Re-Repost: The funding is the science II, "Why do they always drop the females?"

The NIH has recently issued the first round of guidance on inclusion of Sex as a Biological Variable in future NIH research grants. I am completely behind the spirit of the initiative but I have concerns about how well this is going to work in practice. I wrote a post in 2008 that detailed some of the reasons that have brought us to the situation where the Director of the NIH felt he had to coauthor an OpEd on this topic. I believe these issues are still present, will not be magically removed with new instructions to reviewers and need to be faced head-on if the NIH is to make any actual progress on ensuring SABV is considered appropriately going forward.

The post originally appeared December 2, 2008.


The title quote came from one of my early, and highly formative, experiences on study section. In the course of discussing a revised application it emerged that the prior version of the application had included a sex comparison. The PI had chosen to delete that part of the design in the revised application, prompting one of the experienced members of the panel to ask, quite rhetorically, "Why do they always drop the females?"

I was reminded of this when reading over Dr. Isis' excellent post [Update: Original Sb post lost, I think the repost can be found here] on the, shall we say less pernicious, ways that the course of science is slanted toward doing male-based research. Really, go read that post before you continue here, it is a fantastic description.

What really motivated me, however, was a comment from the always insightful Stephanie Z:

Thank you. That's the first time I've seen someone address the reasons behind ongoing gender disparities in health research. I still can't say as it thrills me (or you, obviously), but I understand a bit better now.

Did somebody ring?

As I pointed out explicitly at least once ([Update: Original 2007 post]), research funding has a huge role in what science actually gets conducted. Huge. In my book this means that if one feels that an area of science is being systematically overlooked or minimized, one might want to take a close look at the manner by which science is funded and the way by which science careers are sustained as potential avenues for systematic remedy.

Funding

There are a couple of ways in which the generalized problems with NIH grant review lead to the rhetorical comment with which I opened the post. One very common StockCritique of NIH grant review is that of an "over ambitious" research plan. As nicely detailed in Isis' post, the inclusion of a sex comparison doubles the groups right off the bat but even more to the point, it requires the inclusion of various hormonal cycling considerations. This can be as simple as requiring female subjects to be assessed at multiple points of an estrous cycle. It can be considerably more complicated, often requiring gonadectomy (at various developmental timepoints) and hormonal replacement (with dose-response designs, please) including all of the appropriate control groups / observations. Novel hormonal antagonists? Whoops, the model is not "well established" and needs to be "compared to the standard gonadectomy models", LOL >sigh<.

manWomanControlPanel.jpg
Grant reviewers prefer simplicity
Keep in mind, if you will, that there is always a more fundamental comparison or question at the root of the project, such as "does this drug compound ameliorate cocaine addiction?" So all the gender comparisons, designs and groups need to be multiplied against the cocaine addiction/treatment conditions. Suppose it is one of those cocaine models that requires a month or more of training per group? Who is going to run all those animals ? How many operant boxes / hours are available? and at what cost? Trust me, the grant proposal is going to take fire for "scope of the project".

Another StockCritique to blame is "feasibility". Two points here really. First is the question of Preliminary Data- of course if you have to run more experimental conditions to establish that you might have a meritorious hypothesis, you are less likely to do it with a fixed amount of pilot/startup/leftover money. Better to work on preliminary data for two or three distinct applications over just one if you have the funds. Second aspect has to do with a given PIs experience with the models in question. More opportunity to say "The PI has no idea what s/he is doing methodologically" if s/he has no prior background with the experimental conditions, which are almost always the female-related ones. As we all know, it matters little that the hormonal assays or gonadectomy or whatever procedures have been published endlessly if you don't have direct evidence that you can do it. Of course, more latitude is extended to the more-experienced investigator....but then s/he is less likely to jump into gender-comparisons in a sustained way in contrast to a newly minted PI.

Then there are the various things under grantspersonship. You have limited space in a given type of grant application. The more groups and comparisons, the more you have to squeeze in with respect to basic designs, methods and the interpretation/alternative approaches part. So of course you leave big windows for critiques of "hasn't fully considered...." and "it is not entirely clear how the PI will do..." and "how the hypothesis will be evaluated has not been sufficiently detailed...".

Career

Although research funding plays a huge role in career success, it is only part of the puzzle. Another critical factor is what we consider to be "great" or "exciting" science in our respective fields.

The little people can fill in the details. This is basically the approach of GlamourMagz science. (This is a paraphrase of something the most successful GlamourMagz PI I know actually says.) Cool, fast and hot is not compatible with the metastasizing of experimental conditions that is an inevitable feature of gender-comparison science. Trouble is, this approach tends to trickle down in various guises. Lower (than GlamourMag) impact factor journals sometimes try to upgrade by becoming more NS-like (Hi, J Neuro!). Meticulous science and exacting experimental designs are only respected (if at all) after the fact. Late(r) in someone's career they start getting props on their grant reviews for this. Early? Well the person hasn't yet shown the necessity and profit for the exhaustive designs and instead they just look...unproductive. Like they haven't really shown anything yet.

As we all know splashy CNS pubs on the CV trump a sustained area of contribution in lower journals six ways to Sunday. This is not to say that nobody will appreciate the meticulous approach, they will. Just to say that high IF journal pubs will trump. Always.

So the smart young PI is going to stay away from those messy sex-differences studies. Everything tells her she should. If he does dip a toe, he's more likely to pay a nasty career price.
This is why NIH efforts to promote sex-comparison studies are necessary. Promoting special funding opportunities are the only way to tip the equation even slightly more favorable to the sex-differences side. The lure of the RFA is enough to persuade the experienced PI to write in the female groups. To convince the new PI that she might just risk it this one time.

