How The Media Monkeys Get You Panicked About Sitting Too Long!

From "man is made to move" to "man is not made to sit" is a very recent transition of scientific insight. Let's get our readers panicked over more than not doing exercise, is the response of the media. Here is why you should sit down and get the facts straight before jumping up in fear. [tweet this]. 

"It is now well known that spending too much time sitting down is bad for the heart, even if one takes regular exercise."

That's what the Daily Telegraph told us on 10 July this year. Behind this piece of insight is a study published by Katzmarzyk and colleagues a few days earlier. The authors investigated the question what effect the daily time we spend sitting down has on health and life expectancy. In the USA, that is. 

Maybe the Daily Telegraph lives in a different knowledge universe, but in the one where biomedical research counts, the association between sitting and heart disease is not as clear as the reporters make it out to be. Call me a fusspot, but the only study design, which allows us to draw conclusions about causality, are those where we expose a randomly assembled group of individuals to a certain intervention (in this case: sitting down for extended hours every day) and then we compare the outcome in that group with the outcome of another randomly assembled group which didn't get our intervention. Assuming the two groups didn't differ in any meaningful way from each other at the outset of our experiment, we can, at the end of it, ascribe a possible difference in outcome between the groups to our intervention. That's what I want you to keep in mind while I walk you through the study which had prompted the Daily Telegraph to tell you that sitting too long will cut your life expectancy. 

Let's first look at the background to the authors' research question, which was "To determine the impact of sitting and television viewing on life expectancy in the USA" [1]. Over the past 60 years we have accumulated a vast body of evidence for the benefits of physical activity on health. The results of this research are reflected in every guideline on how and how much we should exercise. You could say "made to move" is written all over our genes. Only very recently are we discovering a sub-clause, written in small-print, saying "man is not made to sit", which we interpret to mean that cramming movement into a brief period of time every day doesn't help us much if sitting around is what we do for the rest of the day. Katzmarzik and Lee simply wanted to extract from the available evidence how a violation of this newly discovered sub-clause impacts our health and longevity.

So, they set out to identify all the studies from which reliable data could be gleaned about the effects of sitting and television time on the risk of dying. Only 5 studies matched those criteria. From these they pooled the relative risk results into a meta-analysis. Then they looked at the sedentary behaviors of the U.S. population. For that purpose they consulted the data of the National Health And Nutrition Surveys (NHANES), and they also looked at the latest life tables for this population as published by the World Health Organization (WHO). We don't need to go into the statistic intricacies of the procedure. They are a very thorough and methodical attempt at coming up with an educated guess about the impact of extended sitting on the life expectancy of a population. By way of analogy: the authors threw all those data into the statistics blender and came up with what we call the population attributable fraction, or PAF, which tells you how many deaths (or disease cases) could be avoided in a population if the risk factor or exposure were eliminated, in our case, the exposure being extended sitting time. 

Fast forward to the results, which the authors comment as follows: "The results of this study indicate that limiting sitting to less than 3 hrs/day and limiting television viewing to less than 2 hrs/day may increase life expectancy at birth in the USA by approximately 2.0 and 1.4 years respectively, assuming a causal relationship." That's what I like about the authors, whose work I have been following for quite some time. They point out that this conclusion is only valid UNDER THE ASSUMPTION that sitting and dying early are causally related. They also go on to emphasize that this is "...a theoretical estimate..." (emphasis in italics by the authors) and that "This should not be interpreted to mean that people who are more sedentary can expect to live 1.4 or 2.0 years less than someone who does not engage in these behaviours as much." That's obviously addressed at those media types who, of course find it far more sexy to tell you that spending too much time on your butt cuts down your life expectancy. 

Now, instead of picking the raisins out of this nicely done study, I want to walk you briefly through the 5 studies from which the authors extracted their results. After that, you can still judge for yourself how much trust you want to put into the Daily Telegraph interpretation. 

The first of the 5 studies was conducted by the same lead author, Dr Katzmarzyk. It was a study of 17,013 adults of the 1981 Canada Fitness Survey (CFS) who had been followed for up for 12 years [2]. At baseline, the survey participants had been asked, among other things, about their time spent sitting. Death from cardiovascular and other causes were the outcome measure. In such a study it wouldn't make sense to simply correlate sitting time with death. After all, there are a lot of other factors which determine our demise. Age being one of them. My chances to die in the next 12 years are quite a bit greater if I'm 70 than if I'm 35. So, believe me when I say that the authors adjusted as much as possible for such factors. And it is this "as much as possible" where we begin to find hairs in the soup. 

