Effecting a public health response to genetic information: Best session at AHA’s EPI / NPAM Day

The talks were semi interesting today; apparently I made a bad pick by missing one on gastric band surgery arguing that whatever section of the stomach you band off – insulin sensitivity goes up. However, only banding off the top part cuases weight loss; the bottom part has no effect. The talks on increasing the accuracy with which we measure energy intake and expenditure were less psychologically informed than I had hoped, and the talks on cardiovascular disease (CVD) risk factors pretty much all contained within the their abstracts – all though all talks were of course very good. The best part of the day for me, was a roundtable discussion on ‘’Genetics and Genomics” – I went thinking that I would be listening to one, but found that the format was to participate in one. I tried to run away, but my friend / colleague Ryan convinced me it would “be OK”. It was an hour long discussion, and there was one strand of conversation that really interested me and is a particular passion of mine, and I would like to share my thoughts on. It is something very dear to my heart, and probably underpinning my interest in obesity research:

How do we get individuals to respond to genetic risk information and alter their lifestyles?

NB: As before, I do not wish to claim that all people currently have the tools (whatever they may be) to reduce their risk of future disease; the question of how to effect pubic health change is a huge puzzle for many professionals to solve: epidemiologists, bench Scientists, policy makers, economists, psychologists, sociologists… to name but a few. This topic, again, is my thoughts on just one tiny thread that may help contribute in a huge tapestry of human health, and I would in no way judge anyone for the lifestyle choices they make.

Some of the participants were clinicians and spoke movingly of patients with a history of CVD heading right down the path themselves, in fact, being clinicians they usually saw them after a cardiac event and still these individuals were smoking, eating a high-fat and high-refined carbohydrate diet and doing little to no exercise. They had treated these people’s fathers, brothers and uncles, yet still saw it passing down the generations. I empathised. Someone very near to me own heart turned his father’s life support machine off ~5 years ago after a cardiac event. He saw the family left behind, he talks movingly about how his niece and nephew found it so hard to lose their grandpa, and now my friend is getting married, has witnessed the disappointment of not being able to at least tell his father in person. Yet, my friend will eat calorically dense (beyond their requirement), and high salt fast food up to three times a day, has more sugar than anyone I have ever met, chews tobacco, has a current BMI classification of ‘clinically obese’ (31; although he is very broad so it is perhaps slightly overstated) and does no regular vigorous exercise. He admits that his father’s untimely death was in no way  unusual for the family: indicating a potentially very high genetic risk.

Why? Why do people ignore these signs? My suspicions are:

(1) Misunderstanding genetic risk. In terms of the spectrum of the potential impact of genetic risk perhaps people fall too far at the tail ends of the distribution. Their attitude is either “it doesn’t really have any effect” or “it is a fait accompli”.  Of course, neither is accurate and despite how Science prevaricates and evolves, I would say we are pretty sure, that genetic risk exists but for a large portion of the population, can be mediated by environmental and lifestyle interventions. Put it this way: you can have all the genes to be the greatest chess player ever, but if no one teaches you chess, they aren’t going to show. Or you can have obesity risk allele there is, but if you don’t get any food… you’re not going to be overweight. Genes are rarely a prescription set in stone, rather they are another increased risk factor. Rather like driving a car: driving a car puts you at increased risk for mortality. But, some people feel they have / want / need to do it – putting themselves at this increased risk. But, they work out ways to minimise this risk: use of traffic signals, driving carefully and with awareness, seatbelts, not talking on the ‘phone. For the majority of people, this will have an effect and prevent mortality, but it won’t be foolproof. We need to get the message to people that if they are at genetic risk, but they can substantially lower their risk.

(2) People don’t want to decrease their obesity / risk of CVD. This is something I struggle with; I came to UAB with an attitude that we must make people reduce their BMI / CVD risk, almost by any means necessary. If that meant making sugar sweetened beverages an unviable option through taxation: so be it! But I think my attitude was very biased towards my own inclinations. I assumed that everyone wanted to be healthy  – they just didn’t know how, or have the psychological tools to be able to. My friend David strongly disagrees. He says some people don’t want to be slimmer, they don’t want to reduce their risk of later disease and that is utterly up to them: surely it is their choice? I raised the issue of socialized medicine, where the rest of society is paying for these choices, but that is not the case here in the US, and possibly not a great argument anyway. But then I raised the issue of familial responsibility. By dramatically increasing your risk of future mortality – Don’t you have a responsibility to your family?

