Re: Implausible results in human nutrition research
We read with great interest Dr. Ioannidis’s paper on “Implausible results in human nutrition research: Definitive solutions won’t come from another million observational papers or small randomized trials” (1). While we can appreciate his editorial on the subject, this general discussion on the strengths and limitations of observational and experimental studies is not unique to nutrition and is commonplace in textbooks on epidemiological methods dating back to MacMahon and Pugh’s first text on the subject in 1970 (2). Strong commentary on the limitations of epidemiology in the study of nutrition can be traced back to Taubes’ article in Science in 1995 (3). A thorough rehashing of his arguments goes beyond the scope of this response, but in all areas of epidemiology (and other areas of scientific study), false positive and false negative results inevitably occur, and many studies lack replication. We discuss some of the main points below.
Dr. Ioannidis’s comment that “Many findings are entirely implausible” is not helpful as implausible finding occur by chance or other reasons in almost all areas of science, and conclusions should not be based on a single finding but rather the plausibility given all available evidence and on replication (1). In nutritional research, we usually evaluate the evidence from animal/mechanistic experiments, biological/metabolic findings, and epidemiological/intervention studies together to reach conclusions (4). No single study should stand on its own, especially now that decades of nutritional research are available. Similarly, no single editorial should completely dismiss the great value the last 50 years of research has provided. Dr. Ioannidis selectively picked a few estimates from the vast amount of nutrition literature without any context. More importantly, he did not include the 95% confidence intervals surrounding those estimates. The 95% CIs can provide important information on both certainty and uncertainty of the point estimates (5). In evidence-based nutrition, meta-analyses and systematic reviews instead of findings from a single study are used to develop recommendations or guidelines. Therefore, consistency and replications of the findings across different populations are extremely important.
If we use dietary fat and heart disease as a first example, the weak and inconsistent results mainly derive from early studies, which were not designed to investigate the fat-CHD association. However, they should not be interpreted as providing strong negative evidence (6). The limitations in early studies include small sample size; use of a single 24-hour recall for dietary assessment; lack of updated dietary measurement during follow-up; and no adjustment for total energy intake or other dietary factors. More recent large prospective cohort studies have addressed these limitations. Results from high quality observational studies correspond well with randomized controlled trials (Table 1). Interestingly, in a publication from 2005, Dr. Ioannidis made the similarly dramatic claim that “Most biomedical research findings are false for most research designs and for most fields” (7). Goodman and Greenland (and others) have provided detailed responses to this claim and identified the logical flaws of Dr. Ioannidis’ assertion (8-13).
Dr. Ioannidis concluded that in future we would need randomized controlled trials (RCTs) 10 times the sample size of the Prevención con Dieta Mediterránea (PREDIMED) study (1). Interestingly, the majority of nutrition trials, even the size of PREDIMED, would not have been proposed or conducted had there not been very compelling evidence of the benefits of the Mediterranean diet, olive oil, and nuts from short term trials with intermediate endpoint and observational studies with coronary heart disease - the exact studies Dr. Ioannidis argues against performing. Does Dr. Ioannidis suggest that we conduct randomized trials 10 times the size of PREDIMED based on no more than simple conjuring of hypothetical biological pathways connecting nutrition with long term health?
Contrary to common beliefs, RCTs are not immune to confounding and serious bias even if they are large, and they can provide seriously misleading answers (14). For example, RCT's of smoking cessation showed no benefit on mortality (15), very low birth weight, neonatal death or perinatal mortality (16). Also, studies such as the Women’s Health Initiative, with a $400 million arm to test the benefits of a very low fat diet, failed to test the fat hypothesis due to low compliance with the dietary intervention (17). The earlier Multiple Risk Factor Intervention Trial (MRFIT) also failed to test its original hypothesis due to poor adherence and found no significant effect of an intervention combining diet, smoking cessation and hypertension treatment on coronary disease (18). These issues will not simply disappear by increasing sample size and they will worsen with longer follow-up(14). Randomized trials are randomized and free of confounding only at baseline, and their interpretation is complicated by attrition and non-compliance that is subject to confounding and selection bias - the same issues we are concerned about in observational studies.
Finally, Dr. Ioannidis comment that “Definitive solutions won’t come from another million observational papers or small randomized trials” (1) over simplifies the conduct of nutrition research and shows a deeper misunderstanding of the field. Because of the complex nature of our field, conclusions need to be based on the broader totality of evidence from human observational and clinical studies. In the past decades, cardiovascular mortality has decreased dramatically in Finland, US, and other developed countries, and more than half of the decline is attributable to improvement in diet and lifestyle factors. The landmark North Karelia study (44), the Seven Countries Study (45), the Framingham Heart study (46), the Minnesota Heart Health Program (47), and many other studies have shown that his claim of implausible nutrition finding does not hold water. A recent example would be trans fat. Well conducted long term observational studies and small randomized trials provided consistent and convincing evidence of the adverse effects of trans fat on lipid levels, inflammation, endothelial dysfunction, and significantly increased risk of coronary heart disease (48, 49). Despite the lack of large, long-term trials (48, 49) important changes were made to nutritional labels and policies across the globe, and food companies have removed up to 80% of trans fat in foods in the US. This clear public health advance was made with just the evidence that Dr. Ioannidis scorned; millions of premature deaths will be prevented that would not have been had we waited to conduct a mega-trial of trans fat to prove harm, and which could easily provide misleading results if it had the same fate as the WHI or MRFIT trials.
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Competing interests: No competing interests