First of all, cardiovascular disease (CVD) is a main cause of death today. So, we should account for all those people who already had CVD when they entered the study. But that's not as simple as it sounds. CVD has a mean streak in that it remains asymptomatic for years, often decades, before it hits you with a heart attack or stroke. So, eliminating those cases who had reported such events at baseline, doesn't mean our survey participants had a clean bill of cardiovascular health.  At the average age of over 40, there will certainly have been quite a number of people who had such silent stages of CVD. The principal manifestation of "silent" cardiovascular diseases are those atherosclerotic plaques which narrow the arteries and arterioles. While the authors used the PAR-Q (physical activity readiness questionnaire) which asks, in five questions, about symptoms of CVD, silent CVD would have flown below that radar. So, not accounting for those silent cases may, in all likelihood, have biased the results. Think about it, if those with silent CVD don't move as much, simply because exercising causes them discomfort (which happens when narrowed arteries don't supply enough blood to a working muscle, or heart), it is not the sitting time, but the silent CVD which correlates with an earlier death. 

On to the 2nd study: Author Patel and colleagues looked at 123,216 adults, aged 60+, of the CPS-II nutrition cohort, who had been followed up for 14 years [3]. Again the results support an association between sitting time and CVD mortality, but, again, silent asymptomatic disease had not been assessed. Interestingly, in this study the association was far stronger in women than in men. Tellingly, age 60+ is also the age at which women start to "catch up" with their male peers in respect to CVD risk.

In the third study, Dunstan and colleagues had looked at the correlation between television viewing time and death among 8,800 adults aged 50+ with a median follow-up period of 6.6 years. In contrast to the previous 2 studies, the authors were able to adjust for known CVD risk factors such as hypertension, blood lipids, blood glucose and diabetic status. Those who reported sitting in front of the TV for more than 4 hours per day, had a 50% higher risk of dying from any cause and an 80% higher risk of dying from CVD causes. But adjusting for risk factors of CVD is not the same as adjusting for CVD. 

In the fourth study, Stamatakis and colleagues had looked at the data of 4512 people, aged 57+, of the Scottish Health Survey, who had been interviewed in 2003 and followed up until 2007. Those who had reported watching more than 2 hours of TV per day had an increased risk of CVD events (not of CVD death), and only those who had reported watching TV for more than 4 hours per day had a statistically significant risk increase of dying from any cause.

In the fifth and final study Wijndaele investigated the data of 13,197 adults aged 60+ of the EPIC study cohort. Those people had been assessed at the 1998-2000 baseline and followed up for 9.5 years. Like in the other 4 studies, the association between increased TV viewing time and all-cause and CVD death was evident. This observation prompted the authors to say that: "Given the high prevalence of excessive TV watching, ...  these results indicate the importance of public health recommendations aimed at decreasing TV time and possibly overall sedentary behaviour." So, will throwing away your TV make you live longer? 

You'll probably appreciate the difference between Wijndaele's and Katzmarzyk's way of interpreting essentially similar results. I personally go with Katzmarzyk's more careful interpretation. It does not outright assume a causal correlation to exist. There are still too many question marks. For example: We know that self-reported physical activity, self-reported screen time, well, self reported anything, is inherently fraud with over- and under-reporting of facts. Dunstan and colleagues were adamant at pointing out that this couldn't have affected their results. But when you look at how well, or how poorly, their questionnaire really performs, you will be forgiven to be less enthusiastic than the authors. Use that questionnaire twice on the same person to assess same-level PA, and chances are you'll get two different answers. That's not just me being the party pooper, it has been confirmed in validation studies which have shown, at best, only a moderate level of agreement between two rounds of questioning (the parameter is the intraclass correlation coefficient, or ICC) [4]. If repeated questioning is already fraud with inconsistencies, how large, do you think, such inconsistencies will be between the answers of any given respondent and his actual physical activity level? 

So, what are we to make of all this? I can only give you my personal opinion. I tend to believe that there is a threshold volume and intensity of DAILY physical activity, which protects you against the effects of extended sitting time. Only we can't see this level in the 5 discussed studies for obvious reasons. Their ways of assessing PA were not accurate enough.

