Sex and Gender Differences Research Design for Basic, Clinical, and Population Studies: Essentials for Investigators

Abstract

<jats:title>Abstract</jats:title> <jats:p>A sex- and gender-informed perspective increases rigor, promotes discovery, and expands the relevance of biomedical research. In the current era of accountability to present data for males and females, thoughtful and deliberate methodology can improve study design and inference in sex and gender differences research. We address issues of motivation, subject selection, sample size, data collection, analysis, and interpretation, considering implications for basic, clinical, and population research. In particular, we focus on methods to test sex/gender differences as effect modification or interaction, and discuss why some inferences from sex-stratified data should be viewed with caution. Without careful methodology, the pursuit of sex difference research, despite a mandate from funding agencies, will result in a literature of contradiction. However, given the historic lack of attention to sex differences, the absence of evidence for sex differences is not necessarily evidence of the absence of sex differences. Thoughtfully conceived and conducted sex and gender differences research is needed to drive scientific and therapeutic discovery for all sexes and genders.</jats:p>

Sex Differences in Long-Term Mortality and Functional Outcome After Rehabilitation in Patients With Severe Stroke

“…While sex refers to biological and physiological characteristics, gender refers to "psychological, social, and cultural factors that shape attitudes, behaviors, and knowledge" (42). Sex and gender are both important determinants of health and response to interventions (42,43). Thus, integrating sex-and gender-based analysis can lead to improved research methodology and improved assessment of differences in disease outcomes (42,43).…”

“…Sex and gender are both important determinants of health and response to interventions (42,43). Thus, integrating sex-and gender-based analysis can lead to improved research methodology and improved assessment of differences in disease outcomes (42,43). As an example, using a binary gender index (masculinity vs. femininity), Pelletier et al found that feminine traits of personality were associated with adverse outcomes in young patients with acute coronary syndromes, regardless of sex (44).…”

“…Potential pathways by which gender might affect post-stroke rehabilitation outcomes include social isolation, socioeconomic status, education, marital status, poorer pre-stroke function, level of anxiety, depression, and interaction with rehabilitation team and the doctor. Because of the complex and multidimensional nature of gender and the lack of standardized methods of analysis, however, operationalizing the intersection of gender and sex into scientific research remains a very challenging task (42,43).…”

Sex differences in metabolic regulation and diabetes susceptibility

“…In the last few years, addressing gender and sex differences has emerged as a priority topic in several medical areas, including metabolic diseases [1]. While gender mainly refers to the socially constructed identities of individuals, sex dimorphism relies on the fundamental biological disparities that differently influence physiological or pathophysiological processes in males and females.…”

Paucity and disparity of publicly available sex-disaggregated data for the COVID-19 epidemic hamper evidence-based decision-making

“…Guidelines to design such studies have been published (e.g. 16 ). However, while researchers are now routinely reporting sex ratios in their cohorts, the full potential of analyzing sex-disaggregated data to uncover potential sexual dimorphisms has yet to be realized.…”