Schrodinger's research

Cutting (or not!!) research on women and sex disaggregating Alzheimer's data

Good morning GFPs! Do you always hear that in the Robin Williams Good morning Vietnam voice, because that’s how I’m always saying it — not deliberately, it’s just my brain and I can’t make it stop. And now you probably won’t be able to make it stop either, you’re welcome.

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The fertilization president

It’s been an eventful few weeks from the perspective of women’s health research in the US — which means it’s been an eventful few weeks from the perspective of women’s health research everywhere and not just in a “when America sneezes the cold catches a way” way. Very simply, what the US government chooses to fund is hugely important for us all, because it is one of the major global funders healthcare research. For example, an analysis by the US Congressional Budget Office found that between 2010 and 2016, “every drug approved by the FDA was in some way based on biomedical research funded by NIH [the National Institute of Health, the US's primary biomedical and public health research agency].” And no, the US is not approving a vastly different swathe of drugs from the rest of world.

All this means that it matters far beyond the US’s borders when, as I noted in a previous edition of this newsletter, words including “female” and “women” (but not “male” or “men” — although to be fair, “male-dominated” is also now a bad word) have been pretty much outlawed from US government funded research.

Invisible Women: diversity on the naughty step

Of course, the Trump administration’s savage cuts do not only affect women (they have terminated more than 1,700 medical research grants), but since women’s health is already chronically “underfunded, under-researched and under-prioritised”, women are particularly disadvantaged. And the strictures against even mentioning women make it somewhat difficult for researchers to address the data gaps and study women or indeed females of any species. Meanwhile, going by the querulous notice the US Department of Health added to some FDA guidance on studying sex differences (it had previously deleted this guidance from the internet but was forced by court order to restore it), this administration seems ideologically opposed to the study of sex differences at all. Then again, putting a notice about “gender ideology” on some guidance about sex differences does imply that this administration does not in fact understand the difference between sex and gender. So who knows. Listen, I’m as baffled as the rest of you.

Weirdly, for a country presided over by a self-declared “fertilization president”, one of the worst affected areas seems to be research on maternal health. Examples include the cancellation of a programme that tracks IVF outcomes (despite the executive order calling for, er, better access to IVF); a study on the prevention of domestic violence in pregnancy (in a country where the leading cause of death in pregnant and postpartum women is homicide by an abusive partner); and the interruption of data collection for PRAMS, “a comprehensive federal database with detailed information about Americans’ pregnancy-related health outcomes” (in a country that continues to have the worst rates of both maternal and infant mortality in the OECD). In these last two examples, DEI has been cited as the reason, and to be fair, preventing the egregious continuation of any research that mentions the word “equity” or “female” in the title is unarguably more important than saving women’s lives.

The big headline cut, however, has been the Women’s Health Initiative (WHI). On the 21st April, the study investigators announced that they had been “informed that the Department of Health and Human Services (HHS) will terminate WHI Regional Center (RC) contracts at the end of their current fiscal year (September 2025).” They were “initially given verbal notice,” shortly followed by “an email confirming that these funding decisions had been approved by NIH leadership.” At the time of the announcement they were waiting for formal notice.

This announcement was huge. The WHI, launched in 1992, was the first and remains the largest clinical trial in history to involve only women (started, coincidentally or not you tell me, under the leadership of Bernadine Healy, the first woman to serve as director of the NIH). It is a randomized double-blind placebo-controlled clinical trial, which, among other things, investigated whether hormones worked to prevent various diseases in menopausal women, and has provided us with invaluable insights into the health of older women, a group for which good health data is sorely lacking.

“This was really meant as a makeup project for women, because women have been excluded from research for so many years,” says Garnet Anderson, a biostatistician who runs the WHI coordinating center. (Source)

The WHI has received a bad rep recently that is unwarranted. It is certainly true that the fallout from the WHI led to a sharp decline in the prescription of hormonal treatment for menopausal women, and that many menopausal women suffered as a result, but it does not therefore follow, as some menopause celebrities might have you believe, that the WHI was a bad study. Rather, its findings were misrepresented and misapplied; it was never intended to answer the question of whether hormones are a good treatment for menopausal symptoms (we already knew it helped there) only whether they work to prevent or increase the risk of disease, and the study has in fact taught us a lot about disease prevention in older women.

