Statistics in randomised controlled trials

The use of statistics in randomised controlled trials is central to the whole exercise and it is a terrible waste of everyone’s time when this is neglected. This timely paper in the BMJ id worth the attention of anyone undertaking such trials.
The importance of sample size determination in randomised controlled trials has been widely asserted, and must be reported in published articles. An a priori sample size calculation will determinate the number of participants needed to detect a clinically relevant treatment effect.
The conventional approach is to calculate sample size with four parameters: type I error, power, assumptions in the control group (response rate and standard deviation), and expected treatment effect. Type I error and power are usually fixed at conventional levels (5% for type I error, 80% or 90% for power). Assumptions related to the control group are often prespecified on the basis of previously observed data or published results, and the expected treatment effect is expected to be hypothesised as a clinically meaningful effect. The uncertainty related to the rate of events or the standard deviation in the control group and to treatment effect could lead to lower than intended power.
Charles and his colleagues assessed the quality of reporting sample size calculation in published reports of randomised controlled trials, the accuracy of the calculations, and the accuracy of the a priori assumptions.
In this survey of 215 reports published in 2005 and 2006 in six general medical journals with high impact factors, only about a third (n=73, 34%) adequately described sample size calculations-that is, they reported enough data to recalculate the sample size, the sample size calculation was accurate, and assumptions in the control group differed less than 30% from observed data. This study raises two main issues. The first is the inadequate reporting and the errors in sample size calculations, which are surprising in high quality journals with a peer review process; the second is the large discrepancies between the assumptions and the data in the results, which raises a much more complex problem because investigators often have to calculate a sample size with insufficient data to estimate these assumptions.
Reporting of the sample size calculation has greatly increased in the past decades, from 4% of reports describing a calculation in 1980 to 83% of reports in 2002. This review highlights that some parameters for sample size calculation are frequently absent and that miscalculations occur.
They also found large discrepancies between values for assumed parameters in the control group used for sample size calculations and estimated ones from observed data. Assumed values were fixed at a higher or lower level than corresponding data in the results sections in roughly even proportions, a finding different from the results of a previous study.
These results suggest that researchers, reviewers, and editors do not take reporting of sample size determination seriously. An effort should be made to increase transparency in sample size calculation or, if sample size calculation reporting is of little relevance in randomised controlled trials, perhaps it should be abandoned, as suggested by Bacchetti.

. After years of trials with supposedly inadequate sample sizes, it is time to develop and use new ways of planning sample sizes.

Charles et al 2009 Reporting of samle size calculation in randomised controlled trials: review. BMJ vol 338, pp 1256-1259

Food Waste

The affluent countries waste millions of tons of edible food. Supermarkets, restaurants, canteens and manufactures are identifiable in this respect. For example nearly 500 million pots of yoghurt are thrown away every year in Britain. 50% of food disappears between the plough and the plate. Up to a third of school meals are thrown away, A quarter of food products purchased are thrown away. The Cooperative Supermarket wastes the least food of the British Supermarkets, followed by Morrisons, Tesco, Asda , Waitrose and the worst is Sainsbury’s with over 50 % more waste than the Cooperative Supermarket.
Poor and misunderstood labelling can lead to good food being thrown away.
Obviously food poisoning is a real problem But one can be ultra cautious.
EU food-labelling law require most pre-packed food to carry a “use-by” or “best-before” date, the “best-before” date is a mark of quality, “use-by” date of food safety. But the date may mean that the food could be past its prime but safe to eat. Sell by is for the convenience of the shop and does not reflect any nutritional. Value. All very confusing.
A ridiculous example is bottled water which has been in the ground for thousands of years , but once in a bottle has a brief use by label.

Tristam Stuart No appetite for waste Financial Times Weekend Magazine July 4/5 2009. p 30-35
Based on an important book
Waste: uncovering the Global Food Crisis Author Tristram Stuart : Penguin Publication.

Garlic

This is a very interesting paper in Critical Reviews in Food Science and Nutrition 2009 on the merit of garlic in the diet.
Natural plant products have a real place in combating various physiological threats including oxidative stress, cardiovascular problems, cancer, and immune dysfunction.
Garlic (Allium sativum} holds a unique position in history and was recognized for its therapeutic potential. Recent advancements in the field of immunonutrition, physiology, and pharmacology have emphasised its importance as a functional food against various pathologies. Extensive research work has been. carried out on the health promoting properties of garlic, often referred to its sulfur containing metabolites i.e. allicin and its derivatives.
Alicin
Diallyl sulfide, Diallyl disulfide Diallyl trisulfide AllylMethyl sulfide AllylMethyl disulfide Allylmethyl trisulfide 2-vinyl-4H-I,3-dithiin
3-vinyl-4H-l,2-dithiin
E- Ajoene , Z-Ajoene


