Advancing Research on Chronic Conditions in Women (2024)

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1 Introduction A recent World Economic Forum report revealed that although women generally outlive men, they spend approximately 9 more years in a state of suboptimal physical, social, and psychological well-being, which can hinder their ability to actively participate and contribute in the home, workforce, and community and lead to diminished earning prospects. The report also highlights that when evaluating the global burden of disease, 47 percent of conditions disproportionately affect women, 4 percent affect them differently, and 5 percent are exclusive to females. Among those affecting women are several chronic conditions. In a concluding observation, the report stated that the health of women is not an isolated concern; it serves as a foundation for societal welfare and advancement. Improved women’s health and well-being have a cascading effect that touches families, communities, and nations (Ellingrud et al., 2024). In the U.S., chronic conditions are the leading causes of illness and death and associated with significant social and economic burden (CDC, 2023). Women experience chronic conditions differently than men; some are specifically influenced by women’s biology and hormonal makeup, and others are influenced by gender differences related to how women access health services, their life roles, environmental exposures, and other factors. In 2021, cardiovascular disease (CVD), stroke, and Alzheimer’s disease (AD) were among the top five leading causes of death in women (Xu et al., 2021). In addition, women experienced a 1.3–2 fold increased prevalence of arthritis, depression, AD, and asthma, and an 11 fold increased prevalence of osteoporosis in comparison to men based on data from the Centers for Medicare & Medicaid Services (CMS, 2023). Female-specific and gynecologic conditions have a significant impact, with a prevalence of endometriosis and uterine fibroids of 1.9–62 percent (Christensen et al., 2021; Janssen et al., 2013) and 4.5–68.5, respectively, based on the study sample (Giuliani et al., 2020; Marsh et al., 2013); these wide ranges represent the challenges in measuring certain chronic conditions in women. Those over 18 had a greater prevalence of multiple chronic conditions (MCC), with 28.4 percent of women having two chronic conditions versus 25.9 PREPUBLICATION COPY: UNCORRECTED PROOFS 

2 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN percent of men (Boersma et al., 2020). The impact of chronic conditions is further exacerbated in women by race, 1 ethnicity, sexual orientation, gender identity, and rurality. REPORTS ON WOMEN’S HEALTH Reports from the National Academies of Sciences, Engineering, and Medicine (NASEMs) and other organizations have provided important background, evidence, and recommendations to advance women’s health (IOM, 1993, 2001, 2010; NASEM, 2022). The committee built on this work and references it throughout the report. The most relevant reports and recommendations are summarized briefly. In 2001, the Institute of Medicine (IOM) 2 released the report Exploring the Biological Contributions to Human Health: Does Sex Matter? (IOM, 2001). The report discusses basic biochemical sex differences in cells and health variability between the sexes over the life course. The committee concluded that sex and gender differences are an important human variable and that the study of sex differences was “evolving into a mature science.” It also provided recommendations for advancing that study and recommended that at all levels of biomedical and health-related research should consider sex differences and similarities (IOM, 2001). Furthermore, the report recommended considering sex as a biological variable in all biomedical and health-related research across the life span. In 2015, the National Institutes of Health (NIH) instituted its Sex as a Biological Variable policy. 3 In 2010, IOM released Women’s Health Research: Progress, Pitfalls and Promise (IOM, 2010), which assessed progress in addressing health conditions that are important to women’s health. The committee noted progress in some areas, in part because of translating new research findings to treatment of breast cancer, CVD, and cervical cancer, for example. However, it found little research-led progress for other conditions, such as unintended pregnancy, maternal morbidity and mortality, autoimmune diseases, alcohol and drug addiction, lung cancer, other gynecologic cancers, non-malignant gynecologic disorders, and AD. The report identified barriers to progress, including the following: • Inadequate attention to the social and environmental factors that influence health, • Inadequate enforcement of requirements that clinical trials include representative numbers of women and that women’s results be reported, • Lack of accounting for sex and gender differences in the study design and analysis, and • Lack of reporting on sex and gender differences. 1 The committee distinguishes between race and ancestry and acknowledges that these two concepts are sometimes used interchangeably and inaccurately. The committee refers to race as a social construct and ancestry when the research is describing biological make-up and line of descent. 2 As of March 2016, the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine continues the consensus studies and convening activities previously carried out by the Institute of Medicine (IOM). The IOM name is used to refer to reports issued prior to July 2015. 3 Sex as a biological variable is expected to be factored into research designs, analyses, and reporting in vertebrate animal and human studies supported by NIH https://orwh.od.nih.gov/sex-gender/orwh-mission- area-sex-gender-in-research/nih-policy-on-sex-as-biological-variable (accessed March 7, 2024). PREPUBLICATION COPY: UNCORRECTED PROOFS 

