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Thursday, 7 March 2013

More Junk Epidemiology - Cataracts and Vitamin C

This study on supplement use hasn't come up on the paleo radar, but it's a good example of how to expose junk epidemiology. It's from the Orthomolecular Medicine News Service - you can subscribe here and it's well worth doing, they don't mail often and are in the process of becoming  accepting of low-carb science (such as ketogenic diets for cancer) while trying to cling to the saturated fat is bad, only vegetables and supplements are healthy message. Because these are not stupid people, and they already have methods that work, it's an interesting struggle to follow. Their archives link is here.
It's another junk study from Sweden - what is it about those Swedes? Is it a case of scientific suevism?
I love that he refers to Bayesian analysis as the way to proceed in these cases. I'm no mathematician, but it makes sense to me.

At the foot of the page I've included an abstract from a review of vitamin C for prevention of Complex Regional Pain Syndrome. This is an impressive result; 0.22 relative risk of this debilitating after-effect of fracture surgery from supplementing 500mg or more ascorbic acid daily for 45-50 days. An unusually effective clinical use for any supplement.
While the authors of the various trials cite the antioxidant effect of ascorbic acid and the toxicity of ROS as a mechanism, I suspect that improved integrity of the collagen matrix in the early stages of bone regrowth might also account for these benefits. After all, that's why ascorbic acid is a vitamin.

Music; Intermezzo from Cavalleria Rusticana by Pietro Mascagni.

Cataracts and Vitamins: The Real Story

by Damien Downing, MBBS, MSB, and Robert G. Smith, PhD
(OMNS Mar 5, 2013) "Hidden danger of everyday supplements is revealed" blared the headline in the UK Daily Mail [1] - a newspaper that is well known for declaring that, for example, "coffee causes cancer" and "coffee reduces cancer risk" on different pages of the same issue. This time it is reporting on a study out of Sweden that appears to show that taking vitamin C or vitamin E supplements increases your risk of developing a cataract - by about 20% for C and 60% for E. [2] It makes a good headline, but does it make sense?

Is this research?

No. They didn't give anybody anything, or do anything to them, This was just a computer exercise in which they re-analyzed postal questionnaires sent to the entire male population aged between 45 and 79 in an area of Sweden, and matched the responses to another database of cataract operations. Although the title says that it is "a population-based prospective cohort study," prospective would really mean that they followed the group of subjects, the cohort, closely over a period of time, without losing many of them. In fact they simply had their computer go through some old electronic records. Nobody was interviewed, and no checks or validation exercises were carried out. No researcher met any of the men in the study, ever.

Is it reliable?

No. The first really serious shortcoming of this paper, the gorilla in the room, is that half the men never replied in the first place, and then the authors deliberately excluded a lot more for reasons such as diabetes - one of the other main "outcomes" of the study and a big risk factor for cataracts. Finally, they omitted to account for another few thousand people, so that in the end they were only studying 27 percent of the original population. If they had randomly selected this sample of the population that would be fine, but in fact the subjects selected themselves by bothering to fill in and return the questionnaire, or not. What were their reasons? We know not. That means that already several types of selection bias have been introduced, and all the results are now meaningless.
There could even be what's known as indication bias - when cause and effect get mixed up. So, for instance, cataracts can take decades rather than years to develop, and people with early symptoms might be more likely to take supplements to ease their eyestrain. If the study goes on entirely in a computer, there's no way of telling.

Is it scientifically plausible?

No. The study contradicts many other studies that have shown either no effect or actual benefits of vitamin C and E for preventing cataracts and other eye diseases. Cataracts are common among older people, and it is well known that antioxidants can reduce the risk of developing them if taken long-term. Smoking, obesity, and diabetes are well-known risk factors for cataracts, and antioxidants are known to prevent the damage caused by these factors. [References below]. In one study, vitamin C supplements taken over 10 years or more reduced the risk of cataracts by about 80%.This is a huge dose-related effect, strongly suggesting the benefit of antioxidants in preventing cataracts. The effect was not apparent for short-term use, suggesting that any shorter-term study may not identify the benefit. (Jacques et al, 1997).
Studies should not be viewed in isolation, because that leads to the "coffee causes cancer" and "coffee reduces cancer risk" absurdity. The effect of a discrepant study such as this is to marginally adjust the current information about risk. Let's say that based on previous studies, as listed below, we thought there was an 80 percent probability that taking vitamins would help to prevent cataracts; after this one we might revise that to 75 percent. This is known as Bayesian probability [after an English minister 300 years ago] and makes a whole lot more sense than the supposedly black-and-white, 95% confidence-interval type of statistics used here. If a gambler isn't a Bayesian he's an idiot; every hand, every throw, alters the odds. So does every study.
The conclusions here are also dodgy because there is no real data on the amounts of the vitamins taken - only a guesstimate from an earlier study of 248 men - and even occasional use was tabulated as use of supplements. For this to make a substantial difference to the health outcome isn't really plausible.

