To the Editor: 
 
 Because of irregularities in the randomization procedures, we wish to retract the following article: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. DOI: 10.1056/NEJMoa1200303.1 We have reanalyzed the data and have published a new report: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. DOI: 10.1056/NEJMoa1800389.2 
 
 Ramón Estruch, M.D., Ph.D. 
 
 CIBEROBN, Madrid, Spain 
 
 Emilio Ros, M.D., Ph.D. 
 
 Instituto de Investigaciones Biomédicas Augusto Pi Sunyer, Barcelona, Spain 
 
 Jordi Salas-Salvadó, M.D., Ph.D. 
 
 Rovira i Virgili University, Tarragona, Spain 
 
 Maria-Isabel Covas, D.Pharm., Ph.D. 
 
 Hospital del Mar Medical Research Institute, Barcelona, Spain 
 
 Dolores Corella, D.Pharm., Ph.D. 
 
 University of Valencia, Valencia, Spain 
 
 Fernando Arós, M.D., Ph.D. 
 
 University Hospital Araba, Vitoria, Spain 
 
 Enrique Gómez-Gracia, M.D., Ph.D. 
 
 University of Malaga, Malaga, Spain 
 
 Valentina Ruiz-Gutiérrez, Ph.D. 
 
 Instituto de la Grasa, Seville, Spain 
 
 Miquel Fiol, M.D., Ph.D. 
 
 Institute of Health Sciences, Palma de Mallorca, Spain 
 
 José Lapetra, M.D., Ph.D. 
 
 Distrito Sanitario Atención Primaria, Seville, Spain 
 
 Rosa M. Lamuela-Raventos, D.Pharm., Ph.D. 
 
 University of Barcelona, Barcelona, Spain 
 
 Lluís Serra-Majem, M.D., Ph.D. 
 
 Research Institute of Biomedical and Health Sciences, Las Palmas, Spain 
 
 Xavier Pintó, M.D., Ph.D. 
 
 Bellvitge University Hospital, Barcelona, Spain 
 
 Josep Basora, M.D., Ph.D. 
 
 Miguel A. Muñoz, M.D., Ph.D. 
 
 Instituto de Investigación en Atención Primaria J. Gol, Barcelona, Spain 
 
 José V. Sorlí, M.D., Ph.D. 
 
 University of Valencia, Valencia, Spain 
 
 J. Alfredo Martínez, D.Pharm., M.D., Ph.D. 
 
 Miguel A. Martínez-González, M.D., Ph.D. 
 
 University of Navarra, Pamplona, Spain 
 
 [email protected] 
 
 This letter was published on June 13, 2018, at NEJM.org. 
 
 Editor’s note: An analysis of reports of randomized trials for improbable distributions of baseline data included 934 reports published in the Journal and identified 11 with distributions of baseline variables that did not appear consistent with randomization (Carlisle JB. Anaesthesia 2017;72:944-52. DOI: 10.1111/anae.13938. Epub 2017 June 4). We reviewed these 11 trial reports and replicated the Carlisle analysis. In 5 reports, standard errors were inadvertently reported as standard deviations, or vice versa. These errors explained the findings and have been corrected; the 5 reports are as follows: High-Dose Atorvastatin after Stroke or Transient Ischemic Attack (N Engl J Med 2006;355:549-59), Treatment of Periodontitis and Endothelial Function (N Engl J Med 2007;356:911-20), Extended Antiretroviral Prophylaxis to Reduce Breast-Milk HIV-1 Transmission (N Engl J Med 2008;359:119-29), Effect of Bronchoconstriction on Airway Remodeling in Asthma (N Engl J Med 2011;364:2006-15), and Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia (N Engl J Med 2011;365:430-8). For 5 other reports, limitations in the Carlisle analysis, such as lack of accounting for correlation among baseline variables, most likely explained the findings. 
 
