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A sex- and gender-informed perspective increases rigor, promotes discovery, and expands the relevance of biomedical research. In the current era of ability to present data for males and females, thoughtful and deliberate methodology can improve study de 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.

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.

Methods exist to test sex and gender differences as interactions; inference from sex- and gender-stratified data should be viewed with caution. Without careful methodology, the pursuit of sex and gender difference research as a poorly considered mandate will result in a literature of contradiction. However, given the paucity of sex and gender differences research, the absence of evidence for differences is not necessarily evidence of the absence of differences. Many compelling publications have argued why sex and gender should be considered in preclinical, clinical, and population research 1—4.

Both sex the biological attributes of females and males and gender socially constructed roles, behaviors, and identities in a spectrum, including femininity and masculinity affect molecular and cellular processes, clinical traits, response to treatments, health, and disease 1. In , the European Commission issued the Horizon guideline, which makes explicit the rules for sex and gender inclusion as elements of European Union grant evaluation and monitoring 6 , 7.

Although the National Institutes of Health NIH Revitalization Act required the inclusion of women in NIH-funded clinical research, it was not until that the NIH announced policies requiring the consideration of sex as a biological variable in study de, analysis, and reporting 1 , 8— Such mandates to include females are not mere political correctness A sex-informed and gender-informed perspective is essential to increase rigor, promote discovery, expand the relevance of research, and improve patient care. At the very least, it will allow readers of the scientific literature to critically assess the validity of what they read.

Investigators who wish to—or now find themselves required to—include both sexes in their studies are faced with a of methodological questions, including issues of motivation, subject selection, sample size, data collection, analysis, and interpretation. We provide an overview of these issues in this review as they pertain to basic, clinical, and population research Table 1. This review builds on earlier discussions of sex differences research methodology 11—18 in several ways: we consider gender as well as sex differences; we examine the entire research process, from motivation to analysis and presentation; and we discuss nuances of statistical de and interpretation, particularly how to plan robust tests of sex or gender interactions that can help minimize statistical artifacts.

Rather than assume ubiquitous sex and gender differences in biology, health, and disease, we propose methods and interpretation that will increase the likelihood of detecting true differences where they exist. There is ample evidence of sex differences—at the level of the cell, organism, and population—to motivate sex differences research. Sex chromosomes encode sexual differentiation through three mechanisms: 1 presence of Y genes; 2 increased dose of X genes in XX vs XY cells; and 3 X chromosome inactivation and imprinting These primary chromosomal differences lead to sexual differentiation and the somatic and gonadal expressions of sex The sex-informed framework considers sex differences in anatomy and physiology, understood within a lifespan perspective of sensitive periods of fetal and childhood development, differential pace and timing of puberty, reproductive events, and senescence.

This is critical given that timing is everything when it comes to identifying developmental sex effects 14 , 21 , Furthermore, sex differences in treatment abound: pharmacokinetics and pharmacodynamics of medications often vary by sex, as may effects of other treatment modalities Gender, too, is a determinant of health, influencing the physical and social environments to which individuals are exposed, their access to resources that affect health, their agency to seek health care and receive treatment, and the equitability of research that drives medical discovery 14 , 17 , 24— This sex- and gender-informed perspective is necessitated by widespread differences in disease incidence, prevalence, and survival that have been reviewed elsewhere 2 , 26— There are sex and gender differences in symptoms and clinical presentations of illness, reliability of diagnostic tests, and response to treatment.

Investigators seeking to construct a sex- and gender-informed framework for their research may be disappointed by a lack of systematic evidence regarding sex and gender differences in the literature. The historic neglect of women in clinical studies and the sex of animals and cells in basic research should be kept in mind when gathering evidence of sex and gender differences.

Although data to interrogate sex differences may exist in some studies, they have yet to be examined. In other cases, sex-informed questions have yet to be posed. Furthermore, as argued below, the proliferation of ill-considered and often unplanned sex difference inquiries le to a literature of contradictions. Thus, the absence of evidence for sex differences is not necessarily evidence of the absence of sex differences.

In most cases, the choice of overarching study de, whether experimental or observational, is little affected by considerations of sex and gender. Exceptions to this are experiments precluded by ethical considerations, such as inclusion of pregnant women for trials of potentially teratogenic drugs. However, nearly every other feature of study de necessitates a sex-informed perspective, including subject selection, randomization, sample size, and data collection.

Inclusion of both sexes is more nuanced than deciding that the sample should be equally divided by sex. Sex-specific age incidence of disease, reproductive stage, reproductive cycle, and environment need to be considered to optimize the validity, generalizability, and efficiency of a study sample. More often than not, investigators have to compromise between competing goals of validity by narrowing subject selection to increase the likelihood that findings are true for a specific population and generalizability by widening subject selection to make broad inference at the risk of overgeneralizing across true differences between groups.

