Systematic review and meta-analysis of sex differences in preclinical ischaemic stroke research

• Applicant: Dr. Sarah McCann
• Subject Area: Epidemiology and Medical Biometry/Statistics ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504323693

Stroke is a devastating disease and despite decades of research, treatment options remain severely limited. New stroke treatments are often found to be effective in animal experiments but fail to show benefit for patients. One of the reasons for this “translational failure” is thought to be that animal models often lack important patient characteristics. In particular, stroke research is usually carried out on male animals but findings are generalised to all stroke patients, who are predominantly female. Women suffer from worse stroke outcomes than men and can respond differently to experimental treatments. Preclinical research involving animal or cell-based models suggests there are complex biological mechanisms underlying these sex differences, however our current understanding is incomplete.Further clouding our comprehension is the dispersion of evidence across individual studies, each of which form only part of a whole. The most value is extracted from research when we understand how these parts fit together. Systematic review and meta-analysis are transparent, reproducible methods to objectively synthesise and interpret evidence. They provide a comprehensive understanding of collected scientific results to identify new hypotheses and support decision making. Systematic review is routinely used in clinical research to support evidence-based healthcare decisions but remains underutilised in preclinical research. Our aim is to systematically review all preclinical stroke research investigating sex differences. We will characterise and quantify sex-specific responses to stroke and experimental treatments. This will allow us to identify high priority knowledge gaps and avoid unnecessary duplication; vital considerations for ethical animal research. We will analyse the sex-specific limits to efficacy of different treatments, and identify any commonalities in treatments that work more effectively in one sex. We will then integrate and evaluate what is known about the biological mechanisms behind these differences. Our results will form a resource for the stroke research community to evaluate the potential for sex-dependent efficacy in new treatments, and provide a comprehensive basis to guide future research decisions. Finally, we will create a “living” review of studies investigating sex differences in stroke, where new research is automatically synthesised as it is published, enabling stakeholders to efficiently utilize this evidence. Our living review will also incorporate additional studies related to generalisability, such as those using animal models with advanced age, high blood pressure, and diabetes. While our focus here is stroke research, our approach will form a prototype to apply across biomedical domains.A better understanding of the mechanisms underlying sex differences in stroke, and clear research prioritisation will help to enable more effective therapeutic development for women and men.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Emily Sena, Ph.D.