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GEN Exclusives: July 06, 2017

Considering Sex as a Biological Variable in Biomedical Research

Factoring Sex into Research Designs, Analyses, and Scientific Study Reports

  • In an article, “Considering Sex as a Biological Variable in Biomedical Research,” in Gender and Genome, the authors state that they would like investigators to consider how sex plays a role in the work that they are doing—not to adhere to a policy just to adhere to a policy. They want researchers to consider and rethink how (and if at all) sex may be playing a role in their work, in their observations, in their experimental materials, in their study designs, in the data, in how the data are analyzed, in how the data are interpreted, and, of course, in how the data are reported.

  • Abstract

    In June 2015, the National Institutes of Health (NIH) announced a new policy highlighting the expectation that sex as a biological variable (SABV) be factored into research designs, analyses, and reporting of vertebrate animal and human studies. NIH-funded research grants and career-development grants are now under this new policy and the first scientific reviews are complete.

    Since implementation of this policy, the research community has voiced concern about exactly how to study males and females, particularly in basic research. Investigators are asking: ‘‘What does it mean to consider SABV?’’ 

  • Purpose and Background

    The Sex as a Biological Variable (SABV) policy is part of the National Institutes of Health's (NIH's) reenergized focus on the importance of rigor and transparency to reproducibility, including appropriate accounting for the potential influence of sex on experimental outcomes in preclinical research.1–3 Just like randomization, blinding, sample-size calculations, and other basic design elements, consideration of sex is a critical component of experimental design.2,4 Specifically:

    • The NIH expects investigators to explain how relevant biological variables, such as sex, age, weight, and underlying health condition, are factored into research designs and analyses of studies in vertebrate animals and humans.
    • This applies to basic, preclinical, and clinical research.
    • Studies proposing to use only one sex should provide strong justification from the scientific literature or preliminary data to support this decision.
    • Cost alone and absence of known sex differences are inadequate justifications for not addressing SABV.5,6

    These are not new expectations. The NIH has always sought the most rigorous science—strict application of the scientific method to ensure robust and unbiased experimental design, methodology, analysis, interpretation, and reporting of results5—and assessment of these factors has always been implicit in peer review. However, the NIH has now formalized these expectations for grant applications and peer review.

    It is important to point out that the language of the policy is purposefully broad and not prescriptive. The intrinsic goal is to encourage—never limit—the creative thinking and innovative ideas within each investigator. How researchers consider SABV must be driven by the science and context of the individual research question.6

    Sex is a fundamental biological variable with profound consequences.7 Underrepresenting female cells and animals in preclinical research has resulted in a poorer understanding of the biological, physiological, and pathophysiological mechanisms in the female compared with the male. Without data from females, it is impossible to determine whether results obtained in male cells and animals also apply to female cells and animals. Historical reliance on male vertebrate animals (e.g., rats, mice) in preclinical research has resulted in the generation of incomplete data available to inform translation to clinical trials enrolling both men and women.8,9 And, these issues are not limited to the basic biological fields. A report of studies from the surgical literature revealed that for female-prevalent diseases, of those studies that stated the sex of the animals, only 12% studied female animals.10

    We are asking investigators to consider the potential influence of sex and to address sex in the design and analysis of biomedical research. We would like to ensure that, from the very first idea about a biomedical research area, sex influences are examined. This will lead to a stronger foundation on which to build clinical research and trials and inform the community as to whether such influences will need to be factored into the design and power calculations in clinical trials.