Ensuring accountability for consideration of sex as a biological variable in research.

The National Institute of Health (NIH) policy, Consideration of Sex as a Biological Variable (SABV) in NIH-funded Research (2015), focuses on the expectation that researchers account for the influence of SABV in vertebrate animal and human studies and provide a strong justification for single-sex investigations. When SABV is considered in the research design, data analyses, and reporting, the rigor and reproducibility of the research are elevated and inform best practices and precision health for all people. Additional recommendations include the appropriate use of terminology, integration into curricula, intersection with social determinants of health, and application of sex and gender equity guidelines when disseminating research. This paper is a "call to action" for nurse researchers to lean into and apply this policy's principles and our recommendations, from the bench to the bedside, to advance the equity and health of all people.

Sex/gender influences on the nervous system: Basic steps toward clinical progress.

A Commentary highlighting the progress that sex-based data and research have made in neuroscience and the complexities that research has revealed thus far. Basic and preclinical neuroscientific research that considers sex as a biological variable will continue to build on the foundation of knowledge that has been started by multiple predecessors. The expansion of knowledge in preclinical neuroscience that integrates the study of both sexes will have a significant role in informing clinical trial design. We applaud the efforts of the editors and authors who have contributed to this issue. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Studying both sexes: a guiding principle for biomedicine.

In May 2014, the U.S. National Institutes of Health (NIH) announced that it will ensure that investigators account for sex as a biological variable (SABV) in NIH-funded preclinical research as part of the agency's rigor and transparency initiative. Herein, I describe in more detail the rationale behind the SABV policy component and provide additional detail about policy goals. In short, studying both sexes is a guiding principle in biomedical research that will expand knowledge toward turning discovery into health. NIH expects that considering SABV in preclinical research will help to build a knowledge base that better informs the design of clinical research and trials in humans. Integrating the practice of studying both sexes in preclinical research will, over time, expand our currently incomplete knowledge base that plays a critical role in informing the development of sex- and gender-appropriate medical care for women and men.

Inclusion of Sex and Gender to Improve the State of the Science in Women's Health.

ABSTRACT: The influence of sex and gender-related factors on health and disease at all levels of scale, across all health conditions, and throughout the entire life course is increasingly clear. A series of policies instituted by the National Institutes of Health (NIH) that require researchers to include appropriate populations and to analyze the data accordingly have strengthened the evidence base around the health of women. Translating these advances to the entire research ecosystem can catalyze rigorous biomedical discovery that can improve health. We encourage journals, publishers, and funders to align their policies and expectations regarding sex and gender considerations in research with those of the NIH and other international funding agencies.

Workshop summary: National Institutes of Health (NIH) 2022 scientific workshop on gender and health.

In this manuscript, we summarize the goals, content, and impact of the Gender and Health: Impacts of Structural Sexism, Gender Norms, Relational Power Dynamics, and Gender Inequities workshop held by the National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) in collaboration with 10 NIH Institutes, Centers, and Offices. Specifically, we outline the key points emerging from the workshop presentations, which are the focus of the collection of articles in this supplement. The overarching goals of the workshop were to convene NIH staff, the external scientific community, and the public to discuss methods, measurement, modifiable factors, interventions, and best practices in health research on gender as a social and cultural variable and to identify opportunities to advance research and foster collaborations on these key topics. Themes emerging from the workshop include the need for intersectional measures in research on gender and health, the role of multilevel interventions and analyses, and the importance of considering gender as a social and structural determinant of health. Careful, nuanced, and rigorous integration of gender in health research can contribute to knowledge about and interventions to change the social and structural forces that lead to disparate health outcomes and perpetuate inequities.

Web-based versus paper administration of common ophthalmic questionnaires: comparison of subscale scores.