My suspicion is that it is not enough. Beyond the simple need to take a stepwise approach to the science as detailed by Isis, the career and funding pressures are irresistible forces.

9 responses so far

  • Amboceptor says:

    Before reading various things on this blog, I never would have thought that addressing sex differences in an experimental plan was a feminist issue, i.e. all this research gets done on male mice just because they're slightly easier to work with, and it ends up being maybe not applicable to females. In my experience the default experiment is done on females, primarily for the reason that females aren't constantly fighting with each other and being euthanized because of bite wounds halfway through the experiment. And also females are generally smaller and require less reagents, thus more cost-effective. And they are less fat and thus easier to anesthetize. All kinds of small things point toward using females and ignoring males.

    It must depend on the field.

  • drugmonkey says:

    Yes of course it depends on the field and some do better than others to use females and even to do sex-comparisons. The broad strokes show a problem at NIH, however, going by this initiative.

    Not sure what you mean about it being a "feminist" issue?

  • qaz says:

    DM - is a "feminist" issue because typical "default" is male, even though females are half the population. Is a "feminist" issue because effect is that females are ignored, which causes health problems for women.

    I don't think there are very many fields (outside of "sex difference" fields) that do a good job of dealing with sex differences. I think that it really is that (as you say) it is easier to use males for many of the experiments. But the use of males and females is very field and species dependent. The proof that it is really about simplicity rather than something more nefarious is that fields where females are easier (like primate neurophysiology) tends to use females more than males. (At least that's my anecdata observation.)

    I think it is a feminist issue because it is very analogous to when one makes a list of speakers not paying attention to making sure you get diversity and you end up with all white males. Being aware of the issue means proactively looking for women and minorities to be speakers.

    What NIH really should do is use directed funds to fund sex-difference research. The market will fill that space out very quickly. There are a lot of young PIs eager to get funded. If there were extra funds allocated to sex-difference research, there'd be a lot of people doing it. This would be a better system because the people doing that research (who would get funded more easily!) would do it right. Rather than trying to force everyone else to do it wrong.

  • SidVic says:

    I am still unclear about what problem this solution from NIH is supposed to correct. Is women's health effected? I'm not trolling, but genuinely mystified.

  • shrew says:

    SidVic, you may appreciate this layman's presentation of the problem - wide sex-based disparities in the efficacy and side effects of many pharmaceuticals, which are based on poorly-understood, or in many cases completely unknown, differences in metabolism and cell biology.

    http://well.blogs.nytimes.com/2013/01/28/the-drug-dose-gender-gap/?_r=0

    Beyond this, there are also obvious disparities in the diagnosis, symptoms, and prognosis of many, many disease states between the sexes. Autism without intellectual disability affects 7 times as many boys as girls. Women's symptoms of heart attacks include nausea frequently, and rarely includes pain in the left arm. (And it appears that should they survive the heart attack, the aspirin their doctor will recommend based on research performed predominantly on men may do fuckke-alle.) There is an elevated risk of opioid addiction in women linked with apparent sex differences in the distribution, abundance, and signaling of opioid receptors in the brain.

    So, this is bullshit. As a bitchy woman, I don't like taking fucking drugs with fingers crossed that they will work a given way on the assumption that I am just a man with extra hormones. Sex is a biological variable down to gene dosage.

    Furthermore, the admission that monkey neurophysiologists (and by the way rodent immunologists also) work with females because they are "easier" to handle gives the lie to the "males are simpler" argument.

    Males also express an abundance of hormones which vary in abundance and function in response to the environment. Males express a cadre of Y-chromosome specific transcription factors which, contrary to original assumptions, are expressed beyond the testes with unknown influence. For example, the "testes determining factor" SRY is also expressed in midbrain dopamine neurons, where its transcription factor function governs the expression of tyrosine hydroxylase, and thus the production of dopamine, in male rodents and humans. But not in females. Somehow I manage to produce dopamine in my brain without the benefit of SRY - how? what role does this play in the vast preponderance of Parkinson's disease diagnoses (among others) in men over women?

    Are you convinced yet?

  • drugmonkey says:

    I am.

  • Evelyn says:

    I second Amboceptors experience: most of our labs (cancer department) use female mice. I never thought much about it but it may have to do with the strength of Komen in the funding game (if you are studying a potential new drug, you can easily use the same biodistribution figure for many cancers and when Komen apps roll around, everyone becomes interested in breast cancer).

  • SidVic says:

    Shrew- thank for the info. Reading the RFA. I was happy to see that they limit it to vertebrate animals.
    Yes, of course, there are differences in drug metabolism among men; women; ethnic groups; adults, children etc. NIH has health race/gender disparity programs and the clinical trails are 50/50 m/f. I can see arguing for more breast cancer money or something that disproportionately effects your tribe where a case can be made that it is underfunded. I just don't understand the broad brush mandate to tack on sex differences to every NIH study.

    BTW "gives the lie to the "males are simpler" argument". Male monkeys (and rats too) are meaner and bite more. The only thing this example shows is that scientists are pragmatic and not motivated by sexist impulses.

  • chall says:

    I had always done female mice work with my infectious diseases, as a young in the field person I thought it was b/c of the "easier keeping them in groups even if they aren't sisters" . That was part of it. The other part? That the male mice are more sensitive to the infectious agents we used (influenza virus and bacteria). Colour me surprised when I found that out. It seemed at the time, to be a "thing that everyone knew but did't really write out clearly". That means, you have to redo all the experiments if you shift from females to males.... like when you change mice strains. Not everything has to be done only in Balbc (or Bl56CJ).

    Anyhoo... just thought I throw it out there.

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