How to study the impact of sex and gender in medical research: a review of resources.

There is a growing appreciation by the biomedical community that studying the impact of sex and gender on health, aging, and disease will lead to improvements in human health. Sex- and gender-based comparisons can inform research on disease mechanisms and the development of new therapeutics as well as enhance scientific rigor and reproducibility. This review will assist basic researchers, clinical investigators, as well as epidemiologists, population, and social scientists by providing an annotated bibliography of currently available resource tools on how to consider sex and gender as independent variables in research design and methodology. These resources will assist investigators applying for funding from the National Institutes of Health since all grant applicants will be required (as of January 25, 2016) to address the role of sex as a biological variable in vertebrate animal and human studies.

p16 Staining of Cervical Biopsies May Decrease the Frequency of Unnecessary Loop Electrosurgical Excision Procedures.

OBJECTIVE: Loop electrosurgical excision procedures (LEEPs) are negative for high-grade cervical intraepithelial neoplasia (CIN 2+) after a hematoxylin and eosin-based CIN 2+ colposcopic biopsy diagnosis in 14% to 24% of cases. This may be due to diagnostic errors or biopsy-related regression of the dysplasia. Because p16 immunohistochemical staining of cervical biopsies improves diagnostic accuracy, we hypothesized that p16-based cervical biopsy diagnoses may reduce the frequency of negative LEEPs. MATERIALS AND METHODS: We performed a retrospective cross-sectional study of all cervical LEEPs completed at our institution from 2002 to 2012. We recorded patient age, sexual history, smoking history, pathologic diagnoses (including whether the diagnosis was p16 based), the number of days from biopsy to follow-up LEEP, and clinical follow-up. This yielded 593 study subjects meeting inclusion criteria of CIN 2+ colposcopic diagnoses with follow-up LEEP and 2 years of clinical follow-up. Colposcopic biopsies and follow-up LEEPs were reviewed and p16 immunostaining was performed on all samples to provide criterion standard results. Data were analyzed by χ and regression modeling. RESULTS: Our practice employed p16 to aid cervical biopsy diagnoses by 2006. The frequency of negative LEEPs before 2006 was 12 (10%) of 126. The frequency dropped during the p16 era (2006-2012) to 23 (5%) of 467. Overall, we observed an inverse relationship between the frequency of p16 employment and the frequency of negative LEEP outcomes (R = 0.71; p < .001), independent of potential covariates. CONCLUSIONS: Our data suggest that more accurate p16-based diagnoses may reduce the frequency of unnecessary LEEPs.

Atopic Dermatitis Is Associated With Cervical High Risk Human Papillomavirus Infection.

OBJECTIVE: High-risk human papillomavirus (hrHPV) infection is more likely to persist and cause cervical cancer in immunosuppressed women. Atopic dermatitis, which is known to affect cell-mediated immunity and skin barrier function, is associated with recalcitrant warts; therefore, we hypothesized that women with atopic dermatitis may be more likely to be positive for hrHPV infection and progress to high-grade cervical dysplasia. MATERIALS AND METHODS: A retrospective case-control study of 1,160 women who were either positive or negative for hrHPV in their index cervical cytology. Patient age, race, history of atopic dermatitis, allergic rhinitis, smoking, body mass index, socioeconomic status, marital status, hormone contraceptive use, and 2-year clinical outcomes (follow-up hrHPV testing and cervical biopsy results) were recorded. All cases with atopic dermatitis (n = 74) were confirmed by a dermatologist. Analyses were restricted to females with documented clinical follow-up, which yielded 577 hrHPV-positive and 583 hrHPV-negative cases for comparison. Associations were examined by t test, χ test, and multivariate logistic regression. RESULTS: Atopic dermatitis was more common in the hrHPV-positive cases (48/577, 8.3%) compared with HPV-negative controls (26/583, 4.5%, p = .007). Multivariate logistic regression analysis revealed an adjusted odds ratio of 3.75 (95% CI = 1.3-10.9, p = .02) after controlling for significant covariates, such as age and marital status. Smoking was not associated with hrHPV infection, persistence, or high-grade cervical dysplasia in these cases. CONCLUSIONS: Atopic dermatitis is associated with cervical hrHPV infection in adult women.

Immunocytochemical analysis of the cervical Pap smear.