INTRODUCTION 3 The report noted that these barriers “hindered identification of potentially important sex differences and slowed progress in women’s health research and its translation to clinical practice” (IOM, 2010). Based on these findings, the report recommended that: • Research funders should sustain and strengthen their focus on women’s health (conducting women-only research as appropriate), including genetic, behavioral, and social determinants of health to integrate women’s health research into all health research so that difference differences between subgroups of men and women are routinely assessed in all health research. • Cross-institute initiatives at NIH—such as those in the Division of Program Coordination, Planning, and Strategic Initiatives—should support research on common determinants and risk factors that underlie multiple diseases. • Research funders should ensure adequate participation of women, analysis of data by sex, and reporting of sex-stratified analyses in health research. • The International Committee of Medical Journal Editors and other editors of relevant journals should adopt a guideline that all papers reporting the outcomes of clinical trials should report on men and women separately unless a trial is of a sex-specific condition (such as endometrial or prostatic cancer). NIH should sponsor a meeting to facilitate establishment of the guidelines. • Researchers should study how to translate research findings on women’s health into clinical practice and public health policies rapidly. Despite progress, many of the identified gaps remain and are explored in the present report as they relate to chronic conditions in women. One area where NIH has acted based on a recent NASEM report was creating the Office of Autoimmune Disease Research (OADR) under the Office of Research on Women’s Health (ORWH) in the Office of the Director. Enhancing NIH Research on Autoimmune Disease (NASEM, 2022), considered five options for enhancing the research and resulting outcomes and recommended creating such an office within the NIH Office of the Director. The report pointed to several gaps this office would fill, such as facilitating cross-NIH multidisciplinary collaboration to stimulate autoimmune research innovation; offering priority setting, strategic planning, and implementation; and providing visible leadership on autoimmune disease research. Congress directed NIH to create OADR in the Consolidated Appropriations Act, 2023 (Public Law 117–328); this report reviews several chronic conditions that fall under OADR’s purview. Philanthropic and nonprofit organizations have also issued several recent noteworthy reports. For example, as part of an initiative of the Women's Health Access Matters nonprofit foundation, RAND Corporation researchers developed a series of reports examining the effect of increasing funding for women's health for coronary artery disease, rheumatoid arthritis, and AD and related dementias. The authors quantified the potential effects of increasing funding for women’s health on health outcomes, and the ultimate societal costs, such as health care expenditures, labor productivity for patients, and quality-adjusted life years (Baird et al., 2021). The authors calculated the effects across 30 years of doubling the current funding provided by the NIH extramural portfolio devoted to women’s health. 4 Overall, the report concluded that investing in women’s health research yields benefits beyond investing in general research, with 4 The effect of a current investment was assumed to occur in 10 years, with benefits accruing after that. PREPUBLICATION COPY: UNCORRECTED PROOFS 

