Sex as a biological variable

Sex as a biological variable (SABV) is a research policy recognizing sex as an important variable to consider when designing studies and assessing results. Research including SABV has strengthened the rigor and reproducibility of findings. Public research institutions including the European Commission, Canadian Institutes of Health Research, and the U.S. National Institutes of Health have instituted SABV policies. Editorial policies were established by various scientific journals recognizing the importance and requiring research to consider SABV.

Background

Public research institutions
Gillian Einstein in 2015 speaking on the importance of SABV in preclinical research.

In 1999, the Institute Of Medicine established a committee on understanding the biology of sex and gender differences. In 2001, they presented a report that sex is an important variable in designing studies and assessing results. The quality and generalizability of biomedical research depends on the consideration of key biological variables, such as sex. To improve the rigor and reproducibility of research findings, the European Commission, Canadian Institutes of Health Research, and the U.S. National Institutes of Health (NIH) established policies on sex as a biological variable (SABV).[1] Enrolling both men and women in clinical trials can impact the application of results and permit the identification of factors that affect the course of disease and the outcome of treatment.[2]

In 2003, the European Commission (EC) began influencing investigators to include sex and gender in their research methodologies. The Canadian Institutes of Health Research (CIHR) requires four approaches: sex and gender integration in research proposals, sex and gender expertise among research teams, sex and gender platform in large consortiums, and starting in September 2015, the completion of sex and gender online training programs.[1]

The NIH 4 Cs of Studying Sex to Strengthen Science.[3]

In May 2014, the NIH announced the formation of SABV policy.[4] The policy came into effect in 2015 which specified that "SABV is frequently ignored in animal study designs and analyses, leading to an incomplete understanding of potential sex-based differences in basic biological function, disease processes, and treatment response. 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 from the scientific literature, preliminary data or other relevant considerations must be provided for applications proposing to study only one sex."[2][1] The review criteria should assess the extent to which the sex of participants has been incorporated into the research plan.[5]

Scientific journals

In 2010, the National Centre for the Replacement, Refinement and Reduction of Animals in Research published the ARRIVE guidelines which promotes incorporating SABV in animal studies.[6] In 2012, the American Physiological Society (APS) journals began requiring sex and gender to be reported in studies involving cells, tissues, animals, and humans.[7] This APS editorial policy was not widely accepted by reviewers and researchers.[8]

The European Association of Science Editors established the gender policy committee (GPC) in 2012. The GPC published Sex and Gender Equity in Research (SAGER) guidelines in 2016.[9] In January 2017, the Journal of Neuroscience Research began requiring the consideration of SABV.[10] The December 2017 ICMJE recommendations encouraged the use of SABV by researchers.[1]

Impact
Janine Austin Clayton in 2016 explaining SABV in clinical trials

Research incorporating sex as a biological variable increases the rigor and reproducibility of results.[11][12] After publishing the NIH published SABV policy, there were increases in the percentage of scientists understanding and recognizing its importance.[13] Some investigators were critical of the NIH SABV policy, saying it would increase cost and labor requirements.[14][15] Including SABV in basic research and preclinical studies can reduce costs and time requirements to test sex differences in clinical trials.[16][17]

Historically, there were concerns among researchers of the female reproductive system impacting findings in animal studies.[18] Other studies using mice models found that despite the estrous cycle, variability was the same among sexes.[19] Studies following SABV policies can identify potential hormonal variability in earlier phases of biomedical research.[20]

In 2020, the NIH Office on Women's Health and the Food and Drug Administration Office of Women's Health created an educational tool, Bench-to-Bedside: Integrating Sex and Gender to Improve Human Health.[21]