There are also compromises between large scientific goals and restricted available funds. Such trade-offs are best made as choices informed by already known sex and gender differences. Sex differences in incidence and age-incidence trajectories are important considerations in subject selection. For example, at ages 55 to 64 men have more than double the rate of coronary heart disease CHD of women. Thus, an investigator wishing to enroll a cohort of year-olds to study CHD incidence will need to enroll two to three times as many women as men to ensure equivalent statistical power, or consider selecting older women.

For example, the Vitamin D and Omega-3 Trial study of dietary supplements to reduce heart disease, stroke, and cancer includes women aged 55 or older and men aged 50 or older to for the later onset of disease in women Sex differences in disease incidence exist in animals as well. For example, in the nonobese diabetic mouse, diabetes is more prevalent in females, so that more male mice must be included to yield the same of affected animals of each sex Females outlive males in most vertebrate species In mammals, the heterogametic XY sex may have a shorter lifespan because of the unguarded expression of harmful recessive alleles on the Y sex chromosome.

Similarly, the homogametic XX sex may be protected by the stochastic X-inactivation that creates mosaics of females; although female neonates are a mosaic of maternal and paternal allele expression, over time that ratio becomes skewed to favor the cellular population whose active X presumably confers a survival advantage 32— Sex differences in the rate of aging and the incidence of disease onset are reflected at the cellular level.

For example, there are sex differences in the length of telomeres, noncoding DNA sequences that cap and protect chromosomes, the length of which are correlated with longevity. Although similar at birth, male telomeres shorten faster during the lifespan than do female telomeres This difference could be the result of sex or gender; most likely, it is a combination of biological sex differences and gendered experiences such as smoking Similarly, although stem cell populations decline with aging, this loss is earlier and more rapid in male than in female mice Methylation patterns also differ between the sexes, likely influencing DNA expression over the life course 38 , As research further clarifies sex-specific or sex-dependent mechanisms of senescence, investigators may want to consider sex differences in the cellular age and methylation patterns of their subjects, be they cells, animals, or people.

All animals, regardless of sex or species, go through a process of reproductive maturation whose timing, duration, and outcome are subject to physical and social cues from the environment. In mammals, puberty involves sex-specific, but variable, changes in central neural systems, gonadal steroid production, and the emergence of secondary sexual characteristics, including behaviors.

When a study investigates adolescence or young adulthood, ing for sex differences in the pace and timing of puberty will be critical for identifying sex effects Mature mammals of both sexes have variations in gonadal steroid levels that may affect subject selection. In males, testosterone levels have circadian and perhaps seasonal variations and vary with age, physical activity, and energy homeostasis 40 , Reproductive age females have menstrual or estrous cycles.

On top of natural variability, women may use hormonal contraceptives or menopausal hormone therapy; many men use exogenous androgens and anabolic steroids. These factors are important in subject selection if an investigator wants to understand how the exposure—outcome associations under study are impacted by sex hormones. Researchers may decide to include a representative range of reproductive phases or cycles. For example, cyclical patterns of DNA synthesis and rates of cell division and death would not have been discovered if females in different cycle phases had not been studied 42 , The knowledge that natural killer cell activity peaks during the luteal phase came from studies of cycling women Understanding of the roles of neurokinin B and kisspeptin in reproduction has been facilitated by studying male and female animals at varying reproductive stages, with and without gonadectomy Sex differences in physiology and behavior have been observed even in the prepubertal and peripubertal periods, before the pubertal activation of the hypothalamic—pituitary—gonadal axis and production of gonadal sex steroid hormones.

These prepubertal sex differences have been largely attributed to the effects of prenatal and perinatal activity of the hypothalamic—pituitary—gonadal axis and resultant sex steroid hormone production and actions. Among the best described effects are the so-called activational and organizational effects of gonadal hormones on brain development The first robust sex difference described in the mammalian brain was the sexually dimorphic nucleus of the preoptic area More recently, a sexually dimorphic population of kisspeptin neurons was identified that is present in higher s in the anteroventral periventricular nucleus in prepubertal females than in males, to which the sexually dimorphic preovulatory luteinizing hormone surge that occurs in adult females but not males is attributed Thus, to the extent that hormone levels affect study outcomes, researchers may need to examine subjects who are premenopausal or postmenopausal, in the follicular or luteal phase, and with or without hysterectomy or gonadectomy.

Including or excluding participants using hormonal therapies, such as contraceptives and female and male hormone replacement or suppression therapies, is another potentially important de choice. To fully capture between-sex variability, it may be of use to compare men to two or more groups of women. For example, a study of brain activity in the stress response circuitry found few differences between healthy men and women in the early follicular phase, but striking differences between men and the same women at midcycle Furthermore, sex differences in brain activity in memory circuitry were statistically ificant in premenopausal and perimenopausal women, but attenuated in postmenopausal women compared with men To capture within-sex variability, studies compare the same females at different cyclical stages, perhaps in crossover fashion.

