Letters
Meta-analysis in Research on Nutrition 1. Barnard ND, Willett WC, Ding EL. The misuse of meta-analysis in nutrition
To the Editor Dr Barnard and colleagues1 questioned the valid-
ity of meta-analyses in nutrition research, highlighting the
industry-funded meta-analysis by Chowdhury et al in 2014
that failed to support the diet-heart hypothesis, that excess
saturated fat intake causes cardiovascular disease. Their
argument was that nutritional epidemiological studies are
complex interventions that do not lend themselves to aggre-
gation, compared, for example, with drug trials. However,
meta-analyses are useful summaries, offering the reader an
overview of the available literature, while addressing the
issue of type 2 error by pooling associations or effect mea-
sures of individual studies or trials.
For example, Barnard and colleagues faulted the 2014
meta-analysis for giving more weight to the Malmö Diet and
Cancer Study2 (n = 28 098) than to the Oxford Vegetarian Study
(n = 1100), which had results strongly supportive of the diet-
heart hypothesis. They pointed out that mean saturated fat in-
takes in the Malmö study were not low enough to test the hy-
pothesis that very low intakes of saturated fat protect against
cardiovascular disease. However, intakes did have sufficient
range to test the hypothesis that very high intakes of satu-
rated fat are harmful compared with intakes closer to those
specified by dietary guidelines. Men in the Malmö study in the
highest quartile of fat intake (average 47.7% of energy) expe-
rienced the lowest rate of cardiovascular disease deaths (haz-
ard ratio [HR], 0.65 [95% CI, 0.45-0.94]).2 There was no dif-
ference between highest vs lowest saturated fat intake for
cardiovascular disease mortality in men (22.3% vs 12.3% of en-
ergy; HR, 0.94 [95% CI, 0.58-1.53]) or for any cause of death
in men or women.2 If the hypothesis were true that excess satu-
rated fat intake caused cardiovascular disease, a dose-
response relationship would likely be observed. Yet other re-
cent meta-analyses, including several not funded by industry,
also fail to support the hypothesis.3,4 Barnard and colleagues
ignored both evidence of publication bias in favor of the diet-
heart hypothesis4 and evidence that the sugar industry in the
1960s and 1970s supported fat research to deflect attention
away from sugar as a cause of cardiovascular disease.5
We believe that the authors missed the bigger picture
shown by the many meta-analyses that address the question
of the health effects of saturated fat. Statistical evidence sup-
porting advice to limit saturated fat intake, after decades of re-
search, is still extremely weak. These meta-analyses should be
taken seriously and dietary guidelines changed accordingly.
Simon Thornley, MBChB, MPH
George Henderson
Grant Schofield, BSc, PhD
Author Affiliations: Millennium Institute, Auckland University of Technology,
Auckland, New Zealand.
Corresponding Author: George Henderson, Auckland University of
Technology, PO Box 92006, Auckland 1142, New Zealand
(puddleg@gmail.com).
Conflict of Interest Disclosures: The authors have completed and submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Schofield
reported receiving royalties for a book on low-carbohydrate eating. No other
disclosures were reported.
1050 JAMA March 13, 2018 Volume 319, Number 10 (Reprinted)
© 2018 American Medical Association. All rights reserved.
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research. JAMA. 2017;318(15):1435-1436.
2. Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G. Dietary fat
intake and early mortality patterns—data from the Malmö Diet and Cancer
Study. J Intern Med. 2005;258(2):153-165.
3. de Souza RJ, Mente A, Maroleanu A, et al. Intake of saturated and trans
unsaturated fatty acids and risk of all cause mortality, cardiovascular disease,
and type 2 diabetes: systematic review and meta-analysis of observational
studies. BMJ. 2015;351:h3978.
4. Hamley S. The effect of replacing saturated fat with mostly n-6
polyunsaturated fat on coronary heart disease: a meta-analysis of randomised
controlled trials. Nutr J. 2017;16(1):30.