Although immunostained cervical Pap smears are not yet FDA approved for clinical use, it is very likely that they will become widely employed in the near future to identify neoplastic squamous and iendocervical glandular cells when screening liquid-based cytological preparations (i.e., SurePath™ or ThinPrep™). The current problem with cytology complemented by high-risk human papillomavirus (HPV) testing is poor specificity. HPV testing provides superior sensitivity, but many women are infected with the virus, while very few have had persistent infections leading to carcinoma. Pathologists routinely use antibodies directed against the cyclin-dependent kinase inhibitor p16 (p16(INK4a)) or a combination of antibodies directed against topoisomerase-2-alpha and minichromosome maintenance protein-2 (as in ProEx™ C) to improve diagnostic precision and accuracy in cervical tissue biopsies. This chapter will describe the immunocytochemical methods used by our group to immunostain cervical Pap smears and provide significantly improved positive predictive value when screening for cervical cancer.

Faculty development initiatives to advance research literacy and evidence-based practice at CAM academic institutions.

OBJECTIVES: To present the varied approaches of 9 complementary and alternative medicine (CAM) institutions (all grantees of the National Center for Complementary and Alternative Medicine) used to develop faculty expertise in research literacy and evidence-based practice (EBP) in order to integrate these concepts into CAM curricula. DESIGN: A survey to elicit information on the faculty development initiatives was administered via e-mail to the 9 program directors. All 9 completed the survey, and 8 grantees provided narrative summaries of faculty training outcomes. RESULTS: The grantees found the following strategies for implementing their programs most useful: assess needs, develop and adopt research literacy and EBP competencies, target early adopters and change leaders, employ best practices in teaching and education, provide meaningful incentives, capitalize on resources provided by grant partners, provide external training opportunities, and garner support from institutional leadership. Instructional approaches varied considerably across grantees. The most common were workshops, online resources, in-person short courses, and in-depth seminar series developed by the grantees. Many also sent faculty to intensive multiday extramural training programs. Program evaluation included measuring participation rates and satisfaction and the integration of research literacy and EBP learning objectives throughout the academic curricula. Most grantees measured longitudinal changes in beliefs, attitudes, opinions, and competencies with repeated faculty surveys. CONCLUSIONS: A common need across all 9 CAM grantee institutions was foundational training for faculty in research literacy and EBP. Therefore, each grantee institution developed and implemented a faculty development program. In developing the framework for their programs, grantees used strategies that were viewed critical for success, including making them multifaceted and unique to their specific institutional needs. These strategies, in conjunction with the grantees' instructional approaches, can be of practical use in other CAM and non-CAM academic environments considering the introduction of research literacy and EBP competencies into their curricula.

Reducing misclassification bias in cervical dysplasia risk factor analysis with p16-based diagnoses.

OBJECTIVE: Conventional hematoxylin and eosin (HE)-based diagnoses have been the reference standard for cervical cancer risk factor analyses. However, this HE-based method is known to have modest interobserver reproducibility and only moderate predictive value. In contrast, more recent immunohistochemical-based diagnoses using the neoplastic marker p16 are known to improve diagnostic accuracy. Our objective was to test whether p16-based diagnoses would significantly affect high-grade dysplasia (cervical intraepithelial neoplasia 2+) risk factor analysis compared with the current reference standard (HE). MATERIALS AND METHODS: Retrospective cohort of 500 index cases were randomly selected from a series of more than 5,000 cervical biopsies performed at Kaiser Permanente Northwest from 1997 to 2003 after a patient's first abnormal cervical Pap smear (positive for atypical squamous cells of undetermined significance). Subjects were subsequently excluded if they did not have at least 5 years of clinical follow-up, including cervical biopsies, or 3 reproducibly negative Pap smears. This yielded 358 cases for risk factor analysis. The index biopsies and all follow-up biopsies were immunostained for p16 and the proliferation marker Ki-67, which were then independently reviewed by 2 pathologists blinded to clinical outcomes. Data were analyzed by χ test and logistic regression modeling. RESULTS: We observed clinically significant diagnostic errors in 22% of index biopsies. Improved accuracy using p16 strengthened the risk estimate of low family income for cervical intraepithelial neoplasia 2+ (odds ratio = 1.71, 95% confidence interval = 1.09-2.63) compared with HE-based diagnoses (odds ratio = 1.12, 95% confidence interval = 0.72-1.72). The addition of Ki-67 staining did not significantly influence these results. CONCLUSIONS: p16-based diagnoses may affect the power of risk factor analysis, especially when using small cohorts.

Health disparities between women with and without disabilities: a review of the research.