Possibly not to your parents, because you did not choose them. So despite the fact that they may have raised you, provided for you and given their life to you, you do perhaps have moral justification to look them in the eye and say

“I’m sorry Mum. Despite everything you have given me, material and non, and despite all my love for you, I am not going to return that gesture and be there when you most need me, because, literally, eating the majority of my meals, to caloric excess, is more important than helping you through your latter years”

Possibly you don’t have a moral obligation to your partner, because he / she had some say in choosing you. So, I guess, you are also justified in saying:

“Thank you for making a lifelong commitment to me, I am afraid I cannot do the same to you, and now, I must leave you to nurse me through ill health, and then face life alone, without the man you built you life around, because, again, lying on the sofa was just way more important to me than doing some regular exercise”.

OK, but what about children (and I know not everyone has children. Nor life partners or parents anymore, so perhaps they do indeed get a free pass). Once you bring a child into the world, is it not your responsibility to do the best by them? Is it morally acceptable to look into your daughter’s eyes and say:

“I am afraid I won’t be there to walk you down the aisle on your wedding day, you must find a surrogate – that tobacco was just too tasty”

I am not entirely sure people should have the right to make those decisions. Yes – nanny state and all, but if we don’t have the right to decide to take other’s material things, to intrude on their time with loud music, or take a lot of other liberties with them: I am not convinced people have the right make these decisions either.

(3) Science doesn’t know enough to quantify risk, or how mitigate it. Science is working… Science is improving our understanding, but it’s a two-way street. Science may not have quite such a hard job if people listened to, and effected, healthy lifestyle advice. We don’t know which genes cause CVD, we don’t know how each risk allele interacts with lifestyle factors, and some lifestyle factors, sure, there is debate about the efficacy of reducing CVD by changing them. But Science is pretty sure about some things:

• There are genetic risk factors that increase your risk for CVD, although they vary in the magnitude of individual effect in the population
• Tobacco for sure, vastly increases your risk
• Being overweight (BMI over 25) increased your risk, especially in the absence of regular, strenuous exercise (sorry, walking across the street to Wendy’s doesn’t count)
• High-fat, combined with high-carbohydrate, in the absence of endurance athlete training, will vastly increase your risk.

(4) A lack of understanding that change needs to happen today: not tomorrow, or after the weekend, or after school finishes, or when you have a child, or when you get sick. TODAY. And an understanding that it will be hard, and something you do have to work at all your life – although it will become easier.

So, how to move forward from this? What do we need?

-Better understanding of genetics in the general population. Perhaps it now needs to come into the high school curriculum: not the biology of genetics, but the use of genetic information and an understanding of what “genetic risk” means. And more research from Scientists to understand it themselves

-Perhaps some way of empowering people to believe they can make a difference, and to help them have the physical, economic and psychological tools they need to. And of course, more research into what those tools are, and how to give them to people

-Better education about the efficacy of lifestyle interventions, and better research on what they need to be

-Better research on individual differences in what people need to effect change in their life.

But, bottom line: although imperfect, Science has given you the tools to reduce your risk of all cause mortality: use them!!

The rationale behind obesity prevention: personal and public challenges – best talk at AHA EPI/NPAM conference, Day 1

Apart from mine of course ☺

The keynote speaker in the ‘obesity’ section was Robert H Eckel from the University of Colorado. The title of his talk was “The rationale behind obesity prevention: personal and pubic challenges”. He touched on three issues: the role of fats and carbohydrates (CHO) in obesity, the difficulty in maintaining a normal bodyweight for the previously obese and challenges and new directions in pubic policy in preventing obesity.