5. Kearns CE, Schmidt LA, Glantz SA. Sugar industry and coronary heart disease
research: a historical analysis of internal industry documents. JAMA Intern Med.
2016;176(11):1680-1685.
In Reply A thorough systematic review does provide a helpful
overview of the literature. However, meta-analysis is a sepa-
rate step, and study findings can be buried in a poorly planned
meta-analysis.
The meta-analysis by Chowdhury et al1 illustrates the chal-
lenges. As we noted in our Viewpoint, it combined findings
from heterogeneous populations with very different diet pat-
terns. In making a case for the relative weights given to the
Oxford Vegetarian Study and the Malmö Diet and Cancer Study
in the Chowdhury et al meta-analysis, Dr Thornley and col-
leagues incorrectly reported the sizes of their data sets. There
were 20 440 (not 28 098) participants reported for Malmö and
10 802 (not 1100) in Oxford.1 As noted by the authors of the
Malmö study, the high range of saturated fat intake made their
study of limited value for testing the association between satu-
rated fat intake and cardiovascular disease, and saturated fat
was not compared with other sources of calories.2
Thornley and colleagues cite 2 additional meta-analyses
as evidence of the innocuous nature of saturated fat. Al-
though our commentary focused on the limitations of meta-
analysis rather than a readjudication of saturated fat’s risks,
we note that one of Thornley and colleagues’ suggested ar-
ticles reported, “In large prospective studies, when polyun-
saturated fats replace saturated fats, risk of CHD [coronary heart
disease] is reduced.”3 Had Chowdhury et al used participant-
level data rather than published aggregate data, such a sub-
stitution analysis would have been possible. Participant-
level data are not always available; accessing them requires the
cooperation of the original investigators.
However, the value of substitution analyses in this area
was demonstrated in a study of participants in the Nurses’
Health Study and the Health Professionals Follow-up Study
in which replacement of 5% of energy from saturated fat with
equivalent energy from unsaturated fat was associated with a
27% lower risk of total mortality and lower mortality due to
cardiovascular disease, cancer, and neurodegenerative
disease.4 Similarly, in an earlier pooled analysis of individual-
level data from prospective studies, replacing 5% of energy
from saturated fat with an equivalent quantity of polyunsat-
urated fat was associated with a 26% lower risk of coronary
heart disease death.5 This finding is supported by controlled
feeding studies showing that this substitution leads to ben-
eficial effects on blood lipids.6 In the pooled analysis, replac-
ing saturated fat with carbohydrates (mainly refined starch
jama.com

and sugar in most populations) was associated with a some-
what higher risk of coronary heart disease. The Chowdhury
et al analysis was not able to distinguish between the sources
of energy that would replace saturated fat. Had it pursued
stronger methods, it may have yielded something other than
a null result.
Well-conducted systematic reviews are helpful. To the ex-
tent that meta-analysis is done only when appropriate and uses
the best available methodology, consumers of research find-
ings are better served.
Neal D. Barnard, MD
Walter C. Willett, MD, DrPH
Eric L. Ding, ScD
Author Affiliations: Physicians Committee for Responsible Medicine,
Washington, DC (Barnard); Department of Nutrition, Harvard T.H. Chan School
of Public Health, Boston, Massachusetts (Willett, Ding).
Corresponding Author: Neal D. Barnard, MD, Physicians Committee for
Responsible Medicine, 5100 Wisconsin Ave, Ste 400, Washington, DC 20016
(nbarnard@pcrm.org).
