Addressing sex as a biological variable
Eric M Prager PhD
First published: 07 November 2016
https://doi.org/10.1002/jnr.23979
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Neuroscience today relies on the overwhelming belief that biological sex does not matter and can be safely ignored in preclinical research. Common practice within neuroscientific research is that findings in one sex (usually males) can be generalized to the other sex (usually females). Authors will even take the extreme approach of developing questionable methods to “prove” that sex differences are not present in the brain.
Sex matters not only at the macroscopic level, where male and female brains have been found to differ in size and connectivity, but at the microscopic level too. This themed issue of the
Journal of Neuroscience Research highlights sex differences of the brain at all scales, from the genetic and epigenetic, to the synaptic, cellular, and systems differences—differences known to be present throughout the life span. The work published in this issue powerfully illustrates that sex matters and that researchers can no longer rely on extrapolation from research on male animals and cells, which obscures key differences that might influence clinical studies.
Neuroscience today is at a crossroads. Do we continue the status quo and ignore sex as a biological variable, or do we acknowledge that sex influences the brain at all levels and address the major gaps in knowledge? The National Institutes of Health now mandates the inclusion of sex as a biological variable. Without this mandate, scientific discoveries that could benefit the health of both men and women would be hampered. At the
Journal of Neuroscience Research, we recognize that sex fundamentally influences the brain and have now established policy requiring all authors to ensure proper consideration of sex as a biological variable. These are as follows:
- Any paper utilizing subjects (cells, animals, humans) of only one sex must state the sex of the samples in the title and abstract of the paper, with the obvious exception of sex‐specific issues (e.g., prostate or ovarian function). Authors must also state the rationale for using samples from one sex rather than from both.
- All papers must clearly state in the methods section the number of samples/subjects of each sex used in the research. For cellular work, the sex of origin of cells used should be reported in most cases. If cells or tissue from both sexes were used without regard to sex, this fact should be indicated.
- JNR is particularly interested in experiments involving both male and female subjects studied at the same time, and with sufficient sample size to ensure meaningful statistical comparisons. The inability for any reason to study sex differences where they may exist should be discussed as a study limitation.
- Manuscripts reporting exploratory analyses of potential sex differences in studies not explicitly designed to address them are encouraged. JNR understands the real risk of false‐positive errors associated with subgroup analysis, but that risk is balanced by the equal or greater risk of false‐negative errors resulting from a failure to consider possible sex influences. JNR also understands that false‐negative results may result from underpowered analyses, but given the dearth of such analyses in neuroscience to date, and the now clear imperative to change the status quo on this issue, explicitly exploratory analyses are called for in many circumstances.
- Clinical work should be be designed with stratified randomization by sex. Post hoc analyses may also be useful, again perhaps explicitly designated as exploratory.
Consistent with NIH policy towards grant applications as of February 2016 (see
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html), the lack of an existing literature concerning the likelihood of a sex influence in a given domain does not constitute an adequate rationale for failing to examine a dataset for potential sex differences. Rather, testing for sex as a biological variable will give us the power to both transform our understanding of female and male biology and pathophysiology and, most importantly, inform clinical research. It is an issue whose time has come.
Eric M Prager, PhD
Editor‐in‐Chief, Journal of Neuroscience Research