There is growing recognition of sex and gender as important determinants of health outcomes, disparities in disease incidence, and healthcare system utilization.1 According to the World Health Organization,2 sex represents a biological characteristic of an individual while gender refers to the array of socially constructed roles, attitudes, personality traits, and behaviors. These concepts are conceptually distinct, and each may affect patient outcomes.
Sex- and gender-based analyses have been implemented in several specialties3,4 and are increasingly recognized as crucial to the development of comprehensive evidence that will ultimately lead to guidelines and policies.5,6 Sex- and gender-based analyses offer a systematic approach to examine the impact of sex and/or gender on population health-related outcomes. Acknowledging the importance of sex and gender in medicine, and also recognizing the crucial need to consider the impact of sex as a biologic variable in basic biomedical preclinical research (ie, cells and animal models), the Canadian Institutes of Health Research has been prompting researchers to indicate how their proposed research accounts for sex or gender since 2010.5 Since 2016, the US National Institutes of Health has also been requesting researchers to outline how sex will be considered in study design and analysis.7 More recently, a systematic approach to scientific reporting on sex and gender across disciplines has been promoted by the Sex and Gender Equity in Research guidelines.6,8
In the context of solid organ, tissue, and cell transplantation, the sex of donors and transplant candidates and recipients has been shown to influence health outcomes. Gender differences in organ donation patterns, access to the waiting list, access to transplantation, patient participation, and healthcare utilization have also been observed.9 Careful consideration of sex and gender in allotransplantation and donation research may help outline personalized strategies to inform donor–recipient compatibility, aid in decisions on organ allocation, and improve transplant outcomes. Such considerations may also highlight disparities in care, optimize patient experience, and inform policy changes geared towards greater equity.
Expecting sex to be frequently considered in allotransplantation and donation research, and the literature on sex and gender to be complex and heterogeneous, we pursued a scoping review to comprehensively capture the consideration of sex and gender within the existing literature on human allotransplantation and donation. Specifically, this review sought to (1) assess the correct application of sex and gender concepts within the published literature, (2) ascertain whether (and how) sex and gender were considered at the stages of study design and analysis, (3) identify the key outcomes for which effects of sex and gender were considered, and (4) outline strategies for integrating sex and gender in human allotransplantation and donation research at the time of study design and analysis.
MATERIALS AND METHODS
We conducted a scoping review to map the literature on sex and gender in human allotransplantation and donation research. This approach allowed us to explore whether sex and gender were studied across the entire age span, in hematopoietic, tissue, and solid organ transplantation and among transplant candidates, recipients, and donors. Scoping reviews follow the principles of systematic reviews with the exception of a formal quality (risk of bias) appraisal. The study protocol was published elsewhere.10
Literature Search Strategy
The electronic database search strategy was developed in consultation with an information specialist. Text words and relevant indexing were used to identify articles discussing sex and/or gender issues in transplantation (hematopoietic, tissue, and solid organ) and donation. MEDLINE and Embase were searched from inception (preceding the introduction of the concept of “gender” by Money11) using the following keywords: sex or gender difference, characteristic, factor, imbalance, issue, specific in combination with tissue, cell or hematopoietic transplant, organ transplantation (eg, heart, cardiac, liver, hepatic, kidney, renal, lung, pulmonic, pancreas) as well as donor and donation.
Studies were included if they satisfied all the following criteria: (1) the target population consisted of humans of any age who were donors, candidates, or recipients of stem cell (eg, allogeneic or mesenchymal), tissue (eg, allogeneic skin, bone, and cornea grafts), or solid organ transplantation; (2) the terms “sex” and/or “gender” were mentioned in the title or abstract of the manuscript; (3) the manuscript reported original research, was written in English, and was published from January 1, 1946, to October 17, 2016; (4) the study design was a randomized controlled trial (RCT), observational study, case series with at least 20 participants, registry/population report, validation survey, or method comparison with at least 20 participants.
Studies were excluded if they (1) discussed ventricular assist devices not serving as bridges to transplantation, vein allografts for cardiac bypass, homografts (heart valves), transfusion/donation of blood products, tumor/cancer transplants, embryo oocytes or sperm donation, brain or body donation for research, and autologous grafts; (2) were not original research studies (letters, editorials, news, replies, comments); or (3) were conference abstracts.
Two reviewers (C.L. and V.S.S.) independently evaluated the eligibility of all identified titles and abstracts for inclusion in the full-text review. The same reviewers evaluated full-text articles for inclusion using similar inclusion and exclusion criteria. Disagreements were resolved by consensus or by a third reviewer (R.S-P.). The Endnote bibliographic software package and Covidence, a systematic review software developed in partnership with the Cochrane Collaboration, were used to manage all references. Figure 1 presents a PRISMA flow diagram12 outlining the study selection process.
