Considering sex as a biological variable in preclinical research

doi:10.1096/fj.201600781R

Review

. 2017 Jan;31(1):29-34.

doi: 10.1096/fj.201600781R. Epub 2016 Sep 28.

Considering sex as a biological variable in preclinical research

Leah R Miller¹, Cheryl Marks², Jill B Becker³, Patricia D Hurn⁴, Wei-Jung Chen⁵, Teresa Woodruff⁶, Margaret M McCarthy⁷, Farida Sohrabji⁵, Londa Schiebinger⁸, Cora Lee Wetherington⁹, Susan Makris¹⁰, Arthur P Arnold^{11

12}, Gillian Einstein^{13

14

15}, Virginia M Miller^{16

17}, Kathryn Sandberg^{18

19}, Susan Maier²⁰, Terri L Cornelison²⁰, Janine A Clayton²⁰

Affiliations

¹ Office of Research on Women's Health, National Institutes of Health, Bethesda, Maryland, USA; leah.miller@nih.gov.
² Division of Cancer Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
³ Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA.
⁴ School of Nursing, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA.
⁶ Women's Health Research Institute, Northwestern University, Chicago, Illinois, USA.
⁷ Department of Pharmacology, University of Maryland, Baltimore, Maryland, USA.
⁸ History of Science, Stanford University, Stanford, California, USA.
⁹ National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA.
¹⁰ Office of Research and Development, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, D.C., USA.
¹¹ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, USA.
¹² Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
¹³ Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
¹⁴ The Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Women's College Research Institute, Toronto, Ontario, Canada.
¹⁶ Department of Surgery and Physiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁷ Department of Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
¹⁸ Department of Medicine, Georgetown University Medical Center, Washington, D.C., USA.
¹⁹ Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, Washington, D.C., USA.
²⁰ Office of Research on Women's Health, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 27682203
PMCID: PMC6191005
DOI: 10.1096/fj.201600781R

Review

Considering sex as a biological variable in preclinical research

Leah R Miller et al. FASEB J. 2017 Jan.

. 2017 Jan;31(1):29-34.

doi: 10.1096/fj.201600781R. Epub 2016 Sep 28.

Authors

Affiliations

¹ Office of Research on Women's Health, National Institutes of Health, Bethesda, Maryland, USA; leah.miller@nih.gov.
² Division of Cancer Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
³ Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA.
⁴ School of Nursing, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA.
⁶ Women's Health Research Institute, Northwestern University, Chicago, Illinois, USA.
⁷ Department of Pharmacology, University of Maryland, Baltimore, Maryland, USA.
⁸ History of Science, Stanford University, Stanford, California, USA.
⁹ National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland, USA.
¹⁰ Office of Research and Development, National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, D.C., USA.
¹¹ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, USA.
¹² Laboratory of Neuroendocrinology of the Brain Research Institute, University of California, Los Angeles, Los Angeles, California, USA.
¹³ Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
¹⁴ The Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Women's College Research Institute, Toronto, Ontario, Canada.
¹⁶ Department of Surgery and Physiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁷ Department of Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.
¹⁸ Department of Medicine, Georgetown University Medical Center, Washington, D.C., USA.
¹⁹ Center for the Study of Sex Differences in Health, Aging and Disease, Georgetown University Medical Center, Washington, D.C., USA.
²⁰ Office of Research on Women's Health, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 27682203
PMCID: PMC6191005
DOI: 10.1096/fj.201600781R

Abstract

In June 2015, the National Institutes of Health (NIH) released a Guide notice (NOT-OD-15-102) that highlighted the expectation of the NIH that the possible role of sex as a biologic variable be factored into research design, analyses, and reporting of vertebrate animal and human studies. Anticipating these guidelines, the NIH Office of Research on Women's Health, in October 2014, convened key stakeholders to discuss methods and techniques for integrating sex as a biologic variable in preclinical research. The workshop focused on practical methods, experimental design, and approaches to statistical analyses in the use of both male and female animals, cells, and tissues in preclinical research. Workshop participants also considered gender as a modifier of biology. This article builds on the workshop and is meant as a guide to preclinical investigators as they consider methods and techniques for inclusion of both sexes in preclinical research and is not intended to prescribe exhaustive/specific approaches for compliance with the new NIH policy.-Miller, L. R., Marks, C., Becker, J. B., Hurn, P. D., Chen, W.-J., Woodruff, T., McCarthy, M. M., Sohrabji, F., Schiebinger, L., Wetherington, C. L., Makris, S., Arnold, A. P., Einstein, G., Miller, V. M., Sandberg, K., Maier, S., Cornelison, T. L., Clayton, J. A. Considering sex as a biological variable in preclinical research.