 For the remaining report, Primary Prevention of Cardiovascular Disease with a Mediterranean Diet (N Engl J Med 2013;368:1279-90), the authors’ subsequent review of their data and randomization procedures identified protocol deviations, including the enrollment of participants who were not randomized. The authors have therefore withdrawn their original report (Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. N Engl J Med. DOI: 10.1056/NEJMc1806491). The Journal has now published their new report of the study, which describes the protocol deviations and reports reanalyses of the data (Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. N Engl J Med. DOI: 10.1056/NEJMoa1800389). ||||| Study Design 
 
 The PREDIMED trial (Prevención con Dieta Mediterránea) was a parallel-group, multicenter, randomized trial. Details of the trial design are provided elsewhere.10-12 The trial was designed and conducted by the authors, and the protocol was approved by the institutional review boards at all study locations. The authors vouch for the accuracy and completeness of the data and all analyses and for the fidelity of this report to the protocol, which is available with the full text of this article at NEJM.org. 
 
 Supplemental foods were donated, including extra-virgin olive oil (by Hojiblanca and Patrimonio Comunal Olivarero, both in Spain), walnuts (by the California Walnut Commission), almonds (by Borges, in Spain), and hazelnuts (by La Morella Nuts, in Spain). None of the sponsors had any role in the trial design, data analysis, or reporting of the results. 
 
 Participant Selection and Randomization 
 
 Eligible participants were men (55 to 80 years of age) and women (60 to 80 years of age) with no cardiovascular disease at enrollment, who had either type 2 diabetes mellitus or at least three of the following major risk factors: smoking, hypertension, elevated low-density lipoprotein cholesterol levels, low high-density lipoprotein cholesterol levels, overweight or obesity, or a family history of premature coronary heart disease. Detailed enrollment criteria are provided in the Supplementary Appendix, available at NEJM.org. All participants provided written informed consent. 
 
 Beginning on October 1, 2003, participants were randomly assigned, in a 1:1:1 ratio, to one of three dietary intervention groups: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with nuts, or a control diet. Randomization was performed centrally by means of a computer-generated random-number sequence. 
 
 Interventions and Measurements 
 
 Table 1. Table 1. Summary of Dietary Recommendations to Participants in the Mediterranean-Diet Groups and the Control-Diet Group. 
 
 The dietary intervention8,10-13 is detailed in the Supplementary Appendix. The specific recommended diets are summarized in Table 1. Participants in the two Mediterranean-diet groups received either extra-virgin olive oil (approximately 1 liter per week) or 30 g of mixed nuts per day (15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of almonds) at no cost, and those in the control group received small nonfood gifts. No total calorie restriction was advised, nor was physical activity promoted. 
 
 For participants in the two Mediterranean-diet groups, dietitians ran individual and group dietary-training sessions at the baseline visit and quarterly thereafter. In each session, a 14-item dietary screener was used to assess adherence to the Mediterranean diet8,14 (Table S1 in the Supplementary Appendix) so that personalized advice could be provided to the study participants in these groups. 
 
 Participants in the control group also received dietary training at the baseline visit and completed the 14-item dietary screener used to assess baseline adherence to the Mediterranean diet. Thereafter, during the first 3 years of the trial, they received a leaflet explaining the low-fat diet (Table S2 in the Supplementary Appendix) on a yearly basis. However, the realization that the more infrequent visit schedule and less intense support for the control group might be limitations of the trial prompted us to amend the protocol in October 2006. Thereafter, participants assigned to the control diet received personalized advice and were invited to group sessions with the same frequency and intensity as those in the Mediterranean-diet groups, with the use of a separate 9-item dietary screener (Table S3 in the Supplementary Appendix). 
 