It’s also worth noting that it was data from this much-maligned study that first pointed us toward the “timing hypothesis”: that the risk-benefit ratio for hormonal therapy is connected to when in your menopause transition your start treatment (in brief: earlier is better). And of course the women who are still enrolled in the study continue to provide us with invaluable data on healthy ageing for women, including predicting cognitive decline and managing chronic disease. (I go into more detail on the WHI in the current draft of my new book, so if you like this sort of thing, well have I got a treat in store for you in about two years’ time 😘)

But GFPs, do not despair. It’s not all bad news. Three days after the initial WHI announcement, and following a huge uproar over the cancellation of this landmark study, the US’s joke of a Health Secretary tried to pretend this was all “fake news,” nothing to see here, we were never going to cancel it in the first place — a claim undermined by his own staff who confirmed that there had indeed been a reversal of the cuts. This reversal has yet to be confirmed “in any form” to the WHI investigators themselves, who are therefore remaining cautious, as should we all in the context of this headless chicken of an administration, but cautiously, this is a moment of hope in the midst of a seemingly endless series of moments of hopelessness. Perhaps, just perhaps, if enough of us shout loud enough, we are not completely powerless?

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Simulating the new dawn

In less hopeful news, though I guess, in a way, still good news from the perspective that sex disaggregated data is ALWAYS good news, remember how a while back I wrote about lecanemab, the new wonder drug that represented a “new dawn” in Alzheimer’s treatment?

Invisible Women: default male miracles

I’ve just reread the piece now, and man that was infuriating! I had forgotten quite how bad Alzheimer’s research is at adequately representing women and doing sex-based analysis — for a disease, that, remember, is female dominated!

A choice quote from the newsletter:

“just 12% – $280 million of the $2.4 billion NIH Alzheimer’s research budget went to studying just women. That’s like spending $3 in research on each woman over 35, and $24 on every man.”

ARGH!

Anyway, as you may remember, my main focus was quibbling with the top-level results that presented lecanemab as a wonder drug because while it did seem to perform admirably in men, it wasn’t clear from the data that it was a wonder drug for women. You know, the majority of patients.

Anyway, it turns out that I was not alone in raising an eyebrow at the apparent disparity in results between male and female patients. According to an article in Science, the “sizeable gap” in drug effect was also “a red flag” for some scientists. The difficulty was that the original trial’s sample size “was not large enough to compare male and female subgroups directly” (which is in itself enraging), so unless someone runs a trial with an adequate number of male and female participants, we will never get fully to the bottom of this disparity.

BUT! Not to be entirely deterred, researchers in Canada and Italy used the data we do have from this (under-powered if you care about sex differences which I do) study to run 10,000 simulated trials, and they found that “the difference between sexes only occurred randomly in 12 out of 10,000 simulations.” This does not mean that lecanemab is definitively clinically ineffective in women, because only a proper trial can tell us for sure. But it is certainly suggestive — not least of the fact that instead of racing to approve drugs that have not been definitely proven to work equally well in women and men, regulators should instead compel pharmaceutical companies to run trials that actually can prove that.

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Research opportunity of the week

Ok, GFPs, so as I said, the US is a major player in funding crucial medical research, but it’s not the ONLY player. Step forward, the University of Cambridge, which is launching a new study on pregnancy and women’s long-term health, investigating why some women develop pre-eclampsia and other placental complications and why these conditions have an adverse effect on women’s future heart health (from my research for my new book I can confirm there is a HUGE data gap here). They are looking for volunteers (reimbursement is provided for time, inconvenience and travel) aged between 18 and 45 who are planning their first pregnancy, so if that sounds like you, click here to watch one of their official recruitment videos. You can also check out their website and you can find them on instagram, Facebook, and twitter.

The study, by the way, is called THE POPPY STUDY, which leads me nicely on to the content I know you all actually sign up to this newsletter for…

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Poppy pic of the week

That’s it! Until next time, my dear GFPs….xoxoxo