NIH All About Grants Podcast � Sex As a Biological Variable

Narrator: From the National Institutes of Health in Bethesda, Maryland, this is "All About Grants."

David Kosub: Hello and welcome to another virtual edition of NIH's "All About Grants" podcast. I'm your host David Kosub with the NIH's Office of Extramural Research. And today, we're going to be talking about a very important policy that we've had in place for a few years now, and that's the sex as a biological variable policy or SABV, and I'm glad to say that we have with us Dr. Chyren Hunter. She is the associate director for basic and translational research with the NIH's Office of Research on Women's Health, and I welcome you to the show.

Chyren Hunter: Well, thank you very much, David. I'm happy to be here today to talk about this very important topic.

David Kosub: Great. Well, let's jump right in. I'll give you a softball. What is the SABV policy, and where did it come from?

Chyren Hunter: Uh-huh, glad to answer that question, but when I talk about the SABV policy and before we dive in, I usually like to start off the discussion with a few definitions. Let's talk about sex. Sex refers to biological factors including chromosomes, gonadal organs and hormonal profiles, and NIH research usually categorizes the sex in vertebrate and animal subjects and human participants as male or female, although we do know that variations sometimes occur, so that's sex. Gender refers to socially constructed and enacted roles of behaviors which occur in a historical or cultural context and also varies across societies and over time. But what we do know is that both sex and gender affect our health. So what about the SAB clause, and where did it come from? The SABV policy states that unless there's a clear and strong justification for a single-sex study that the NIH, and I'm quoting here, "The NIH expects that sex as a biological variable will be factored into research designs, analyses and reporting in vertebrate, animal and human studies," and important to note that the policy pertains both to preclinical as well as clinical research.

David Kosub: Well, I appreciate those definitions. That's actually really helpful because it kind of helps me ask the next question of, well, why is this policy important?

Chyren Hunter: Right. I can say a little bit more about the policy and give you a little bit more background which I hope will be helpful. So really the policy was established to improve the overall rigor and reproducibility of research. Now we had seen from data from published studies that some of the studies could not be reproduced either because there was no information provided on the sex, or if the sex was specified, typically there was an overreliance on use of male animals and cells, and this leads to a knowledge gap on sex effects, and so that's a problem. Another thing that we found is that clinical trials were failing, and sometimes this was in part due to the lack of consideration of possible sex-and-gender-specific effects, so not considering sex has real-world implications for the health of women and men because we don't have a complete knowledge base on which to build treatments and cures.

David Kosub: So thank you for that. Let's kind of get into some of the nuts and bolts. Do all applicants need to address SABV as they're putting together an application?

Chyren Hunter: Great question, I get that all the time, and the short answer here is yes, and I'll emphasize the policy here that NIH expects that sex as a biological variable will be factored in all types of studies, vertebrate animal and human studies, so yes, and it's so important that we like to promote our free resource which is the SABV primer, which it's a four-module online e-learning course that tells you about the background for the SABV policy, why it's important, how to build your ... how to design your study, how to analyze your study and how to report your study, and it's a great resource for both the beginning investigator as well as that seasoned investigator who's trying to adhere to the policy, and on the ORWH website, and it's part of a larger e-learning section which I hope your audience will avail themselves of.

David Kosub: Definitely, I will encourage them to do so. So how should someone be considering or addressing sex in their research? Do you have to consider sex differences or the influences of sex, things like that?

Chyren Hunter: Okay, great. So let's talk about considering SABV generally. In your application, there are three areas where it's important for you to identify the consideration of sex, and I would say up front that's in the abstract of your application that you can identify yes, you're looking at considering both males and females in your study. But when we really drill down, you really want in the vertebrate animals section discuss the sex of the animals that you're using in addition to the species, age and the number of animals. But the key place is in your research strategy and your research plans specifically. That's where you're going to provide a description of how sex factors impact your experimental design, so you should be designing your experiment so that you can look at sex-specific factors. And in the same research plan, that's where you also want to describe how you're going to analyze the data. For example, investigators should discuss how they're going to disaggregate the results of their study so they can look at females and males separately and report out the data by sex. Also in your preliminary data and any publications of your work, you should report on sex-specific results of your treatment paradigm. So considering SABV is important in those three areas, and also the consideration of the design and the analysis and the reporting is important.