 A general medical questionnaire, a 137-item validated food-frequency questionnaire,15 and the Minnesota Leisure-Time Physical Activity Questionnaire were administered on a yearly basis.10 Information from the food-frequency questionnaire was used to calculate intake of energy and nutrients. Weight, height, and waist circumference were directly measured.16 Biomarkers of compliance, including urinary hydroxytyrosol levels (to confirm compliance in the group receiving extra-virgin olive oil) and plasma alpha-linolenic acid levels (to confirm compliance in the group receiving mixed nuts), were measured in random subsamples of participants at 1, 3, and 5 years (see the Supplementary Appendix). 
 
 End Points 
 
 The primary end point was a composite of myocardial infarction, stroke, and death from cardiovascular causes. Secondary end points were stroke, myocardial infarction, death from cardiovascular causes, and death from any cause. We used four sources of information to identify end points: repeated contacts with participants, contacts with family physicians, a yearly review of medical records, and consultation of the National Death Index. All medical records related to end points were examined by the end-point adjudication committee, whose members were unaware of the study-group assignments. Only end points that were confirmed by the adjudication committee and that occurred between October 1, 2003, and December 1, 2010, were included in the analyses. The criteria for adjudicating primary and secondary end points are detailed in the Supplementary Appendix. 
 
 Statistical Analysis 
 
 We initially estimated that a sample of 9000 participants would be required to provide statistical power of 80% to detect a relative risk reduction of 20% in each Mediterranean-diet group versus the control-diet group during a 4-year follow-up period, assuming an event rate of 12% in the control group.10,17 In April 2008, on the advice of the data and safety monitoring board and on the basis of lower-than-expected rates of end-point events, the sample size was recalculated as 7400 participants, with the assumption of a 6-year follow-up period and underlying event rates of 8.8% and 6.6% in the control and intervention groups, respectively. Power curves under several assumptions can be found in Fig. S1 in the Supplementary Appendix. 
 
 Yearly interim analyses began after a median of 2 years of follow-up. With the use of O'Brien–Fleming stopping boundaries, the P values for stopping the trial at each yearly interim analysis were 5×10−6, 0.001, 0.009, and 0.02 for benefit and 9×10−5, 0.005, 0.02, and 0.05 for adverse effects.18 The stopping boundary for the benefit of the Mediterranean diets with respect to the primary end point was crossed at the fourth interim evaluation; on July 22, 2011, the data and safety monitoring board recommended stopping the trial on the basis of end points documented through December 1, 2010. 
 
 All primary analyses were performed on an intention-to-treat basis by two independent analysts. Time-to-event data were analyzed with the use of Cox models with two dummy variables (one for the Mediterranean diet with extra-virgin olive oil and another for the Mediterranean diet with nuts) to obtain two hazard ratios for the comparison with the control group. To account for small imbalances in risk factors at baseline among the groups, Cox regression models were used to adjust for sex, age, and baseline risk factors. We tested the proportionality of hazards with the use of time-varying covariates. All analyses were stratified according to center. Prespecified subgroup analyses were conducted according to sex, age, body-mass index (BMI), cardiovascular-risk-factor status, and baseline adherence to the Mediterranean diet. Sensitivity analyses were conducted under several assumptions, including imputation of data for missing values and participants who dropped out (see the Supplementary Appendix). ||||| Errors Trigger Retraction Of Study On Mediterranean Diet's Heart Benefits 
 
 Enlarge this image toggle caption Westend61/Getty Images Westend61/Getty Images 
 
 Ask just about anybody, and you'll probably hear that a healthy diet is one full of fruits and vegetables, olive oil, nuts and fish — what's called Mediterranean diet. A lot of research has suggested people who eat this way tend to be healthier, but it's been harder to prove whether that is because of the diet or some other factor. 
 
 So in 2013, many took notice of a study in the New England Journal of Medicine that seemed to provide some proof. The study found that people eating the Mediterranean diet supplemented with olive oil were 30 percent less likely to experience a heart attack, stroke, or death from cardiovascular causes than people assigned to a low-fat diet. People who stuck with a Mediterranean diet supplemented with mixed nuts had a 28 percent lower risk than those asked to follow a low-fat diet. 
 
