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What Does It Mean to Consider Sex as a Relevant Biological Variable in Your NIH Grant Application?

In 2014, NIH announced plans for policy changes to ensure that NIH-supported investigators consider relevant measures, including sex as a biological variable (SABV), in preclinical research. NIH solicited feedback through a request for information, and we invited the research community to participate in workshops and resource development. These activities led to new guidelines for addressing SABV as an aspect of rigor and reproducibility in NIH research project grant applications and mentored career development award applications due January 25, 2016, and beyond.

As you prepare applications and think about addressing the new instructions we wanted to offer some reminders about the policy’s origin, and about the application and review information.  In particular, we wanted to point out what including SABV does not mean.

Dr. Janine Clayton, Director of the NIH Office of Research on Women’s Health, just published an article in The FASEB Journal that provides background and additional detail about the policy and its goals. The article clears up some potential misunderstandings. We have heard concerns about needs to double the numbers of animals used or to reduce project aims to accommodate additional costs. Others have interpreted the policy to mean that NIH is now mandating all experiments to be powered for both sexes. Not so. To quote from Dr. Clayton’s article:

In its efforts to enhance reproducibility and transparency by expecting investigators to consider SABV, NIH will not require any specific research design or method for accomplishing this goal. Rather, the existing state of knowledge in a particular scientific area and the specific research question under study will both affect how an investigator considers sex and other basic biological variables. On that note, it is important to point out that NIH policy changes to ensure the consideration of basic biological variables like sex do not imply the necessary doubling of research animals in every experiment, contrary to what some in the research community have assumed. It is true, however, that investigators aiming to differentiate sex effects—that is, to look explicitly for sex differences—may require larger numbers of animals, or equal numbers of animals of both sexes, for adequate power to detect statistically significant effects. Typically, these types of projects grow from preliminary data that provide hints of sex-based influences that generate a testable hypothesis in larger sample sizes.

In other words, “considering sex as a biological variable” is not the same as “sex differences research.”

We’d also like to remind you of the specific revised application instructions and review language related to rigor and reproducibility. Relevant biological variables such as sex will be assessed as part of the approach review criterion for research project grant applications, and as part of the research plan criterion for mentored career development award applications.

As previously noted by NIH leadership, consideration of relevant biological variables, such as sex, is crucial in the development of rigorous and reproducible experimental design.  We hope you find helpful our posted guidance, ORWH additional guidance, and Dr. Clayton’s recent article, and we look forward to ongoing dialogue as we work to maximize the impact of our nation’s investment in biomedical research.

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6 thoughts on “What Does It Mean to Consider Sex as a Relevant Biological Variable in Your NIH Grant Application?

    • “Gender” is neither appropriate nor neutral term. Up to very recently, “gender” was reserved only to grammar or humorous use. This newspeak was pushed to everyday use, though. Currently, to cite the NIH sources, “NIH follows the Institute of Medicine report, Exploring the Biological Contributions to Human Health: Does Sex Matter? “Sex is defined as a biological variable defined by characteristics encoded in DNA, such as reproductive organs and other physiological and functional characteristics. Women and men are characterized by both sex and gender. Gender refers to social, cultural, and psychological traits linked to human males and females through social context. In most cases, ‘sex’ should be used when referring to animals. Both sex and gender and their interactions can influence molecular and cellular processes, clinical characteristics, as well as health and disease outcomes.””

  1. Gender is a construct related to humans. Biological sex refers to biological and behavioral differences between male and female organisms (and variations in between).

  2. We have just received our institutional interpretation of the Policy, which explicitly states: “In most cases, use of both animal genders will be required, unless specific exclusions apply.”

  3. The guidance offered in the above article does not seem to conform with the statement on SABV in the announcement NOT-OD-15-103. “NIH expects that sex as a biological variable will be factored into research designs, analyses, and reporting in vertebrate animal and human studies. Strong justification… must be provided for applications proposing to study only one sex.” This sounds to me like the only result will be greatly increasing animal numbers in research, and I suppose this is how it will be interpreted in study sections.

  4. Here’s my take on the topic and then a question:
    NIH does not want all investigators doing vertebrate research to automatically double the number of animals in their study, to include both males and females. Instead, if there is no prior indication of possible sex differences in the variable being studied, NIH wants the investigator to include animals of both sexes and then analyze (and report) the data, including any hint of sex differences, in the outcome. (Hint because the study would not have been powered to identify significant difference and sex was not an experimental variable being tested.)

    That’s fine! But, let’s say I’m testing a specific drug and that the animals in my test show sexual a dimorphism in body weight of say, >20%. Do I adjust for that difference initially, giving the smaller animals less drug, or do I look for effects of the same dose on the heavier (male) and lighter (female) after the study is done?

    Feedback appreciated, especially from our NIH host.

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