So, in real life?

To prevent age-related diseases of the eye including cataracts, the best current advice is to lower oxidative stress by stopping smoking, reduce excess weight (diabetes again), eat an excellent diet along with a multivitamin supplement and additional supplements of vitamin C (3,000 - 6,000 mg/day in divided doses), vitamin E (400-1,200 IU of natural mixed tocoperols and tocotrienols). This will greatly help prevent oxidation of the tissues of the eye. Artificial forms of vitamin E (dl-alpha-tocopherol) are only 50% as biologically active as the natural form (d-alpha-tocopherol). Taking alpha-tocopherol alone is thought to lower the effective uptake of the other beneficial forms of vitamin E, so it's important to take the natural form of mixed (alpha-, beta-, gamma-, delta-) tocopherols.
(Dr. Damien Downing is a practicing physician specializing in orthomolecular medicine in London, UK, and Dr. Robert G. Smith is a neurophysiologist specializing in eye research at the University of Pennsylvania.)

(I don't have a picture of a Swedish epidemiologist, so here's a Swedish battleship. Technically a Sverige class coastal defense ship, a small battleship of limited speed and range built for defending Sweden's shoreline and harbours.)


2. Selin JZ, Rautiainen S, Lindblad BE, Morgenstern R, Wolk A High-Dose Supplements of Vitamins C and E, Low-Dose Multivitamins, and the Risk of Age-related Cataract: A Population-based Prospective Cohort Study of Men (2013) American Journal of Epidemiology, published online. DOI: 10.1093/aje/kws279

Vitamin C lowers cataract risk:

Head KA. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Altern Med Rev. 2001 Apr;6(2):141-66. [vitamin C alone or with vitamin E reduces risk of cataracts]
Jacques PF, Taylor A, Hankinson SE, Willett WC, Mahnken B, Lee Y, Vaid K, Lahav M. Long-term vitamin C supplement use and prevalence of early age-related lens opacities. Am J Clin Nutr. 1997 Oct;66(4):911-6. [Huge effect, 77% - 83% decrease in lens opacities]

Vitamin E lowers cataract risk:

Rouhiainen P, Rouhiainen H, Salonen JT. Association between low plasma vitamin E concentration and progression of early cortical lens opacities. Am J Epidemiol. 1996 Sep 1;144(5):496-500.
Nourmohammadi I, Modarress M, Khanaki K, Shaabani M. Association of serum alpha-tocopherol, retinol and ascorbic acid with the risk of cataract development. Ann Nutr Metab. 2008;52(4):296-8. doi: 10.1159/000148189.
Seth RK, Kharb S. Protective function of alpha-tocopherol against the process of cataractogenesis in humans. Ann Nutr Metab. 1999;43(5):286-9.
Engin KN. Alpha-tocopherol: looking beyond an antioxidant. Mol Vis. 2009;15:855-60. [ vitamin E likely plays a role in preventing cataracts]

Smoking increases risk:

Mosad SM, Ghanem AA, El-Fallal HM, El-Kannishy AM, El Baiomy AA, Al-Diasty AM, Arafa LF. Lens cadmium, lead, and serum vitamins C, E, and beta carotene in cataractous smoking patients. Curr Eye Res. 2010 Jan;35(1):23-30. doi: 10.3109/02713680903362880.
Hiller R, Sperduto RD, Podgor MJ, Wilson PW, Ferris FL 3rd, Colton T, D'Agostino RB, Roseman MJ, Stockman ME, Milton RC. Cigarette smoking and the risk of development of lens opacities. The Framingham studies. Arch Ophthalmol. 1997 Sep;115(9):1113-8.

Healthy diet prevents cataracts:

Mares JA, Voland R, Adler R, Tinker L, Millen AE, Moeller SM, Blodi B, Gehrs KM, Wallace RB, Chappell RJ, Neuhouser ML, Sarto GE; CAREDS Group. Healthy diets and the subsequent prevalence of nuclear cataract in women. Arch Ophthalmol. 2010 Jun;128(6):738-49. doi: 10.1001/archophthalmol.2010.84.
Williams DL. Oxidation, antioxidants and cataract formation: a literature review. Vet Ophthalmol. 2006 Sep-Oct;9(5):292-8.