4 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN large returns resulting from very small health improvements attributable to increased women’s health research funding (Baird et al., 2021). In 2023, the Bill and Melinda Gates Foundation and NIH published the Women's Health Innovation Opportunity Map 2023 after engaging in a consultive, multidisciplinary, cross-sector effort (Scharp et al., 2023). The report is global but relevant to the U.S. and identified six action areas: (1) data and modeling, (2) research design and methodologies, (3) regulatory and science policy, (4) innovation, (5) structural and social determinants of health, and (6) training and careers. The committee discusses several of these areas as they relate to chronic conditions in women throughout the report; for example, the committee notes important considerations for including the structural and social determinants of health in various levels of research. CURRENT LANDSCAPE AND BACKGROUND The health of women in general, and the impact of chronic conditions in particular, has prompted increased concern among congressional and government leaders. Congressional leaders have raised questions about the knowledge and gaps in the science of prevention, diagnosis, and treatment of chronic conditions in women, and research related to women’s health overall. For example, in fiscal year (FY) 2021, House and the Senate appropriations committees requested that NIH convene a conference to evaluate that ongoing research. NIH held a conference titled Advancing NIH Research on the Health of Women, with chronic debilitating conditions as one of its three focus areas (NIH, 2021a), that identified important knowledge gaps related to chronic conditions in women, including an understanding of the effect of sex and gender influences on the outcomes that individuals experience. This led NIH to request that the National Academies produce a report that describes current gaps in evidence and proposes a research agenda for the future (more information is provided in the following sections). Since that request, the federal government has made additional efforts and requests regarding women’s health. In 2023, Congress mandated a National Academies study on the assessment of NIH research on women’s health (NASEM, 2024) in the Consolidated Appropriations Act of 2023. 5 On November 13, 2023, President Biden established the White House Initiative on Women’s Health Research (White House, 2023) and called for leaders from executive departments and federal agencies and offices to develop actions that federal agencies could take to advance women’s health research, including research on chronic conditions. In February 2024, the initiative announced its first action—$100 million in federal funding for research and development by the Advanced Research Projects Agency for Health, part of the Department of Health and Human Services (White House, 2024). In March 2024, an executive order 6 was created to advance women’s health research and innovation, which focused on prioritizing federal investments. It mentioned that agency members of this initiative should prioritize and promote interagency alignment, establish and implement data standards, create programs/funding for innovation to advance the research, and fill research gaps. 5 Public Law 117–328 6 Exec. Order No. 14120, 89 FR 20095 (March 2014) PREPUBLICATION COPY: UNCORRECTED PROOFS 

INTRODUCTION 5 National Institute of Health Office of Research on Women’s Health NIH ORWH coordinates, promotes, and supports research to advance women’s health. 7 It collaborates with the 27 NIH Institutes and Centers and the broader scientific community. Since its inception more than 30 years ago, ORWH has achieved notable progress in coordinating research on women's health at NIH; enhancing studies that affect women; ensuring they are included in biomedical and biobehavioral research; and promoting their recruitment, retention, and re-entry in clinical studies and advancement in biomedical careers (ORWH, 2023). As noted, ORWH responded in 2021 to a Committee on Appropriations request 8 (U.S. Congress et al., 2020) to convene a conference on women’s health prioritizing three topics: (1) rising rates of maternal morbidity and mortality, (2) rising rate of chronic debilitating conditions in women, and (3) stagnant cervical cancer survival rates (NIH, 2021b; Temkin et al., 2022). ORWH staff collaborated with a planning committee comprising members of the NIH Advisory Committee on Research on Women’s Health to organize the conference and review pertinent NIH research portfolios and funding. This analysis revealed that an estimated 10.8 percent of NIH’s FY 2020 budget, $4.466 billion, was allocated to research on women’s health (Temkin et al., 2022). The conference identified specific gaps and opportunities in research pertaining to the priority topics, along with the scarcity of research on female-specific conditions and the effect of multimorbidity on women. The resulting report, Perspectives on Advancing NIH Research to Inform and Improve the Health of Women (NIH, 2021b), also emphasized the lack of clear definitions of chronic debilitating conditions specific to women and of an NIH Research, Condition, and Disease Categorization (RCDC) code for identifying specific research topics in NIH-funded studies, thus making it difficult to quantify relevant research activities. The report underscored the lack of a framework for how to best categorize female-specific chronic diseases (Temkin et al., 2022). ORWH developed a framework to address this gap (see Figure 1-1) that organizes select chronic conditions in women in four categories: (1) female-specific (2) more common in women or greater morbidity in women, (3) occurring in both sexes but potentially understudied in women, and (4) having high morbidity in women. When available, the report provided estimated associated disability-adjusted life years (DALYs) as a measure of disease burden (Temkin et al., 2023). The World Health Organization defines a DALY as a “summary measure which combines time lost through premature death and time lived in states of less than optimal health, loosely referred to as ‘disability.’ DALYs are a generalization of the well-known Potential Years of Life Lost measure to include lost good health” (WHO, 2020). For chronic conditions with assigned RCDC codes, the ratio of FY 2020 research spending per DALY was calculated and reported (Temkin et al., 2023). Examining the framework led to the conclusion that NIH spending, in general, is misaligned with the impact of diseases that women experience. 7 Public Law 103–43, section 486. 8 H.R.7614, 116th Congress, Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriations Act, 2021. PREPUBLICATION COPY: UNCORRECTED PROOFS 