The role of fats and carbohydrates (CHO) in obesity

The first issue he did not go into in adequate depth to glean something really meaningful for general dietary guidelines. I suspect this was for three reasons:

1. Limited time for a hugely controversial and complicated topic
2. This topic is often best discussed with people more focussed on combining physiology with epidemiology, rather than policy with epidemiological observations
3. The data he presented was more about understanding people’s baseline CHO storage and utilization proclivities, to understand individual differences in responses to weight gain / loss and to set the stage for later data that were prevented, than to make generalized dietary recommendations.

But this part of the talk was interesting. He showed that when physically inactive and eating ad libitum, people handle CHO intake differently; some people naturally burn their CHO, leading to a negative CHO balance. Others, store, not burn, CHO when physically inactive, leading to a positive carbohydrate balance. This latter group (the storers) were, perhaps unexpectedly, protected against future weight gain. You can access the full paper here. What does this mean? A full interpretation was not given in the talk. But here are my thoughts (disclosure: I am currently a low-carb diet fanatic; in fact, I am munching an Atkins Daybreak bar right now…). Burning CHO requires insulin, or at least, is the result of insulin action. Insulin is not the evil it is made out to be – in fact, it is pretty darn vital (ask any type I diabetic). But, it does inhibit lipolysis (fat burning). Perhaps those who naturally burn CHO have naturally higher insulin levels? Or perhaps those who do not burn CHO are more insulin impaired – which is why they don’t burn so much CHO and turn to fat for fuel. Maybe if they are naturally more prone to burning dietary fat & storing CHO, they ultimately store less fat than those who stroe fat and burn CHO (it is difficult / costly to store CHO as fat) and / or they burn more body fat as their body is already ‘fat burning’? Who knows… just my suggestion.

new directions in pubic policy in preventing obesity

The third part of the talk was on pubic intervention strategies and was so-so. There was a lot of ‘we must act in childhood’ – while I have yet to see any convincing (let alone conclusive) evidence that childhood based intervention has long term effects on either BMI or adult health outcomes. Also lots of vilifying fast food (with Ronald McDonald as the poster child) which I believe is too simplistic of a view to be useful.

The difficulty in maintaining a normal bodyweight for the previously obese

However, this middle part was very interesting. It focussed on how hard it is to lose weight, and keep it off. As Eckel put it “once obesity occurs, body fat is defended”. After touching on a purely observational (but well designed study) showing (1) an association between keeping weight off and (a) avoiding fried foods (b) substituting low fat foods for high fat [yes really. Not the topic for this post, but don’t overlook that] (c) increase in strenuous activity and (d) regular ‘sweat’ sessions and that (2) this is in the context of the majority of successful weight reducers regaining all the weight within a year, Eckel examined this second issue only – that weight reducers tend to regain weight no matter how they initially lose the weight. So why is it so hard to keep weight off? Eckel showed in press data revealing structural and functional differences between previously obese and non obese, where body weight was the same between the groups. His 2008 NEJM paper showed that once you have been overweight and reduce body fat a decrease in leptin and GLP-1 and an increase in grehlin (among other factors) leads to

• Higher appetite
• Increased preference for energy dense foods
• Increased CHO oxidation and so (in line with the evidence in part 1) increased fat storage (or my interpretation: decreased lipolysis or fat -burning)
• Decreased preference for physical activity
• Reduction in the intensity of physical activity conducted.

Being ‘reduced obese’ changes your brain and endocrine physiology. But then, even normal weight women who have liposuction replace all the lose body fat within 1 year (albeit it in different places to the site(s) of extraction). Once you get fat; once you enlarge those fat cells, it seems that your body will try to return again and again to this state. As Eckle put it:

“Brain cells come,
And brain cells go.
But fat lives on forever”.

What does this mean?

1) I would argue, that given the relative lack of success at long term obesity ‘cures’, we need to start to focus more efforts on obesity prevention. This way, if we prevent people from becoming obese, we negate the problem of a temporary cure – it may be easier to prevent obesity ever occurring than to prevent it reoccurring. We don’t know this, but it may be worth finding out.
2) Keeping weight off is difficult. There is no quick fix. You cannot go on a temporary diet and expect this to solve the problem. If you want to safeguard your health – You have to go on a permanent guard. And it will be tough. You need to constantly evaluate, revise and watch your motivation. It will likely never become easy or second nature. It doesn’t have to be miserable and it certainly isn’t impossible impossible – but it will be an everyday fight.