As part of a women's health center project, we reviewed 16 years of research to examine health disparities between women with and without disabilities. We reviewed MEDLINE-indexed articles between 1990 and 2005 with data on women with and without physical, sensory, intellectual, developmental, or psychiatric disabilities. Our review found few articles examining health disparities in chronic disease, cancer, mental health and substance abuse, preventive screening, health-promoting behaviors, and health services utilization. Results reflect apparent health disparities between women with and without disabilities. Challenges for the field exist in standardizing disability definitions and determining a future course for health disparity research and policy.

Progress and priorities in the health of women and girls: a decade of advances and challenges.

OBJECTIVE: Following the initial wave of federal support to address women's health, there is a need to assess successes and determine the next priorities to advance the health of women. The objective of this study was to systematically collect expert opinion on the major advances in women's health in the past decade and priorities for women's health research and service in the coming decade. METHODS: We utilized a Delphi method to query the leadership from academic and community Centers of Excellence in Women's Health, as designated by the Department of Health and Human Services. Leaders from 36 of the 48 centers responded to a series of questions about the major advances and critical indicators to evaluate future needs in women's health. We utilized a social ecology model framework to organize the responses to each question. RESULTS: The experts identified increased health education for women and increased empowerment of women across multiple spheres as the major advances positively impacting the health of women. The experts selected the following areas as the most important indicators to measure the status of the health of women in the future: health education and promotion, rates and impact of interpersonal violence against women, and access to healthcare. The major advances and measures of the health of women did not focus on specific changes to individual women in illness management, clinical care, or individual behavioral change. CONCLUSIONS: As we move to address health reform, we must be able to recognize and incorporate a broad perspective on public health and policy initiatives critical to the health and wellness of women and girls and, therefore, central to the well-being of the nation.

Women's health policies associated with obesity, diabetes, high blood pressure, and smoking: a follow-up on the women's health report card.

This study sought to elucidate associations between state-level policies related to women's health and state prevalence of obesity, smoking, high blood pressure, and diabetes among women. Using data from national sources compiled for Making the Grade on Women's Health: A National and State-by-State Report Card, state policies on key women's health issues were evaluated on the degree to which policies adequately protected women's health. Blocked regressions assessed the policies associated with state outcomes. Antidiscrimination policies were prominent for high blood pressure, smoking, and obesity; models accounted for significant variance for all outcomes. State policies that support women may improve women's health.

Impact of raloxifene or tamoxifen use on endometrial cancer risk: a population-based case-control study.

PURPOSE: Raloxifene reduces breast cancer risk in women with osteoporosis, and both tamoxifen and raloxifene prevent breast cancer in high-risk women. However, in vitro, raloxifene does not share the pro-estrogenic effects of tamoxifen on the endometrium. Randomized trials of these agents have provided limited information about endometrial cancer risk in the general population. We sought to compare endometrial cancer risks associated with raloxifene, tamoxifen, and nonusers of a selective estrogen receptor modulator (SERM) in the general population and characterize the endometrial tumors occurring in these groups. METHODS: We performed a case-control study of white and African American women age 50 to 79 years in the Philadelphia area. Patients were diagnosed with endometrial cancer between July 1999 and June 2002. Controls were identified through random-digit dialing. RESULTS: We analyzed 547 cases and 1,410 controls. Among cases, 3.3% had taken raloxifene; 6.2% had taken tamoxifen. Among controls, 6.6% had taken raloxifene; 2.4% had taken tamoxifen. After adjustment for other risk factors, the odds of endometrial cancer among raloxifene users was 50% that of nonusers (odds ratio [OR] = 0.50; 95% CI, 0.29 to 0.85), whereas tamoxifen users had three times the odds of developing endometrial cancer compared with raloxifene users (OR = 3.0; 95% CI, 1.3 to 6.9). Endometrial tumors in raloxifene users had a more favorable histologic profile and were predominantly International Federation of Gynecology and Obstetrics stage I and low grade. CONCLUSION: Raloxifene users had significantly lower odds of endometrial cancer compared with both tamoxifen users and SERM nonusers, suggesting a role for raloxifene in endometrial cancer prevention and individualization of SERM therapy.

Pairwise combinations of estrogen metabolism genotypes in postmenopausal breast cancer etiology.