I have to admit, that my belief is biased: I don't know about you, but less than 3 hours of sitting time appears unachievable for most of us today. And while I'm working at a desk, which allows me to alternate between standing and sitting, seen through the lenses of these 5 studies, I still have what those studies proclaim to be a risk factor for premature death: extended sitting time. But I also do exercise on a daily basis at an intensity and with a volume which far exceeds what 90% of the population is doing. That's why I love to think of this effort as being CVD-protective. This belief is founded in a large body evidence which essentially says: exercise triggers biochemical reactions and mechanisms with a vast array of protective effects. In a dose-dependent way. 

Fortunately, I'm able to measure the effects of my personal dose of exercise in my health lab. And from doing the same thing for our clients, I happen to know that everyone is unique in his response to intervention, be that exercise or diet or a pharmacological treatment. Which is why I am quite confident when I tell you not to lose any sleep over those attention grabbing headlines. Especially, when they suggest cause-effect relationships from studies which simply can't establish such relationships. In the case at hand, none of the 5 studies could have adjusted for pre-existing silent CVD. CVD is a cause of premature death and, as I have argued, it can be a reason for people to avoid exercise and spend more time sitting, simply because exercise causes them discomfort. So, here is my question: Are people dying early because they sit too long, or are they sitting so long because they'll die earlier? Stay skeptic! [tweet this]. 

1. Katzmarzyk PT, Lee IM: Sedentary behaviour and life expectancy in the USA: a cause-deleted life table analysis. BMJ Open 2012, 2(4).

2. Katzmarzyk PT, Church TS, Craig CL, Bouchard C: Sitting time and mortality from all causes, cardiovascular disease, and cancer. Med Sci Sports Exerc 2009, 41(5):998-1005.

3. Patel AV, Bernstein L, Deka A, Feigelson HS, Campbell PT, Gapstur SM, Colditz GA, Thun MJ: Leisure Time Spent Sitting in Relation to Total Mortality in a Prospective Cohort of US Adults. Am J Epidemiol 2010:kwq155.

4. Brown WJ, Trost SG, Bauman A, Mummery K, Owen N: Test-retest reliability of four physical activity measures used in population surveys. J Sci Med Sport 2004, 7(2):205-215.

Katzmarzyk PT, & Lee IM (2012). Sedentary behaviour and life expectancy in the USA: a cause-deleted life table analysis. BMJ open, 2 (4) PMID: 22777603

Katzmarzyk PT, Church TS, Craig CL, & Bouchard C (2009). Sitting time and mortality from all causes, cardiovascular disease, and cancer. Medicine and science in sports and exercise, 41 (5), 998-1005 PMID: 19346988

Patel AV, Bernstein L, Deka A, Feigelson HS, Campbell PT, Gapstur SM, Colditz GA, & Thun MJ (2010). Leisure time spent sitting in relation to total mortality in a prospective cohort of US adults. American journal of epidemiology, 172 (4), 419-29 PMID: 20650954

Brown WJ, Trost SG, Bauman A, Mummery K, & Owen N (2004). Test-retest reliability of four physical activity measures used in population surveys. Journal of science and medicine in sport / Sports Medicine Australia, 7 (2), 205-15 PMID: 15362316

Will The Polypill Prevent Your Heart Attack?

Giving the polypill to everybody above the age of 55 kills two birds with one stone: cardiovascular risk and preventive medicine. That's what the proponents of the polypill say. The medical establishment is in uproar. Here is why you should be, too. But for a different reason. [tweet this].

   

We are typically sold on the notion, that heart disease and stroke have become today's major killer, for one simple reason: We live far longer than our ancestors of a hundred years ago, whose major cause of death were infectious diseases. Their eradication has brought upon us the blessings of longer lives, and with it the detriments of aging related cardiovascular disease. It's root cause is elevated cholesterol, a theory enshrined in the so-called lipid hypothesis. Questioning it is to the medical establishment what Galileo's theories were to the catholic church: plain heresy. After all, cholesterol lowering drugs, the statins, are a blessing to mankind and substantial reducer of cardiovascular death. 

    

This is what nearly everyone believes.
The Chinese Tao has a quote for such situations. It goes something like this: "when everyone knows something is good, this is bad already." You might reject my suggestion that such ancient wisdom could possibly apply to modern medicine.  So, let's get cracking at those facts which everyone knows. 