6 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN FIGURE 1-1 National Institute of Health, Office of Women’s Health Research (NIH OWHR) framework for chronic debilitating chronic conditions in women. NOTE: The table arrays chronic conditions by condition analysis category (female specific, more common in women and/or morbidity is greater for women, potentially understudied in women, high morbidity for women), and provides information on DALYs where available. Dollars represent NIH spending per DALY in women for the specific condition. SOURCE: NIH (2021b). PREPUBLICATION COPY: UNCORRECTED PROOFS 

INTRODUCTION 7 CHARGE TO THE COMMITTEE AND APPROACH In response to a request from NIH ORWH, the National Academies convened an ad hoc interdisciplinary committee to review the literature on chronic debilitating conditions specific to women. Specifically, the Statement of Task (SOT) (see Box 1-1) guiding the study charged the committee to review the literature on chronic conditions specific to women, with attention to the epidemiology, contributing factors, prevention, diagnosis, treatment, and social and economic impact that chronic conditions have on women. The SOT also tasked the committee with describing how social determinants of health (SDOH) such as gender, race, ethnicity, socioeconomic status, and sexual and gender orientation, influence chronic conditions in women. Last, the SOT requested describing gaps in evidence and providing a research agenda. BOX 1–1 Statement of Task An ad hoc committee of the National Academies of Sciences, Engineering, and Medicine will: Review the existing literature on chronic debilitating conditions specific to women. The review will consider: • The epidemiology of chronic debilitating conditions including gender and racial and ethnic differences in clinical presentation and outcomes • How the development and accumulation of chronic debilitating conditions in women are influenced by factors such as menopause, aging-related skeletal muscle dysfunction (loss of muscle mass, muscle strength, and muscle function), and frailty • Prevention, diagnosis, and treatment of female-specific gynecologic conditions • To the extent possible, the social and economic impact of chronic debilitating conditions. • Assemble evidence-based findings on chronic debilitating conditions in women. • The findings should incorporate the influence of social determinants of health, including but not limited to gender, race and/or ethnicity, socioeconomic status, sexual and gender minorities, and underserved rural populations. • Produce a report that describes current gaps in evidence and provides a suggested research agenda for the future. PREPUBLICATION COPY: UNCORRECTED PROOFS 