This brings me to something I have been thinking about for a while (and ironically, a topic of conversation between a very close group of friends, this week when I was asleep). Maintaining a low body weight is not easy. I do it, through caloric restriction or carbohydrate restriction (depending on my mood) and intense exercise. I eat a lot of bland foods fairly repetitively: I ate oatmeal for breakfast almost every day for about 3 months; I once spent several weeks starting my day with only egg white and a light laughing cow. I eat a lot of plain grilled chicken and salad; I drink a lot of water. People think I am ‘lucky’ to like this. Lucky? Like it? Heck, it is a PITA. Sure I do it, and sure it doesn’t bother me too much (and sure, I don’t like a lot of fast food restaurants) but don’t think for a freaking second I wouldn’t much rather eat (home made or restaurant) tacos, fries, pasta dishes. Don’t ever think that I wouldn’t like dessert after just about every meal or that waffles with (full sugar) syrup and fruit on top is ever not my ideal breakfast. And don’t think that eating out and consuming beautiful food is not a borderline orgasmic pleasure for me. NOT EVEN JOKING. Just see me photograph and write about all my amazing meals while traveling. I am constantly in denial (because I constantly want ice cream), with one of two free meals per week. I look forward to those meals, because I know I have earned them, and I know my abstemiousness means they won’t unduly raise my BMI.

As for exercise: people think I love it. Mostly I hate it. I hate running, I am not so keen on kickboxing and I have a sense of dread whenever it comes to plyo sessions. I do it because I want the results. I like weight lifting and zumba, sure, but quite often, lying on the couch watching movies (and yes, eating popcorn and pic n mix) would be my preferred option. When I bike home from work, I often fight the urge to call my boyfriend for a lift.

You live in a world with delicious, affordable, accessible, socially acceptable excess calories, and where laziness is only a ‘car ride between shops’ at the mall away. If you want to lose weight, if you want to keep off weight loss, you are simply going to have to put yourself through deprivation / hardship – unfortunately, even more so if you have previously been heavier. But it is worth it: stop the cycle (it’s hard to lose, so you gain more, which is hard to lose so you gain more…) and man up to saying no, to being hungry for an hour before dinner, to not watching American idol ‘coz you have to go to the gym, to having sore arms and legs, to bothering to shop and buy and cook your food sometimes, to eating grilled chicken AGAIN, to watching everyone eat cake at work but not joining in because you have already had it twice this week, to not drinking alcohol sometimes, to getting up at 5 am because you work 8-8.

You need to, to protect your health and be there for your friends and family.

NB: I appreciate obesity is NOT simply a case of lack of will power / refusal to be discomforted. This is merely a statement that I think some people would be helped by understanding, and incorporating in their fight against obesity / weight gain.

Weekly work summary – K99 thoughts & new directions

This has not been a rockstar week of productivity. Had a lot of admin-y type stuff to do – collecting signatures for my ADA abstract submission, informally reviewing a colleague’s paper (check out his non work related blog if you are interested) and doing a presentation. My presentation, which you may download – but not hold me to (as there are some inaccuracies – such as you CAN have your salary topped up by your institution in the K99 phase), was on my experience writing a K99 / R00 application. A summary of everything I had learned about this mechanism. In summary, what I felt was most useful and what I really wished I had known (and I have touched on this previously) was:

I had a shot. The belief that I could achieve it was eventually beaten out of me by everyone around me. They were wrong.

Some people just can’t be relied on. They won’t come through at the last minute and you definitely need a contingency plan

It takes up a lot of your time, even your free time. It is exhausting as I never really ‘switched off’ from it – even when swimming or running (my ‘chill time’) I was writing and rewriting in my head, addressing issues, thinking about it.

The ‘admin’ – description of UAB, letters of support etc – took forever.

The personal statement part of the Biosketch is extremely important and extremely difficult. Try to get hold of good ones from people around your level, doing the same thing as you.

You need very broad future directions. So if you find a gene associated with CVD, the future direction is not to deeper sequence that gene and get more data, it is to use the information from that aim to improve human health – e.g. use it in a predictive algorithm, use it to inform biology.