S-allyl-Lcysteines
S-allylmercaptocysteine


Garlic has many modes of preparation which are believed to be effective against health risks and even used as dietary supplements such as age garlic extract (AGE) and garlic oil etc. Its components/formulations can scavenge free radicals and protect membranes from damage and maintains cell integrity. It also provides cardiovascular protection by lowering of cholesterol, blood pressure, anti-platelet activities, and thromboxane formation thus providing protection against atherosclerosis and associated disorders. Besides this, it possesses antimutagenic and antiproliferative properties that are interesting in chemoprevenrive interventions. Several mechanisms have been reviewed in this context like activation of detoxification phase-I and II enzymes, reactive oxygen species (ROS) generation, and reducing DNA damage etc. Garlic could be useful in preventing the suppression of immune response associated with increased risk of malignancy as it stimulates the proliferation of lymphocytes, macrophage phagocytosis, stimulates the release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma, and enhances natural killer cells.
Masood Sadiq Butt et al 2009 Garlic : Nature’s protection against physiological threats, Critcal Reviews in Food Science and Nutrition vol 49, pp 538-5551

plant hormones

Recent advances and emerging trends in plant hormone signalling
Aaron Santner ' & Mark Estelle have reviewed plant homones in Nature 25th June 2009

In eating frit and vegetables there are many different molecules whose function when eaten by man is unknown included in these are plant hormones.
Plant growth and development is regulated by plant hormones. During the last 15 years the number of known plant hormones has grown from five to at least ten. Furthermore, many of the proteins involved in plant hormone signalling pathways have been identified, including receptors for many of the major hormones. Strikingly, the ubiquitin-proteasome pathway plays a central part in most hormone-signalling pathways. In addition, recent studies confirm that hormone signalling is integrated at several levels during plant growth and development.


Because plants have a sessile lifestyle, they must adjust to numerous external stimuli and coordinate their growth and development accordingly. The plant hormones, a group of structurally unrelated small molecules, are central to the ntegration of diverse environmental cues with a plant's genetic program. The 'classical' phytohormones, identified during the first half of the twentieth century, are auxin, abscisic acid, cytokinin, gibberellin and ethylene.
More recently, several additional compounds have been recognized as hormones, including brassinosteroids, jasrnonate, salicylic acid, nitric oxide and strigolactcnes

Plants also use several peptide hormones to regulate various growth responses, Most hormones are involved in many different processes ( hormone synthesis, transport and signalling pathways, as well as by the diversity of interactions among hormones) to control growth responses. throughout plant growth and development. Genetic screens have identified many of the proteins involved in hormone signalling
Receptors for auxin, gibberellin , jasmonate and abscisic acid have now been identified. . Some hormones (cytokinins, ethylene and the brassinosteroids) use well-characterized signalling mechanisms.
The auxin and jasmonate receptors, as well as proteins in gibberellin signalling, have highlighted a novel mechanism for hormone perception in which the ubiquitin--proteasome pathway.
Has this any relevance to human nutrition? Who knows , but we do know that eating fruit and vegetables is good for health, and these plant hormones may be of biological value.
Santner and Estelle 2009 Recent advances and emerging trends in plant hormone signalling. Nature vol 459 pp 1071-78

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trans fats in the diet

A review of trans fats by D Mozaffarian, A Aro and W C Willett indicating that these ar not too good for out health.
Growing evidence indicates that trans-fatty acids (TFA) adversely affect cardiovascular health. As part of the World Health Organization (WHO) Scientific Update on TFA, we reviewed the evidence for effects of TFA consumption on coronary heart disease (CHD).
The effects of TFA consumption on risk factors most consistently seen in both controlled trials and observational studies included adverse lipid effects (for example low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total/HDL-C ratio), proinflammatory effects (for example tumor necrosis factor- activity, interleukin-6, C-reactive protein) and endothelial dysfunction. These effects were most prominent in comparison with cis unsaturated fats; adverse effects on total/HDL-C and endothelial function were also seen in comparison with saturated fatty acids (SFA). TFA may also worsen insulin sensitivity, particularly among individuals predisposed to insulin resistance; possible effects on weight gain and diabetes incidence require further confirmation. Five retrospective case–control studies and four prospective cohort studies demonstrated positive associations between TFA consumption and CHD events. A meta-analysis of prospective studies indicated 24, 20, 27 and 32% higher risk of myocardial infarction (MI) or CHD death for every 2% energy of TFA consumption isocalorically replacing carbohydrate, SFA, cis monounsaturated fatty acids and cis polyunsaturated fatty acids, respectively. The differential effects of specific TFA isomers may be important but are less well established. The available evidence indicates that trans-18:1 and particularly trans-18:2 isomers have stronger CHD effects than trans-16:1 isomers. The limited data suggest that the experimental effects of ruminant and industrial TFA are similar when consumed in similar quantities, but very few persons consume such high levels of ruminant TFA, and observational studies do not support adverse CHD effects of ruminant TFA in amounts actually consumed.
Conclusions:
Controlled trials and observational studies provide concordant evidence that consumption of TFA from partially hydrogenated oils adversely affects multiple cardiovascular risk factors and contributes significantly to increased risk of CHD events. The public health implications of ruminant TFA consumption appear much more limited. The effects of specific TFA isomers require further investigation.
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D Mozaffarian, A Aro and W C Willett (2009)Health effects of trans-fatty acids: experimental and observational evidence European Journal of Clinical Nutrition 63, S5–S21;