Claim 1: Heart disease, stroke and cancer are today's major killers 

Undeniably.  Cardiovascular disease accounts for roughly one in three deaths (30%), followed by cancer, which kills another one in four (23%) [1]. Which means your chance of dying of any one of those two clusters is fifty-fifty. By the way, these data, and the ones which follow, are drawn from U.S. statistics. Unfortunately they are typical for the rest of the developed world and pretty close to what the developing nations experience, too. 

Claim 2: One hundred years ago, Infectious diseases were the main killers

Yes, indeed. In 1900, one third of all deaths were due to tuberculosis and influenza alone. 

Claim 3: Since we eliminated those infectious diseases we have a longer life expectancy and therefore we simply die of aging related diseases.
This is where it starts to get hairy. First, you must NOT confuse life expectancy with life span. Life expectancy is typically quoted as life expectancy at birth. It is an average value of all the years lived divided by the number of those born alive. You can imagine how this number is very sensitive to the rate of infant deaths and of deaths during the early adult years. Particularly when one third of all newborns die within the first 12 months. Which was a typical infant death rate, not only in ancient Rome but throughout most of modern history until the 17th century. While this infant mortality rate made Roman's have an average life expectancy at birth of a little less than 30 years, a considerable part of the population lived to their sixties and seventies. In fact, very few people will have died at age 30, most either having done so way earlier or much later. Back to 1900. 

In 1900, U.S. females had a life expectancy at birth of 51 years, whereas those who reached 50 had a remaining life expectancy of another 22 years, to reach 72. Today these numbers stand at 80 years life expectancy at birth and 82 years at the age of 50. Which means two things: First, while life expectancy at birth has increased dramatically by more than 30 years over the past 100 years, life span hasn't increased that much. Second, life expectancies at birth and at age 50 have become virtually the same. The reason is a substantial reduction in infectious diseases, which killed considerable numbers of infants, of women giving birth, and of young adults. Which brings us to ...

Claim 4: Cardiovascular disease and cancer are diseases of old age, which is why they are more prominent today than 100 years ago. 
When we compare today's death rates with those of the past, we need to keep in mind that the age distribution in 1900 was substantially different to what it is today. In 1900 there were a lot less people of age 65 and older than there are today. So, we need to answer the question, what would the CVD mortality have been in 1900 if the population had had the same age distribution as ours has today. Thankfully, the U.S. CDC provides us with a standardization tool, which allows us to answer this question. They simply use the U.S. population at the year 2000 as the standard to which all other population data can be standardized. The process is called "adjustment for age" and, when applied to mortality rates, they become truly comparable as  so-called age-adjusted mortality rates. So, in the future, when you read something about mortality rates or disease rates, make sure to check which rates he uses for comparison. If he doesn't say which is which, you need to be very skeptical about his interpretation. 

Now here comes the surprise: The mortality rate for cardiovascular disease in 1900 was 22% vs. today's 31%. At first blush, this doesn't sound that much different. But think about it: If CVD is merely the disease of old age, why should there be a difference at all? And if there is a difference, why should we be dying of this disease at a 50% higher rate when we have all the medical technology, and the statins, which our grand parents didn't have.  

The entire issue becomes even weirder when you look at the development of the CVD mortality rate over the 11 decades from 1900 to today (Figure 1). CVD rose to a 60% prominence in 1960 before steeply falling to today's level. You can see that in the 1950s and 1960s people died of "age-related" heart attacks and strokes at a 50% higher rate than 50 years earlier. Another 60 years later we die at a quarter the rate of the 1960s. Which begs the question: What happened?

Figure 1

Actually, there are two parts to this question: If heart disease is age-related, why was there such a dramatic rise in age-adjusted mortality over the first half of the past century, when there should have been none. I have my theories, but I will keep them for one of my next posts.

Far more pertinent to this post's subject is the second part of the question: What did happen in the 1960s and thereafter? If you think the answer is "statins happened, stupid", then you are in for a surprise. The first statin to hit the market was Merck's Lovastatin. In 1987! Its the red vertical line in the chart of figure 1. Almost 30 years after CVD mortality rate began its steep descent. A descent, which did not accelerate with the introduction of statins to the market.  

