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Getting Personal: Omics of the Heart

Mar 21, 2018

Jane Ferguson:                 Hello, welcome to Getting Personal: Omics of the Heart, episode 14 from March, 2018. I'm Jane Ferguson, and this podcast is brought to you by Circulation Genomic and Precision Medicine, and the AHA Council on Genomic and Precision Medicine. This month I talk to Deirdre Tobias about her research on branch gene amino acids and incident cardiovascular disease in women, and I got the chance to talk to Kiran Musunuru, the new editor in chief of Circulation Genomic and Precision Medicine, about his take of the publishing process and new directions the journal has been taking.

                                                I'm joined today by Dr. Deirdre Tobias who is an instructor in medicine at the Brigham and Women's Hospital in Boston. Dr. Tobias is the first author of a paper entitled Circulating Branch Chain Amino Acids and CBD Risk in Women that is published this month in Circulation Genomic and Precision Medicine. Deirdre is also presenting this work at the lifestyle sessions in New Orleans this month, where she is receiving the Scott Grundy fellowship award for excellence in metabolism research. Deirdre, thank you so much for joining us, and congratulations on your manuscript and your upcoming award.

Deirdre Tobias:                 You're very welcome, and thank you.

Jane Ferguson:                 Could you tell us a little bit more about your background, and what led you to this specific research focus?

Deirdre Tobias:                 Sure. I am an epidemiologist, and I investigate risk factors for type two diabetes and other obesity related chronic diseases. Most recently I've been interested in looking at the mechanisms linking obesity with many of it's associated risk factors through metabolomics. Metabolomics is a field that's relatively new, and it identifies, or seeks to identify small circulating molecules throughout the blood, or urine, or other specimen samples, and then relate those levels to risk of disease.

                                                Type two diabetes has had large successes with finding markers that are novel, and these are often consistently identified across studies, which is very reassuring, and not always the case for many risk factors of chronic diseases. Branch chain amino acids in particular have been consistently associated with diabetes risk across study populations, and tissue type samples, and methodologies for measuring metabolites. This is reassuring that these metabolite markers might really be picking up on an important signal in diabetes risk.

Jane Ferguson:                 For any of our listeners who haven't had a chance to read your paper yet, I wondered. Can you give us sort of a brief overview of what you did, and a summary of your findings?

Deirdre Tobias:                 Sure. Metabolomic studies, as I mentioned, have been successful in the field of type two diabetes, but less so for cardiovascular disease endpoints. With branch chain amino acids being a risk factor for type two diabetes we then thought to establish, or to examine whether they were also associated with incidents of cardiovascular disease risk. In our study we had branch chain amino acids measured on over 27,000 women from their baseline blood samples, and these women were participants in the women's health study in the US.

                                                This cohort already has over 18 years of mean follow up with a number of CBD and diabetes cases already accrued, so we used these baseline measures of branch chain amino acids measured from plasma samples to then relate these to incident CBD risk. We had over 22,000 MI, stroke, and revascularization events in these women. What we then did was analyze the relationship between branch chain amino acids levels with incident in CBD.

Jane Ferguson:                 That's a really amazing data set. I mean, that's a huge number of subject, so that's really, really powerful.

Deirdre Tobias:                 Yeah. For metabolomics most of the prior evidence has come from smaller case control studies, so this is really an unprecedented number of women participants in general that have had metabolomics with this much follow up. It was definitely a rich resource to be able to address this question and with a substantial amount of statistical power.

Jane Ferguson:                 Right. I know you ran a large number of different models, and you looked at a lot of different covariances, so what were the primary findings?

Deirdre Tobias:                 The main results indicated that even adjusting for the traditional CBD risk factors, including behavioral, and lifestyle, smoking status, family history, race and ethnicity, even body mass index which is a strong predictor of branch chain amino acids levels, we observed a striking association indicating that higher levels of branch chain amino acids were associated with a greater risk of MI stroke or revascularization during follow up.

Jane Ferguson:                 Yeah, and I thought it was really interesting that you saw this in the whole sample, and then you also saw this sort of same association, in sort of like attenuated strengths in individuals without type two diabetes. Then, when I was looking I suppose you had adjusted for a number of different biomarkers, and then when you adjusted for the biomarkers as pre diabetic risks, so hemoglobin A1C or insulin resistance, the association went away. I wonder, even in your subjects who didn't have diabetes yet, were the association between the branch chain amino acids and CBD events was significant, but do you think that this was primarily driven by the pre-diabetes level, where these women are probably on track to developing diabetes, and just haven't hit that threshold for diagnosis yet?

