Whole grains - when old-fashioned common sense meets the scientific method
The meta-analysis of Aune et al attempts to put a value on old-fashioned common sense, but risks exaggerating its value by its narrow focus on a single class of unrefined food.
As David Colquhoun has noted in these responses, confounding in regard to this question is a complex problem.
People who pay the extra money for whole grains and go out of their way to prepare them are, overall, a breed apart. (Indeed, one of the benefits of refined grains in the past was a shorter cooking time, and thus a lower expenditure on fuel, perhaps a critical advantage in highly populated, deforested nations). People who chose whole grains may thus have more money and leisure time, or be better educated or more interested in health, or, in some cultures, be more connected to family and cultural traditions.
Perhaps more significantly, people who use whole grains are likely to be opposed to the consumption of highly refined grains and other processed foods. Thus, they are not exposed to high-GI carbohydrates, the supplementary vitamins and minerals added to refined flour (including iron), and bleaching agents, and are perhaps less exposed to the baffling array of food additives that seem to be necessary for the modern production of bread. They are also unlikely to be people who consume deep-fried foods often.
All these factors predict good health in people who eat whole grains, without requiring that specific nutritional and non-nutritive factors in whole grains provide the benefit. In fact it may be that people who ate most whole grains when questioned at the beginning of the more recent long term diet studies were the most likely to have given up grains altogether, or to have eliminated gluten grains from their diets, by the end of the study, as these practices have partly replaced wholegrain eating as health fads.
We can reduce such confounding by looking at an RCT where whole grains (by one possible definition among many) were part of an intervention where mortality was an endpoint. The Diet and Reinfarction Trial (DART), 1989, took 2,033 British men who had already suffered from an acute MI and divided them into six groups to test dietary advice to a) decrease saturated fat and replace it with polyunsaturated fat, b) increase fish intake, c) increase cereal fibre intake by the use of wholegrain bread and extra bran. Only the higher fish group saw a significant reduction in MI and all-cause mortality; the other interventions saw large (but non-significant, given the small n= and moderate duration of 2 years) increases in MI and all-cause mortality.
"Those randomized to the cereal fibre group were advised to have at least six slices of wholemeal bread per day, or the equivalent amount of cereal fibre from a mixture of wholemeal bread, high fibre breakfast cereals and wheat bran. An exchange list was provided for these items. Bran tablets (Fybranta, Norgine Ltd, UK) were offered as a supplement where necessary." These tablets were only used by two subjects, while 71 of the subjects in this intervention "added wheat bran to cereals, soups or stews.". This resulted in a doubling of cereal fibre intake, and would also have increased intake of lignans and betaine.
The long term effect of the various advice, reported in 2002, is also of interest.
"By February 2000, after 21147 person years of follow-up, 1083 (53%) of the men had died. Completed questionnaires were obtained from 879 (85%) of the 1030 men alive at the beginning of 1999. Relative increases in fish and fibre intake were still present at 10 y but were much smaller. The early reduction in all-cause mortality observed in those given fish advice (unadjusted hazard 0.70 (95% CI 0.54, 0.92)) was followed by an increased risk over the next 3 y (unadjusted hazard 1.31 (95% CI 1.01, 1.70). Fat and fibre advice had no clear effect on coronary or all-cause mortality. The risk of stroke death was increased in the fat advice group - the overall unadjusted hazard was 2.03 (95% CI 1.14, 3.63)."
The value of such RCT information is that it underscores the extreme difficulty of translating observational findings such as those of Aune et al into beneficial interventions or dietary advice.
It is wholly plausible - indeed, it is old-fashioned common sense - that eating whole grains in place of refined grains is a healthful habit. Medical men of the past such as TL Cleave and Sir Robert McCarrison were probably not deluded when they insisted on this.[6, 7] However, both men saw wholegrain consumption as beneficial in the context of a diet relatively high in fatty animal foods (including dairy, eggs, and organ meats), fruit, and vegetables, and low in sugar and highly processed foods. They did not say that cereal consumption needed to be increased at the expense of animal foods, as it was in the late 20th century.
It is notable that the association between wholegrain intake and diabetes mortality in Aune et al is a U-shaped curve with lowest mortality at an amount that would supply 35-45g carbohydrate/day, depending on the type of grain, which is not a biologically implausible association. A pre-existing diabetes diagnosis is usually an exclusion criteria in diet studies of the type analysed in Aune et al.
Populations which had zero grain consumption prior to the arrival of colonists did not suffer from high rates of diabetes, cancer, or cardiovascular disease, but do suffer from very high rates of these diseases today following the introduction of refined grains, sugars, and oils. Thus, if there are in fact essential protective nutrients and other factors in whole grains, these must have also been available from the other foods that make up natural and minimally processed diets, and are as likely to continue to be available from these foods today.
 Aune D, Keum M, Giovannucci E et al. Whole grain consumption and risk of cardiovascular disease, cancer, and all cause and cause specific mortality: systematic review and dose-response meta-analysis of prospective studies. BMJ 2016;353:i2716
[3} Burr ML1, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989 Sep 30;2(8666):757-61.
 Fehily AM, Vaughan-Williams E, Shiels K et al. The effect of dietary advice on nutrient intakes: evidence from the diet and reinfarction trial (DART). Journal of Human Nutrition and Dietetics. Volume 2, Issue 4, pages 225–235, August 1989
 Ness AR, J Hughes J, Elwood PC et al. The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART). EJCN. June 2002, Volume 56, Number 6, Pages 512-518
Competing interests: No competing interests