8 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Committee’s Approach Selection of Chronic Conditions The SOT charged the committee with reviewing the epidemiology of chronic debilitating conditions. Given the number and diversity of conditions and the timeframe for conducting its work, the committee identified a select number of conditions to review. The committee notes the lack of any formal or consistent definition or classification of chronic debilitating conditions. Consequently, the committee based its selection of chronic conditions on informed judgment. As a first step, the committee turned to the SOT for direction. The SOT specifies female- specific gynecologic conditions and aging-related skeletal muscle dysfunction. The committee then reviewed the ORWH framework, which includes 44 chronic conditions arrayed in four categories: one includes female-specific conditions; two include conditions that have a higher prevalence or higher morbidity among women than men; and one lists understudied conditions (see Figure 1-1). The committee acknowledges that ORWH developed the framework to assess NIH’s investment in research related to chronic conditions in women and that DALYs and funding data were not available for each its 44 conditions. Thus, the committee did not consider DALYs and funding as factors. In its final selection of conditions, the committee sought to include an array of conditions representing those the SOT specified (female-specific and gynecologic conditions 9 and conditions related to skeletal/muscle dysfunction, conditions that predominately impact or affect women differently across different organ systems), and an infectious disease. The conditions also reflect the four NIH framework chronic debilitating conditions categories (see Table 1-1). Substance use disorder and HIV predominantly affect men; they are included because they impact women differently. 9 For the purposes of this report, the committee chose to refer to female-specific and gynecologic conditions. Female-specific conditions include infertility and urinary incontinence associated with female organs and systems, and post-partum depression. Gynecologic conditions are related to the reproductive organs and systems. Conditions that occur during pregnancy were highlighted when appropriate, for example, when they are linked to the development of other chronic conditions included in this report. PREPUBLICATION COPY: UNCORRECTED PROOFS 

INTRODUCTION 9 TABLE 1–1 List of Chronic Conditions in This Report Chronic Condition NIH Categorization Female-Specific and Gynecologic Endometriosis / dysmenorrhea / chronic pelvic pain Female-Specific Uterine fibroids Infertility Vulvodynia Pelvic floor disorders (including female urinary incontinence, pelvic organ prolapse) Menopausal symptoms (including exogenous hormone use) Pain Disorders Migraine/headache More common or greater morbidity in women Chronic pain Potentially understudied in women Fibromyalgia More common or greater morbidity in women Myalgic encephalomyelitis/chronic fatigue syndrome More common or greater morbidity in women Conditions Affecting Musculoskeletal System Osteoporosis More common or greater morbidity in women Sarcopenia Not included in NIH Framework Conditions Related to Mental Health 10 Depression More common or greater morbidity in women Substance use disorder Higher morbidity in women Conditions Affecting Neurocognitive System Alzheimer's disease Potentially understudied in women Conditions Related to Cardiometabolic Disease Cardiovascular disease Higher morbidity in women Stroke Higher morbidity in women Metabolic (Type 2 diabetes, metabolic syndrome, obesity) Higher morbidity in women Autoimmune Diseases Systemic lupus erythematosus More common or greater morbidity in women Multiple sclerosis (also affects neurocognitive system) More common or greater morbidity in women Infectious Disease Human immunodeficiency virus Potentially understudied in women NOTE: Bold conditions represent those specified in the Statement of Task. 10 The committee notes there is no consensus in the research on language relating to “mental health conditions” and the terminology often varies in different contexts. The committee refers to mental health conditions according to the Rehabilitation Act of 1973 Part 84, section 504, and recent U.S. Department of Health and Human Services revisions to update and amend its section 504 regulation, 45 CFR Part 84 RIN 0945–AA15, Nondiscrimination on the Basis of Disability in Programs or Activities Receiving Federal Financial Assistance. Federal Register 89(9) May 9, 2024, Rules and Regulations. PREPUBLICATION COPY: UNCORRECTED PROOFS 