Deirdre Tobias:                 I suspect that could be the case. We do know that diabetes is a risk factor for CBD, and as I mentioned with the strong, consistent evidence indicating branch chain amino acids as a risk factor for type two diabetes we wanted to disentangle any association that we would see with branch chain and CBD to be able to show if that was independent of intermediate type two diabetes or not. When we did stratify by diabetes, clearly the majority of that risk seemed to be driven through type two diabetes.

                                                The women who had diabetes prior to their CBD event, clearly we saw the relationship much stronger for them. The residual is still there among those without type two diabetes, could be some clinical diabetes or pre-diabetes. It's hard to really say for sure, but we do have additional models where we adjusted for biomarkers that were measured in the same baseline blood samples as the branch chain amino acids.

                                                When we adjust for these markers that are more related to insulin resistance and glycemic control we see that the relationship between branch chain amino acids and CBD becomes attenuated. We can interpret this as being that the branch chain amino acids may be mediating the relationship with CBD through these markers of insulin resistance and glucose metabolism. If we similarly adjust for cholesterol, LDL or HDL, the relationship between branch chain amino acids and CBD didn't budge.

                                                That would indicate that perhaps branch chain amino acids and CBD risk is being mediated largely through this diabetic pathway rather than other more traditional CB pathways such dyslipidemia or inflammation.

Jane Ferguson:                 Right, so it's an entirely independent pathway, I guess, that probably adds to the risk rather than being complimentary with traditional risk factors like LDL cholesterol.

Deirdre Tobias:                 Yeah. The common soil hypothesis which has been around for many years suggests that there's a common set of risk factors, or cardio metabolic dysfunction, that leads to both diabetes and CBD. This suggests that branch chain amino acids and impaired branch chain amino acid metabolism could be one pattern or marker of this common predisposition to both type two diabetes and CBD.

Jane Ferguson:                 Right. It's really interesting stuff, and I think this field, it's so challenging following up these markers when you're trying to find out, is a biomarker, when it's associated with a disease is it actually causal, is it a bystander? Are branch chain amino acids increased by insulin resistance, but don't actually themselves contribute to disease, or are they also individually contributing to disease. I know there's been some papers trying to address this through Mandelian randomization approach.

                                                It's indicated that the genetic predictors of branch chain amino acids aren't necessarily causal for diabetes, but that's sort of a consequence for insulin resistance. I wonder how that fits into your findings with, then, the additional associations with cardiovascular disease where we think of this pathway where we get this increased diabetic risk, and then perhaps as a consequence of the increased diabetic risk you have increased branch chain amino acids. Are these, then, themselves increasing oxidative stress or some other mechanism that's then leading to pro-atherogenic, pro-cardiovascular risk, or is it still just, well, it's a bystander, and they're there?

                                                They're a biomarker, but they're maybe not great targets for therapeutic interventions. I don't know what you think of this.

Deirdre Tobias:                 Yeah. No, that's a completely fair interpretation of the data, and the literature overall. I think with observational epi, disentangling not only the causality but the temporality, so which biomarker is really, if it is causal, occurring first on this pathophysiology from say obesity or lifestyle to ultimately CBD? I think that it's difficult to really determine from one single study what that directionality is. Looking to the other literature we do see that there is the Mandelian Randomization. I think there have been more than one now, but one did indicate that genetic predictors of circulating branch chain amino acid levels were associated with type two diabetes risk, which supports there being a causal relationship between branch chain and diabetes.

                                                I haven't seen that also done for CBD, but that could be a next step. I think another next step for branch chain amino acids and metabolomics in general is to establish whether or not these are modifiable. If they're just along for the ride, or they're even just a strong biomarker, what does that mean clinically? I think it's still a very open question for many of these metabolomic studies, and even when we have these metabolites that really rise to the top as strong biomarkers, what do they mean?

                                                It could even be that we know they're causal, but that they're not entirely modifiable. Maybe they are just very strongly genetically determined. I think the next step might be to then identify what modifies levels of branch chain amino acids, whether it's lifestyle, or pharmacologic therapies, I think is still unknown, but if we can identify what can modify branch chain amino acids and then answer that next step of, "Well, does the modifying branch chain amino acids then confer a lower risk in disease," that would be an ultimate question to answer.

