Total Pageviews

Sunday, April 19, 2015

Personalised Nutrition: A look into the future

Personalised nutrition is the future. When the sequence of the human genome was first announced, it was believed that human biology had set a new boundary around its research challenges. It was believed to herald a new dawn in cancer prevention when President Bill Clinton and Prime Minister Tony Blair launched the human genome sequence project in June 2000. Clinton commented: “In fact it is now conceivable that our children’s children will know the term ‘cancer’ only as a constellation of stars” to which Blair added the this heralded: “a breakthrough that opens the way for massive advances in the treatment of cancer”. The era of personalised medicine had arrived and the road ahead was envisaged thus: You doctor would have your genome scanned to check some conditions such as blood pressure where your measurements were marginally high. She or he might find you had a genetic predisposition too high blood pressure and based on your genetic information, the ideal pharmaceutical treatment to stave off hypertension would be identified. Armed with a prescription from your doctor you would go to your high street pharmacist and buy the prescribed drugs and maybe what today is called a ‘companion diagnostic’, a home blood pressure monitoring machine.

The temptation to translate this model to human nutrition was very attractive and so genetic testing companies were set up where for about  €200 a pop, you could be screened for genetic variants associated with diet related diseases. The industry flopped for two reasons. Firstly, when someone is told to eat more fish oil because they have some genetic variant indicative of declining cognitive function in which fish oil fatty acids might play a protective role, it has to be borne in mind that those same fish oil fats influence blood clotting, blood lipids, inflammation, vision and so on. So how could they be sure that what was good for treating cognitive function was maybe bad for your vision or inflammation? Drugs have one single point of action. Nutrients have multiple points of action. The second is that it’s not good enough to tell Homer Simpson he has a genetic variant which influences his cardiac electrophysiology and thus he needs to “watch” his lipids and salt. No, Homer wants a solution, not a problem. There is no wonder drug and no pharmacist to help him. He has to go to the supermarket and start making choices as to the foods that will help balance his lipids and salt. So, he needs customised solutions.

Enter Food4Me, a €9m EU funded project, which looked at all aspects of personalised nutrition: Consumer attitudes, business opportunities, legal and ethical issues, new emerging technologies which give biofeedback and most importantly, an internet based proof-of-principle study of the value of fully internet delivered personalised nutrition which involved providing genetic information, blood analysis and a personalised dietary analysis with feedback and coaching. The latter was the biggest hit with the 1,300 subjects who too part in the 7-centre pan EU study. Subjects entered their data on habitual food intake following a simple template across the Internet. That food intake data was translated into actual weekly nutrient intake and these data were compared to established international standards. The feedback was graphic. If the little cartoon man was in red for calcium you had a major problem to tackle, if it was in amber, it was in need of addressing soon and if in green, it was ok. The subject then was told why they had the problem they had with each nutrient based on their habitual food choice. A high intake of cheese might put calcium in green but saturates in red. A high intake of soup might put energy in green but salt in red. So for the three most urgent nutrients, they received detailed coaching on how to change their food choice to optimise their diet. Unlike Homer walking into the supermarket knowing his problem but not his solution, our subjects went to the supermarket knowing exactly, for them, what foods to chose to optimise their diet. Did it work? Yes it did when compared to a control group who were not given personalised dietary analysis but generalised population healthy eating guidelines.

