Invisible Women: Exposing Data Bias in a World Designed for Men

having an impact on outcomes. So far, menstrual-cycle impacts have been found for antipsychotics, antihistamines and antibiotic treatments as well as heart medication.⁵⁸ Some antidepressants have been found to affect women differently at different times of their cycle, meaning that dosage may be too high at some points and too low at others.⁵⁹ Women are also more likely to experience drug-induced heart-rhythm abnormalities⁶⁰ and the risk is highest during the first half of a woman’s cycle.⁶¹ This can, of course, be fatal.

Finally, the authors didn’t consider the number of drug treatments that might be beneficial to women but never even reach human testing because they were ruled out at the cell and animal trial stage. And this number could be substantial. Sex differences in animals have been consistently reported for nearly fifty years, and yet a 2007 paper found that 90% of pharmacological articles described male-only studies.⁶² In 2014 another paper found that 22% of animal studies did not specify sex, and of those that did, 80% included only males.⁶³

Perhaps most galling from a gender-data-gap perspective was the finding that females aren’t even included in animal studies on female-prevalent diseases. Women are 70% more likely to suffer depression than men, for instance, but animal studies on brain disorders are five times as likely to be done on male animals.⁶⁴ A 2014 paper found that of studies on female-prevalent diseases that specified sex (44%), only 12% studied female animals.⁶⁵ Even when both sexes are included there is no guarantee the data will be sex-analysed: one paper reported that in studies where two sexes were included, two-thirds of the time the results were not analysed by sex.⁶⁶ Does this matter? Well, in the 2007 analysis of animal studies, of the few studies that did involve rats or mice of both sexes, 54% revealed sex-dependent drug effects.⁶⁷

These sex-dependent effects can be extreme. Dr Tami Martino researches the impact of circadian rhythms on heart disease, and during a 2016 lecture to the Physiology Society she recounted a recent shock discovery. Together with her team, she conducted a study which found that the time of day you have a heart attack affects your chances of survival. A heart attack that hits during the day triggers, among other things, a greater immune response. In particular, it triggers a greater neutrophil response (neutrophils are a type of white blood cell that are usually first on the scene in response to any injury), and this response correlates with a better chance of survival. This finding has been replicated many times over many years with many different animals, becoming, explained Martino, the ‘gold standard for survivorship in the literature’.

So Martino and her team were ‘quite surprised’ when in 2016 another group of researchers released a paper which also found that daytime heart attacks triggered a greater neutrophil response – but that this correlated with a worse chance of survival. After a substantial amount of head-scratching, they realised there was one basic difference between the historic studies and this one new study: the old studies had all used male mice, while this new paper had used female mice. Different sex: totally opposite result.

As for cell studies, a 2011 review of ten cardiovascular journals found that when sex was specified 69% of cell studies reported using only male cells.⁶⁸ And ‘when sex was specified’ is an important caveat: a 2007 analysis of 645 cardiovascular clinical trials (all published in prominent journals) found that only 24% provided sex-specific results.⁶⁹ A 2014 analysis of five leading surgical journals found that 76% of cell studies did not specify sex and of those that did, 71% included only male cells and only 7% reported sex-based results.⁷⁰ And again, even for diseases that are more prevalent in women, researchers can be found ‘exclusively’ studying XY cells.⁷¹

As in animal and human studies, when sex has been analysed in cell studies, dramatic differences have been found. For years researchers were puzzled by the unpredictability of transplanted muscle-derived stem cells (sometimes they regenerated diseased muscle, sometimes they didn’t do anything) until they realised that the cells weren’t unpredictable at all – it’s just that female cells promote regeneration and male cells don’t. Perhaps of more urgent concern for women’s health is the 2016 discovery of a sex difference in how male and female cells respond to oestrogen. When researchers⁷² exposed male and female cells to this hormone and then infected them with a virus, only the female cells responded to the oestrogen and fought off the virus. It’s a tantalising finding that inevitably leads to the following question: how many treatments have women missed out on because they had no effect on the male cells on which they were exclusively tested?

In light of all this evidence, it’s hard to see how researchers can continue to argue in good faith that sex doesn’t matter. Rather, it seems clear that McGill University neuroscientist Jeffrey Mogil was right when he told the Organisation for the Study of Sex Differences that failing to include both sexes ‘right at the very beginning’ of your research ‘is not only scientifically idiotic and a waste of money, it is an ethical issue as well’.⁷³ Nevertheless, women continue to be routinely under-represented in medical research, and you can’t even expect sex-specific trials to adequately represent women. When the ‘female Viagra’⁷⁴ that was released with much fanfare in 2015 was found to potentially interact negatively with alcohol (as most readers will know, the absorption of alcohol differs between men and women⁷⁵), its manufacturer, Sprout Pharmaceuticals, quite rightly decided to run a trial – for which they recruited twenty-three men and two women.⁷⁶ They did not sex-disaggregate the data.

In this latter failure, they are not alone. Several reviews of papers published in major journals over the past ten years have all identified a routine failure to either present results by sex, or to explain why the influence of sex has been ignored.⁷⁷ A 2001 US Government Accounting Office (GAO) audit of FDA records found that about a third of