 The results got wide media attention, including from NPR. 
 
 But the New England Journal of Medicine retracted the paper Wednesday because of problems in the way the study was carried out. 
 
 A retraction is a last resort for medical and scientific journals, a sign to readers that the results are no longer trustworthy and are beyond correcting. Although retractions are relatively rare — taking down fewer than 1 in 1,000 published articles — the rate is increasing. 
 
 The authors of the NEJM paper are replacing the 2013 paper with a corrected version that shows people following the diet had a similarly reduced level of heart attacks and strokes. The major change is softer language about the conclusions. 
 
 The revised paper says only that people eating the Mediterranean diet had fewer strokes and heart attacks, not, as the original paper claimed, that the diet was the direct cause of those health benefits. 
 
 Of course, a change in one paper — even a high-profile one — doesn't mean that researchers have lost faith in the benefits of the Mediterranean diet. "I don't know anybody who would turn around from this and say, 'Now that this has been revealed, we should all eat cotton candy and turn away from the Mediterranean diet,' " says David Allison, dean of the School of Public Health at Indiana University in Bloomington. 
 
 Still, without the strong language touting the benefits of the diet in the original paper, "the legs have been kicked out from under it, in some sense," says Allison, a longtime nutrition researcher whose research has at times been partially funded by the food industry. 
 
 What prompted the Mediterranean diet researchers to soften their language? 
 
 A persistent British anesthesiologist named John Carlisle. 
 
 He knew very little about analyzing the details behind clinical trials until a few years ago, when he wrote a letter to an anesthesiology journal bemoaning the fact that his field was polluted by one researcher's data that many suspected were problematic. The journal editor told Carlisle, a practicing anesthesiologist at Torbay Hospital in Torquay, England, to prove it. 
 
 So Carlisle did. He read up on statistical methods and looked over more than 160 trials by the researcher, Dr. Yoshitaka Fujii, and analyzed how likely it was that the people had been randomized to different treatments. Randomization is part of the gold standard for clinical studies because it reduces the risk of bias and allows researchers to determine cause-effect relationships. 
 
 Carlisle found the odds were infinitesimally small that Fujii had randomized people properly. Since Carlisle's findings were published in 2012, medical journals have retracted more than 160 papers by Fujii — the most retractions for any one researcher, by a large margin, according to Retraction Watch. 
 
 Carlisle's analysis drew accolades — and added him to the ranks of a small but growing number of such sleuths. The success of the approach prompted Carlisle to expand his scope to include randomized trials from other researchers and in other fields. 
 
 After the Fujii paper, he spent two years applying the "Carlisle method" to thousands of clinical trials published in eight journals. In 2017, he reported that roughly 2 percent showed signs of problems. 
 
 Among the more than 5,000 trials Carlisle analyzed, 934 were published by the New England Journal of Medicine. He flagged 11. One was the 2013 study showing the Mediterranean diet was responsible for the reduced rates of heart attack and stroke. 
 
 Today, NEJM is replacing the 2013 study and correcting five others on different topics. The Mediterranean diet paper is being retracted because it turns out Carlisle was correct. When the lead author of the paper, Dr. Miguel Ángel Martínez González of the University of Navarra Medical School, saw Carlisle's analysis, he conducted a detailed audit of the study and quickly noticed some problems. 
 
 It turns out approximately 14 percent of the more than 7,400 study participants hadn't been assigned randomly to either the Mediterranean diet or a low-fat one. When couples joined the study together, both had been picked to follow the same diet. At one of the 11 participating study sites, the lead investigator had assigned the same diet to an entire village and didn't tell the rest of the investigators. 
 
 "This affected only a small part of the trial," says Martínez González. When the researchers reanalyzed the data excluding the nonrandomized people, the results were the same, he adds. 
 