So the future is thus. Whether by smart phone or a home computer, food choice is inputted and nutrient intake calculated by the service provider who then tells the used the top three problems to solve and what food choices to make to improve things. In fact, the advice won’t be at food level but at a weekly menu level taking into account data on personal taste, access to food, allergies and intolerances and price. This data will be shared with three other players: your smart fridge, a range of supermarkets and your work canteen. The supermarkets will translate the weekly menu into a shopping list and give you a price whereupon you will make your choice and the groceries will be delivered to your door. The smart fridge knows what’s ay home and expects you to interact with the touch screen on the door to indicate what you’ve taken out. I log on: “Good morning Mick” it says and I press a button marked ‘the usual so it deducts a bowl of porridge with milk and sugar, a glass of orange juice and tea. The information is shared with my computer, which now builds up my weekly aggregation of nutrients. Now it re-adjusts its record of the food store. In work I pick a soup and roll and using my swipe card at the check out, and both my computer and smart fridge are informed. On Thursday, I choose fish and chips at work and I swipe my card and I now get a text telling me that I have now reached my 90% limit of salt intake and I have a shortfall in fibre intake. When I get home, my smart fridge that now knows this problem and knows what’s in the kitchen offers several menus to boost my fibre with low salt meal recipes. I pick one but don’t know how to cook it so the smart fridge scans You Tube for demo and away I go.  It’s the future. The white goods industry, the IT industry, retailers, caterers and the food sector are hatching it.

In this analysis I have left out genetic based information, which is a long way off and the postal based blood biochemistry, which is presently operational. If you’d like to read about the project click here and if you’re a little lazy, then watch a 15-minute video on the findings here.  

Wednesday, April 15, 2015

Scientific norms and the WHO

In 2007, a paper was published in the medical journal The Lancet that sought to study how the WHO expert panels reach their conclusions, which are profoundly important in shaping global policy on public health [1]. The study, conducted jointly between the Norwegian Centre for Health Services and the Centre for Health Economics at McMaster University in Canada, and funded by the EU concluded systematic reviews were rarely used and the favoured way of developing a report was to use an expert committee or individual experts. One interview among the 29 directors or equivalents commented thus: “There is a tendency to get people around a table and get consensus – everything they do has a scientific part and a political part. This usually means you go to the lowest common denominator or the views of a ‘strong’ person at the table.” This criticism was bad enough but worse was to come. Two papers were published subsequently in the Lancet, one by researchers looking at insecticide treated anti-malarial bed-nets and another looking at child mortality [2]. For the first paper, the authors outline the success of the programme but, importantly, they also outlined some important uncertainties in the data. The WHO received drafts of the data and ahead of the Lancet publication, issued a press release claiming that the data “ends the debate about how to deliver long-lasting insecticidal nets”.  The second paper from researchers at Harvard and Queensland universities reported disappointing progress I the rate of reduction of childhood mortality. UNICEF contacted the Lancet about the paper but after considerable consultation with individual experts the Lancet decided to publish and informed UNICEF of the intended data of the publication. UNICEF then fast tracked the publication of its annual State of the World’s Children Report and made claims contrary to the paper. These two actions by the UN agencies, caused the Lancet to pen an editorial which concluded thus: “But the danger is that by appearing to manipulate science, breach trust, resist competition and reject accountability, WHO and UNICEF are acting contrary to scientific norms that one would have expected UN technical agencies to uphold. Worse, they risk inadvertently corroding their own long-term credibility” Scornful criticism for a top class medical journal!!