                                                I think these large scale epidemiological studies are very important as that first step in telling us whether we're even going in the right direction, and then subsequent studies will only strengthen these results, especially when it comes to the causality point.

Jane Ferguson:                 Right. Right. I know in your current study, you're limited somewhat by the data, but I wonder. Were you able to look at whether dietary factors, or physical activity and exercise levels were even associated with branch chain amino acids. Obviously protein intake, or carbohydrate, sort of a prudent versus a western diet, were you able to look at that, or is that something that you may be able to look at in the future?

Deirdre Tobias:                 Right. In the future we are hoping to disentangle what the determinants are for branch chain amino acids in this cohort, so looking at the role of physical activity, or dietary patterns, or specific foods and nutrients might play. But for this analysis here, we adjusted for all of those factors, and when we do compare, the first model where we only adjust for age, with the second model where we include adjusting for all the more traditional CBD factors as well as the behavioral, lifestyle, dietary patterns or et cetera, we see that there is quite an attenuation.

                                                This does suggest that there is some room for modifiability, because these other potential confounders are impacting the association that we see. If there was no effect in our results when we adjusted for all of these behavioral factors then they might not be that strong determinant of branch chain amino acids, but we do see some attenuation. It is possible that many of these factors, or maybe collectively they impact branch chain amino acid levels. But that's another next step, and I think that's something that we can address very well with the data that we have in our current data set, the women's health study.

Jane Ferguson:                 Right. I mean, given the large number of subjects, even with messy dietary or exercise data, I think you'll have a lot of power to at least get you in the right direction to then define interventional trials that could specifically address that issue.

Deirdre Tobias:                 Right. Another thing to keep in mind about branch chain amino acids is that they're essential amino acids, meaning that they're derived from diet and not synthesized within our bodies, but surprisingly the correlation between dietary intake and circulating levels is quite low. This, to me, tells the message that metabolism of branch chain amino acids, more so than their dietary intake, is what's driving these elevated levels, and what leads to this impaired ability to break down branch chain amino acids leaving these higher circulating levels, I think that's the risk factor that might predispose to these other cardio metabolic conditions down the road.

                                                Really I think the next steps would be to determine why certain people have more impaired metabolism of branch chain than others. Body mass index is highly correlated with branch chain amino acid levels, that's, you know, an obvious next direction would then be to look at lifestyle factors and anthropometrics to see where those lead us.

Jane Ferguson:                 Right. Right, and I wonder, is there some genetic [inaudible 00:16:05] where you could maybe find the people who don't fit the profile, like say somebody who has really dysregulated glucose and insulin homeostasis but actually has very low branch chain amino acids, or the converse, where they have very high branch chain amino acids but actually their insulin levels seem fine, and see. Is there something special about those groups of people, if they even exist? I'm sure there's probably some disconnect sometimes. It's not obviously perfectly predicted.

Deirdre Tobias:                 Right. Sometimes looking at those discordant phenotypes can be really informative, and I think that could be interesting to look at as well. I think the genetic predictors, the few snips that have been associated with circulating branch chain amino acid levels from some of the Mandelian Randomization studies indicate that heritability might not be that strong, but certainly there are genetic factors that influence levels. But a lot of it is likely to be more of the modifiable, or environmental risk factors.

Jane Ferguson:                 Right. Right.

Deirdre Tobias:                 Which I think is an important message for prevention, or motivation towards prevention, because if we can modify this important risk factor, then we can ultimately reduce risk. It's certainly a lead worth investigating.

Jane Ferguson:                 Yes, absolutely. Yeah, what's next for you. Are you going to keep working on some branch chain amino acids? Are there other metabolites that you're interested in as well?

Deirdre Tobias:                 The overall metabolome is something I'm still very interested in. Branch chain amino acids have risen pretty quickly to be among my favorite metabolites, if I'm allowed to have a favorite metabolite, but I think that although an overall metabolomic pattern identifying what the overall pattern or profile of metabolites looks like for individuals who go on to develop certain diseases, and using those patterns as predictors, or again looking to see what we can modify about them I think is also really interesting. But branch chain amino acids clearly have an important role either as a predictor, a bystander along for the ride, or possibly even causal, yet to be determined.

                                                Yeah, next steps would be to, like I said, identify, what are the determinants of higher levels, and whether or not these can then be modified to reduce risk.

