What is Actionable Intelligence? or is there enough evidence to tell you to eat nuts?
Jacob Schor, ND, FABNO
December 1, 2013
It is often difficult to know when there is adequate information to put some action into motion. I suppose it depends on the risk involved, the risk of doing nothing versus the risk of doing something.
I’m thinking about this because of the paper published by the New England Journal of Medicine by Bao et al on November 21, 2013. In it Bao’s team elegantly suggest that nut consumption has an inverse association with mortality, that is the more nuts people eat, the longer they live. 
Bao and colleagues analyzed data from two large, long-term, prospective cohort studies separately and then in combination checking for an association between nut consumption and mortality, both total mortality and cause-specific mortality.
They used large cohorts, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPS). The NHS is a prospective cohort of 121,700 female nurses enrolled in 1976. The HPFS is a prospective cohort of 51,529 male health professionals enrolled in 1986. The current study eliminated participants without complete data or who had a history of cancer, heart disease or stroke so in the final analyses data from only 76,464 women and 42,498 men were included. Still if you multiply those people by thirty years the researchers still had 3,038,853 person-years of data to analyze. During that time 16,200 women and 11,229 men died
Nut eating patterns were tracked using food-frequency questionnaires administered every 2 to 4 years. The primary study end point was death from any cause. The researchers also sought associations with specific causes of death.
The bottom line was that the more nuts these people ate, the less likely they were to die: nut consumption was inversely associated with total mortality among both women and men. The more nuts they ate, the lower their risk of dying during the study. Eating nuts daily was associated with a 20% lower risk of dying compared to those who didn’t eat nuts at all.
Eating nuts even less than once per week lowered risk of dying 7% compared to never eating nuts. Eating nuts once per week cut risk by 11%, two to four times per week cut risk by 13%, five to six times cut risk by 15% and daily nut eating was associated with a 20% lower risk. This inverse association was also statistically significant for deaths from cancer, heart and respiratory disease.
This study is likely the strongest epidemiological evidence ever published suggesting we should eat more nuts. The size and length of the study added power to the statistics, the three million patient years of data is huge. This wasn’t a hasty or sloppy study. In analyzing the data, these Harvard epidemiologists made every effort they could to counter possible confounders that could have been responsible.
Still when it came time for the conclusion, they wrote, “… epidemiologic observations establish associations, not causality, and not all findings from observational studies have been confirmed in controlled, randomized clinical trials.”
True enough I suppose but if this isn’t enough evidence, what is?
Our kitchen counter: Pecans, English Walnuts, Black Walnuts and Almonds
This is like that elephant and blind men story. Epidemiologists and public health researchers see the world different from the way we do, with greater caution. Where we might jump to translate this information into clinical practice, these researchers hold back, afraid to commit.
They have reason to be reticent. Randomized controlled trials (RCTs) have had mediocre success in confirming epidemiologic predictions. Recall that 2013 paper by Moorthy et al that compared the findings of RCTs with the epidemiological data that the trials were meant to confirm. In only 23 out of 34 associations did the results from meta-analyses of epidemiological studies and of RCTs point in the same direction, and in only 6 of those 23 associations, were the findings statistically significant. In the remaining 11 out of 34 associations, meta-analyses of epidemiological studies and of RCTs pointed in opposite directions. Of the 12 out of 34 associations in which the association between RCT and epidemiology was statistically significant, only 6 of the results were in the direction predicted by epidemiological studies; the results of the other 6 were in the opposite direction. Basically it seems that it’s kind of a coin-flip whether past epidemiological associations will be confirmed in RCTs. We should probably give Bao et al, a bit of slack if they sound hesitant.
Moorthy’s results should be taken with a grain of salt. They considered studies conceived back in the age when nutritional interventions were simple, when nutrient uni-deficiencies were the cause of diseases. Unfortunately not every disease has proven to be as straightforward to treat as scurvy or pellagra.
If modern nutritional researchers seem shy, remember they have survived the ignominy of the Caret Trial failure. That was the study in which beta-carotene increased rather than lowered risk of lung cancer in smokers.[3,4,5] They were also left with pie on their faces when the SELECT trials found that vitamin E and selenium supplements were associated with a higher risk of getting prostate cancer. [6,7] Same with the more recent SELECT paper that reported increased omega-3 fats in the blood were associated with an increased risk for prostate cancer. It’s easy for us on the outside to think we know why their studies failed. It’s got to be a huge disappointment and embarrassment for the people involved.
These past failures though are from studies that looked at single nutrients. Nuts may be a different story as they are not a single nutrient but complex biological substances. It makes more sense to test “food supplementation or broad dietary change” in populations. It’s more likely that these food study results will hold.