References
  1. Lee, Suk Kyeong (April 2018). "Sex as an important biological variable in biomedical research". BMB Reports. 51 (4): 167–173. doi:10.5483/BMBRep.2018.51.4.034. ISSN 1976-6696. PMC 5933211. PMID 29429452.
  2. "NOT-OD-15-102 Guidance: Consideration of Sex as a Biological Variable in NIH-funded Research" (PDF). National Institutes of Health. 2015. Retrieved 2021-02-26.{{cite web}}: CS1 maint: url-status (link) This article incorporates text from this source, which is in the public domain.
  3. "NIH Policy on Sex as a Biological Variable | Office of Research on Women's Health". orwh.od.nih.gov. Retrieved 2021-02-26.
  4. Clayton, Janine A.; Collins, Francis S. (2014-05-15). "Policy: NIH to balance sex in cell and animal studies". Nature News. 509 (7500): 282–3. doi:10.1038/509282a. PMC 5101948. PMID 24834516.
  5. "Sex & Gender: Questions & Answers". NIH Office of Research on Women's Health. Retrieved 2021-02-26.{{cite web}}: CS1 maint: url-status (link) This article incorporates text from this source, which is in the public domain.
  6. Kilkenny, Carol; Browne, William J.; Cuthill, Innes C.; Emerson, Michael; Altman, Douglas G. (2010-06-29). "Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research". PLOS Biology. 8 (6): e1000412. doi:10.1371/journal.pbio.1000412. ISSN 1545-7885. PMC 2893951. PMID 20613859.
  7. Miller, Virginia M. (2012-05-01). "In pursuit of scientific excellence: sex matters". American Journal of Physiology. Gastrointestinal and Liver Physiology. 302 (9): G907–G908. doi:10.1152/ajpgi.00101.2012. ISSN 0193-1857. PMID 22421621.
  8. Shah, Kalpit; McCormack, Charles E.; Bradbury, Neil A. (2014-01-01). "Do you know the sex of your cells?". American Journal of Physiology. Cell Physiology. 306 (1): C3–C18. doi:10.1152/ajpcell.00281.2013. ISSN 0363-6143. PMC 3919971. PMID 24196532.
  9. De Castro, Paola; Heidari, Shirin; Babor, Thomas F. (April 2016). "Sex And Gender Equity in Research (SAGER): reporting guidelines as a framework of innovation for an equitable approach to gender medicine. Commentary". Annali dell'Istituto Superiore di Sanità. 52 (2): 154–157. doi:10.4415/ANN_16_02_05. ISSN 2384-8553. PMID 27364388.
  10. Prager, Eric M (2017-01-02). "Addressing sex as a biological variable: Editor's Column". Journal of Neuroscience Research. 95 (1–2): 11. doi:10.1002/jnr.23979. PMID 27870455. S2CID 12566403.
  11. Clayton, Janine A. (2018-04-01). "Applying the new SABV (sex as a biological variable) policy to research and clinical care". Physiology & Behavior. 187: 2–5. doi:10.1016/j.physbeh.2017.08.012. ISSN 0031-9384. PMID 28823546. S2CID 3810367.
  12. Khosla, Sundeep; Amin, Shreyasee; Orwoll, Eric (2008-06-01). "Osteoporosis in Men". Endocrine Reviews. 29 (4): 441–464. doi:10.1210/er.2008-0002. ISSN 0163-769X. PMC 2528848. PMID 18451258.
  13. Mannon, Elinor C.; Ray, Sarah C.; Ryan, Michael J.; Sullivan, Jennifer C. (2020-02-01). "Does sex matter?: an update on the implementation of sex as a biological variable in research". American Journal of Physiology. Renal Physiology. 318 (2): F329–F331. doi:10.1152/ajprenal.00575.2019. ISSN 1931-857X. PMC 7052660. PMID 31904284.
  14. Fields, R. Douglas (June 2014). "NIH policy: Mandate goes too far". Nature. 510 (7505): 340. Bibcode:2014Natur.510..340F. doi:10.1038/510340a. ISSN 0028-0836. PMID 24943947. S2CID 52850338.
  15. Sandberg, Kathryn; Verbalis, Joseph G.; Yosten, Gina L. C.; Samson, Willis K. (2014-08-15). "Sex and basic science. A Title IX position". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 307 (4): R361–R365. doi:10.1152/ajpregu.00251.2014. ISSN 0363-6119. PMC 5504397. PMID 24944252.
  16. McCullough, Louise D; de Vries, Geert J; Miller, Virginia M; Becker, Jill B; Sandberg, Kathryn; McCarthy, Margaret M (December 2014). "NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics". Biology of Sex Differences. 5 (1): 15. doi:10.1186/s13293-014-0015-5. ISSN 2042-6410. PMC 4360141. PMID 25780556.
  17. Sandberg, Kathryn; Umans, Jason G.; Group the Georgetown Consensus Conference Work (May 2015). "Recommendations concerning the new U.S. National Institutes of Health initiative to balance the sex of cells and animals in preclinical research". The FASEB Journal. 29 (5): 1646–1652. doi:10.1096/fj.14-269548. ISSN 0892-6638. PMC 6137686. PMID 25713032.
  18. Wald, C.; Wu, C. (2010-03-26). "Of Mice and Women: The Bias in Animal Models". Science. 327 (5973): 1571–1572. doi:10.1126/science.327.5973.1571. ISSN 0036-8075. PMID 20339045.
  19. Prendergast, Brian J.; Onishi, Kenneth G.; Zucker, Irving (March 2014). "Female mice liberated for inclusion in neuroscience and biomedical research". Neuroscience & Biobehavioral Reviews. 40: 1–5. doi:10.1016/j.neubiorev.2014.01.001. PMID 24456941. S2CID 6553804.
  20. Becker, Jill B.; Arnold, Arthur P.; Berkley, Karen J.; Blaustein, Jeffrey D.; Eckel, Lisa A.; Hampson, Elizabeth; Herman, James P.; Marts, Sherry; Sadee, Wolfgang; Steiner, Meir; Taylor, Jane (2005-04-01). "Strategies and Methods for Research on Sex Differences in Brain and Behavior". Endocrinology. 146 (4): 1650–1673. doi:10.1210/en.2004-1142. ISSN 0013-7227. PMID 15618360.
  21. Arnegard, Matthew E.; Whitten, Lori A.; Hunter, Chyren; Clayton, Janine Austin (2020-06-01). "Sex as a Biological Variable: A 5-Year Progress Report and Call to Action". Journal of Women's Health. 29 (6): 858–864. doi:10.1089/jwh.2019.8247. ISSN 1540-9996. PMC 7476377. PMID 31971851.
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