obesity epidemiology

The vol 87 (2009) of the Millbank Quarterly contains a big review on obesity. Sallis and Glanz ( vol 87 pp 123-154) have written a timely reminder that where there is little provision for exercise then obesity is more prevalent. : Numerous cross-sectional studies have consistently demonstrated that some attributes of built and food environments are associated with physical activity, healthful eating, and obesity. Residents of walkable neighborhoods who have good access to recreation facilities are more likely to be physically active and less likely to be overweight or obese. Residents of communities with ready access to healthy foods also tend to have more healthful diets. Environmental, policy, and societal changes are important contributors
to the rapid rise in obesity over the past few decades, and there has been substantial progress toward identifying environmental and policy factors related to eating and physical activity that can point toward solutions

ageing and vitamin D

This is a good review by Oudshoorn et al on the important subject of vitamin D in the elderly.
Vitamin D is a pleiotropic hormone. Besides the effects on classical tissues like bone and intestine, vitamin D has an effect on many more tissues. Effects of vitamin D metabolites can occur via endocrine, paracrine or autocrine mechanisms.
Ageing increases the risk of vitamin D deficiency and is associated with vitamin D resistance and less efficient intestinal Ca absorption and renal reabsorption. Vitamin D supplementation doses needed to treat vitamin D deficiency and secondary hyperparathyroidism vary considerably between individuals. This makes it necessary for clinicians to give tailored advice to patients when treating hypovitaminosis D, taking into account these age-related effects and other characteristics that influence vitamin D status and Ca homeostasis.
In general, mobile, Caucasian community-dwelling elderly, who have a varied diet, need vitamin D supplementation of 10-20 μg (400 IU – 800 IU ) /d to reach serum vitamin D levels of 50-75 nmol/l. Frail or institutionalised elderly on the other hand are suggested to need up to 50 ug (2000 IU)/). The effectiveness of this high-dose vitamin D supplementation in raising serum 250HD3 levels adequately has been demonstrated in several clinical trials. However, good evidence for the optimal dose of vitamin D supplementation in specific high-risk groups is still lacking.
Oral supplementation is the most effective intervention to treat vitamin D deficiency. Ergocalciferol is equally as effective as cholecalciferol in raising serum 250HD3 levels. Daily dosing is the most efficient interval to raise serum 250HD3 concentrations when compared with weekly or monthly administration.
Although vitamin D supplementation therapy is generally regarded as safe, cases of iatrogenic and accidental overdose with cholecalciferol have been reported. . Most safety data concerning the use of high-dose cholecalciferol supplementation come from observations in relatively young individuals. Few studies have used high-dose cholecalciferol supplementation for longer periods in frail, older patients. Frail old people, particularly the institutionalised, often have poor daily fluid intake, use diuretics and have less thirst sensation than younger persons.
All clinicians who frequently treat older patients should take a proactive approach to screening at-risk individuals for vitamin D deficiency, as this condition is still very prevalent. When treating patients for vitamin D deficiency, Ca intake should be assessed. Possible unwanted effects of long-term vitamin D supplementation and the effects of hypervitaminosis D should be studied in forthcoming trials.
Oudshoorn et al Ageing and vitamin D deficiency : effects on calcium homeostasis and consideration or vitamin D supplementation .

minerals and vitamins in bone health

This is a very good review of such an important topic. Very thoughtful
Nutrition is important to bone health, and a number of minerals and vitamins have been identified as playing a potential role in the prevention of bone diseases, particularly osteoporosis. Despite this, there is currently no consensus on maximum levels to allow in food or as dietary supplements. The benefits of supplementation of populations at risk of osteoporosis with Calcium and vitamin D are well established. Prolonged supplementation of Ca and vitamin D in elderly bas been shown to prevent bone loss, and in some intervention studies to prevent fragility fractures.
Calcium intakes and recommendations vary form country to country but range between 700 mg/d to 1200 mg depending on age and gender.
Vitamin D 1000 IU ( 25 μg/d ) has been recommended but not yet achieved.

