Studying both sexes: a guiding principle for biomedicine
Open accessAbstract
In May 2014, the U.S. National Institutes of Health (NIH) announced that it will ensure that investigators account for sex as a biological variable (SABV) in NIH‐funded preclinical research as part of the agency's rigor and transparency initiative. Herein, I describe in more detail the rationale behind the SABV policy component and provide additional detail about policy goals. In short, studying both sexes is a guiding principle in biomedical research that will expand knowledge toward turning discovery into health. NIH expects that considering SABV in preclinical research will help to build a knowledge base that better informs the design of clinical research and trials in humans. Integrating the practice of studying both sexes in preclinical research will, over time, expand our currently incomplete knowledge base that plays a critical role in informing the development of sex‐and gender‐appropriate medical care for women and men.—Clayton, J. A. Studying both sexes: a guiding principle for biomedicine. FASEB J. 30, 519‐524 (2016). www.fasebj.org
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Some treatments that currently exist for several diseases are not adequately evaluated in women, who are likely to be underrepresented in clinical trials, especially in Phases I and II.
“some of the treatments that currently exist for several diseases are not adequately evaluated in women27,28 who are likely to be underrepresented in clinical trials29,30, especially in Phases I and II31,32.”
From Sex and gender differences and biases in artificial intelligence for biomedicine and healthcare (2020) · cites this paper as [28]
Most researchers avoid using female animals in research, primarily because of hormonal changes across the estrus cycle.
“For many years, the default model in human studies has been a 70 kg male [187] and most researchers avoid using female animals in research [188], primarily because of hormonal changes across the estrus cycle [187].”
From Temperature regulation in women: Effects of the menstrual cycle (2020) · cites this paper as [187]
For many years, the default model in human studies has been a 70 kg male.
“For many years, the default model in human studies has been a 70 kg male [187] and most researchers avoid using female animals in research [188], primarily because of hormonal changes across the estrus cycle [187].”
From Temperature regulation in women: Effects of the menstrual cycle (2020) · cites this paper as [187]
Cites
Toward discovery science of human brain function
Biswal, B. B., Mennes, M., Zuo, X.-N., Gohel, S., Kelly, C., Smith, S. M., Beckmann, C. F., Adelstein, J. S., Buckner, R. L., Colcombe, S., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911855107 · Cited by 2,970 · see citing works
A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women
Ridker, P. M., Cook, N. R., Lee, I.-M., Gordon, D., Gaziano, J. M., Manson, J. E., Hennekens, C. H., & Buring, J. E. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050613 · Cited by 1,945 · see citing works
Policy: NIH to balance sex in cell and animal studies
Clayton, J. A., & Collins, F. S. (2014) · Nature · doi:10.1038/509282a · Cited by 1,816 · see citing works
Self-citationSex bias in neuroscience and biomedical research
Beery, A. K., & Zucker, I. (2011) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.07.002 · Cited by 1,763 · see citing works
Different immune cells mediate mechanical pain hypersensitivity in male and female mice
Sorge, R. E., Mapplebeck, J. C. S., Rosen, S., Beggs, S., Taves, S., Alexander, J. K., Martin, L. J., Austin, J.-S., Sotocinal, S. G., Chen, D., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4053 · Cited by 1,442 · see citing works
Policy: NIH plans to enhance reproducibility
Collins, F. S., & Tabak, L. A. (2014) · Nature · doi:10.1038/505612a · Cited by 1,247 · see citing works
Studying sex and gender differences in pain and analgesia: a consensus report
Greenspan, J. D., Craft, R. M., LeResche, L., Arendt-Nielsen, L., Berkley, K. J., Fillingim, R. B., Gold, M. S., Holdcroft, A., Lautenbacher, S., Mayer, E. A., et al. (2007) · Pain · doi:10.1016/j.pain.2007.10.014 · Cited by 1,033 · see citing works
Deaux, K. (1985) · Annual Review of Psychology · doi:10.1146/annurev.ps.36.020185.000405 · Cited by 904 · see citing works
Strategies and Methods for Research on Sex Differences in Brain and Behavior
Becker, J. B., Arnold, A. P., Berkley, K. J., Blaustein, J. D., Eckel, L. A., Hampson, E., Herman, J. P., Marts, S. A., Sadée, W., Steiner, M. S., et al. (2004) · Endocrinology · doi:10.1210/en.2004-1142 · Cited by 799 · see citing works
Female mice liberated for inclusion in neuroscience and biomedical research
Prendergast, B. J., Onishi, K. G., & Zucker, I. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.01.001 · Cited by 788 · see citing works
Exploring the Biological Contributions to Human Health
Institute of Medicine (2001) · National Academies Press eBooks · doi:10.17226/10028 · Cited by 658 · see citing works
Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators
Bellott, D. W., Hughes, J. F., Skaletsky, H., Brown, L. G., Pyntikova, T., Cho, T.-J., Koutseva, N., Zaghlul, S., Graves, T., Rock, S., et al. (2014) · Nature · doi:10.1038/nature13206 · Cited by 638 · see citing works
Exploring the Biological Contributions to Human Health: Does Sex Matter?