OBJECTIVE: To compare participants' responses to Web-based and paper-and-pencil versions of an ophthalmic, patient-reported outcome (PRO) questionnaire. DESIGN: Questionnaire development. PARTICIPANTS: Matched subjects with ocular surface disease (OSD) (n = 68) and without OSD (controls, n = 50). METHODS: Subjects completed a standard, paper-and-pencil and a Web-based version of the same questionnaire in randomized order. The administered questionnaire included several ophthalmic PRO subscales: the National Eye Institute's (NEI's) Refractive Error Quality of Life Instrument's Clarity of Vision, Near Vision, Far Vision, Glare, Symptoms, Worry, and Satisfaction with Correction subscales; the Ocular Surface Disease Index's (OSDI's) Symptoms subscale; and the NEI's Visual Function Questionnaire's Driving subscale. Possible scores for each subscale ranged from 0 (no difficulty) to 100 (most difficulty). Agreement of subscale scores between modes of administration was assessed using the Bland-Altman approach and multivariable logistic regression. MAIN OUTCOME MEASURES: Subscale scores and an unweighted average total score for each mode of administration. RESULTS: Mean differences in scores between modes of administration ranged from -2.1 to +2.3 units. Although no differences were found to be statistically significant, the Worry and Satisfaction with Correction subscales approached statistical significance (P = 0.07 and 0.08, respectively). Although most subscale mean differences in score did not differ significantly by gender, age (≥40 vs. <40 years), disease status (OSD vs. control), order of administration, or time between completion of the questionnaires, women had slightly greater score differences than men for the Driving (P = 0.04) and Clarity of Vision (P = 0.03) subscales; those with OSD had greater score differences for Clarity of Vision than did controls (P = 0.0006); and those aged ≥40 years had slightly greater differences in OSDI Symptoms subscale than those aged <40 years (P = 0.04). CONCLUSIONS: To our knowledge, this Food and Drug Administration and NEI collaboration is the first study to evaluate the equivalence of Web-based and paper versions of ophthalmic PRO questionnaires. We found no evidence of clinically significant differences between scores obtained by the 2 modes for any of the examined subscales. A Web-based instrument should yield scores equivalent to those obtained by standard methods, providing a useful tool that may facilitate ophthalmic innovation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Sex as a Biological Variable in Cardiovascular Diseases: JACC Focus Seminar 1/7.

Sex and gender influence all aspects of cardiovascular health and disease-including epidemiology, pathophysiology, diagnosis, clinical manifestation, disease progression, and response to treatment-in complex and interrelated ways. Sex-based and gender-based differences have been identified in risk and presentation of cardiovascular diseases (CVDs); however, failure to address sex and gender as key variables in CVD research and reporting and limited understanding of differences have contributed to disparities in risk assessment, prevention, diagnosis, treatment, and outcomes. Improved consideration of both sex and gender in all phases of the biomedical research continuum, along with educational and training curricula focused on the role of sex and gender in CVD, are needed to provide targeted therapies and improve cardiovascular health outcomes for all.

Research on Women's Health: Ready for the Future.

The National Institutes of Health (NIH) Office of Research on Women's Health (ORWH) was established in 1990. With the completion of the office's 30th anniversary year, we look back and recount some of the key events and overall zeitgeist that led to ORWH's formation, and how it became the focal point at the nation's primary biomedical research agency for coordinating research on science to improve the health of women. We discuss ORWH's mission and signature programs and the bold vision that drives the NIH-wide strategic, interdisciplinary, and collaborative approach to research on women's health and efforts to promote women in biomedical careers. Also discussed are several of the many scientific advances in research on the health of women, policy innovations and their effects, and career advancements made by women in medicine and related scientific fields. We also highlight key challenges for the health of women, the need to continue pushing for equity in biomedical research careers, and NIH's approach to addressing these problems to ensure progress for the next 30 years and beyond.

A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change.

The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials.

Developing the Process and Tracking the Implementation and Evaluation of the National Institutes of Health Strategic Plan for Women's Health Research.