Although Phosphorous is essential to bone health, the average intake is considered to be more than sufficient and supplementation could raise intake to adverse levels. The role of vitamin K in bone health is less well defined, though it may enhance the actions of Calcium and vitamin D. Strontium administered in pharmacological doses as the ranelate salt was shown to prevent fragility fractures in postmenopausal osteoporosis. However, there is no hard evidence that supplementation with Strontium salts would be beneficial in the general population. Magnesium is a nutrient implicated in bone quality, but the benefit of supplementation with foodstuffs remains to be established. A consensus on dietary supplementation for bone health should balance the risks, for example, exposure of vulnerable populations to values close to maximal tolerated doses, against evidence for benefits from randomised clinical trials, such as those for Ca and vitamin D. Feedback from community studies should direct further investigations and help formulate a consensus on dietary supplementation for bone health.
Bonjour J-P et al 2009 Minerals and vitamins in bone health : the potential value of dietary enhancement. Brit J Nutrition vol 101 pp 1581-1596

bone density measurements

Accurate measurements are critical to any scientific exercise. Bone mineral density monitoring is by dual energy x ray absorptiometry which is costly . A well recognised method. Bisphonate treatment( alendronate ) reduces the risk of fractures ,but does not relief pain from existing fractures and may have side effects. A side product of a trail of the effectiveness of bisphonate treatment was an evaluation of dual energy x ray absorptiometry and its ability to show significant change in bone mineral density and predict if any changes in bone mineral density were valuable in predicting fractures.
The results for an individual over time were so variable and the results did not allow prediction of fracture risk.
Another variable is that compliance with treatment is not god.

Bell et al 2009 Value of routine monitoring of bone mineral density after starting bisphonate treatment : secondary analysis of trail data. BMJ vol 338 1553
Compston 2009 Monitoring bone mineral density during antiresorptive treatment for osteoporosisisBMJ vol 338 1511-1513

Triathlon suggestions

Many people progress from marathon running to triathlon events which is a very taxing riding , swimming and running trial.
Maybe
Swim 2.4 miles! Bike 112 miles run 26.2 miles
A real challenge.
This is an interesting summary of needs in the Financial Times Weekend Magazine
Triathlon kit
Seasoned triathletes are well known for forking out a lot of money on gear, but you don’t need to spend a fortune when you’re starting out ...
~ Goggles are a must. Those for “open water” swimming often use a mask style, which offers greater peripheral vision..
~ A wet suit is compulsory for most UK open water triathlons. But if your triathlon might be a one-hit wonder, hire a wet suit for the season instead of shelling out.
~ Many triathletes wear a “tri-suit”, beneath their wet suit, in which they can perform the cycle and run. But swim wear or close-fitting sportswear is fine.
~ You don’t need a super-light road bike (let alone a tri-specific bike), although it will be faster than a mountain bike or other upright. Use an aluminium-framed road bike with carbon forks.
~ Clipless pedals and cycle shoes fitted with cleats enable you to apply more power to the pedals, but they aren’t essential. . Ensure you get a good-fitting, well-vented helmet that meets British safety standards and fits snugly, even without the strap fastened.
Any old running shoes will do –But good shoes with the all-important elastic laces for quick access and a chafe-free interior for wearing sock-free. ~ Finally, a race belt with race number belt, to which you attach your race number, dispenses with the need for safety pins. Simply twist it to the back for the cycle and the front for the run.

Nutrition tips

1. Three to four days before the race, increase your carbohydrate intake to maximise stores of glycogen
in the muscles (the fuel your body breaks down for energy). Aim for 7g per kg of body weight per day.
2. Start the race well fuelled and hydrated. Many triathlons begin at dawn, which means getting up even earlier to eat a light breakfast of cereal or toast. If you can't face food,
at least have a smoothie or sports drink.

3. Consider drinking a cup of coffee 01' taking a caffeine gel an hour before the race starts. Caffeine has been shown to boost endurance performance.

4. Find out what - if any - sports drink is provided during the race so that you can try it out in training. Research has shown that isotonic sports drinks containing carbohydrate and electrolyte salts are more effective than plain water. Sip frequently, don't guzzle ..

5. As the bike leg is the longest part of a triathlon (and given that you can't drink during the swim), this is when to fuel up. Take an energy gel as soon as I get on the saddle, and another shortly before I get off, as well as drinking 500ml-750ml of sports drink. Jelly Babies are a good energy gel alternative.

6. Refuel afterwards to replenish energy, fluid and electrolytes, A milky drink, salty snack and fruit are ideal.

My only concern with this very good advice is the use of caffeine supplements, which are also cardio toxic at the wrong time. I would avoid them.
Source Sam Murphy FT weekend June 6/7 p 41
Sam Murphy “Triathlon start to finish “ Kyle Cathie p £14 .99.

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