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Annual Report on Sex in Preclinical Studies

2019; Lippincott Williams & Wilkins; Volume: 40; Issue: 1 Linguagem: Inglês

10.1161/atvbaha.119.313556

1524-4636

Hong Lü, Ann Marie Schmidt, Robert A. Hegele, Nigel Mackman, Daniel J. Rader, Christian Weber, Alan Daugherty,

Reproductive System and Pregnancy

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 40, No. 1Annual Report on Sex in Preclinical Studies Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAnnual Report on Sex in Preclinical StudiesArteriosclerosis, Thrombosis, and Vascular Biology Publications in 2018 Hong S. Lu, Ann Marie Schmidt, Robert A. Hegele, Nigel Mackman, Daniel J. Rader, Christian Weber and Alan Daugherty Hong S. LuHong S. Lu Correspondence to: Hong S. Lu, MD, PhD, Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, Email E-mail Address: [email protected] From the Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington (H.S.L., A.D.) , Ann Marie SchmidtAnn Marie Schmidt Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University Langone Medical Center, New York, NY (A.M.S.) , Robert A. HegeleRobert A. Hegele Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada (R.A.H.) , Nigel MackmanNigel Mackman Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC (N.M.) , Daniel J. RaderDaniel J. Rader Departments of Medicine and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.J.R.) , Christian WeberChristian Weber Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität (LMU) and German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (C.W.). and Alan DaughertyAlan Daugherty Alan Daugherty, PhD, DSc, Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, Email E-mail Address: [email protected] From the Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington (H.S.L., A.D.) Originally published23 Dec 2019https://doi.org/10.1161/ATVBAHA.119.313556Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:e1–e9To comply with the National Institutes of Health guidelines for rigor and reproducibility on reporting sex as a biological variable, the editors of Arteriosclerosis, Thrombosis, and Vascular Biology(ATVB) previously reviewed 295 preclinical articles published in ATVB in 2017 and 2016 and provided detailed analysis on "Reporting sex and sex differences in preclinical studies" (published in the October 2018 issue1). The editors have decided to continuously monitor and document the reporting of sex and sex differences in ATVB on an annual basis. Here, we provide the annual report for preclinical studies published in 2018 in this Recent Highlights series.A total of 186 preclinical science research articles2–187 published in 2018 were reviewed by the editors. Twenty-five articles were excluded from further analysis because they only studied human samples or cell lines. There were 6 species reported in the remaining 161 articles (Table 1), including zebrafish, mice, rats, rabbits, pigs, and nonhuman primates. Among these 161 articles, 6 studied only embryos or neonates. Therefore, 155 publications with in vivo animal studies reporting sex were analyzed.Table 1. Reporting Sex of Animals in Preclinical Studies of ATVB Publications in 2018SpeciesTotal Article NumberReporting Sex, N (%)Reporting Both Sexes, N (%)Zebrafish4……Mouse142132 (94%)42 (30%)Rat87 (88%)0Rabbit43 (75%)0Pig11 (100%)1 (100%)Primate22 (100%)1 (50%)ATVB indicates Arteriosclerosis, Thrombosis, and Vascular Biology.In 2018, 145 articles (94%) reported sex for in vivo models, compared with 92% and 79% of those published in 2017 and 2016, respectively. Among all species, 28% reported studies from both male and female animals, compared with 21% and 11% of publications in 2017 and 2016, respectively. Eighty-two of the 155 articles (53%) articles reported findings from primary cells isolated from either mouse or rat. Forty-nine of the 82 articles (60%) reported sex, whereas 27% articles published in 2017 and 28% in 2016 provided sex information for primary cells. Eight articles in 2018 and 2 in both 2017 and 2016, respectively, reported findings from cells from both male and female animals.For in vivo studies among the 161 publications in 2018 (Table 1), 4 articles reported data from zebrafish during embryonic development, 4 articles studied rabbits with 3 that reported only male data and 1 that did not define the sex that was studied, 1 article studied both male and female pigs, 2 articles studied nonhuman primates with 1 reporting only male data and 1 reporting both male and female data.Rodents are the predominantly studied species, with most publications using mice and a lesser number using rats. Of the 161 articles published in 2018, 142 (88%) reported mouse models, and 8 (5%) reported rat models. For in vivo studies, 132 (94%) of 140 articles reported sex in mouse models after excluding 2 articles that studied only embryos or neonates, and 7 of 8 (88%) articles reported sex in rat models. For studies of primary cells, 44 of 74 (59%) articles in mice reported sex, and 5 of 8 (63%) articles in rats reported sex.For mouse studies (Table 2), 78 of 140 (56%) articles published in 2018 reported data only from male mice, 12 (9%) articles reported data only from female mice, and 42 (30%) reported data from both male and female animals. Among the 90 articles in mice that studied only