention was conducted in half of Kaiser Permanente Northern California ob-gyn departments. To make comparisons between the intervention and comparison sites, we surveyed clinicians in both groups before and after the intervention about their IUC knowledge, attitudes as well as practice patterns and collected utilization data for 27 months. RESULTS: Statistically significant changes in attitudes and practice patterns were reported by the intervention group as compared with the usual care comparison group. By the end of the study, change in IUC utilization was significantly greater in the intervention group (utilization rate=9.57/1000) as compared with the comparison group (utilization rate=7.35/1000) (p=.02). CONCLUSION: A multifaceted approach to providing evidence-based clinician and patient education resulted in statistically significant reported changes in attitudes and practice patterns and in greater IUC utilization as compared with usual practice.

Hysterectomy rates for benign indications.

OBJECTIVE: To investigate the annual rates, types, and indications for hysterectomies performed for benign disease in Kaiser Permanente Northern California from 1994 to 2003. METHODS: All women, 20 years or age or older, who were undergoing hysterectomy for benign indications in Kaiser Permanente Northern California from 1994 to 2003 were identified. We analyzed hysterectomy rates by type, indication, and age group. Changes over time were analyzed with the Cochran-Armitage test for linear trend. RESULTS: From 1994 to 2003, there were 32,321 hysterectomies performed for benign indications. Hysterectomy rates showed a significant decline, from 4.01 per 1,000 women in 1994 to 3.41 per 1,000 women in 2003 (P for trend < .001). The relative proportions of all hysterectomies performed as laparoscopically assisted vaginal hysterectomy (LAVH) peaked at 13.0% in 1995 and then steadily declined to 3.9% in 2003 (P for trend < .001), whereas the relative proportion of subtotal abdominal hysterectomy increased from 6.9% in 1994 to 20.8% in 2003 (P for trend < .001). Hysterectomy rates declined 11.2% for uterine leiomyoma (relative risk [RR] 0.89, 95% confidence interval [CI] 0.83-0.95), 33.1% for endometriosis (RR 0.67, 95% CI 0.59-0.76), and 18.6% for uterine prolapse (RR 0.81, 95% CI 0.72-0.92). The relative proportion performed for uterine leiomyoma was consistently greater than for all other indications combined. CONCLUSION: The rates of hysterectomy for benign indications are decreasing. The type of hysterectomy changed significantly, with LAVH performed less frequently and subtotal abdominal hysterectomy increasing in popularity. Uterine leiomyoma remains the most common indication for benign hysterectomy. LEVEL OF EVIDENCE: II-2.

A conversation with Ruth Shaber, MD.

A fundamental aspect of preventive health care for women includes the provision of contraceptive benefits. However, birth control coverage in managed care plans is often limited. Ruth Shaber, MD, Director, Women's Health Services at Kaiser Permanente, Northern California, San Francisco, discusses the plan's philosophy regarding the fundamental nature of contraceptive benefits for women, and the various ways in which Kaiser Permanente is a leader in offerering women a more complete health program.