The National Institutes of Health (NIH) released Advancing Science for the Health of Women: The Trans-NIH Strategic Plan for Women's Health Research, 2019-2023 (Strategic Plan) in February 2019. The NIH Office of Research on Women's Health (ORWH) engaged staff members from across NIH to develop recommendations on the implementation and evaluation of the Strategic Plan. OBJECTIVE: This paper describes the process used to develop recommendations for tools and approaches that NIH Institutes, Centers, and Offices (ICOs) could apply when implementing and evaluating the Strategic Plan. METHODS: A Trans-NIH Strategic Plan Implementation and Evaluation Guidance Development Team conducted meetings and individual interviews with 69 NIH staff members knowledgeable about research on the health of women and sex and gender differences and met with 11 Advisory Committee on Research on Women's Health Strategic Plan Evaluation Working Group members. The purpose of these stakeholder meetings and interviews was to obtain recommendations for implementing the Strategic Plan and identify measures for evaluating implementation success. A thematic analysis was performed to synthesize and map the recommendations to the Strategic Plan goals and objectives. RESULTS: The process resulted in the Guide for Implementing and Evaluating the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research Across NIH Institutes, Centers, and Offices (the Guide), which includes both a conceptual and logic model for implementation and evaluation. CONCLUSIONS: The Guide offers methods, tools, and suggestions that ICO planning and evaluation staff, as well as national and international entities, can choose from when determining how to implement the Strategic Plan through ICO activities, programs, and research initiatives and how to evaluate their efforts in the context of their unique mission.

Sex as a Biological Variable: A 5-Year Progress Report and Call to Action.

A little over 5 years ago, the U.S. National Institutes of Health (NIH) announced the intention to develop policies to require applicants to report plans to balance male and female cells and animals in preclinical investigations. Soon thereafter, the NIH issued a request for information from the scientific community and consulted with various stakeholders. The feedback received was considered during development of policy requiring the consideration of sex as a biological variable (SABV) in NIH-funded research on vertebrate animals and humans, which went into effect for applications due on or after January 25, 2016. We identified NIH programs related to SABV and reviewed SABV-relevant scientific literature. We find that the application of SABV throughout the research process can serve as a guiding principle to improve the value of biomedical science. The NIH is engaged in ongoing efforts to develop resources to help investigators consider SABV in their research. We also provide an update on lessons learned, highlight ways that different disciplines consider SABV, and describe the opportunities for scientific discovery that applying SABV offers. We call on NIH's various stakeholders to redouble their efforts to integrate SABV throughout the biomedical research enterprise. Sex- and gender-aware investigations are critical to the conduct of rigorous and transparent science and the advancement of personalized medicine. This kind of research achieves its greatest potential when sex and gender considerations are integrated into the biomedical research enterprise in an end-to-end manner, from basic and preclinical investigations, through translational and clinical research, to improved health care delivery.

Applying the new SABV (sex as a biological variable) policy to research and clinical care.

Sex as a biological variable (SABV) is a key part of the new National Institutes of Health (NIH) initiative to enhance reproducibility through rigor and transparency. The SABV policy requires researchers to factor sex into the design, analysis, and reporting of vertebrate animal and human studies. The policy was implemented as it has become increasingly clear that male/female differences extend well beyond reproductive and hormonal issues. Implementation of the policy is also meant to address inattention to sex influences in biomedical research. Sex affects: cell physiology, metabolism, and many other biological functions; symptoms and manifestations of disease; and responses to treatment. For example, sex has profound influences in neuroscience, from circuitry to physiology to pain perception. Extending beyond the robust efforts of NIH to ensure that women are included in clinical trials, the SABV policy also includes rigorous preclinical experimental designs that inform clinical research. Additionally, the NIH has engaged journal editors and publishers to facilitate reproducibility by addressing rigor and promoting transparency through scientifically appropriate sex-specific study results reporting. The Sex And Gender Equity in Research (SAGER) guidelines were developed to assist researchers and journal editors in reporting sex and gender information in publications [1].

Reversing the Trends toward Shorter Lives and Poorer Health for U.S. Women: A Call for Innovative Interdisciplinary Research.