one sex, 39 (43%) provided a brief justification. For the 8 rat studies, 7 (88%) reported data only from male rats, and 1 article did not provide the sex information.Table 2. Percent of Articles Reporting Sex in Mouse Studies of ATVB Publications in 2018Reporting SexArticles (Number)Articles (%)Male7856Female129Both male and female4230ATVB indicates Arteriosclerosis, Thrombosis, and Vascular Biology.On the basis of this data analysis, 3 significant improvements were noted in the 2018 publications, compared with the publications from 2017 (Figure). First, more animal studies provided a justification on why a specific sex (either male or female) was used. Second, more studies reported data derived from both male and female animals. Third, an increased number of articles reported the sex of primary cells isolated from animals. The latter improvement is largely attributed to the implementation of the Major Resources Tables started in the late 2018.Download figureDownload PowerPointFigure. Percent of articles that reported both sexes or provided a justification why only one sex was studied.Arteriosclerosis, Thrombosis, and Vascular Biology publications of preclinical research in 2017 and 2018 were analyzed. The x axis represents the month of publications. The y axis represents percent of monthly publications that either reported data from both male and female animals or provided a justification why the authors only studied one sex.Table 2 shows clearly that most animal studies published in 2018 reported data only from male animals (89 articles for male versus 12 articles for female), similar to the publications from 2017 (75 articles for male versus 18 articles for female). The major reason given by authors for studying only male animals is that the short estrus cycle in murine females may have confounding effects on data interpretation. Many provided literature evidence that estrogen had effects on the physiological or pathophysiological phenotype, whereas some did not provide solid evidence to support their use of male animals. Other reasons include (1) previous studies in the literature or the authors' laboratory showed that interventions in female animals had milder effects on cardiovascular diseases; (2) the relevant prior literature had exclusively reported data only from male mice; (3) previous studies did not note sexual dimorphism; or (4) the authors had studied the same sex previously and aimed to be consistent with their previous study designs. For the articles that only studied female animals, the authors stated that (1) male animals tend to show aggressive behavior; (2) no sex difference was found, but female animals were easier to handle; (3) female animals had more severe disease; or (4) female had a more modest phenotype. Among the 44 articles that reported on both male and female animals, 2 articles found a sex difference, which prompted for the authors to consider sex-related mechanisms.The editors acknowledge the significant improvement on reporting sex in most preclinical studies published in 2018. The editors also acknowledge that experimental designs and reporting sex in preclinical studies still need to be improved. For example, for articles that reported both male and female data, many studies pooled data from male and female animals. Some stated this approach was appropriate because male and female animals had no sex difference, while others did not provide a reason. The editorial process has now been modified to require analysis of data in a sex-specific manner. Pooling of data from both sexes may be permitted following the demonstration of no statistically significant difference between the 2 sexes.188ATVB will continuously make efforts to encourage authors to report both sexes and analyze data from each sex separately to explore sex differences. In addition to the ATVB Technical Review mechanism and the editors' annual review, the editors hope that more authors routinely study both sexes to explore new mechanisms of sex-mediated cardiovascular functions and diseases.1,189AcknowledgmentsThe Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB) editors in this writing group would like to thank the ATVB editorial office, the editors, the reviewers, and the authors for their tremendous efforts in supporting publishing high-quality research articles that report sex and sex differences.DisclosuresNone.FootnotesFor Disclosures, see page e3.Correspondence to: Hong S. Lu, MD, PhD, Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, Email hong.[email protected]eduAlan Daugherty, PhD, DSc, Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington, Email alan.[email protected]eduReferences1. Lu HS, Schmidt AM, Hegele RA, Mackman N, Rader DJ, Weber C, Daugherty A. Reporting sex and sex differences in preclinical studies.Arterioscler Thromb Vasc Biol. 2018; 38:e171–e184. doi: 10.1161/ATVBAHA.118.311717LinkGoogle Scholar2. Yu P, Xiong T, Tenedero CB, Lebeau P, Ni R, MacDonald ME, Gross PL, Austin RC, Trigatti BL. Rosuvastatin reduces aortic sinus and coronary artery atherosclerosis in SR-B1 (Scavenger Receptor Class B Type 1)/ApoE (Apolipoprotein E) double knockout mice independently of plasma cholesterol lowering.Arterioscler Thromb Vasc Biol. 2018; 38:26–39. doi: 10.1161/ATVBAHA.117.305140LinkGoogle Scholar3. 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