Data Abstraction and Synthesis
Five reviewers (C.L., K.C., V.S.S., T.M., and C.C.) independently abstracted the data in 2 steps. First, descriptive data of interest were extracted from the selected studies, including year of publication, study population (waitlisted candidates, transplant recipients, donors), study design, sample size, transplanted cells/tissues/organs, and main outcomes. Second, for each selected study, 2 reviewers independently evaluated whether the terms “sex” and “gender” were used according to the correct definition or whether they were used interchangeably and/or erroneously. Accordingly, outcomes associated with proper usage of the term “gender” included adherence, donation, employment, healthcare utilization, health service access, hospitalizations, mental health and substance abuse, preferences and health literacy, quality of life, and social support network. Outcomes deemed to be more appropriately associated with sex included: patient and graft survival, transplant complications, graft health, costs, therapies, systems pharmacology issues, and transplant epidemiology. When the term “gender” was used in relation to outcomes more appropriately associated with sex, its application was deemed to be erroneous. In the subsequent analyses, when the terms “sex” or “gender” were deemed to have been used erroneously, the terms were reassigned to gender or sex, respectively, based on the main outcome under study.
Reviewers then abstracted data on how sex and/or gender were handled at the level of study design by verifying whether sex and/or gender were considered in the primary research question, were used for participant selection, were discussed in the study objectives and rationale, or were considered as the main exposure. Finally, we reported on the handling of sex and/or gender in statistical analyses (eg, as covariates in multivariable models, effect measure modifiers included as interaction terms in multivariable models, or as part of sensitivity and/or subgroup analyses). Discrepancies were discussed and resolved by consensus or by 2 reviewers (C.L., R.S-P.).
We report on the proportion of manuscripts applying the terms “sex” and “gender” correctly, the study setting and characteristics, and, finally, provide narrative synthesis on how sex and gender were handled at the levels of study design and data analysis. Stata 13.1 (Stata Corp., College Station, TX) was used for statistical analysis.
The initial literature search yielded 7565 manuscripts. Following the exclusion of 1482 duplicates and 3640 manuscripts that did not meet the eligibility criteria, 2443 full-text manuscripts were reviewed (Figure 1). Of those, 336 manuscripts were excluded because they did not meet the inclusion criteria. The remaining 2107 articles were included in the final scoping review. Most of the manuscripts were cohort studies including adult solid organ transplant recipients. Study characteristics for these manuscripts are presented in Table 1.
Of the 2107 selected manuscripts, 2055 manuscripts mentioned the term “sex” and 1264 mentioned the term “gender.” Altogether, 843 manuscripts mentioned only “sex,” 52 manuscripts mentioned only “gender,” and 1212 manuscripts mentioned both terms. Figure 2 presents the number of manuscripts discussing sex and gender over the past 3 decades.
The main outcomes studied in the publications discussing sex and gender are presented in Figure 3. Considering World Health Organization definitions of the concepts of sex and gender and the primary study outcome, 1763 manuscripts were classified as manuscripts in which sex was the relevant variable, whereas 344 manuscripts were classified as studies in which gender was the relevant variable. Guided by this principle, Table 2 presents the distribution of manuscripts in which the terms “sex” and/or “gender” were mentioned appropriately or erroneously. Sex and gender were applied interchangeably in more than half of the studies (57.5%). Forty percent of the manuscripts mentioned only the term “sex” (accurately in 88.5% of these) and 2.5% mentioned only “gender” (accurately in 78.9% of these).
Table 3 presents sex and gender considerations at study design and analysis levels. Only 15.2% (321/2107) of the studies considered sex or gender in the main objectives or rationale. Of those, 86.9% considered sex in the context of solid organ transplantation, while 12.1% and 1.0% discussed sex in the context of stem cell and tissue transplantation, respectively. Sex or gender was considered in the main objectives and/or rationale infrequently (13.3% and 25.0%, respectively). When considered in the main objectives or rationale, the main outcomes under study in many of the manuscripts relevant to sex concerned patient and graft survival (54.5%) and transplant complications (20.9%). In contrast, many of the manuscripts reporting on main outcomes relevant to gender were focused on donation (30.2%), health services access (32.6%), and quality of life (15.1%). Most of the studies considered sex and gender variables as confounders, defined as variables distorting the estimates of exposure-outcome associations (74.6% for sex and 68.2% for gender), and a minority considered them as effect measure modifiers, resulting in different effects of the exposure on outcome as a function of sex or gender subgroups (2.8% for sex and 5.0% for gender). The main exposures studied in this context were patient demographic and/or morphometric characteristics, comorbidities, therapies, transplant status, biomarkers, and graft health. The main outcomes under study for manuscripts handling sex as an effect measure modifier concerned patient and graft survival (27.9%) and transplant complications (48.8%). Authors often reported on effect estimates in sex subgroups and whether those reached statistical significance. However, testing for interactions between sex/gender and main exposures was conducted inconsistently.