Note that the effects of sex steroid hormones extend beyond estradiol and testosterone. There are multiple types of estrogens produced by the ovaries and other tissues, as well as multiple androgens beyond testosterone. Progesterone levels also need to be considered. In addition to the multiple ERs, tissue-specific responses to estrogens can occur through the presence of modulating proteins such as coactivators and corepressors, among others. Varying tissue-specific responses are exemplified by the action of synthetic agonists and antagonists such as the selective ER modulators, including tamoxifen, raloxifene, and toremifene.

These selective ER modulators are competitive inhibitors of estrogen binding to ERs, with mixed agonist and antagonist activity, depending on the target tissue For example, tamoxifen is used in the prevention and treatment of breast cancer as an ER antagonist, but it has ER agonist activity in some other tissues such as bone and endometrium. Progesterone also acts through multiple receptors, which are generated as splice variants from a single gene Many determinants of disease, both physical and social, are differentially distributed by gender.

Some of these factors may confound experiments if not carefully ed for in study de and analysis. For example, in many societies, women are more likely to have vitamin D deficiency 56 , affecting multiple tissues and systems, and men are more likely to smoke cigarettes and drink alcohol.

Men and women are exposed differentially to types of violence and trauma 57— Such stressors may affect gonadal steroid secretion in a sex- and hormone-dependent fashion In the case of powerful covariates strongly associated with gender or sex, investigators may want to select participants to ensure these covariates are balanced in male and female samples. Historical reliance on male animal models e. Basic studies can complement clinical studies by investigating mechanisms of sex-dependent or sex-specific processes in greater depth by manipulating genotypic and phenotypic sex experimentally Beyond simply studying both male and female animals as they age naturally, studies can include classic gonadectomy with or without hormone replacement: prenatally and perinatally to address developmental effects; in juvenile animals to study postnatal developmental and differentiation effects; in adults to assess the effects of sex steroid hormones at the time of testing; and in aging animals to study effects of sex steroids in models of aging.

Several new genetic and epigenetic animal models have increasing translational validity to represent human ovarian failure and menopause Some alternative models of menopause or ovarian failure include Foxl2-deficient mice with accelerated rates of decline in ovarian reserve Additionally, targeted mutagenesis can be used to address the role of specific domains or specific functions of a sex steroid receptor.

For example, as noted above, estradiol is critical to the regulation of energy balance and body weight. In this model, the testis-determining gene Sry is deleted from the Y chromosome and inserted onto an autosome. In this manner, XX and XY mice with the same type of gonad can be compared to assess phenotypic effects of the sex chromosome complement in cells and tissues 12 , These models permit investigators to observe, for the most part, the independent effects of sex chromosomes and hormones on physiologic and pathophysiologic processes.

Although it is facile to insist that basic researchers use and report on both XX and XY cells in their experiments, this is not always possible In fact, cell lines are a poor model with which to study sex differences, even when the sex of the lineage is specified. By definition, immortalized cell lines, chosen for their peculiarities and derived from a single organism, may be inherently impossible to cull or create from a second organism of any sex.

Even where it is possible to create cell lines from a male and female similar enough to interrogate a particular question, inferences about sex differences cannot reliably be made. Cell lines may have sex-dependent features other than the sex chromosome complement, including differences in hormone production or hormone responses related to variation in steroidogenic enzyme expression or expression of sex steroid hormone receptors.

There may also be differences in expression of other genes related to imprinting or epigenetic differences. Moreover, each cell line is clonal in origin and has unique characteristics based on the experimental conditions in which it was derived and propagated—even two cell lines derived from the same organism may have different characteristics.

It is more reasonable to request that investigators specify the sex of a cell line used in a study i. However, even this is not always possible, as cell lines can lose their sex chromosome complement over time Although primary cultures can isolate cells directly from the body, permitting the creation of a small population of male or female cells, the procedure may be technically difficult and time-consuming, and the cells may be short-lived, limited in , difficult to manipulate, and can change their characteristics over time in culture.

Furthermore, Miller et al. Finally, comparisons of isolated male and female cells oversimplify the question of sex, let alone gender, because such cells are removed from the complex interactions with other cells, hormones, neurotransmitters, nutrients, pathogens, and environmental exposures, which themselves vary in living organisms by sex and gender In such cases, the absence of evidence for sex differences in vitro may well be absence of any evidence at all, a straw man or woman of an experiment purportedly about sex. In preclinical experiments, this is known as a factorial de Such stratified randomization retains the advantages of standard random allocation, effectively creating a mini-trial within each sex stratum Stratified randomization can accommodate a study plan with unequal s of male and female subjects, especially helpful when men and women a study at different rates or in different time periods.

Stratified randomization can also be used to balance follicular vs luteal phase participants, or any other marker of sex or gender. Unless preplanned, most studies are underpowered to examine associations separately for males and females. This is particularly true of secondary data analyses of studies never deed to examine subgroup differences. This lack of statistical power to detect sex and gender differences can lead to the premature conclusion that such differences do not exist; in fact, most studies are simply too small to fairly test all but the most pronounced sex and gender differences.

In the current era of ability to analyze and present sex-stratified data, it is worth considering ideal practice and reality with respect to power and sample sizes to detect sex differences.

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