The UN moves slowly and thus in 2012, in response to such scathing criticism, it issued a specific handbook for guideline development and they established a Guideline Review Committee to be involved in evaluating all subsequent guidelines. Central to this process was the internationally accepted approach to the development of guidelines called the GRADE (Grading of Recommendations Assessment, Development and Evaluation) process. Grade is used to evaluate confidence in the effect of some action or intervention and classifies this confidence as high, moderate, low or very low. If there is more than on effect possible, the overall grading is based on the weakest measure of confidence. In addition to the strength of evidence on outcomes from actions or interventions, GRADE also rates the overall recommendations as strong or conditional. An international panel set out to examine how guidelines and recommendations of the WHO adhered to the GRADE system since its introduction in 2007 up to the year 2012 [3]. A total of 160 recommendations were found and reviewers worked in pairs to evaluate adherence to GRADE guidelines. Of the guidelines deemed to be strong, 56% were found to have low or very low confidence in estimates. Only 17% had high confidence in estimates. . Turning to the 167 recommendations that were considered weak, 85% were indeed based on low to very low confidence in the estimates of the effect of the action or intervention. Thus for example, 100% of the strong recommendations were found to be based on low to very low effects estimates for guidelines on nutrition and influenza. Half of the recommendations in the area of maternal and reproductive health, child health, HIV/AIDS and TB were deemed to be strong recommendations based on low to very low confidence in the outcome effects.
The same set of researchers went one step further in a follow up paper. Sometimes, expert committees have to make judgments [4]. The confidence in the true significance effect estimate might not be as strong as they’d like but the expert committee feels that a strong recommendation is warranted for whatever reason. These are called discordant recommendations and GRADE recognised 5 situations where a discordant recommendation is warranted. Given the very high number of strong recommendations with weak effect evidence observed in the previous study, the researchers set out to see how many of these met any one of the five situations, which GRADE allows a discordant recommendation. Only 16% of the discordant recommendations met any one of the 5 situations where GRADE accepts a discordant recommendation. In all, 84% of the discordant recommendations did not meet the GRADE guidelines. 46% of the discordant recommendations (strong recommendation but low supporting evidence) should have been classified as simply conditional recommendations. These two papers show that the WHO still has a long way to go to meet reasonable levels of scientific integrity. It may well be that expert panels make strong recommendation based on weak evidence of effect because otherwise their recommendations will be ignored. The problem is that in many countries, a strong recommendation from the WHO is the first step in the development of national policies and such is the respect that many national public health agencies have in the WHO and their guidelines that they go unquestioned. Anyone who has had dealings with large UN agencies knows that they are frequently short of resources and given that they answer to multiple national governments and to multiple non-governmental organisations, it is correct to have some level of understanding of their constraints. However, failure to rigorously embed their guidelines in the highest quality of science and the repeated issuing of strong recommendations based on weak to very weak evidence based outcomes, means that they cannot be excused. They may keep most non-governmental activists happy but in the long term, global trust is more important. It is hard won and easily lost.

[1] Oxman AD et al (2007) Lancet, 369, 1883-1889
[2] Lancet editorial (2007) Lancet, 370, 1007
[3] Alexander PE ((2014) J Clin Epidemiology 67, 629-634
[4] Alexander PE (2015) J Clin Epidemiology e pub ahead of print

Tuesday, March 17, 2015

Getting old and fat ~ no problem!

Growing old and fat ~ no problem

In today’s obesocentric (a new word I’ve coined) world, there are certain things that are given. These are the immutable facts about obesity. One of them is that the link between obesity, as measured by Body Mass Index (BMI = kg/m2), is U shaped. Over the range corresponding to desirable weight (BMI =20 to 24.99), there is no relationship between BMI and mortality or morbidity. Below 20, there is a rise in the risk of mortality as one gets skinnier. Above 24.99, mortality rises as BMI increases and it soars when obesity exceeds 30. No matter where you look, this is a given. It’s on the WHO website. It’s in your pharmacy window. It’s in schools, in textbooks and its like the boiling point of water, a given, never to be challenged.

Recently, in writing my new book on obesity, I re-discovered a set of data that was 30 years old. The data were published in a Working Party Report of the Royal College of Physicians of London in 1983[1]. It looked at the association between mortality and BMI over decades of age. Among 20 and 30 year olds, the rise in mortality with increasing BMI was quite dramatic above25. So far so good. Among 40 and 50 year olds, we begin to see the emergence of a U shaped curve, rising at both low and high BMI values. However, among 60 year olds, whereas BMI cause rising mortality at very low values, there was no relationship between BMI and mortality above a BMI value of 20. Of course, death rates rose with age but the pattern of mortality with BMI was very much influenced by age.