Estrogen exposures have been associated with breast cancer risk, and genes involved in estrogen metabolism have been reported to mediate that risk. Our goal was to better understand whether combinations of candidate estrogen metabolism genotypes are associated with breast cancer etiology. A population-based case-control study in three counties of the Philadelphia Metropolitan area was undertaken. We evaluated seven main effects and 21 first-order interactions in African Americans and European Americans for genotypes at COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, SULT1A1, and SULT1E1 in 878 breast cancer cases and 1,409 matched random digit-dialed controls. In European Americans, we observed main effect associations of genotypes containing any CYP1A1*2C (odds ratio, 1.71; 95% confidence interval, 1.09-2.67) and breast cancer. No significant main effects were observed in African Americans. Three significant first-order interactions were observed. In European Americans, interactions between SULT1A1*2 and CYP1A1*2C genotypes (P(interaction) < 0.001) and between SULT1E1 and CYP1A2*1F genotypes were observed (P(interaction) = 0.006). In African Americans, an interaction between SULT1A1*2 and CYP1B1*4 was observed (P(interaction) = 0.041). We applied the false-positive report probability approach, which suggested that these associations were noteworthy; however, we cannot rule out the possibility that chance led to these associations. Pending future confirmation of these results, our data suggest that breast cancer etiology in both European American and African American postmenopausal women may involve the interaction of a gene responsible for the generation of catecholestrogens with a gene involved in estrogen and catecholestrogen sulfation.

A retrospective case-control study of the use of hormone-related supplements and association with breast cancer.

Hormone-related supplements (HRS), many of which contain phytoestrogens, are widely used to manage menopausal symptoms, yet their relationship with breast cancer risk has generally not been evaluated. We evaluated whether use of HRS was associated with breast cancer risk, using a population-based case-control study in 3 counties of the Philadelphia metropolitan area consisting of 949 breast cancer cases and 1,524 controls. Use of HRS varied significantly by race, with African American women being more likely than European American women to use any herbal preparation (19.2% vs. 14.7%, p=0.003) as well as specific preparations including black cohosh (5.4% vs. 2.0%, p=0.003), ginseng (12.5% vs. 7.9%, p<0.001) and red clover (4.7% vs. 0.6%, p<0.001). Use of black cohosh had a significant breast cancer protective effect (adjusted odds ratio 0.39, 95% CI: 0.22-0.70). This association was similar among women who reported use of either black cohosh or Remifemin (an herbal preparation derived from black cohosh; adjusted odds ratio 0.47, 95% CI: 0.27-0.82). The literature reports that black cohosh may be effective in treating menopausal symptoms, and has antiestrogenic, antiproliferative and antioxidant properties. Additional confirmatory studies are required to determine whether black cohosh could be used to prevent breast cancer.

Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk.

BACKGROUND: Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use. METHODS: A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk. RESULTS: Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A1*2C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A1*3 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A1*2 genotype: the SULT1A1*2 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use. CONCLUSIONS: Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.

Case-control study of postmenopausal hormone replacement therapy and endometrial cancer.

This study evaluated recent inconsistent findings that adding progestins to postmenopausal estrogen replacement therapy protects against endometrial cancer. Using a population-based case-control study, the authors compared 511 endometrial cancer cases aged 50-79 years in the Philadelphia, Pennsylvania, region during 1999-2002 with 1,412 random-digit-dialing controls regarding postmenopausal hormone replacement therapy (HRT) use. Telephone interviews were performed with memory aids mailed in advance. An increased risk of endometrial cancer was observed among postmenopausal women using only unopposed estrogen for 3 or more years, compared with women who never used HRT (adjusted odds ratio = 3.4, 95% confidence interval (CI): 1.4, 8.3). Using combination HRT (of any duration) was associated with a substantial reduction in risk (odds ratio = 0.8, 95% CI: 0.6, 1.1). Comparing women using only combined estrogen and progestin for 3 or more years with women using only unopposed estrogen for 3 or more years, the authors found that the adjusted odds ratio was 0.2 (95% CI: 0.1, 0.6). Long-term use of unopposed estrogen is associated with increased risk for endometrial cancer, whereas combined estrogen plus progestin hormone therapy is not. Thus, if HRT is to be used in women with an intact uterus, this study confirms the benefit of adding progestins to the regimen.

Relating health policy to women's health outcomes.

Individuals' social and economic circumstances, including socioeconomic status and medical care availability, are central to health outcomes, particularly for women. These factors are often mediated by governmental policies. This exploratory study found associations between women's health outcomes and state-level policies related to women's health. Outcomes were mortality rates for four leading causes of death for women in the US (heart disease, stroke, lung cancer, and breast cancer), infant mortality, and a mental health outcome variable. State policies on key women's health issues were evaluated on the degree to which they adequately protected women's health. Our regression models accounted for significant variance in mortality rates and substantial variance in the mental health outcome. Policies affecting access to care (Medicaid eligibility and efforts to expand Medicaid) and community (environmental health tracking and violence against women) were significantly associated with mortality outcomes. State health policies should be examined further for their relationship to health outcomes.