Jane Ferguson:                 Important work. Is there anything else you want to add that I haven't asked you about yet?

Deirdre Tobias:                 The other findings in the paper were that it seemed fairly consistent across the three branch chain amino acids that we investigated, so isoleucine, leucine, and valine, which share a similar catabolic pathway. Again, maybe the overall breakdown of this metabolite type rather than any one metabolite might be what's relevant to [inaudible 00:19:01].

Jane Ferguson:                 Right. Yeah, so a defect, if there is one, is a stream of all of the branch chain amino acid processing.

Deirdre Tobias:                 Mm-hmm (affirmative). Yeah.

Jane Ferguson:                 Yeah, really interesting. Well, thank you again for joining this, and for talking about your work. Congratulations again on it. It's a really interesting paper, and your presentation and award at EPI Lifestyle, it's great stuff.

Deirdre Tobias:                 Great. Well, thank you very much. I appreciated talking to you.

Jane Ferguson:                 Thanks. As many of you may know, Dr. Kiran Musunuru is an associate professor of medicine at The University of Pennsylvania, Perelman School of Medicine. More pertinent for this conversation, he assumed the role of editor in chief of Circulation Genomic and Precision Medicine this year. Welcome Kiran, and congratulations on your appointment as editor in chief. That's a fantastic achievement.

Kiran Musunuru:              Thank you.

Jane Ferguson:                 With great power comes great responsibility. I know you've been making a lot of changes to the types of content available on the journal website, and finding new ways to ensure the journal is publishing best science and keeping up with changing technologies and capabilities. I'd love to hear about some of the initiatives that you've been putting in place and what your vision is for the journal going forward.

Kiran Musunuru:              Sure. I think it's not just about publishing the best science, although I think that's obviously the core mission, but I think also publicizing the good science that we're publishing. With that in mind, the name change of the journal to Circulation Genomic and Precision Medicine really indicates our desire to go beyond what can seem like the very limited scope of cardiovascular genetics, and really take advantage of the rich work, and the energy that's now being infused into whatever you want to call it, Omics, or precision medicine, or so forth. It really is much more than just cardiovascular genetics.

                                                We're casting a wider net. We want to publish a more diverse group of articles. In a sense, we want to be a player in the field. We have a nice opportunity where there is this thing called precision medicine, but everyone is hard pressed to define exactly what that means. I think what that signifies is that it's just so new, and still in the process of early evolution, that the journal I think will have a part to play in helping to define the field over the next few years. I think that's very exciting. It's a very exciting opportunity for any journal, or any journal editor, to be able to contribute in that way.

                                                But as I said, it's not just about publishing the best science. It's also about really trying to make maximum possible impact with that science. With that in mind we're working very hard to introduce elements in the publication process to really expand the reach of the work that is published. The way I like to think of it is, traditional journals a paper is published on the printed page. It gets mailed out to it's subscribers. Some people read it. Some people don't, but within a few weeks after the issue is published basically that's it.

                                                No one really, certainly is not going to casually pick up an issue and look at it, and only a very limited number of people are going to come across the paper on PubMed or whatnot, and actually go track the paper down. I think it should not be the end of it. I think that should just be the beginning. I think the day that it's published online, or in the formal journal, is really just the beginning of the opportunity to make that work known, and really try to make an impact on the field.

                                                Some of the things that we are doing in that spirit include this podcast series, that chain. You've taken the leadership, and have been doing a wonderful job with in terms of promoting some of the science that we're publishing, as well as just general issues in the field that I think that will be of broad interest to the same people who are interested in the content of the journal, and interested in the science that's encompassed by the Genomic and Precision Medicine Council, The American Heart Association.

                                                One element beyond that is what we call our calling, I think of as video summaries. Some journals have been experimenting with this in a sort of exploratory way inviting authors to make their own videos and submit them so that they can be placed on the journal website. Of course that demands a lot of authors 'cause there's a lot of inconsistency in the tone and the quality of those videos because they are coming from very diverse people rather than being centrally produced with the journal.

                                                Some of the very high profile journals have a substantial enough budget that they can actually internally produce, with high production values, very nice videos, but again, they tend to focus on just one or two key articles in each issue. Our ambition is to have a video summary for every original research article that's published in the journal bar none. We think that plays a very useful purpose.