Finally, Table 4 presents the characteristics of 240 manuscripts, which considered sex and/or gender as primary exposures. Most of the studies focused on transplant recipients (89.3% and 62.5%, respectively), adults (52.4% and 62.5%, respectively), and solid organ transplantation (87.5% for both sex and gender). The proportion of female participants exceeded 45% of the overall sample size in 26.2% of the manuscripts, which considered sex as the main exposure, and in 43.1% of the manuscripts, which considered gender as the main exposure.
This scoping review sought to describe the treatment of the terms “sex” and “gender” in human allotransplantation and donation research. We found that many manuscripts integrating sex and gender applied the terms erroneously. Rarely were sex or gender mentioned in the main objectives or rationale. Most of the studies considered these variables as confounders, and a minority considered them as effect measure modifiers. This scoping review points to the need for educating the allotransplantation and donation community regarding the concept of gender and how sex and gender should be integrated into human allotransplantation and donation research.
Similar to other health research fields,13 we found that a nonnegligible proportion of manuscripts reporting on sex and gender applied the terms inaccurately and often interchangeably. Although the choice of terminology does not change the presence or absence of associations, application of accurate terminology is important in any scientific endeavor to avoid measurement bias and ensure observations are interpreted correctly. In clinical research, for example, RCTs and observational studies are conducted to make causal inferences about relationships between exposure(s) and outcome(s), or at least to verify independent associations between exposure(s) and outcome(s). Unless investigators understand the difference between sex and gender, they will not be able to accurately assess their impact. Here, we offer some suggestions on how sex and/or gender can be effectively incorporated into allotransplantation and donation studies.
The first consideration is whether sex, gender, or both are relevant to the study question. A report by the Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Difference notes that “there are multiple, ubiquitous differences in the basic cellular biochemistries of males and females that can affect an individual’s health that are a direct result of genetic differences between the 2 sexes.”14 Thus, if biologic differences between males and females are relevant when assessing the relationship between the exposures and outcomes of interest, then sex must be considered when establishing the selection criteria (to avoid underrepresentation of men or women among the study participants) as well as when identifying confounders and effect measure modifiers.15-20 In contrast, if the exposure–outcome relationships are influenced mainly by preferences, behaviors, or social norms, gender (or gender-related variables) must be considered. Of course, there is a correlation between sex and gender in most human populations, but this correlation is far from perfect within individuals because gender is more diverse than sex (which is binary).
If gender is deemed relevant, the next step is to determine how gender should be measured. Currently, gender effects may be sought by applying second-level disaggregation by sex (ie, data on individuals is broken down by sex and presented as stratified or subgroup analysis). This may be exemplified by analyses evaluating gender disparities in access to health services.21-31 Gender effects may also be evaluated by using gender-related variables such as gender roles (eg, housework, child care), gender identity (how individuals and groups perceive and present themselves), institutionalized gender (eg, education level, profession, income), and behavioral and cultural variables (eg, profession, smoking and drinking).32,33 Alternatively, underlying gender-based constructs may also be captured and implemented using factor analysis. In this context, a “factor” represents a set of variables that may be associated with gender. Factor analysis allows the incorporation of several relevant variable into a single gender index or score. The Gender Inequality Index (GII) and GENESIS-PRAXY Gender Score (GPGS) are examples of such tools. GII is a composite measure which shows the loss in human development due to inequality between female and male achievements in 3 dimensions: (1) reproductive health, (2) empowerment, and (3) the labor market. The index ranges from 0, which indicates that women and men fare equally, to 1, which indicates that women fare as poorly as possible in all measured dimensions.34 The second example, GPGS, has been recently developed in young patients with acute coronary syndrome to obtain a composite measure of socially constructed roles, attitudes, personality traits, and behaviors traditionally ascribed to men and women in society.4 In the context of allotransplantation and donation, gender disparities, secondary to patient preferences and physician practices, both of which may be influenced by social norms,24,35-39 undoubtedly affect individual patients’ access to and utilization of health services as well as their health outcomes. However, the gender construct in the context of allotransplantation and/or donation may not be identical to that of GII or GPGS.32,33 The absence of standardized tools for measuring gender-related dimensions in the context of allotransplantation and donation is a major barrier to evaluating the impact of gender in this field. Moreover, gender-related variables are infrequently captured in end-stage disease and transplant registries, which are often used for the conduct of health services research. To overcome these gaps, there is a need to identify a minimal set of variables, which are capable of capturing the gender dimensions pertinent to the context of allotransplantation and donation and evaluate whether and how they relate to the effects observed by participants’ sex. Access to such data can then be used to detect modifiable gender-related factors that can be targeted to optimize health while at the same time informing policies to ensure equity in care.