David Kosub: So thank you for all that. It sounds like you need to be thinking about this in all facets of the research, and if I'm a researcher out there, now I've got to be thinking about both male and female and sex and gender, all those things in my research. What's the implication for the budget?

Chyren Hunter: Right, right, right. Yeah, yeah, and this is really, really so important, and I'll say that when you're designing a study just to build this out a little bit, when you're first thinking about a research project, you should also be thinking about at the very beginning think about any possible consideration of sex, so from the very outset when you're building the research question all the way through to reporting out the data, the consideration of sex should be part of your research plan. One thing I'll also say is that we're not asking all investigators to become a sex differences researcher. What we are asking however is for you to, if you don't know the role of sex in your study that you plan and design your study so that you can make some assessment of that consideration. Now there are sex differences researchers out there�and they are going to power their investigations because they're looking specifically at sex differences. You as a researcher don't have to power for sex, but you need to design and report out sex-specific considerations in research. So you asked about the budget. Am I right?

David Kosub: Yeah, that's right. It's all about the money.

Chyren Hunter: All about the money, okay. Yeah, so about the budget, one thing that's important to say is that any of you out there who have been on a study section or know about study sections, you might know that some researchers think that often, they have the impression that if they have a smaller budget, they have a better chance at funding. First of all, that's not the case. And about the budget, NIH first of all wants research that is rigorous and reproducible and contributes to our knowledge base to build treatments, so build the budget that you need to do the research correctly the first time. Now ... And reviewers are really expecting that you are savvy enough to build a budget that's appropriate for the study you prepare. Now I will say that correctly accounting for sex may certainly impact your budget. I think it's a misnomer to say that it's going to double your budget, not true, and you can find that out by really strategizing with a biostatistician who can help you identify the appropriate analytical framework for your study, so not every study that considers SABV really means that you're going to have to double your budget or even double the number of animals, so work with a biostatistician. But overall, the goal here really is to have more rigorous and reproducible research.

David Kosub: So building off what you were just talking about, you were mentioning study sections and the peer reviewers and things like that as it relates to the budget, but what else are they looking at as they're reviewing your application in the context of SABV?

Chyren Hunter: Yeah, so certainly. I have read a lot of summary statements and sat on a lot of peer review meetings and recognize that peer reviewers are researchers just like yourself and they're taking time out of their busy schedules to review hundreds of applications, and so make it easier on them to find the information that they need, and what they need is they need to find the information on how you're assessing SABV. Now what they see and what I've seen in some summary statements that a reviewer might say, well, this investigator is using males and females in the study, but they pull males and females into the control and treatment groups. Thereby it's difficult to assess sex-specific effects. That's something you would see in a summary statement. That's not a good thing because you're not looking at sex-specific effects. A description in the application that might raise a red flag for a reviewer is they might see a statement that mice of both genders will be used. Now we talked a lot earlier about the fact that sex and gender are different. Mice do not have a gender as far as we know, and so conflating sex and gender is a no-no, and I've seen that in applications, and sometimes reviewers do comment on that. With regard to preliminary data, if the preliminary data does not report on the effect of sex, then the reviewer might comment on that as not being appropriate for SABV. So those are some things that reviewers see, and the comment that I mentioned to you would really reduce your score and lower your chance of funding.

David Kosub: So actually building on that lowering your score and chance of funding, you mentioned SABV must be considered by everyone basically. What if I don't? Is that going to impact my chance of being funded?

Chyren Hunter: So the consideration of SABV is a scorable criteria, and reviewers are asked to comment on that, and if you don't, it certainly can impact. It is supposed to lower your impact score, and that does in fact reduce your chance of funding.

David Kosub: So definitely want to consider it, it sounds like. So thank you. This has been a good kind of framework and foundation, so we've talked about what SABV is. What is it not? What are some myths and misperceptions about this policy?