Making your own diagrams is not very difficult and extremely helpful for people reading it.

Do not lie, do not fudge the truth, do not over grandise things. And there is no need to do any of that. It is unnecessary and it doesn’t work as it doesn’t ‘ring true’ or ‘hold together’ well if you do. Be selective in what you say, tell a story (this is the hardest thing) but be honest and straight forward about what you have achieved, not hiding behind jargon.

So, aside of writing and delivering that, and being pathetically distracted by being newly engaged (vomit-y I know, but so true) I spent some time deciding and developing my next projects. Currently I have shown that in one sample, the size of your fasting lipoproteins may help us find those with the worst features of the metabolic syndrome (MetS, a cluster of features indicating insulin resistance and possibly pre-type II Diabetes) – we already ‘knew’ that the Mets was marked by smaller low-density lipoprotein (LDL) particles but in GOLDN (Donna Arnett’s study) severe MetS is also marked by large very low-density (VLDL) particles. Although, without the small LDL particles, those large VLDL diameters are uninformative for insulin resistance.

Now, I am going to look further into this: I want to see if changes in the lipoprotein lipase gene predict this pattern of small LDL and large VLDL particles. I have tested three single nucleotide polymorphisms (SNP: single changes in the long code of the gene) and found one significant difference between those with the MetS who have large VLDL and those with the MetS who do not. I want to take more SNPs across the whole gene, and see if I can put all the information together in a gene based approach to see if the gene itself, rather than single isolated changes within the gene, can be said to be associated with a worsening of Mets features. This would be great support for a K99 resubmission, so in the words of my mentor Donna: I need to get cracking!!

Tapping out for a minute

So, the old saying goes that in business you can’t have things that are cheap, quick and good. You have to only pick three of them – if you want them quick and good, you gotta pay. If you can’t pay, it is going to take a long time, or not be done well. I applied this framework to my life a while ago. I said that I would like to be healthy (eat nourishing, home cooked meals and work out twice a day), pretty (nails done, hair dried, smart clothes) and smart (excel at work). But, I found I always had to pick two: if I was putting in all my hours at work, then in was early morning and late afternoon gym times, and I simply did not have time to style my hair and do my make up. If I was dressing myself smartly, and painting my nails I had to go home from the gym (which cut into my work time) or not cook dinner every night. I had to pick two, and I picked smart and healthy – I spend a lot of my time looking a mess (I gave a presentation in mismatched shoes on Thursday…). I told my friend David this on a hike, and he came to me and said that he had been thinking about what I said it essentially came down to:

You can’t do everything.

Along those lines, when I was crazy busy with my first grant submission, writing papers and working out up to 3 hours a day (I am so over that now), the same David said I was pushing too much: something would have to give, and he asked it not to be me. Well, it is good advice. Until last Sunday I was super busy: pushing it at work, working out every morning and evening, being hyper careful with my diet, balancing cooking, fish keeping, cleaning and so on in with all of that. It worked, it was good. Then my boyfriend proposed and long story short: we ended up with 3 months to plan a full wedding from scratch, for about $5,000 (£3,000) total (ceremony, venue, clothes, food, alcohol, rings, the works). Then I got my K99 score back, and it looks like I could have a great shot at a resubmission BUT I need to really work not to miss this opportunity: I need to get CVD publications, I need to get some gene papers together and I need to work on writing and selling my Science. In about 3-6 months.