Keywords: gender; methods; sex differences; sex influences.

PubMed Disclaimer

Conflict of interest statement

The Office of Research on Women’s Health thanks all speakers who presented at the Methods and Techniques workshop and those who have contributed to this manuscript. The views expressed in this manuscript are those of the authors and do not necessarily reflect the views or policies of the authors affiliated organizations. The authors declare no conflicts of interest.

Figures

**Figure 1.**
Schematic of a 2×2 factorial design showing test of the main effects of sex and drug treatment. Various possible outcomes are shown. The top line of outcomes shows a finding of significant main effect only of drug, a significant main effect only of sex, and significant main effects of both without interaction. The bottom line shows 3 different outcomes that are all significant interactions of sex and drug, which means that the effect of drug depends on sex and, reciprocally, the effect of sex depends on the level of drug. DV, dependent variable.

See this image and copyright information in PMC

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References

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1. Landis S. C., Amara S. G., Asadullah K., Austin C. P., Blumenstein R., Bradley E. W., Crystal R. G., Darnell R. B., Ferrante R. J., Fillit H., Finkelstein R., Fisher M., Gendelman H. E., Golub R. M., Goudreau J. L., Gross R. A., Gubitz A. K., Hesterlee S. E., Howells D. W., Huguenard J., Kelner K., Koroshetz W., Krainc D., Lazic S. E., Levine M. S., Macleod M. R., McCall J. M., Moxley R. T. III, Narasimhan K., Noble L. J., Perrin S., Porter J. D., Steward O., Unger E., Utz U., Silberberg S. D. (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature , 187–191 - PMC - PubMed
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[1] National Research Council (2001) Exploring the Biological Contributions to Human Health: Does Sex Matter? National Academies Press, Washington, DC, USA - PubMed

[2] National Research Council (2001) Exploring the Biological Contributions to Human Health: Does Sex Matter? National Academies Press, Washington, DC, USA - PubMed

[3] Landis S. C., Amara S. G., Asadullah K., Austin C. P., Blumenstein R., Bradley E. W., Crystal R. G., Darnell R. B., Ferrante R. J., Fillit H., Finkelstein R., Fisher M., Gendelman H. E., Golub R. M., Goudreau J. L., Gross R. A., Gubitz A. K., Hesterlee S. E., Howells D. W., Huguenard J., Kelner K., Koroshetz W., Krainc D., Lazic S. E., Levine M. S., Macleod M. R., McCall J. M., Moxley R. T. III, Narasimhan K., Noble L. J., Perrin S., Porter J. D., Steward O., Unger E., Utz U., Silberberg S. D. (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature , 187–191 - PMC - PubMed

[4] Landis S. C., Amara S. G., Asadullah K., Austin C. P., Blumenstein R., Bradley E. W., Crystal R. G., Darnell R. B., Ferrante R. J., Fillit H., Finkelstein R., Fisher M., Gendelman H. E., Golub R. M., Goudreau J. L., Gross R. A., Gubitz A. K., Hesterlee S. E., Howells D. W., Huguenard J., Kelner K., Koroshetz W., Krainc D., Lazic S. E., Levine M. S., Macleod M. R., McCall J. M., Moxley R. T. III, Narasimhan K., Noble L. J., Perrin S., Porter J. D., Steward O., Unger E., Utz U., Silberberg S. D. (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature , 187–191 - PMC - PubMed

[5] Zucker I., Beery A. K. (2010) Males still dominate animal studies. Nature , 690 - PubMed

[6] Zucker I., Beery A. K. (2010) Males still dominate animal studies. Nature , 690 - PubMed

[7] Collins F. S., Tabak L. A. (2014) Policy: NIH plans to enhance reproducibility. Nature , 612–613 - PMC - PubMed

[8] Collins F. S., Tabak L. A. (2014) Policy: NIH plans to enhance reproducibility. Nature , 612–613 - PMC - PubMed

[9] National Institutes of Health. (2015). Consideration of sex as a biological variable in NIH-funded research. Accessed June 30, 2016, at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html.

[10] National Institutes of Health. (2015). Consideration of sex as a biological variable in NIH-funded research. Accessed June 30, 2016, at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html.

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Considering sex as a biological variable in preclinical research

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Considering sex as a biological variable in preclinical research

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