10 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Examining the Evidence Base and Identifying Research Gaps When examining the research, the committee considered several questions to identify the evidence base in the literature on chronic conditions in women: • What is known about the impact of chronic conditions and MCC in women? • What biological mechanisms contribute to the sex differences in chronic conditions and MCC in women regarding clinical presentation, diagnosis, treatment, and outcomes? • What is known about the factors that contribute to chronic conditions in women? • What is known about how to diagnose and manage/treat chronic conditions and MCC in women? • What structural and social determinants play a role in the occurrence and experience of chronic conditions and MCC in women? Throughout its review, the committee considered the progress made and research gaps across the translational science spectrum, which “represents each stage of disease to interventions that improve the health of individuals and the public” (NCATS, 2023). The research spectrum is often described from basic science to preclinical, clinical, and population research (see Box 1-2) (NCATS, 2023). The committee aimed to identify at a high level the knowledge gaps in the relevant basic science, preclinical research, clinical, and population research and in applying research findings to clinical practice to improve health outcomes. Evidence and research gaps are highlighted for the conditions in Table 1-1 and commented upon where appropriate throughout the report. An important component of the committee’s review was to identify progress and gaps across the research continuum. The committee considered the following areas to identify gaps in chronic conditions in women (Nyanchoka et al., 2019): (1) knowledge-based—missing research BOX 1–2 Translational Science Continuum • Basic science research (e.g., animal models that have examined sex differences to study mechanisms of chronic diseases in females) • Preclinical research that connects basic science research with human medicine to understand the basis of a disease or disorder and find ways to treat it (includes research on biomarkers) • Clinical research that includes testing new technologies or interventions, behavioral and observational studies, and outcomes and health services research • Population-based research that focuses on health outcomes at the population level to determine the effects of diseases and efforts to prevent, diagnose and treat them SOURCE: NCATS (2023). PREPUBLICATION COPY: UNCORRECTED PROOFS 

INTRODUCTION 11 that could potentially answer the question; (2) methodological—related to study design, sampling, and analysis; and (3) population based—the evidence does not adequately represent subpopulations or subpopulations are underresearched. The committee notes it is difficult to comprehensively identify and consolidate the spectrum of research gaps for each of the conditions it considered due to their complexity and variability and the evolving nature of evidence generation. However, it is important to provide examples of the types of research gaps that exist for these conditions to inform a broad research agenda. Key Report Definitions The committee provides definitions for several terms that have varied definitions or uses in the literature. For example, “female” and “woman” are used differently according to context and perspective, which may cause confusion. In this report, the committee defines “woman” to include any individual who considers themselves to be a woman or was assigned female sex at birth. This inclusive definition recognizes individuals who have been affected by a set of biological and social variables that influence women differently than men. Throughout the report, when citing research findings and study results, the committee used “female" to refer to biological factors related to animal research and “women” in human research that describes sex and gender differences. If researchers misclassified or incorrectly used sex when referring to gender or vice versa, the term “woman” was used. In specific cases a researcher referred to sex as “assigned female at birth”; this terminology was used in those instances. Women differ from men in several ways, including a host of factors that vary along biological, social, and psychological dimensions. Biological differences are generally classified as sex differences, whereas those associated with the social environment are considered gender differences. Animals commonly studied in research do not experience the rich social forces that make women different from men, and thus are not often studied to understand gender. Rather, animal research is suited for studying specific biological factors that contribute to sex differences across vertebrate species. When discussing biological factors leading to sex differences in mammals, “female” is defined as an XX chromosome individual who has or has had ovaries, and “male” as an XY individual who has or has had testes. Comparing females and males not only illuminates factors that cause differences between them, but also provides information about variation among individuals who are not members of those groups. In specific cases, differences are discussed for other groups, including XO, XX, XY, XXY, and XYY individuals with either ovaries or testes. The committee faced several challenges in defining specific terms. To start, no formal definition exists for “chronic debilitating conditions.” The committee adopted the U.S. Department of Health and Human Services (Warshaw, 2006) definition as those that last 1 year or more and require ongoing medical attention or limit self-care, independent living, social interactions, or quality of life (HHS, 2010; Warshaw, 2006). In lieu of seeking a specific definition for “chronic debilitating conditions,” the committee chose to remove “debilitating.” The committee believes that the term negates the experiences of women who live with chronic conditions and have developed coping mechanisms that help them function more fully. Therefore, in this report, the committee refers to “chronic conditions in women.” Per the SOT, the report discusses SDOH and MCC. SDOH are the conditions in which people are born, grow, work, play, worship, live, and age, along with the wider set of forces and systems shaping the conditions of daily life (CDC, 2022). They include access to education and quality health, economic stability, neighborhood and built environment, and social and PREPUBLICATION COPY: UNCORRECTED PROOFS 