Don’t get me wrong: I am joyfully happy and loving it. I love making strides at work, and thrive off success and a certain amount of pressure. Planning a wedding is fun and my fiance is super helpful and involved. But this first part is extremely time consuming. We need to move stat on a venue, a cake, a dress, the catering and a basic plan. It just takes time to trawl the internet, take notes, visit bridal shops, visit places and people and put the bones together. While getting these papers out. And preparing my presentation for the AHA Young Investigator competition in which I am one of 6 finalists. It’s fun, but I quickly got very run down. After the 6th day straight of an upset stomach (that ended up keeping me up all night), and pale skin I am tapping out. My priority is work, the next is getting this wedding together. Weight lifting, eating salad, and getting the cardio in is going to have to wait a minute, in favour of doing those and actually having some down time for my sanity. We’ve come to Florida where I can read my trashy novel, write my presentations and manuscript proposals, spend some time with my kitt-ehs (yes, they came on the road trip, they get the same privileges as the dog!) and not think about health. Tapping out is the point in a UFC fight in which one of the fighters taps the ground twice to indicate they don’t want to go on and concede the fight. Either it is maturity, or the David effect, but this time I am tapping out of trying to do everything. I skipped the gym on Friday (partially due to not having held on to any food for so long). Last night I drank a bottle of wine. Today I had TOAST for breakfast with my omelet, and a subway sandwich for lunch. I am just back from eating a waffle cone ice cream at the beach. No run today in favour of just sitting on the beach and splashing, although I will go back to the gym in Alabama. It’s doing me and my mind a world of good.

Oh, and don’t get me wrong – I have had so many genuine offers of help (which I am happily utilizing) and some wonderful support, especially from my buddy Holly who has answered 75000 emails about dresses with a lot of understanding and patience. But, when the presentation is done, and the manuscript proposals are written, and the venue booked and the cake, catering and dress ordered, and the invites out: well, then we’ll work on getting that bench press back over 120lb and the body fat back below 17%.

Till then *taps out*.

K99 score

The K99/R00 came back – I made a very respectable 37 (although I prefer Donna’s ‘outstanding’). Only 50% of applications are scored (the other 50% considered ‘triaged’). The grants are scored from 10-90, with 10 being the very highest. 10-30 is considered ‘high impact’ and the cut-off for funding (the ‘payline’). 40-60 is ‘medium impact’ and 70-90 ‘low impact’. Yes, I am aware of NHLBI’s terrible grasp of maths there 🙂 So, I got a good score, and I am particularly pleased given that

-This was my first ever grant

-I was only a first year postdoc,

-I was entirely new to the scientific area of the grant submission

-I wrote it largely on my own, with very little scientific feedback

So, now I am going to get it ready for a resubmission. Of course, my resubmission changes will depend on the comments, which although they will be painful, I am actually looking forward to receiving. But I already know some areas to improve:

-The writing. I tried to hide behind jargon to make my trait sound more important than it was. So, instead of calling it ‘particle size pattern’, I called it ‘dyslipidemia’. To me that sounded more fancy, to scientists I think it just sounded confused. I am much better at taking the time to write about why particle size patterns are important, and then just calling it that.

-The future directions for my research. I thought that ‘future directions’ meant how will you deepen and further these findings, but actually, they want to know broader future directions. So, as an example, if I found a positive gene association, I said that the future direction was to investigate this gene finding further with more complex data. Actually, a better future direction is to use this gene finding in a predictive algorithm to predict health outcomes. So, not more targeted subsequent research directions for me, but broader implications for aiding future health.

-The power calculations. They were rubbish. I have learned to do them better.

-Candidacy. This was a big one. I had no publications in the area, had only been a postdoc for a year (with a PhD in a different area) and the personal statement of my biosketch was so bad I was told (after) that people didn’t even know where to begin in helping me change it.

So, at the ‘end’ of this round, I am feeling pretty positive. Here are things I wish I had known before writing my K99 / R00 application:

-I stood a chance. This was the biggest thing I wish I had known. I would have pushed for more help with the Science from more experienced people, if I had known this. I would have kept chasing some leads at NIH, except that I felt I was wasting their time as everyone kept telling me I had absolutely no shot. David was the only person who really encouraged me to shoot fully for it. I wish I had listened more.

-How willing some junior people are to help. That is helps them too to get an idea of what other people’s grants look like, what goes into them, so it is OK to ask for help more.

-How time consuming it was. I underestimated how very much it takes to get everything together for the first submission. It will be (and has been) much easier from here on.

-The myriad of benefits that come from putting together a grant. I met people got PIs interested in my project, developed my writing, in fact – got a whole Science project together.

Overall though, this experience has been wonderful. Just one more (less) point in 7 out of 9 categories and it would have met the payline. And I have a whole year and a half left of postdoc to make up for it.