Reporting Sex and Sex Differences in Preclinical Studies.

Abstract

ATVB aims to publish research work that advances scientific fields in a rigorous and reproducible manner. We have implemented multiple approaches to follow the National Institutes of Health (NIH) guidelines for rigor and reproducibility. In 2013, ATVB developed a “checklist” in the peer review process to facilitate comments on multiple technical requirements, including the sex of animals used in preclinical studies. We have also emphasized the NIH guidelines that encourage researchers to study both sexes in preclinical animal models. These include publishing a review1 entitled “Sex differences in the development of cardiovascular diseases” and an ATVB Council statement2 to encourage authors to consider sex differences in designing and reporting experimental arterial pathology studies that details the mode by which ATVB complies with the NIH guidelines.3 The journal appointed a technical review editor, Dr. Hong Lu, who assumed the role in September 2017 in order to assess the many elements required for adherence to the NIH guidelines. These include issues such as the rigor of statistical analyses and animal background strain, age, and sex. The designation of sex of origin in studies of primary cells derived from cell culture is not as common as it is in whole animal studies. This is probably due to the unproven assumption that the lack of the hormonal environment in cell culture eliminates the need for designation of sex. However, since the differences of X and Y sex chromosomes and possibly sex-related differences in genomic imprinting are preserved in cultured cells, these cells could theoretically retain the ability to respond in a sex-dependent manner.4 Therefore, we also encourage and will monitor the reporting of sex in primary cell isolation and culture. In a recent letter to the ATVB editors, Ramirez and Hibbert5 performed a comprehensive literature search and detailed statistical analysis on articles focusing on atherosclerosis and aneurysms from 2006 through 2016. They concluded that publication of guidelines and statements alone is not sufficient to assure the reporting of sex and sex differences in preclinical studies. To more objectively assess whether and how sex information in preclinical research has been reported, the ATVB editors reviewed 332 basic science research articles published in ATVB between 2016 and 2017.6–337 After excluding those that studied only human samples, human cells, cell lines, or computational models, 159 articles published in 2016 and 136 articles published in 2017 were analyzed (Tables ​(Tables11–5), which reported studies in animal models and/or primary cells isolated from animals.6–300 There were 7 species reported in these articles (Table 1), including zebrafish, mouse, rat, rabbit, dog, pig, and nonhuman primates. Among these 295 articles analyzed, 79% and 92% of those from 2016 and 2017, respectively, provided sex information for in vivo models. However, only 11% of the articles in 2016 and 21% in 2017 reported results from both males and females. One hundred and thirty three of 295 articles reported primary cells isolated from mouse, rat, cow, or pig. Twenty-eight percent of the articles in 2016 and 27% in 2017 provided sex information, whereas only 3 articles studied cells from both male and female animals. Table 1. All Animal Species Reported in Preclinical Studies