The SIMI Gender ‘5 Ws’ Rule for the integration of sex and gender-related variables in clinical studies towards internal medicine equitable research

The awareness that biological sex (i.e., sex assigned at birth) and sociocultural gender (i.e., sociocultural norms roles and expectations) are relevant modifiers of health and disease has been a recent achievement by the life sciences researchers and clinicians [1]. Despite the advocacy of international societies and gender champions to promote the knowledge on sex and gender analysis for improving the quality of science, the terms are still often used interchangeably, yet they capture different aspects of a person. Specifically, gender refers to the psychosocial aspects of being a woman or a man (“psychosocial sex”) as opposed to the biological aspects of being male or female (“biological sex”) [2]. However, some males and females may report gender-related characteristics traditionally attributed to the opposite sex, and some individuals may identify as neither male nor female thereby leading to the increasing recognition of gender as a spectrum (rather than binary entity) in social sciences and the general public. As such, the distribution of gender-related characteristics within populations of men and women is likely to influence health differently than biological sex. To underline the different meaning of these terms, from 2012 the Canadian Institute of Gender and Health acknowledges that “Every cell is sexed, and every person is gendered” [3] pointing out how biological factors (sex-based) and psycho-socio-cultural factors (gender-related) contribute profoundly to shape who we are either in maintaining health status or in developing diseases. Furthermore, the concept of intersectionality between sex, gender, and other social factors (e.g., race, immigration status, etc.) is currently emerging to reflect the importance of diversity in health [4, 5]. An intersectional framework assumes that an individual’s experiences are not simply equal to the sum of their parts but represent intersections of social power’s axes. For example, the health-related experiences of immigrant women may be different from those of immigrant men and non-immigrant women. The term intersectionality, originally coined in the critical race theory is considered an extension of sex and gender analysis and can be applied across other social identities or positions in society [4, 5].

The specialty of internal medicine (IM) is an all-embracing medical discipline, dealing with all aspects of pathology and organ-based specialties [6]. The IM specialists face every day the challenges of a 360-degree approach to the care of complex and multimorbid and often older individuals. IM healthcare professional are those that would mostly benefit from a sex- and gender-based evidence as they traditionally build their clinical decisions on a multidimensional evaluation of patients beyond the disease-centered focus. Therefore, clinical investigators working in the IM field should recognize the value of a sex- and gender-oriented approach to answer relevant research questions and should be supported with strategies for incorporating sex and gender-related variables when conducting either pre-clinical or clinical studies.

The aim of this study was to build an operational framework that can guide IM researchers in implementing their approach giving the context and the content on how to practically perform it.

During the 2019 National Congress of the Italian Society of Internal Medicine (SIMI) held in Rome (Italy), a Working Group (WG) on Gender Medicine has been implemented with the specific aim of promoting the integration and application of sex- and gender-oriented approaches in internal medicine (IM) from research to clinical practice. In this context, the first goal of the WG was to implement the strategy for the collection of gender-related variables in the no-profit observational studies promoted by SIMI. Starting from a narrative detailed and extensive literature analysis on the applicable tools for the gender-based data acquisition in human studies, the WG met on regular basis and discussed the most simple and feasible strategy for promoting among the IM community. In a dedicated session of the virtual 2021 SIMI National Congress, the WG collegially agreed on the most appropriate approach for the implementation of a sex- and gender-sensitive framework in clinical studies promoted by the SIMI. Specifically, the WG SIMI Gender has formulated a short three-question questionnaire to assess whether the session participants were able to define properly the terms ‘sex’ and ‘gender’. Then the core dataset of variables to be incorporated in the design of the clinical studies promoted by SIMI was voted, and afterwards the perception of participants regarding the best way to inquire patients on their gender identity was discussed.

The activities of the WG SIMI Gender led to the operational definition of the SIMI Gender ‘5 Ws’ Rule for clinical studies which have been conceptualized as summarized in Who, What, Where, When, and Why (Fig. 1).

The SIMI Gender ‘5 Ws’ Rule represents an easy and pragmatic guide for any internist interested in improving scientific research and disseminating scientific knowledge for the benefit of all patients. In the era of precision medicine, we are currently going through, sex and gender are the gateways to achieve a personalized approach in both research and clinical practice.

The bottom line of the Gender Medicine is that sex and gender permeate the life of people, therefore, when it comes to health they are theoretically always involved. Therefore, a sex and gender-based consideration should be pursued almost always, specifically when an impact on outcomes is envisaged. In fact, gender domains capture a huge group of factors that are broadly recognized as mediators or modifiers of outcomes. The collection of gender-related variables is still an unmet need and the truly gamebreaker when it comes to provide high-quality science. The What of the SIMI Gender ‘5 Ws’ Rule was built upon the previous literature exploring the feasibility of measure gender. In fact, the first hurdle clinician faces in the integration of sex and gender domains is to operationalize the definition of a gender-related variable. Specifically, a gender-related variable is a non-biological variable which differs in terms of magnitude, prevalence, and/or impact between people regardless of the sex they were assigned at birth. As shown by our literature review, there is a lack of a standardized method for embracing the multidimensionality of gender. Depending on the availability of data it might be worthy to test the effect of gender using a composite measure as was performed by GENESIS-PRAXY Investigators [9, 10]. The methodology of constructing the gender score has been validated since the inception in cohorts from retrospective and prospective studies [11‐19]. Furthermore, international scientists have been supporting the assessment of even one domain or few individual gender-related factors depending on the availability of data [20‐22].

The WG also acknowledges that over the last decade both funding agencies and medical journals are promoting for the excellence of science to assess a research protocol or publication based on the integration or omission of sex and/or gender. In fact, Canadian, American, and European research funding agencies supported by governments have implemented different strategies to favor the inclusion of sex and gender-based considerations in the grant’s procedure with the ultimate goal of awarding those protocols that integrate diversity and justify why sex and gender have been evaluated. [23]

Sex and gender matter when it comes to data analysis and reporting the findings of the clinical research. Of interest, stop controlling for sex [24] and favor sex-stratified analyses and interaction analyses [13, 14, 21] are recommendations that the scientific community is promoting to ensure equitable evidence at glance of practitioners for male and female individuals.

Finally, the International Committee of Medical Journal Editors recommends that the use of terms sex (when reporting biological factors) and gender (identity, psychosocial or cultural factors) should be guaranteed throughout the entire manuscript and, unless inappropriate, Authors should report the sex and/or gender of study participants, the sex of animals or cells, and describe the methods used to determine sex and gender [25].

The IM community recognize that biological sex and sociocultural gender (i.e., societal norms, roles, and expectations) are relevant modifiers of health and disease. The application of sex and gender lenses in informing our understanding of health maintenance and disease development is key to personalize approaches and provide patient-centered care. The first obstacle to the integration of sex and gender in clinical practice and research is the lack of the habit to collect a granularity of sex- and gender-related variables in the case report forms of clinical research studies. The Gender WG of the SIMI identified and proposed an operational framework the SIMI Gender ‘5 Ws’ Rule to guide IM researchers in the challenging attempt of performing an equitable research with meaningful findings for improving the health of all patients.