(2001) · Journal of Women s Health & Gender-Based Medicine · doi:10.1089/152460901300233902 · Cited by 606 · see citing works
Arnold, A. P., & Chen, X. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2008.11.001 · Cited by 587 · see citing works
De Vries, G. J., Rissman, E. F., Simerly, R. B., Yang, L.-Y., Scordalakes, E. M., Auger, C. J., Swain, A., Lovell-Badge, R., Burgoyne, P. S., & Arnold, A. P. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09005.2002 · Cited by 509 · see citing works
Collins, L. M., Dziak, J. J., & Li, R. (2009) · Psychological Methods · doi:10.1037/a0015826 · Cited by 431 · see citing works
Fisher, E., Beer‐Romero, P., Brown, L. G., Ridley, A. J., McNeil, J. A., Lawrence, J. B., Willard, H. F., Bieber, F. R., & Page, D. C. (1990) · Cell · doi:10.1016/0092-8674(90)90416-c · Cited by 393 · see citing works
Innate Gender-based Proclivity in Response to Cytotoxicity and Programmed Cell Death Pathway
Du, L., Bayır, H., Lai, Y., Zhang, X., Kochanek, P. M., Watkins, S. C., Graham, S. H., & Clark, R. S. B. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405461200 · Cited by 351 · see citing works
McCullough, L. D., Zeng, Z., Blizzard, K. K., Debchoudhury, I., & Hurn, P. D. (2005) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/sj.jcbfm.9600059 · Cited by 325 · see citing works
Sex bias exists in basic science and translational surgical research
Yoon, D. Y., Mansukhani, N. A., Stubbs, V. C., Helenowski, I. B., Woodruff, T. K., & Kibbe, M. R. (2014) · Surgery · doi:10.1016/j.surg.2014.07.001 · Cited by 270 · see citing works
Sex difference and estrous cycle variations in amphetamine-elicited rotational behavior
Becker, J. B., Robinson, T. E., & Lorenz, K. A. (1982) · European Journal of Pharmacology · doi:10.1016/0014-2999(82)90178-9 · Cited by 268 · see citing works
Deasy, B. M., Lu, A., Tebbets, J. C., Feduska, J. M., Schugar, R. C., Pollett, J. B., Sun, B., Urish, K. L., Gharaibeh, B. M., Cao, B., et al. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200612094 · Cited by 251 · see citing works
Modulation of aggression in male mice: influence of group size and cage size
Van Loo, P. L. P., Mol, J. A., Koolhaas, J. M., Van Zutphen, B. F. M., & Baumans, V. (2001) · Physiology & Behavior · doi:10.1016/s0031-9384(01)00425-5 · Cited by 249 · see citing works
Principles of Gender-Specific Medicine
(2010) · Elsevier eBooks · doi:10.1016/c2009-0-03574-0 · Cited by 212 · see citing works
Sex differences in response to citalopram: A STAR∗D report
Young, E. A., Kornstein, S. G., Marcus, S. M., Harvey, A. T., Warden, D., Wisniewski, S. R., Balasubramani, G. K., D, M. F. M., Trivedi, M. H., & Rush, A. J. (2008) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2008.07.002 · Cited by 186 · see citing works
Fixing problems with cell lines
Lorsch, J. R., Collins, F. S., & Lippincott-Schwartz, J. (2014) · Science · doi:10.1126/science.1259110 · Cited by 179 · see citing works
Neuroendocrinology of Reproduction, Physiology and Behavior
Donovan, B. T. (1982) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.45.2.190-c · Cited by 168 · see citing works
Sex and Gender Aspects in Clinical Medicine
Franconi, F., Straface, E., Chessa, R., Rosano, G., & Sanna, M. (2011) · Springer eBooks · doi:10.1007/978-0-85729-832-4 · Cited by 140 · see citing works
Feder, H. H. (1981) · Springer eBooks · doi:10.1007/978-1-4684-3875-8_10 · Cited by 138 · see citing works
Ritz, S. A., Antle, D. M., Côté, J. N., Deroy, K., Fraleigh, N. L., Messing, K., Parent, L., St‐Pierre, J., Vaillancourt, C., & Mergler, D. (2013) · The FASEB Journal · doi:10.1096/fj.13-233395 · Cited by 137 · see citing works
Estrogen Receptor Knockout Mice as a Model for Endocrine Research
Walker, V. R., & Korach, K. S. (2004) · ILAR Journal · doi:10.1093/ilar.45.4.455 · Cited by 128 · see citing works