Conflict of Interest Disclosures: The authors have completed and submitted
the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Barnard
reported serving as president of the Physicians Committee for Responsible
Medicine and Barnard Medical Center; receiving personal fees for lectures
related to nutrition and health; and receiving royalties for books related to
nutrition and health. Dr Willett reported receiving research support from the
National Institutes of Health and the Breast Cancer Research Foundation;
royalties for books related to nutrition and epidemiology; and honoraria for
lectures with the Culinary Institute of America. Dr Ding reported receiving
research funding from the American Heart Association, American Diabetes
Association, the Robert Wood Johnson Foundation, the Qatar National
Research Fund, and the Nordea Foundation; consulting for the Physicians
Committee for Responsible Medicine and Naturex; receiving personal fees from
the University of Connecticut, the University of Arizona, the University of
California at Berkeley, and the European Commission; and being a board
member of the nonprofit ToxinAlert.org, a minority shareholder in Epidemic
Health, a health economist at the nonprofit Microclinic International, and a
faculty lecturer at Management Center Innsbruck, Austria.
1. Chowdhury R, Warnakula S, Kunutsor S, et al. Association of dietary,
circulating, and supplement fatty acids with coronary risk: a systematic review
and meta-analysis. Ann Intern Med. 2014;160(6):398-406.
2. Wallström P, Sonestedt E, Hlebowicz J, et al. Dietary fiber and saturated fat
intake associations with cardiovascular disease differ by sex in the Malmö Diet
and Cancer Cohort: a prospective study. PLoS One. 2012;7(2):e31637.
3. de Souza RJ, Mente A, Maroleanu A, et al. Intake of saturated and trans
unsaturated fatty acids and risk of all cause mortality, cardiovascular disease,
and type 2 diabetes: systematic review and meta-analysis of observational
studies. BMJ. 2015;351:h3978.
4. Wang DD, Li Y, Chiuve SE, et al. Association of specific dietary fats with total
and cause-specific mortality. JAMA Intern Med. 2016;176(8):1134-1145.
5. Jakobsen MU, O’Reilly EJ, Heitmann BL, et al. Major types of dietary fat and
risk of coronary heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr.
2009;89(5):1425-1432.
6. Mensink RP, Zock PL, Kester ADM, Katan MB. Effects of dietary fatty acids
and carbohydrates on the ratio of serum total to HDL cholesterol and on serum
lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr.
2003;77(5):1146-1155.
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Letters
CORRECTION
Typo in the Discussion: In the Original Investigation entitled “Effect of Antibiotic
Prophylaxis on Surgical Site Infections Following Removal of Orthopedic Implants
Used for Treatment of Foot, Ankle, and Lower Leg Fractures: A Randomized Clinical
Trial”1 published in the December 26, 2017, issue of JAMA, in the Discussion section,
it reads, “There were numerically more deep SSIs in the saline group than in the
cefazolin group (1 patient [0.9%] in the cefazolin group vs 7 patients [2.9%] in
the saline group)….” It should read, “There were numerically more deep SSIs in the
saline group than in the cefazolin group (1 patient [0.4%] in the cefazolin group
vs 7 patients [2.9%] in the saline group)….” This article was corrected online.
1. Backes M, Dingemans SA, Dijkgraaf MGW, et al. Effect of antibiotic
prophylaxis on surgical site infections following removal of orthopedic implants
used for treatment of foot, ankle, and lower leg fractures: a randomized clinical
trial. JAMA. 2017;318(24):2438-2445.