 Still, because everybody wasn't randomly assigned to different groups, the study can no longer claim the diet directly caused those health benefits. "We need to tone down the results, but it is just a little bit," he says. 
 
 Many other studies have shown that people eating the Mediterranean diet have lower risks of various ailments, without claiming cause and effect. 
 
 But would the New England Journal of Medicine, one of the world's most selective and prestigious journals, have published the Mediterranean diet paper from Martínez González if the randomization issues and softened conclusion had been included in the first place? 
 
 "It is difficult to answer hypothetical questions," New England Journal of Medicine spokeswoman Jennifer Zeis says. "We believe the evidence [in favor of the diet] is still strong, but not as strong as a randomized study in which the randomization was executed flawlessly." 
 
 Carlisle praised the journal's response. "I think that the NEJM editorial team responded very maturely to my paper," he says. "They took the possibility of a problem seriously and acted quickly and thoroughly." 
 
 Alison McCook is the editor of Retraction Watch, a website that reports on scientific retractions and related issues. It is a project of The Center for Scientific Integrity, a nonprofit organization that has been funded by the John D. and Catherine T. MacArthur Foundation, the Laura and John Arnold Foundation and the Helmsley Charitable Trust. 
 
 This story is a partnership with Retraction Watch, which you can find on Twitter: @retractionwatch ||||| “We realized we had never reported that,” Dr. Martínez-González said. 
 
 Image Dr. Miguel A. Martínez-González Credit via Wikimedia Commons 
 
 An omission like that erodes the randomized nature of the trial. Family members are likely to share more than just a diet: If a husband and wife both dodge heart disease, it’s difficult to say that their diet is the only reason. 
 
 In their re-analysis, the investigators statistically adjusted data on 390 people who happened to be household members but whose diets were not randomly assigned. 
 
 Then the investigators discovered another problem. 
 
 A researcher at one of the 11 clinical centers in the trial worked in small villages. Participants there complained that some neighbors were receiving free olive oil, while they got only nuts or inexpensive gifts. 
 
 So the investigator decided to give everyone in each village the same diet. He never told the leaders of the study what he had done. 
 
 “He did not think it was important,” Dr. Martínez-González said. 
 
 But the decision meant that participants were not truly randomized and forced Dr. Martínez-González and his colleagues to make another statistical adjustment to data on 652 people in the trial. 
 
 The investigators spent a year working on the re-analysis in collaboration with Dr. Miguel Hernan of the Harvard T.H. Chan School of Public Health. 
 
 In the end, they concluded that the original findings were still accurate. 
 
 “You cannot imagine what it has been like,” Dr. Martínez-González said, adding that he and his team worked through vacations and weekends — and swallowed considerable professional embarrassment.
– The repute of the Mediterranean diet, considered one of the world's healthiest, took a hit this week: Citing methodology errors, authors retracted a landmark 2013 study published in the New England Journal of Medicine that found people who consumed the diet of fruits, veggies, nuts, fish, and olive oil had a 30% reduced risk of heart attack and stroke. But believers still have something to cheer: The authors replaced it with a "re-analysis" that reached essentially the same conclusion, though with what NPR calls "softer language." The key difference: Those on the diet did indeed appear to have a 30% reduced risk of serious health risks, but the authors no longer assert that the diet is the reason—only that they found an association between the two. "After all this long work, I am more convinced [of the findings] than ever," study author Miguel Martínez-González of Spain's University of Navarra tells the New York Times. The big problem in the original study is that it was supposed to be randomized—that is, the nearly 7,500 participants were supposed to be assigned one of three diets in the study at random—but that didn't happen in some cases. One example: A researcher would randomly assign one member of a household to adhere to one of the three diets, but then ask everyone else in the household to follow it as well. That means the other members of the household weren't randomly assigned. "The evidence is still strong, but not as strong as a randomized study in which the randomization was executed flawlessly," says an NEJM spokesperson. (Plenty of other studies tout the diet's benefits.)