Now, don't get me wrong, I'm not saying statins do not reduce the risk of dying from CVD, or the risk of experiencing a non-fatal heart attack or stroke. There is quite some evidence to their benefits. My point is that, whatever statins do, they do not show up on our mortality radar as the grand reducer of CVD death. Not within the current medical practice of risk estimation and subsequent risk-based treatment. 

Enter the proponents of the polypill, which contains a statin, a blood pressure lowering medication, and an aspirin. Are these proponents right to say, give a statin to everyone, who has hit the age of 55? Well, they have a point. Wald and colleagues ran a computer simulation to compare the most simple of all screenings, age, vs. the UK's National Institute of Health guidelines, which recommend screening everybody from age 40 at five-yearly intervals until people reach the risk threshold of a 20% chance of a cardiovascular event in the next 10 years [2]. That's the cut-off for treatment. Astonishingly, the benefits are virtually the same. What this screening routine buys at the costs for doctor visits and blood tests, we get free of charge with the age threshold.  

This paper was so counterintuitive to the established way of medical thinking, that the authors' paper, first submitted to the British Medical Journal in 2009, went through a 2-years Odyssey of being rejected by 4 Journals and 24 reviewers, before finally being published in PLoS One in 2011. 

But costs from a societal perspective are not the costs which interest you. You might be more interested to know, that even at an elevated risk of CVD, 25 people would have to swallow a statin for 5 years to prevent just 1 heart attack. How much larger will this number be, the number needed to treat (NNT), as we call it, if you are simply 55 but with no other CVD risk factor? You won't get an answer anytime soon. Big Pharma is not interested to finance a study, which could deliver the answer. They don't earn much money from polypills which only use generic statins, those whose patent protection has expired. 

To me the NNT is definitely too high. I won't take the polypill, though I just crossed that age threshold a few days back. I pursue another path to health and longevity. And I believe, you might want to look at my reasoning for that path. I will introduce it progressively over the next few posts. Not that I evangelize it, not to worry. I simply believe there is a third alternative to the risk-oriented practice of preventive medicine and to the kitchen-sink approach of its polypill wielding opponents. This third alternative is heresy to both. But with heresy I'm in good company. Dr. Ignaz Semmelweis was a heretic when he suggested in the mid 1800s that the high rate of deadly childbed fever was due to physicians not washing their hands between dissecting dead bodies and helping women deliver their children. It took about 50 years for his ideas to become medical mainstream. 

That's because new ideas become accepted in medicine not upon proof of being better than the old ones, but upon the old professors, who have built their careers on the old ideas, dying out. So, let's try to survive them. 

1. Kochanek, K.D., et al., Deaths: Preliminary Data for 2009, in National Vital Statistics Reports 2011, U.S. Department of Health And Human Services.

2. Wald, N.J., M. Simmonds, and J.K. Morris, Screening for future cardiovascular disease using age alone compared with multiple risk factors and age. PLoS ONE, 2011. 6(5): p. e18742.

Wald NJ, Simmonds M, & Morris JK (2011). Screening for future cardiovascular disease using age alone compared with multiple risk factors and age. PloS one, 6 (5) PMID: 21573224

Do vitamin supplements make you healthier?

The (non-)sense of vitamin supplementation?

Almost one in two American adults is a regular user of vitamin and mineral supplements, either in the form of single- or multivitamin/mineral formulations (MVMS). It all adds up to a market of US$ 9 Billion annually, or one third of the total US supplements market. Does all the pill-popping help their users to achieve better health or longevity? 

That's one question raised by Björn, one of the readers of my blog. Thanks, Björn, I wanted to write on this subject for some time. You just got me going on this a little earlier than I would have otherwise. And also thanks for the second question: Does the latest technology of delivering the drug (not to your house, but within your body to your organism's cells) via "nano-encapsulation" improve that health effect in any way? Let me try to answer these questions one by one.

When you talk about vitamins, you talk about essential micronutrients, for which the human organism has either no or only a very limited ability to produce (e.g. Vitamin D) on its own. If you want to group vitamins according to their solubility you'll find that they come in two flavors: water soluble and fat soluble. Of course, you could group them for any other biochemical characteristic, but grouping them according to their solubility makes immediate sense when you keep in mind that the fat soluble ones (A, D, E and K) can accumulate in your body's tissues, whereas the water soluble Vitamins typically can't. Whatever can accumulate, can also accumulate to the point where there is too much of it in a body's tissue. So, yes, too much of a good thing may turn into a not so good thing, as is the case for vitamins A and E for example. Or, too much of a good thing may just be flushed out of the body, as is the case with water-soluble vitamin C.