The subject has recently been revisited through a systematic review and a meta-analysis[2]. A total of 564 publications were identified in the literature based on key words of which 394 were rejected because of a focus on specific patient groups or non-human studies. Of the remaining 170 papers, a further 150 were excluded because they did not provide two or more age comparisons. That left 20 papers of which 13 were US based, 2 were Finland and Taiwan based and 1 each were from Germany, India and Japan. The increase in the risk of mortality with a BMI greater than 24.9 kg/m2   was assessed for decades of age. Averaging the values for men and women, the increased mortality risk with elevated BMI was 60% among those aged less than 35. That figure the fell progressively: 40% among thev35-45 year olds, 355 for 45-55 year olds, 28% among 55-65 year olds, 20% among the 65 to 75 year olds and a mere 11% in those aged above 75 years. The studies all controlled for the possibility of smoking or a pre-existing illness (e.g. high blood pressure or diabetes) being statistically confounding factors. However, the paper reports that this statistical control had no effect on the outcome. Basically, each increasing decade of life above 35 years of age reduced BMI related mortality by 10%.

Writing as a pensioner, a grandfather and a 67 year old, I say YIPPEE. But my GP doesn’t know this nor does my friends cardiologist and so we grey-heads are demonized unnecessarily by medics into being of adequate BMI. Of course, we do benefit from cardiovascular fitness so a good walk during the day when all the younger folk who kindly earn our pension, work away in a stress-filled environment increasing their BMI mortality risk, is a good idea.

Why does this obesocentric world choose to ignore such data? The answer, it seems to me, is that the simpler the message, the easier is the public health communication. So, they don’t complicate it by absolving older folk from the curse of BMI related mortality. And of course there is the other issue of the obesity paradox[3]. It gets even messier but I love it, the truth, that is!!!

[1] Royal College of Physicians Working Group on Obesity (1983) Journal of the Royal College of Physicians London 17:3-58
[2] Wang Z (2015) Obesity Research & Clinical Practice, 9:1-11
[3] BMI, Obesity & mortality: three grand challenges. Gibneyonfood, December 15th, 2014

Thursday, March 5, 2015

Fats, facts and baloney

In the last year or so, we have seen a number of scientific papers reviewing sets of older scientific publications linking saturated fats to heart disease and calling for a reversal of prevailing wisdom that a change in the composition of dietary fats (less saturates and more unsaturates) would help reduce the public health burden of heart disease. The spin-doctors from the food industry have whipped up the hype and last summer the front cover of Time magazine headlined: “Eat butter. The scientists labeled fat the enemy. Why they were wrong”.
Before I take at look at the detailed issues, I would make two important points. The first is that no matter how unpalatable a critical paper might be to the custodians of some aspect of conventional scientific wisdom, there is an absolute need for continued critical analysis of existing theories. As I have often argued, dissent is the oxygen of science. The second point I would make is that the advent of any one paper is never in itself sufficient to unravel prevailing wisdom. Philosophers of science have the luxury of arguing that the just one black swan demolishes the “All swans are white” theory. Well its not so black and white in an area as complex as public health nutrition.