                                                We think that getting someone to actually download a PDF, and read through it carefully, in this day and age is a harder sell than it has been in the past, and if we want to take full advantage of social media, and the fact that everything is out there on the internet, and can be accessed through devices, through smart phones, et cetera ... We felt the best way to introduce a paper and the content of that paper to the casual viewer, or listener, or reader, if you will, maybe not someone who is super specialized in the topic that's covered by a given paper, but still nevertheless has something the learn from the paper, can get something useful out of it.

                                                We feel that generating a video summary that goes through the high points of the paper, that can actually within the video show the key figures of the paper, and then in, not exactly layman's terms, or lay people's terms, but rather, in a non-specialist sense, so still speaking to the science, but without a lot of jargon, without a lot of specialized vocabulary that's really specific to the specialists in the area that's covered by the paper, but really more broadly speaking to scientists, and even more than that, clinical practitioners, really explain in a very straightforward and simple way exactly what the key message of the paper is and why it is important for genomic and precision medicine.

                                                We have started doing this internally. Starting with the January issue we have had a video accompany every single original research article as well as a scientific statement that we published in the January issue. They are linkable, or linked to, from the website, but they are physically, well, not that anything digital is really physical, but let me put it this way, they're hosted by a YouTube channel under the umbrella of the Circulation Journal. They can be found there because they are on a YouTube channel they are essentially a permanent part of YouTube, so anyone searching YouTube can find them.

                                                Then something we've started doing with the transition internal leadership and the new name of the journal is using Twitter to make people aware of these articles that we are publishing, but one very nice thing we can do since we have video summaries available on YouTube is we can actually link within a Tweet directly to that video, and people can actually watch the video directly within Twitter on their devices, on their smartphones, on their computers, wherever they are, however they're accessing it.

                                                We've been finding that people are watching these videos, regardless of what channel they use to get to the videos. They are watching. I think that's a nice thing, because it is expanding the reach of the journal to an audience that might not necessarily or naturally go to the journal website to see what the latest articles that have been published are. It's a different way of reaching the intended audience.

Jane Ferguson:                 Yeah, I think it's fantastic. I mean, it's much easier to watch a video for a few minutes when you're, I don't know, waiting for the bus or something, rather than take out your PDF and try to read through these dense method sections. It's really fantastic, I think, even for people who are, if it's our field, or if it's something outside of our field, or people who don't typically read scientific articles but are interested in science [inaudible 00:28:24] and learning more. I think it's really nice to offer that sort of alternative format for people to discover a new science.

                                                I wonder, what do you think is the value of commentating an interactivity in scientific publications? I know in some places they allow commenting, whether anonymous, or named. For a lot of people they get a lot of their science on Twitter, and they have Twitter conversations. Do you think that's an important role that needs to grow more in our dissemination, our discussion of science? Do you think there's an ideal forum for this kind of discussion, or is it still something that's evolving, and we'll find our place, whether it's the comments section of the YouTube videos, or on Twitter, or elsewhere?

Kiran Musunuru:              Sure. No, that's a great question. It strikes me that a lot of groups, a lot of organizations, have been hitting upon the same question, and attempting to answer it by generating a forum that's, if not exactly proprietary, is very much under their thumbs, with the intent of fostering conversations about papers published in journals, about content from publishers and so forth. Because everyone is trying to do their own thing it ends up being quite fragmented.

                                                There's not a lot of uptake for any one particular publisher's website, or any one particular mechanism. What has sort of naturally, spontaneously occurred, is a lot of those conversations have just happened on Twitter, which is not intended specifically for scientific discourse, but has cast such a wide net, and has so prevalent a footprint in our society that it serves that purpose just as well as it serves 100 other purposes.

                                                I think it's becoming clear that, increasingly, conversations, discussions, debates, controversies even, are unfolding on Twitter. That's not to say that everyone's on Twitter, or even a large segment of our intended audience is on Twitter, but I think a growing proportion of our audience is on Twitter, and Twitter I think skews younger. But we're a young discipline, and I feel like a lot of the practitioners, a lot of the investigators in our field are of a younger generation who is more ready to embrace Twitter, and is already out on Twitter, on Facebook, on other social media outlets.

                                                I think this is going to be absolutely critical going forward. Twitter, it's not happenstance of course, but it turns out that it lends itself nicely to communication about scientific articles because you can link directly to a paper through Twitter right there in the Tweet, so people don't have to look very far. You can send out your Tweet describing the paper in very brief terms, but then within that Tweet you actually see a box with a description of the paper, with a link to the paper. You can link on it. It takes you directly to the journal's website.