 2013 Jan-Feb;52(1):62-6. doi: 10.1053/j.jfas.2012.08.003. Epub 2012 Sep 15.

Efficacy and safety of high-dose vitamin C on complex regional pain syndrome in extremity trauma and surgery--systematic review and meta-analysis.


Texas A&M Health and Science Center, College of Medicine, Temple, TX, USA.


Complex regional pain syndrome (CRPS) is a devastating condition often seen after foot and ankle injury and surgery. Prevention of this pathology is attractive not only to patients but also to surgeons, because the treatment of this condition can be difficult. We evaluated the effectiveness of vitamin C in preventing occurrence of CRPS in extremity trauma and surgery by systematically reviewing relevant studies. The databases used for this review included: Ovid EMBASE, Ovid MEDLINE, CINAHL, and the Cochrane Database. We searched for comparative studies that evaluated the efficacy of more than 500 mg of daily vitamin C. After screening for inclusion and exclusion criteria, we identified 4 studies that were relevant to our study question. Only 1 of these 4 studies was on foot and ankle surgery; the rest concerned the upper extremities. All 4 studies were in favor of this intervention with minimal heterogeneity (Tau(2) = 0.00). Our quantitative synthesis showed a relative risk of 0.22 (95% confidence interval = 0.12, 0.39) when daily vitamin C of at least 500 mg was initiated immediately after the extremity surgery or injury and continued for 45 to 50 days. A routine, daily administration of vitamin C may be beneficial in foot and ankle surgery or injury to avoid CRPS. Further foot and ankle specific and dose-response studies are warranted.


majkinetor said...

Yeah, pure junk.

Nobody mentioned this one:

George Henderson said...

For some reason I always hit a paywall with medscape unless I go there from a google search...
Thanks for the CRP article by the way. Much appreciated.

George Henderson said...

A free paywall - glad I worked that out thanks!

George Henderson said...

So; we don't know what doses the "subjects" took
We don't know whether the missing 77% had the same results as the 27% still included.
We don't know WHY they were taking the vitamins to begin with;
and we don't know - at all, even from a small sample - whether they took them at all, kept taking them or took them regularly, or made any other changes that might have affected cataract risk.
And we don't know what happened to the high-risk diabetics either...

majkinetor said...

Almost entire study could be read from the preview.

Its embarrassing, really.

Yeah, they are bunch of in-vitro studies that show detrimental effects on cultured cells by AA but those were never replicated in vivo, quite contrary.

Some more:

George Henderson said...

The bottom line is there will be right and wrong ways to use ascorbate and vit E. The latter could well be problematic at some doses or combinations. What's needed is comparative studies of different supplement/diet protocols; get back to the fine art of practicing and perfecting medicine.

Nice evils of processed meat study that finds red meat harmless, and small amounts beneficial, today. Yay!

George Henderson said...


Eating both red meat and poultry were not associated with significant increases in mortality risk, and small quantities of red meat appeared to be beneficial.

The authors pointed out that red meat contains essential nutrients and minerals that might be missing from a vegetarian diet.

George Henderson said...

Suspiciously, in the abstract they do seem to impugn red meat even though the author's interview cleared it!
Perhaps processed meat was a subset of red meat?


Recently, some US cohorts have shown a moderate association between red and processed meat consumption and mortality supporting the results of previous studies among vegetarians. The aim of this study was to examine the association of red meat, processed meat, and poultry consumption with risk of early death in the European Prospective Investigation into Cancer and Nutrition (EPIC).


Included in the analysis were 448,568 men and women without prevalent cancer, stroke, or myocardial infarction, and with complete information on diet, smoking, physical activity and body mass index, who were between 35 and 69 years old at baseline. Cox proportional hazards regression was used to examine the association of meat consumption with all-cause and cause-specific mortality.


Until June 2009, 26,344 deaths were observed. After multivariate adjustment, a high consumption of red meat was related to higher all-cause mortality (HR=1.14, 95% CI 1.01-1.28, 160+ vs. 10-19.9 g/day), and the association was stronger for processed meat (HR=1.44, 95% CI 1.24-1.66, 160+ vs. 10-19.9 g/day). After correction for measurement error, higher all-cause mortality remained significant only for processed meat (HR=1.18, 95% CI 1.11-1.25, per 50 g/d). We estimated that 3.3% (95% CI 1.5-5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g per day. Significant associations with processed meat intake were observed for cardiovascular diseases, cancer, and 'other causes of death'. The consumption of poultry was not related to all-cause mortality.


The results of our analysis support a moderate positive association between processed meat consumption and mortality in particular due to cardiovascular diseases, but also cancer.

George Henderson said...
This comment has been removed by the author.