Last year, a paper was published in the Annals of Internal Medicine[1], which looked at previously published studies that sought to establish links between different types of dietary fats and heart disease. In response to this publication, the journal received many letters most of which were critical of the study. I won’t re-hash their arguments but will offer my own. Back over half a decade ago, Professor Ancel Keys conducted a study across 7 countries in which he showed (a) that measures of the composition of dietary fat could help predict blood cholesterol levels and (b) that the national statistics in these countries showed a link between rising blood cholesterol and higher rates of heart disease. His work is now often referred to as being flawed and certainly, this study, the first of its kind, wasn’t exactly top drawer in today’s standards no more than the falling Newtonian apple can rank with today’s Hadron Collider in the study of gravity. It is not the 7 countries study that mark out the great contribution of Keys to modern nutrition but to the subsequent experiments he conducted on humans to study how precise control over the intake of saturated, monounsaturated and polyunsaturated fatty acids would influence blood cholesterol levels. In this he was joined by two other Doyens of that great nutrition era, Paco Grande and Scott Grundy. They developed equations, which would accurately predict the change in blood cholesterol that would occur with changes in the composition of dietary fats. These were real experiments with human subjects, not some fancy statistical model from the world of epidemiology. What that world delivered, and delivered in spades, was epidemiological data showing that rising population levels of blood cholesterol were associated with rising levels of coronary heart disease.  So here we had dietary data showing an unequivocal link between the compositions of dietary fat and plasma cholesterol and powerful evidence linking elevated plasma cholesterol levels with heart disease. So, it made sense to recommend a reduction in the intake of saturates and their partial replacement with unsaturated fats to minimize population levels of blood cholesterol BUT NOT TO BE THE MAIN DRIVER IN ANY MOVE TO REDUCE OVERALL HEART DISEASE.  Why not? Because heart disease was also partially caused by smoking, by high blood pressure, by the advent of the menopause in women, by blood clotting potential, by bodyweight, by fitness, by family history and by many other factors, some of which were easy to measure on a population basis and some of which were difficult to measure and thus were rarely entered into complex statistical models (platelet aggregation, post-prandial lipemia, cardio-respiratory fitness, family history of heart disease, common known gene variants etc).

So the biggest error in looking at dietary fat and heart disease is that nobody ever said that there was a direct link between heart disease and the composition of dietary fat. All that was ever said and in two very clear stages was (a) that dietary fat for certain, influences blood cholesterol and (b), blood cholesterol along with a wide range of other factors contribute to heart disease. A more recent paper[2] makes the same mistake of attempting to link dietary fat intakes to the incidence of heart disease when the human intervention studies with a focus on fats had blood cholesterol as the end point.

To hammer home this point, consider the generally accepted public health nutrition success that is attributed to the reduction if not elimination of hydrogenated trans fats from the human diets. It was a triumph for NYC Mayor Michael Bloomberg in engineering a citywide movement for their elimination.  What constituted the risk associated with trans fats? It wasn’t mortality from heart disease. It was a series of human experiments conducted by the Dutch researchers Martijn Katan and Ronald Mensink in showing an unequivocal effect of trans fats on adverse levels of blood cholesterol. The epidemiologists contributed both the only actual human studies were on blood cholesterol and trans fats intake[3].

Very recently, the industry spin-doctors debunking the dietary fats heart disease putative link (the true link is dietary fats and blood cholesterol) have acquired a new string to their bow, the 2015 US Dietary Guidelines. The 2015 guidelines make the point that “available evidence shows no appreciable relationship between consumption of dietary cholesterol and serum [blood] cholesterol”. This is simply the conservative policy catching up with the science since it has been know for decades that the main source of cholesterol in our blood is manufactured by our guts and livers and the dietary contribution from ingesting cholesterol is minimal. The report goes on to argue that: “The DGAC encourages the consumption of healthy dietary patterns that are low in saturated fat, added sugars, and sodium. The goals for the general population are: less than 2,300 mg dietary sodium per day (or age-appropriate Dietary Reference Intake amount), less than 10 percent of total calories from saturated fat per day, and a maximum of 10 percent of total calories from added sugars per day”. For many, this is taken to be a major turn around for dietary advice on restriction of sugar intake but I’m afraid its no more than the US catching up with the rest of the world who have held the 10%target for added sugars over several decades now.

Despite the minor adjustments and catch up of the US to dietary guidelines and notwithstanding the odd paper suggesting otherwise, its business as usual for nutritional advisory committees globally. The press will report on dramatic somersaults and loop-the loops and the public will continue to be confused. In effect, nothing has changed.

[1] Chowdhury et al (2014) Ann Intern med, 160, 398-406
[2] Harcombe Z et al (2015) Open Heart, 2, e000196 (BMJ)
[3] Brouwer IA (2010) PLOS one (5) 10, e 9434