                                                You don't have to actually work to find the paper. The same is true of other elements that we've already discussed. If you want to listen to this month's podcast for Circulation Genomic and Precision Medicine, spearheaded by Jane Ferguson, then the Tweet that goes out, and then is retweeted among our network, allows you to click right there and go to the podcast. Again, you don't have to track it down. You don't have to find it. It's just kind of put there, out there, and people will immediately be notified about it because it will be on their feeds, and then they'll see it.

                                                Then, as you say, when you're waiting for the elevator, or you have a little bit of down time, you can go ahead and just click on it and immediately start consuming it, if you will. The same, of course, is true of our videos. Our videos are five to ten minutes, ten minutes maximum. They're intended to be bite sized pieces that you can kind of catch on the run as you described. It's not a matter of you having to download a PDF and read through very dense language and through method sections and try to figure out what's going on.

                                                Then people can access these on Twitter, through other channels. Then a lot of the conversation can happen on Twitter, and on the other channels. I think we're seeing more and more of this happening, among at least that portion of the scientific community that is Twitter savvy.

Jane Ferguson:                 Yes. And I will use this opportunity to plug everybody to follow us on Twitter. You can follow us at @circ_gen, and you can tweet at us and tell us what you think of the journal, of the council, of the podcast, of science in general. We would love to hear your thoughts on that. As we're talking about this, how we're able to access so much information so quickly at our fingertips, the publication process has in some ways still lagged behind, where you submit your manuscript, and it goes out for review, and sometimes you don't hear back for a very long time. I'm wondering how you at the journal are dealing with that aspect of the publication process, and the turnaround time?

Kiran Musunuru:              Sure. I mean, I think it's becoming increasingly less acceptable for what has happened in the past, and it has been highly prevalent in the past to continue to occur. What I mean by that is, a very long, drawn out, peer reviewed process and time to publication of the final project. I mean, it's so unacceptable these days when there's so many avenues through which you can communicate your science.

                                                We're seeing things like pre-print servers that are really getting messages out. Then to have to go through a formal review process, and take many months, even years, to actually get your work actually formally published in a journal with the imprimatur of high quality peer reviewed process is just too long. It's impeding communication among scientists. That's a disservice to the scientific process, especially in a day and age where there is such a rapid evolution of technologies. There's such rapid advances in a field, to think that the journals are having to play catch up with what's actually going on on the ground is really quite frustrating.

                                                It's part and parcel of the publication process as it is, and it's not going to change overnight, but in my own role as editor of a journal I'm doing what I can to remedy it. I've committed, and the journal's editorial staff has committed to really trying to streamline the review process. Now, we're not going to work miracles, but I'm happy to say that, whereas in prior years it would have taken on the order of three, four, five weeks for a paper to be reviewed, we've really worked hard to streamline that to make it much more quick, nimble, and we hope less cumbersome to authors.

                                                For example, I will say in the month of January our average time from submission to first decision was under one week. Part of that is, we've accelerated the review process, engaged high quality reviewers who we know are responsive, and who will turn around papers relatively quickly. We've engineered things so that there's not much delay to any step in the process. Even those papers that are sent out for review we've accelerated the process and decreased the time on that basis alone, but something else we've introduced is a very rapid triage process.

                                                Rather than have a paper sit around, sit around, and then be assigned to somebody to look at, and then have to wait for a weekly conference call among the editors to decide the disposition of that paper, you can see how things can get drawn out. Even before the decision is made to send something for review you might have a paper sitting around for a week or two. That happens, I know from my own personal experience at quite a few journals. We're committed to making the decision, ideally within 24 hours, but certainly within 48 hours.

                                                Our editorial staff is extremely responsive. When a paper is submitted, there's a whole lot of eyeballs among the editorial staff that look at that manuscript from the get go, quite a few opinions, not just one, or two, or three opinions, but more like six or seven opinions within 24 to 48 hours. That's useful in two ways: One, it allows us to make a very informed but rapid decision as to the disposition of a paper.

                                                I think the optimal scenario is where we can forecast whether a paper is not going to fare well in the review process, and is ultimately going to get rejected, without actually having to go through the full length peer review process. If we can predict that outcome occurring, but be able to do that within the first 24 to 48 hours, then we can just make that decision and spare the authors a long delay for what ultimately is likely to be a negative outcome.