Author Added to Byline: In the article entitled “Effect of Therapeutic Hypother-
mia Initiated After 6 Hours of Age on Death or Disability Among Newborns With
Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial,”1 published in the
October 24/31, 2017, issue of JAMA, an author was omitted from the byline due to
an oversight by a principal investigator and coordinator at one of the centers. Amir
M. Khan’s name should have appeared in the byline, which should have read as
follows: Abbot R. Laptook, MD; Seetha Shankaran, MD; Jon E. Tyson, MD, MPH;
Breda Munoz, PhD; Edward F. Bell, MD; Ronald N. Goldberg, MD; Nehal A. Parikh,
DO, MS; Namasivayam Ambalavanan, MD; Claudia Pedroza, PhD; Athina Pappas,
MD; Abhik Das, PhD; Aasma S. Chaudhary, BS, RRT; Richard A. Ehrenkranz, MD;
Angelita M. Hensman, MS, RNC-NIC; Krisa P. Van Meurs, MD; Lina F. Chalak, MD,
MSCS; Amir M. Khan, MD; Shannon E. G. Hamrick, MD; Gregory M. Sokol, MD;
Michele C. Walsh, MD, MS; Brenda B. Poindexter, MD, MS; Roger G. Faix, MD; Kristi
L. Watterberg, MD; Ivan D. Frantz III, MD; Ronnie Guillet, MD, PhD; Uday Devaskar,
MD; William E. Truog, MD; Valerie Y. Chock, MD, MS-Epi; Myra H. Wyckoff, MD;
Elisabeth C. McGowan, MD; David P. Carlton, MD; Heidi M. Harmon, MD, MS; Jane
E. Brumbaugh, MD; C. Michael Cotten, MD, MHS; Pablo J. Sánchez, MD; Anna Maria
Hibbs, MD; Rosemary D. Higgins, MD. In the Author Affiliations section, Dr Khan
should have been listed along with Drs Tyson and Pedroza as follows: “Depart-
ment of Pediatrics, McGovern Medical School at the University of Texas Health Sci-
ence Center at Houston (Tyson, Pedroza, Khan).” The Author Contributions sec-
tion should have read as follows: “Author Contributions: Ms Munoz and Dr Pedroza
had full access to all of the data in the study and take responsibility for the integ-
rity of the data and the accuracy of the data analysis. Concept and design: Laptook,
Shankaran, Tyson, Bell, Parikh, Ambalavanan, Pedroza, Pappas, Das, Ehrenkranz,
Hensman, Chalak, Frantz, Devaskar, Carlton, Sánchez, Higgins. Acquisition, analy-
sis, or interpretation of data: Laptook, Shankaran, Munoz, Bell, Goldberg, Parikh,
Ambalavanan, Pedroza, Pappas, Das, Chaudhary, Ehrenkranz, Hensman, Van Meurs,
Chalak, Khan, Hamrick, Sokol, Walsh, Poindexter, Faix, Watterberg, Frantz, Guillet,
Devaskar, Truog, Chock, Wyckoff, McGowan, Harmon, Brumbaugh, Cotten,
Sánchez, Hibbs, Higgins. Drafting of the manuscript: Laptook, Tyson, Munoz,
Ambalavanan, Pedroza, Khan, Sánchez. Critical revision of the manuscript for im-
portant intellectual content: Laptook, Shankaran, Tyson, Bell, Goldberg, Parikh,
Ambalavanan, Pappas, Das, Chaudhary, Ehrenkranz, Hensman, Van Meurs, Chalak,
Hamrick, Sokol, Walsh, Poindexter, Faix, Watterberg, Frantz, Guillet, Devaskar,
Truog, Chock, Wyckoff, McGowan, Carlton, Harmon, Brumbaugh, Cotten, Sánchez,
Hibbs, Higgins. Statistical analysis: Shankaran, Tyson, Munoz, Pedroza, Das.
Obtained funding: Shankaran, Bell, Ambalavanan, Hensman, Walsh, Faix, Frantz
III, Truog, Carlton, Cotten, Sánchez. Administrative, technical, or material support:
Bell, Goldberg, Chaudhary, Hensman, Chalak, Khan, Hamrick, Faix, Devaskar, Chock,
Wyckoff, McGowan, Carlton, Hibbs, Higgins. Supervision: Shankaran, Bell, Goldberg,
Das, Hensman, Sokol, Poindexter, Faix, Frantz, Truog, Wyckoff, Carlton, Cotten,
Higgins.” This article was corrected online.
1. Laptook AR, Shankaran S, Tyson JE, et al; Eunice Kennedy Shriver National
Institute of Child Health and Human Development Neonatal Research Network.
Effect of therapeutic hypothermia initiated after 6 hours of age on death or
disability among newborns with hypoxic-ischemic encephalopathy:
a randomized clinical trial. JAMA. 2017;318(16):1550-1560.
(Reprinted) JAMA March 13, 2018 Volume 319, Number 10 1051