Although sex and gender are often concordant, there are some scenarios where both sex and gender will be relevant but influence health in different ways. For example, when interpreting the observation that female kidney transplant recipients experience a higher risk of allograft failure than males,40 the influence of both sex and gender must be considered (Figure 4). Members of the female sex may be at higher risk of experiencing immune-mediated graft injuries as a result of immune sensitization than those of the male sex because of pregnancies, stronger immune reactivity, and differential immunosuppressive drug handling (biological phenomena).3,41-47 On the other hand, the risk of graft failure may be mitigated among feminine transplant recipients due to greater participation in care and adherence to immune suppression (behavioral phenomena).48-51 This example demonstrates how appropriate consideration of donor–recipient sex and gender effects may optimize external validity of studies and minimize scenarios in which effects reported in some observational studies may not be reproducible by others. More importantly, this example may also shed light on how effects observed in well-designed RCTs fail to be realized when applied in practice at the individual patient level. To avoid such pitfalls, when designing RCTs in the field of allotransplantation and donation, it is important to ensure that both gender and sex are considered at the levels of study design and analytical plan and that reported results can reveal sex- and gender-related differences. Moreover, to gauge differences in safety profiles of interventions and evaluate the role of participant preferences in adhering to them, it is also important that reports on interventional studies capture study flow (eg, drop out) by sex and gender.32,52,53
Our review established that consideration of sex and gender in the allotransplantation and donation literature often takes the form of a descriptive depiction of population characteristics or as confounders of relationships between outcomes and other primary exposures of interest. In the context of human research in allotransplantation and donation, both sexes were represented in most studies, and only rarely did the authors restrict participation by sex.54-57 When studied as the main exposure, effects of donor–recipient sex pairs were often reported in unadjusted stratified analysis as well as in multivariable regression models.58-70 Interestingly, even manuscripts considering sex as the primary exposure were vulnerable to underrepresentation of female participants, with the majority of the studies including <45% female participants. Of the small number of manuscripts that evaluated sex and gender as effect measure modifiers, testing for interactions was inconsistently reported.71-76 In accordance with Sex and Gender Equity in Research guidelines, future studies considering sex and gender in allotransplantation and donation research should ensure adequate representation of males and females, estimate effect sizes for both, and report results in a transparent fashion regardless of outcomes. If sex and gender analysis are not conducted, a rationale should be provided and the implications of the lack of such consideration on the interpretation of the results should be discussed.
Our scoping review considers all key players in the transplant process across the age continuum, ranging from donors through transplant candidates and recipients to transplant physicians and coordinators. Moreover, we summarize the state of the literature following a comprehensive review of >2000 manuscripts to determine how sex and gender have been considered in the field of allotransplantation and donation. Despite these strengths, a few limitations require mentioning. Our selection criteria may have resulted in exclusion of articles discussing gender/sex concepts in transplantation when “sex” and “gender” were mentioned in the full text but not in the title or abstract of the article. Although, in our effort to assess the appropriate application of the terms “sex” and “gender”, we reclassified some of the manuscripts that only mentioned the term “sex” as manuscripts relevant to gender, we may have excluded manuscripts that assessed gender-related factors but used neither the term “gender” nor “sex.” Also, we excluded smaller case series, potentially leading to underrepresentation of less frequently transplanted cells/tissues/organs. Finally, an inevitable limitation of scoping reviews is the lack of quality assessment (risk of bias) of the included studies. Future-focused systematic reviews can verify quality of published studies to inform the development of best practice guidelines on the integration of sex and gender in allotransplantation and donation research.
In summary, our scoping review findings highlight the need to educate researchers on the appropriate application and consideration of sex and gender in clinical, biomedical, and translational research. Ultimately, high-quality research integrating sex and gender in a manner that minimizes bias and optimizes internal and external validity is expected to enhance translation of research findings into clinical practice in a sex- and gender-sensitive manner. This, in turn, can improve health outcomes and patient experience, reduce disparities in care, and decrease healthcare expenditures. There is a need for good practice guidelines on consideration of sex and gender in human allotransplantation and donation research, but a prerequisite for such guidelines is the definition, and consistent measurement of gender in the context of allotransplantation and donation.
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