The supplement industry certainly does a good job convincing the public that supplementing one's diet with additional vitamin formulations is good for one's health. It's certainly good for the industry's bank accounts. In such cases it always pays to ask one simple question: Where is the evidence?  

In a meta-analysis of randomized clinical trials (RCT, the gold standard of clinical research methodology), the authors investigated the effects of vitamins E and A on the risk of cardiovascular disease and death in altogether 220,000 patients [1]. The effects? Zilch. The authors recommendation? The evidence does not support any recommendation for the use of Vitamins E and A. On the contrary, they found a slight increase in all-cause and cardiovascular disease mortality associated with vitamin A supplementation.

In another 2007 review on the subject, published in the American Journal of Clinical Nutrition, its author came to the same conclusion, stating that "Results to date are not compelling concerning a role for MVMs in preventing morbidity or mortality from cancer or CVD." [2] The two largest trials on Vitamin A and E supplementation in smokers, the Finnish Alpha-Tocopherol Beta-Carotene (ATBC Trial) and the US Carotene and Retinol Efficacy Trial (CARET) enrolled 29,000 and 18,000 smokers. In the Finnish trial, supplementation with Vitamin A increased the risk for lung cancers by 18% within a 5 to 8-year observation period [3]. And the US trial was halted after 2 years for the same reason: a 28% increase in lung cancer risk, a 26% increase in risk for dying from cardiovascular disease [4]. In 22,000 healthy men who had been observed for 12 years, supplementation with vitamin A showed neither benefit nor harm [5].  

So where is the evidence for you to believe that buying Vitamin E and A supplements will make you healthier and live longer? Maybe I'm blinded by a perverse distrust of everything a sales man tells me, but I can't see it.

So, how about multi-vitamins? In the group of people with the highest take-up rate of multivitamins: post-menopausal women? Again, the authors of a study which pooled the data from the Women's Health Initiative trial and observational study cohorts, come to the same conclusion "the WHI CT and OS cohorts provide convincing evidence that multivitamin use has little or no influence on the risk of cancer or CVD in postmenopausal women." [6].

Not even for infections is there any evidence that MVMS have any protective effect on those most vulnerable, the elderly [7]. 

Of course, keeping all this in mind, the nagging question remains: would there be an effect if only the delivery of the drug in the human body was improved? After all, if vitamins are essential for survival, and if vitamin supplementation does not improve health, then there are several possible reasons for this observation. For instance, we might get enough vitamins from our food, and adding vitamins has simply no effect. Or, maybe we have vitamin deficiencies but the supplements are ineffective in delivering their vitamin loads.

Which brings us to Björn's second question: "Does nano-encapsulation improve the effect of MVMS?

And may I add my nagging question: Or is "nano-whatever" just a cool gimmick of the industry to push a market, which currently grows only moderately? In the next post (Monday 16. April) I'll try to answer this question. So, stay tuned. 

1.           Vivekananthan, D.P., et al., Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet, 2003. 361(9374): p. 2017-23.

2.           Prentice, R.L., Clinical trials and observational studies to assess the chronic disease benefits and risks of multivitamin-multimineral supplements. American Journal of Clinical Nutrition, 2007. 85(1): p. 308S-313S.

3.           The Effect of Vitamin E and Beta Carotene on the Incidence of Lung Cancer and Other Cancers in Male Smokers. New England Journal of Medicine, 1994. 330(15): p. 1029-1035.

4.           Omenn, G.S., et al., Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med, 1996. 334(18): p. 1150-5.

5.           Hennekens, C.H., et al., Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease. New England Journal of Medicine, 1996. 334(18): p. 1145-1149.

6.           Neuhouser, M.L., et al., Multivitamin Use and Risk of Cancer and Cardiovascular Disease in the Women's Health Initiative Cohorts.Archives of Internal Medicine, 2009. 169(3): p. 294-304.

7.           El-Kadiki, A. and A.J. Sutton, Role of multivitamins and mineral supplements in preventing infections in elderly people: systematic review and meta-analysis of randomised controlled trials. BMJ, 2005. 330(7496): p. 871.