Sex matters: the frequently overlooked importance of considering sex in computational models.

Personalised medicine and the development of a virtual human or a digital twin comprises visions of the future of medicine. To realise these innovations, an understanding of the biology and physiology of all people are required if we wish to apply these technologies at a population level. Sex differences in health and biology is one aspect that has frequently been overlooked, with young white males being seen as the "average" human being. This has not been helped by the lack of inclusion of female cells and animals in biomedical research and preclinical studies or the historic exclusion, and still low in proportion, of women in clinical trials. However, there are many known differences in health between the sexes across all scales of biology which can manifest in differences in susceptibility to diseases, symptoms in a given disease, and outcomes to a given treatment. Neglecting these important differences in the development of any health technologies could lead to adverse outcomes for both males and females. Here we highlight just some of the sex differences in the cardio-respiratory systems with the goal of raising awareness that these differences exist. We discuss modelling studies that have considered sex differences and touch on how and when to create sex-specific models. Scientific studies should ensure sex differences are included right from the study planning phase and results reported using sex as a biological variable. Computational models must have sex-specific versions to ensure a movement towards personalised medicine is realised.