Sex and the Riddle of Variability

Scientific research associations, funders, and publishers have recently introduced sex inclusion mandates requiring the use of male and female specimens in preclinical research designs and the analysis and reporting of data disaggregated by sex. However, it is not a simple matter to incorporate males and females in the same study design while following best practices for rigorous inference in laboratory science using model organisms. This paper analyzes a current scientific debate over differences in variability between male and female laboratory rodents, and specifically over whether potential sources of sex-specific variability such as the estrous cycle constitute components of sex that should be measured. The variability debate surfaces the trade-offs between constructs of sex difference and similarity that face scientific researchers attempting to meet mandates to include both males and females in research design and report sex-specific results. This “riddle of variability” illuminates how laboratory researchers using model organisms make contextual choices (Richardson 2022) at multiple decision points in order to operationalize sex as a biological variable in a particular research design. These judgments are informed by research context and carry consequences for the validity, precision, and generalizability of claims of sex differences derived from preclinical research models. (Contact Sarah Richardson for advance manuscript.)