Zolpidem and Driving Impairment — Identifying Persons at Risk
Farkas, R. H., Unger, E. F., & Temple, R. (2013) · New England Journal of Medicine · doi:10.1056/nejmp1307972 · Cited by 127 · see citing works
McCullough, L. D., Vries, G. J. D., Miller, V. M., Becker, J. B., Sandberg, K. L., & McCarthy, M. M. (2014) · Biology of Sex Differences · doi:10.1186/s13293-014-0015-5 · Cited by 124 · see citing works
Yuan, M., Siegel, C. S., Zeng, Z., Li, J., Liu, F., & McCullough, L. D. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.02.012 · Cited by 123 · see citing works
Sex and Gender Differences in Pharmacology
Regitz‐Zagrosek, V. (2012) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-30726-3 · Cited by 121 · see citing works
Embedding Concepts of Sex and Gender Health Differences into Medical Curricula
Miller, V. M., Rice, M., Schiebinger, L. L., Jenkins, M., Werbinski, J. L., Núñez, A. E., Wood, S. F., Viggiano, T. R., & Shuster, L. T. (2013) · Journal of Women s Health · doi:10.1089/jwh.2012.4193 · Cited by 104 · see citing works
The national centre for the replacement, refinement, and reduction of animals in research
Singh, J. (2012) · Journal of Pharmacology and Pharmacotherapeutics · doi:10.1177/0976500x20120105 · Cited by 96 · see citing works
Use of Factorial Designs to Optimize Animal Experiments and Reduce Animal Use
Shaw, R., Festing, M. F. W., Peers, I. S., & Furlong, L. (2002) · ILAR Journal · doi:10.1093/ilar.43.4.223 · Cited by 87 · see citing works
Festing, M. F. W. (2014) · ILAR Journal · doi:10.1093/ilar/ilu045 · Cited by 78 · see citing works
Androgen receptor knockout and knock-in mouse models
Kerkhofs, S., Denayer, S., Haelens, A., & Claessens, F. (2008) · Journal of Molecular Endocrinology · doi:10.1677/jme-08-0122 · Cited by 75 · see citing works
Handbook of Clinical Gender Medicine
(2012) · KARGER eBooks · doi:10.1159/isbn.978-3-8055-9930-6 · Cited by 66 · see citing works
Human Biosample Authentication Using the High-Throughput, Cost-Effective SNPtraceTM System
Liang-Chu, M. M. Y., Yu, M., Haverty, P. M., Koeman, J., Ziegle, J., Lee, M., Bourgon, R., & Neve, R. M. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116218 · Cited by 62 · see citing works
Guidance for the Description of Animal Research in Scientific Publications
National Research Council (2011) · National Academies Press eBooks · doi:10.17226/13241 · Cited by 59 · see citing works
Holdcroft, A. (2007) · Gender Medicine · doi:10.1016/s1550-8579(07)80048-9 · Cited by 46 · see citing works
Bringing Gender Expertise to Biomedical and Health-Related Research
Klinge, I. (2007) · Gender Medicine · doi:10.1016/s1550-8579(07)80047-7 · Cited by 22 · see citing works
Adding Sex-and-Gender Dimensions to Your Research
(2014) · AAAS Articles DO Group · doi:10.1126/science.caredit.a1400067 · Cited by 5 · see citing works
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- Authors
- Clayton, J. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Clayton, Janine Austin
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2015-10-29
- Volume
- 30
- Issue
- 2
- Pages
- 519-524
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC4714546
- OpenAlex
- W2193493665
- Cited by
- 358
- References
- 46
- Citations by year
- 2026: 20 · 2025: 47 · 2024: 39 · 2023: 39 · 2022: 40 · 2021: 33 · 2020: 37 · 2019: 19 · 2018: 37 · 2017: 27 · 2016: 20
- FWCI
- 29.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Social Sciences › Gender Studies › Diversity and Career in Medicine
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Health and Medical Research Impacts
- Keywords
- sex as a biological variable, NIH policy, preclinical research, women in medicine
- MeSH terms
- Female, Humans, Male, National Institutes of Health (U.S.), Sex Factors, United States, Biomedical Research
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