                                                Conversely, if we are fairly confident that a paper will ultimately get accepted, we'll need some revisions. Every paper can be improved, and that's what the peer review process at it's best is all about is improving the quality of a paper. But if we can forecast very early, this paper is very likely to be accepted. This is what we should send out for review. Then that allows us to really save everybody time.

                                                It saves author's time, 'cause they're not going through a long, drawn out process before ultimately having a negative outcome, but it also spares reviewers' time. We can focus reviewers' efforts on those papers that are extremely likely to ultimately be accepted, and that's the most constructive use of reviewers' time, I think.

                                                There's a secondary purpose, however, and that is when we do reject a paper without review because we've garnered so many opinions about the paper in a very short time, we're actually in a position where we can offer useful feedback to the authors as to why the paper was felt not to be of high enough priority for the journal. Most journals, and I'm speaking from my own experience as a scientist, as an investigator, as an author, you send the paper, and then it takes them how many days, or weeks to make a decision. Then often they will decide that it's just not for them, and they will reject without review.

                                                That's okay, but it can be very frustrating when the decision is made, and then you get the letter back saying, essentially in effect, "We don't like this paper," without any explanation why. What we have been doing, which I think has been well received by authors, is offering fairly detailed feedback. If you want to think of it as a triage review you can think of it that way, but corporate feedback from not just one or two peer reviewers, but actually six or seven editors who have looked through the paper.

                                                We've actually gotten feedback from a few of the authors, that even though we are not publishing the paper, it's been useful in helping them to revise the paper and then go on to the next journal for submission.

Jane Ferguson:                 Yeah. I think that's fantastic on all fronts. I think making the process faster is better for everybody, and also making it constructive, so that yes, you're not just sending out form rejection letters, but you're actually helping scientists and authors to identify what could be improved in their papers and what sort of things they might not have thought about. I think that's really fantastic. Is there anything else new with the journal, or anything else that we can look to in the next few months coming out?

Kiran Musunuru:              Well, I think we've hit the high points. I think the idea that we want to be friendly to authors, that we want to streamline the review process, that we want to work hard to publicize their work and maximize it's impact in the community. I think by broadening the scope of the journal we're hoping to get substantially more submissions, and more diverse papers. We're very interested in publishing in the area that broadly falls within genomic and precision medicine. We're working hard to generate high value, non-original research articles.

                                                What I mean by that is scientific statements from The American Heart Association, working closely with the Council on Genomic and Precision Medicine to generate scientific statements that are of value to the community. Of course, we would continue to want to publish state of the art reviews, but also partner with other organizations, and publish white papers. For example, we have a couple of white papers on which we're working with The National Heart, Lung, and Blood Institute. That should be coming out in calendar year 2018.

Jane Ferguson:                 Okay.

Kiran Musunuru:              Beyond things you would normally associate with publishers, we're also working hard to increase our presence at meetings. Part of that is what you might expect editors of journals to do, which is being there in person, and attending talks, and attending poster sessions, and pressing the flesh, and inviting promising presentations to be submissions to the journal. Of course, that's part and parcel of what any good, proactive journal is going to do.

                                                But I think going beyond that, and doing more, and actually being involved in contributing educational activities at conferences. As you well know, the Council on Genomic and Precision Medicine in partnership with the journal has been organizing boot camps and workshops at various American Heart Association meetings that have been extremely well received. And we've now started to organize similar sorts of boot camps and workshops at non American Heart Association meetings.

                                                We'll be doing quite a lot of that, at least three or four national or international meetings in calendar year 2018. I think this is all part of a big strategy to not just be a place where papers are published, read for a few weeks, and then never really thought much of again, but really to make it more of a living piece of work that can inform the community, that has a reach beyond the printed page, whether it's through videos, or podcasts, or forming the basis for educational activities, workshops, boot camps, maybe eventually journal clubs, things of that sort. That's what we would really like to do with the journal going forward.

Jane Ferguson:                 That's fantastic. I think it's really great. You're doing some great new initiatives. Congratulations again on your appointment as editor, and on all of the wonderful work you're doing.

Kiran Musunuru:              Thank you, Jane.

Jane Ferguson:                 That's all for this month. As a reminder, you can follow us on Twitter @circ_gen, and you can also now connect with us on Facebook. Find us under Circulation: Genomic and Precision Medicine, and hit like or follow to get the latest in your news feed. Thanks for listening.