Certainly we should consider the results of this current Bao nut study in the context of other earlier studies about nuts. There is a impressive amount of positive work already published on nuts. Observational and clinical trials suggest nut consumption has beneficial effects on coronary heart disease and its intermediate biomarkers. [10,11,12] As early as 2003 the Food and Drug Administration concluded that 1.5 oz of nuts per day “may reduce the risk of heart disease.” 
Granted that epidemiology alone may sometimes steer us off course but we already have RCTs that suggest multiple benefits from eating nuts. The PREDIMED Trial, the Spanish study that gave people at high risk for cardiovascular disease supplemental nuts or extra virgin olive oil to eat, reported significant reductions in cardiovascular events in those consuming about an ounce of nuts per day.  In fact, the PREDIMED trial results may actually trump this current paper as PREDIMED was a randomized prospective primary prevention trial and this Bao study is only observational. Still the shear size of the Bao’s cohorts makes it hard to ignore.
Bao’s numbers are not that different from the numbers that the Adventist Health Study reported about nuts two decades ago. In those early findings, eating nuts five or more times per week compared with less than once per week was associated with reduced total mortality with hazard ratios ranging from 0.56 to 0.82. [15,16,17] That is pretty much the same ballpark.
Since those early Adventist studies, there have been studies associating nut eating with reductions in predictors of chronic disease including oxidative stress, inflammation, visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction.[18-23]
Other prospective cohort studies have associated increased nut intake with reduced risks of type-2 diabetes, metabolic syndrome, colon cancer, hypertension, gallstone disease, diverticulitis, and even death from inflammatory diseases.-30]
This current study is a change in that it does not concern itself with anything other than the bottom line, whether nuts change the risk of dying. One would think that when all this is added together, it would be adequate. What end of the elephant do we have a hold on?
In clinical practice our mission is improving patient outcomes. Our bottom line is disease reduction. We compare risk versus benefit constantly. The potential pay-off from eating more nuts looks good. The risk side of the equation looks empty. If by some fluke confounders exist and it turns out that nuts are a dud, that they don’t really reduce death and morbidity, there’s still likely that our patients will be no worse off, eating nuts will not hurt them.
This is where our perceptions as clinicians differ from the view of researchers. They can debate as long as they want, especially if they have tenure. We need to give our patients sound advice today that will improve their health tomorrow. Association may not be causality but nevertheless, all things considered, particularly the low risk versus potential benefit, it now seems absurd not to tell most of our patients to eat a daily portion of nuts.
1. Bao Y, Han J, Hu FB, Giovannucci EL, Stampfer MJ, Willett WC, Fuchs CS. Association of nut consumption with total and cause-specific mortality. N Engl J Med. 2013 Nov 21;369(21):2001-11. doi: 10.1056/NEJMoa1307352.
Free pdf: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1307352
2. Findings of Epidemiological Studies and Randomized Trials in Nutrition: An Empirical Evaluation and Citation Analysis: Nutritional Research Series, Vol. 6 Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 May. Report No.: 13-EHC067-EF. AHRQ Technical Reviews.
Free full text: http://www.ncbi.nlm.nih.gov/books/NBK138246/
3. Goodman GE, Thornquist MD, Balmes J, Cullen MR, Meyskens FL Jr, Omenn GS, Valanis B, Williams JH Jr. The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping beta-carotene and retinol supplements. J Natl Cancer Inst. 2004 Dec 1;96(23):1743-50.
4. Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, Keogh JP, Meyskens FL, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1150-5.
Free Article http://www.nejm.org/doi/full/10.1056/NEJM199605023341802
5. Omenn GS, Goodman G, Thornquist M, Barnhart S, Balmes J, Cherniack M, Cullen M, Glass A, Keogh J, Liu D, Meyskens F Jr, et al. Chemoprevention of lung cancer: the beta-Carotene and Retinol Efficacy Trial(CARET) in high-risk smokers and asbestos-exposed workers. IARC Sci Publ. 1996;(136):67-85.
6. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).
JAMA. 2009 Jan 7;301(1):39-51.
7. Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, …. Meyskens FL Jr, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011 Oct 12;306(14):1549-56.
8. Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL Jr. et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst. 2013 Aug 7;105(15):1132-41.
9. Meyskens FL Jr, Szabo E. Diet and cancer: the disconnect between epidemiology and randomized clinical trials. Cancer Epidemiol Biomarkers Prev. 2005 Jun;14(6):1366-9.
Free full text: http://cebp.aacrjournals.org/content/14/6/1366.long
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