The United States (U.S.) is a leader and innovator in biomedicine, yet trails behind for many key health indicators, especially for women. This paper highlights key evidence indicating that not only is the state of women's health in the U.S. lagging, but it is at risk for falling off the curve. Women's health care remains fragmented; research in the field can be disconnected and difficult to integrate across disciplines-silos prevail. Structural obstacles contribute to this lack of cohesion, and innovative, interdisciplinary research approaches which integrate the multidimensional aspects of sex and gender, and race and ethnicity, with a life course perspective are sorely needed. Such synergistic, scientific strategies have the potential to reverse the trend towards shorter life expectancy and poorer health for women in the U.S. The National Institute for Health (NIH) seeks to raise the bar for the health of all women by tackling these issues through enhancing the relevance of biomedical research to the health of women and driving the sustained advancement of women in biomedical careers.

Working Together to Address Women's Health in Research and Drug Development: Summary of the 2017 Women's Health Congress Preconference Symposium.

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

A Report of the 24th Annual Congress on Women's Health-Workshop on Transforming Women's Health: From Research to Practice.

Sex and gender are critical contributors to overall health and disease, and considering both in research informs the development of prevention strategies and treatment interventions for both men and women. The National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop on this topic at the 24th Annual Women's Health Congress, which was held in Crystal City, VA, in April 2016. The workshop featured presentations by NIH intramural and extramural scientists who presented data on a variety of topics including polycystic kidney disease, vaccine protection, depression, drug addiction, and cardiovascular disease. In this publication, we discuss the major points of each presentation and demonstrate the importance of considering sex and gender in biomedical research.

Women's Careers in Biomedical Sciences: Implications for the Economy, Scientific Discovery, and Women's Health.

While women have been well represented in medical school and biomedical doctoral degree programs, they do not comprise half of academic medicine faculty positions. Furthermore, there is a significant paucity of women in academic medicine leadership positions, as evidenced by the fact that only 16% of dean positions at United States Medical schools are filled by women. In this commentary, the authors review the state of women in academic medicine and argue that increased representation of women in the academic workforce will lead to economic gains, increased scientific discovery, and improvements to women's health.

Sex influences in neurological disorders: case studies and perspectives.

Beginning in the late 1980s and early 1990s, scientists and the public alike recognized that, for too long, women had been underrepresented in clinical trials. While much progress was made in the following decades, preclinical research still often ignores sex as a fundamental biological variable. Many neurological disorders, including multiple sclerosis and migraine, show strong sex differences in incidence and disease manifestation. In this commentary, we highlight case studies of neurological disorders affecting men and women to demonstrate the need for more such studies. Research conducted in these areas so far has shed light on the underlying mechanisms of the disease and offers the promise to help develop more personalized treatments for both men and women.

Hacia finales de los años 1980 y comienzos de los 90 tanto los cientistas como la población general reconocieron que, por mucho tiempo, las mujeres habían sido sub-representadas en los ensayos clínicos. A pesar de que ha habido mucho progreso en las décadas siguientes, la investigación preclínica aun ignora el sexo como una variable biológica fundamental. Muchos trastornos neurológicos, incluyendo la esclerosis múltiple y la migraña, muestran importantes diferencias por sexo en la incidencia y la manifestación de la enfermedad. En este comentario se destacan los estudios de casos de trastornos neurológicos que afectan a hombres y mujeres, y se demuestra la necesidad de muchos más análisis. La investigación realizada hasta la fecha en estas áreas ha dado luces acerca de los mecanismos subyacentes de la enfermedad y promete ayudar al desarrollo de tratamientos más personalizados tanto para hombres como para mujeres.

À la fin des années 80 et au début des années 90, la communauté scientifique et le public reconnaissent qu'il y a trop longtemps que les femmes sont sous-représentées dans les études cliniques. La situation s'améliore dans les décades qui suivent mais la recherche clinique ignore encore souvent le sexe comme variable biologique fondamentale. L'incidence et le tableau clinique de beaucoup de maladies neurologiques, comme la sclérose en plaques et la migraine, varient fortement selon le sexe. Nous soulignons dans ce commentaire des études de cas de troubles neurologiques affectant des hommes et des femmes, afin de démontrer le besoin d'études supplémentaires. Jusqu'à présent, la recherche dans ces domaines a mis en lumière les mécanismes sous-jacents de la maladie et devrait permettre de développer davantage de traitements personnalisés pour les hommes et les femmes.