12 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN community context. The committee distinguishes between SDOH and structural determinants of health, which are the “macrolevel factors, such as laws, policies, institutional practices, governance processes, and social norms that shape the distribution (or maldistribution) of the social determinants of health (e.g., housing, income, employment, exposure to environmental toxins, interpersonal discrimination) across and within social groups” (NASEM, 2023). A conceptualization of SDOH by the NIH-wide Social Determinants of Health Research Coordinating Committee explicitly included sexism as a structural factor (NINR, n.d.). MCC refers to two or more chronic physical or mental health conditions that co-occur but may or may not directly interact. The concept of MCC differs from comorbidity, which refers to a health condition or conditions present in the context of an index disease (Fortin et al., 2010; Mercer et al., 2009; Uijen and Van De Lisdonk, 2008; Yancik et al., 2007). Information Gathering The committee gathered information in several ways. It convened six times (both in person and virtually) and held additional working group sessions. It held three public information-gathering sessions to collect insights from experts in academia, government, nonprofit, and advocacy organizations. Topics discussed focused on the biological and social determinants of chronic conditions in women, prevention, multimorbidity, the research funding landscape, and research gaps and future considerations. At these sessions, the committee also heard the perspectives of women living with specific chronic conditions. These perspectives were extremely informative and are highlighted within the chapters of the report and in Chapter 9. Appendix B provides open session agendas and presentation topics. Conceptual Framework for Organizing the Report Figure 1-2 provides the conceptual framework that unified the committee’s approach to its task. It describes the primary focus on research on select chronic conditions affecting women—female-specific and gynecologic, predominately impacting or affecting women differently, and MCC—and delineates the key questions that directed the literature review on these conditions. The framework shows the translational research spectrum and how findings may translate into interventions within the health care system. In addition, it highlights the committee's consideration of chronic conditions across the life course and underscores the influence of structural and social determinants of health related to sex and gender as integral components. PREPUBLICATION COPY: UNCORRECTED PROOFS 

INTRODUCTION 13 FIGURE 1-2 The committee’s conceptual framework for organizing this report. The report is organized into 10 chapters. Chapter 1 is the introduction and provides the committee’s approach to its task. Chapter 2 offers background on why women develop chronic conditions differently than men and introduces important multidimensional factors, including the biological factors and structural and social determinants of health that affect these differences. Chapter 3 discusses methodological challenges in studying chronic conditions in women, including defining chronic conditions and study populations, studies of frequency and distribution, experimental studies of interventions, and observational studies. Chapter 4 describes the impact of chronic conditions in women, including the effect on women, differences between women and men, and differences by race and ethnicity, age, economic burden, and quality of life. Chapter 5 discusses the evidence base on prevention, diagnosis, treatment, management, and disparities of female-specific and gynecologic conditions, including vulvodynia, endometriosis (including dysmenorrhea and chronic pelvic pain), uterine fibroids, infertility, chronic conditions related to pregnancy, and menopausal symptoms and transition. Chapter 6 discusses prevention, diagnosis, treatment, and management of and disparities in chronic conditions that predominantly impact or affect women differently. Chapter 6 discusses chronic conditions related to mental health, HIV, cardiometabolic conditions, pain disorder, and autoimmune, neurocognitive, and musculoskeletal conditions. Chapter 7 discusses structural and social determinants of health and chronic conditions in women. Chapter 8 describes the evidence base on MCC, with emphases on definitions, measurement, impact, biological mechanisms, diagnosis, and treatment and management. Chapter 9 provides an overview of challenges and barriers to PREPUBLICATION COPY: UNCORRECTED PROOFS 