A new questionnaire for urinary incontinence diagnosis in women: development and testing.

OBJECTIVE: The purpose of this study was to develop a questionnaire for urinary incontinence diagnosis in women and to test its reliability and validity, with incontinence specialists' clinical evaluations as the gold standard. STUDY DESIGN: One hundred seventeen urogynecology outpatients with urinary incontinence symptoms completed the Questionnaire for Urinary Incontinence Diagnosis at enrollment and 1 week and 9 months later. Baseline clinical diagnoses were compared with Questionnaire for Urinary Incontinence Diagnosis diagnoses (criterion validity). Nine-month Questionnaire for Urinary Incontinence Diagnosis change scores were compared across treatment groups (responsiveness). RESULTS: Clinical diagnoses included stress (n = 15), urge (n = 26), and mixed urinary incontinence (n = 72). Internal consistency and test-retest reliability estimates were good. Sensitivity and specificity were 85% (95% CI, 75%, 91%) and 71% (95% CI, 51%, 87%), respectively, for stress urinary incontinence and 79% (95% CI, 69%, 86%) and 79% (95% CI, 54%, 94%), respectively, for urge urinary incontinence. The Questionnaire for Urinary Incontinence Diagnosis correctly diagnosed urinary incontinence type in 80% of subjects. Questionnaire for Urinary Incontinence Diagnosis Stress and Urge scores decreased significantly in treated subjects. CONCLUSION: The Questionnaire for Urinary Incontinence Diagnosis, a new 6-item questionnaire for female urinary incontinence type diagnosis, is reliable and able to diagnose stress urinary incontinence and urge urinary incontinence in a referral urogynecology patient population with accuracy.

The relationship of health care delivery system characteristics and legal factors to mode of delivery in women with prior cesarean section: a systematic review.

OBJECTIVE: To evaluate the relationship of health care delivery system characteristics and legal factors to mode of delivery in women with prior cesarean section. METHODS: We identified relevant studies by searching MEDLINE and HealthSTAR (1980 to May 2002), reference lists of pertinent articles, and recommendations of local and national experts. We also searched the online Cochrane systematic reviews and controlled trials registries, Database of Abstracts and Reviews on Effectiveness, and EMBASE databases. RESULTS: Studies of guidelines suggested that opinion leaders influence provider behavior regarding repeat cesarean delivery versus trial of labor decisions. Studies of hospital and insurance characteristics provided inconsistent results. There was insufficient evidence to evaluate the relationship between provider characteristics and delivery outcomes. Legislation and liability-related factors effected limited change. CONCLUSION: Studies of health care system characteristics and other factors focused primarily on rates of delivery modes (vaginal birth after cesarean or repeat cesarean delivery) rather than patient safety or health outcomes. Future studies must account for case mix, time trends, and other potential confounders, especially concerning associations of provider characteristics.

Safety of vaginal birth after cesarean: a systematic review.

OBJECTIVE: To evaluate the benefits and harms of vaginal birth after cesarean compared with repeat cesarean delivery. DATA SOURCES: The computerized databases MEDLINE, EMBASE, HealthSTAR, Cochrane CENTRAL, and National Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effectiveness, along with reference lists and national experts, were used to conduct this review. METHODS OF STUDY SELECTION: All studies that reported data for maternal or infant outcomes in women with prior cesarean delivery were eligible. Methodological quality was evaluated for each study with the criteria of the United States Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination. Twenty of 6,828 potentially relevant articles (55,506 patients) were included in the analysis. TABULATION, INTEGRATION, AND RESULTS: Two authors independently abstracted information on study design, sample size, participant characteristics, and maternal and fetal health outcomes by using a standardized protocol. Rates of vaginal delivery in women undergoing a trial of labor ranged from 60% to 82%. There was no significant difference in maternal deaths or hysterectomy between trial of labor and repeat cesarean. Uterine rupture was more common in the trial-of-labor group, but rates of asymptomatic uterine dehiscence did not differ. Studies conflicted on the effect of induction of labor on these outcomes. Data regarding infant outcomes were poor. CONCLUSION: Safety in childbirth for women with prior cesarean is a major public health concern. Methodological deficiencies in the literature evaluating the relative safety of vaginal birth after cesarean compared with repeat cesarean delivery are striking. The identification of high-risk and low-risk groups of women and settings for morbidity remains a key research priority.