In a Nature article published May 14, 2014, NIH Director Dr. Francis Collins and NIH Associate Director for Research on Women's Health Dr. Janine Clayton discussed ways that NIH is addressing the influence of sex as a biological variable in NIH-funded research.
1. What has changed?
Newly revised grant application and review instructions seek to clarify NIH's long-standing expectations to ensure that the best and most rigorous science is funded, highlight the need to describe details that may have been previously overlooked, stress the importance that reviewers consider such details in their reviews, and minimize additional burden.
Among other changes to application instructions, applicants will be required to address consideration of sex as a biological variable in the Research Strategy section of the application. In this section, applicants are asked to explain how relevant biological variables, such as sex, are factored into research designs and analyses for studies in vertebrate animals and human subjects. Strong justification from the scientific literature, preliminary data, or other relevant considerations, must be provided for applications proposing to study only one sex. Review criteria will include evaluation of the adequacy of the research plan with regard to consideration of sex as a biological variable.
These changes will go into effect for research and career development grant applications due January 25, 2016, and beyond, and for fellowship and training grant applications due May 25, 2016, and beyond. These policies are meant to apply to all NIH-funded research grants with few exceptions; contact your Program Officer with any questions about applicability. For further information, please see the following resources:
- NOT-OD-15-102: Consideration of Sex as a Biological Variable in NIH-funded Research
- Additional Guidance (PDF - 74.6KB) on Consideration of Sex as a Biological Variable in NIH-funded Research
- NOT-OD-15-103: Enhancing Reproducibility through Rigor and Transparency
- NOT-OD-16-011: Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications
- NOT-OD-16-012: Implementing Rigor and Transparency in NIH & AHRQ Career Development Award Applications
- NIH's Office of Extramural Research Rigor and Reproducibility page, including Frequently Asked Questions
2. Why is a new policy needed?
NIH's mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability. There is growing recognition that the quality and generalizability of biomedical research depends on appropriate consideration of key biological variables, such as sex. NIH has long appreciated the importance of enrolling men and women in clinical research, as a basis for application of results and to identify factors that affect disease course and treatment outcome. Women now account for roughly half of all participants in NIH-supported clinical research, which is subject to NIH's Policy on the Inclusion of Women and Minorities as Participants in Research.
However, many preclinical research studies continue to rely heavily on male animals and/or omit reporting of the sex of animal subjects. This is particularly problematic in studies intended to inform understanding of diseases and conditions affecting both sexes. Just like randomization, blinding, sample size calculations, and other basic design elements, consideration of the influence of sex is a critical component of rigorous experimental design. Failure to account for sex as a biological variable may undermine the rigor, transparency, and generalizability of research findings. The NIH expects researchers to study both male and female vertebrate animals and human subjects, where applicable, thereby improving our understanding of health and disease in men and women.
3. What does NIH aim to achieve by introducing these changes?
By asking researchers to take sex into account when designing studies and evaluating results, NIH will ensure that the influence of sex is examined across the spectrum of biomedical research. Appropriate consideration of the influence of sex in basic, preclinical, and translational research will lead to a stronger foundation on which to build clinical research and trials.
4. Will the new policy require that I use equal numbers of female and male animals? Does this policy requie to double my sample sizes?
No. NIH does not expect that every study will be designed to detect a sex difference of a particular magnitude at a particular level of statistical power. In exploratory or early mechanistic studies, or in research areas where sex as a biological variable has not previously been considered, an appropriate first step may be to include both sexes, then disaggregate data by sex, report sex-specific results as appropriate, and discuss appropriate generalizations that can be drawn from findings.
Depending on the state of sex-specific knowledge in a field, and on the research hypothesis proposed, the study of both sexes may affect considerations of effect size and power. In these cases, if prior evidence indicates that sex influences the phenomenon under investigation, then it may be necessary to increase sample sizes to permit valid conclusions about that particular phenomenon in both sexes. It may also be possible to design experiments and conduct analyses to investigate interaction effects, and sample sizes should be chosen to appropriately power these analyses. NIH review committees will judge the scientific merit of proposed designs, samples, and analyses as part of the research strategy.
Visit the ORWH Sex in Science Reading Room for scientific publications that outline some of the appropriate ways to design experiments that take sex into consideration.
5. Will my costs increase?
Maybe. If consideration of sex as a biological variable necessitates a change to an investigator's research program, then costs may change. Costs may include the need to purchase or house additional animals. The potential for increased costs also depends on the state of the science about sex as a biological variable in the field under study, the specific questions(s) asked by the investigator, and details of the research design. Justification for budgets will be evaluated by the NIH review committee, relative to the proposed research strategy. Applicants should contact their program officers with questions about establishing and justifying budget requests.
Supporting rigorous research design is the best investment NIH can make. Moreover, by making more sex-specific data available, investigators can more readily ask and answer scientific questions in the future, without additional expense.
6. What has been funded through the ORWH administrative supplement program?
The NIH Office of Research on Women's Health began funding administrative supplements to existing grants in FY 2013, allowing NIH researchers to add a sex/gender lens to their currently funded research. Through this administrative supplement program, scientists obtained extra funds to conduct additional studies that do not stray significantly from the scope of their parent grant but that allow exploration of sex influences not previously considered.