14 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN translating of research across the continuum and improving patient care. Chapter 10 provides the conclusions and the committee’s recommendation for a research agenda. REFERENCES Baird, M. D., M. A. Zaber, A. Chen, A. W. Dick, C. E. Bird, M. Waymouth, G. Gahlon, D. D. Quigley, H. Al-Ibrahim, and L. Frank. 2021. The WHAM report: The case to fund women's health research, an economic and societal impact analysis. Santa Monica, California: RAND Corporation. Boersma, P., L. I. Black, and B. W. Ward. 2020. Prevalence of multiple chronic conditions among us adults, 2018. Preventing Chronic Disease 17. CDC (Centers for Disease Control and Prevention). 2022. Social determinants of health at CDC. https://www.cdc.gov/about/sdoh/index.html (accessed December 21, 2023). CDC. 2023. National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP): About the Center. https://www.cdc.gov/chronicdisease/center/index.htm#:~:text=Chronic%20diseases%E2%80%94 such%20as%20heart,and%20exposure%20to%20secondhand%20smoke (accessed March 4, 2024). Christensen, J., J. K. Beveridge, M. Wang, S. L. Orr, M. Noel, and R. Mychasiuk. 2021. A pilot study investigating the role of gender in the intergenerational relationships between gene expression, chronic pain, and adverse childhood experiences in a clinical sample of youth with chronic pain. Epigenomes 5(2):9. CMS (Centers for Medicare & Medicaid Services). 2023. Chronic conditions. https://www.cms.gov/data- research/statistics-trends-and-reports/chronic-conditions/chronic-conditions (accessed December 1, 2023). Ellingrud, K., L. Perez, A. Petersen, and V. Sartori. 2024. Closing the women's health gap: A $1 trillion opportunity to improve lives and economies. Cologny/Geneva, Switzerland: World Economic Forum. Fortin, M., C. Hudon, J. Haggerty, M. Van Den Akker, and J. Almirall. 2010. Prevalence estimates of multimorbidity: A comparative study of two sources. BMC Health Services Research 10(1):111. Giuliani, E., S. As‐Sanie, and E. E. Marsh. 2020. Epidemiology and management of uterine fibroids. International Journal of Gynecology & Obstetrics 149(1):3–9. HHS (U.S. Department of Health and Human Services). 2010. Multiple chronic conditions—a strategic framework: Optimum health and quality of life for individuals with multiple chronic conditions. Washington, DC: U.S. Department of Health and Human Services. IOM (Institute of Medicine). 1993. An assessment of the NIH Women's Health Initiative. Edited by S. Thaul and D. Hotra. Washington, DC: The National Academies Press. IOM. 2001. Exploring the biological contributions to human health: Does sex matter? Edited by T. M. Wizemann and M.-L. Pardue. Washington, DC: The National Academies Press. IOM. 2010. Women’s health research: Progress, pitfalls, and promise. Washington, DC: The National Academies Press. Janssen, E. B., A. C. M. Rijkers, K. Hoppenbrouwers, C. Meuleman, and T. M. D'Hooghe. 2013. Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: A systematic review. Human Reproduction Update 19(5):570–582. Marsh, E. E., G. E. Ekpo, E. R. Cardozo, M. Brocks, T. Dune, and L. S. Cohen. 2013. Racial differences in fibroid prevalence and ultrasound findings in asymptomatic young women (18-30 years old): A pilot study. Fertilility and Sterility 99(7):1951–1957. Mercer, S. W., S. M. Smith, S. Wyke, T. O’Dowd, and G. C. Watt. 2009. Multimorbidity in primary care: Developing the research agenda. Family Practice 26(2):79–80. PREPUBLICATION COPY: UNCORRECTED PROOFS 

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16 ADVANCING RESEARCH ON CHRONIC CONDITIONS IN WOMEN Yancik, R., W. Ershler, W. Satariano, W. Hazzard, H. J. Cohen, and L. Ferrucci. 2007. Report of the National Institute on Aging Task Force on Comorbidity. The Journals of Gerontology: Series A 62(3):275–280. PREPUBLICATION COPY: UNCORRECTED PROOFS