Chyren Hunter: Right, right, very important, very important. I will say that the SABV primer that we talked about earlier has some really good ... has a whole list of misperceptions about SABV, so I'll talk about a couple. One misperception on the mandate on the SABV policy as a mandate is that we're asking investigators all to be sex differences researchers, and as we said earlier, not true. We just ask you to consider sexes in your application. Again, a misperception about powering, if you're not a sex differences researcher, you don't really need to power your study to look at sex. One big misperception about the inclusion of females that we really, really must dispel because there's data out there in the much earlier data, published data that said one reason for excluding females as subjects in research was because they had greater biological complexity than males because of their gonadal hormones, not true. This is not a valid reason for not having females in your study. As a matter of fact, there's a recent study that has shown that the gonadal hormonal levels in male animals have significant complexity also, and they also vary over the course of the day and based on their housing and a number of different factors. So it is a misperception that females should be excluded subjects because of hormonal variability, and that is ... We really want to make sure that your audience knows that.

David Kosub: Thank you for that. So let's just say I made it through the whole process. I got funded. Now I'm in the reporting part, my annual reporting. Is there anything specific that NIH is going to be asking for so as it relates to reporting on SABV or even when I'm publishing my articles, for instance, my research rather?

Chyren Hunter: Mm-hmm, great question, great question because we know that it's at least almost a year sojourn from application to funding, and now you're funded, and you just want to do your work, and I get that. But remember that part of the work you were funded for was to address the consideration of sex in your study, and so your progress report which is pretty much done annually or semi-annually, in those progress reports, you should be reporting out your preliminary data and any sex effects in your study, absolutely important. Your program director is going to be looking for that to see that you are being a good steward of the funds that you were provided by the NIH, so that's important to include that information in your progress reports. And in addition to the NIH requirements, you should be aware that outside of the NIH, many journals now have their own SABV policies, so in fact a "Nature" editorial explained that from now on, researchers who submit papers, and this is to a subset of their journals, those investigators will need to state whether and how sex and gender were considered, so considering sex is not only important at the NIH and not only important to report at the NIH, but it's important across the entire biomedical research community and also internationally. There's ... Many follow the European Association for Science Editors guidelines for reporting sex and gender. These are called the SAGER Guidelines, and there are many other international organizations that are now asking their investigators to consider the role of sex in their study. And media interest is also very high on this topic.

David Kosub: Well, thank you for all that. This has been great. I always like to have the opportunity to give our guests one final opportunity to say anything else that they think is important about this particular topic, so what would you like to leave with our audience about SABV?

Chyren Hunter: Okay, thank you, David. This has been a great discussion, and I hope that those listening to the podcast have learned about SABV. And we've been talking about applications and where to put it in, but the thing to remember is that the study of sex and gender is part of rigorous and reproducible research, and when we have a complete knowledge base on sex and gender, we can use that to build upon and to build better treatments and cures that are going to take to more personalized medicine and advance the health of all of us. And so we should look at SABV as an opportunity, the inclusion of SABV as an opportunity, not an obstacle. You have data out there, and if you have data on males and females and you're not looking at sex-specific results, that is data hiding in plain sight, data that's important, useful, and it will build our knowledge base as I mentioned before. And the policy is having a positive effect. Many investigators have now seen the value in the policy and are finding that when they look for sex influences, they often find sex influences. And I talked about NIH not being the only institution that's considering SABV. There's the Canadian Institute of Health Research, and the UK's Medical Research Council recently announced plans for its policy. So NIH is the largest funder of biomedical research in the world, and it is our opportunity and our responsibility to contribute to the biomedical data and advance the health of all of us. And I wish you all good research and good results �using SABV.

David Kosub: Hear! Hear! to that. Well, Chyren, this has been a great opportunity to hear more about NIH's sex as a biological variable policy. For those interested, I echo what she mentioned earlier. There's a variety of training opportunities and other information that we highly encourage you all look at. It's on the Office of Research for Women's Health's website, and this has been David Kosub with NIH's "All About Grants." Thank you very much.