Association of Specific Dietary Fats With Total and Cause-Specific Mortality

Importance  Previous studies have shown distinct associations between specific dietary fat and cardiovascular disease. However, evidence on specific dietary fat and mortality remains limited and inconsistent.

Objective  To examine the associations of specific dietary fats with total and cause-specific mortality in 2 large ongoing cohort studies.

Design, Setting, and Participants  This cohort study investigated 83 349 women from the Nurses’ Health Study (July 1, 1980, to June 30, 2012) and 42 884 men from the Health Professionals Follow-up Study (February 1, 1986, to January 31, 2012) who were free of cardiovascular disease, cancer, and types 1 and 2 diabetes at baseline. Dietary fat intake was assessed at baseline and updated every 2 to 4 years. Information on mortality was obtained from systematic searches of the vital records of states and the National Death Index, supplemented by reports from family members or postal authorities. Data were analyzed from September 18, 2014, to March 27, 2016.

Main Outcomes and Measures  Total and cause-specific mortality.

Results  During 3 439 954 person-years of follow-up, 33 304 deaths were documented. After adjustment for known and suspected risk factors, dietary total fat compared with total carbohydrates was inversely associated with total mortality (hazard ratio [HR] comparing extreme quintiles, 0.84; 95% CI, 0.81-0.88; P < .001 for trend). The HRs of total mortality comparing extreme quintiles of specific dietary fats were 1.08 (95% CI, 1.03-1.14) for saturated fat, 0.81 (95% CI, 0.78-0.84) for polyunsaturated fatty acid (PUFA), 0.89 (95% CI, 0.84-0.94) for monounsaturated fatty acid (MUFA), and 1.13 (95% CI, 1.07-1.18) for trans-fat (P < .001 for trend for all). Replacing 5% of energy from saturated fats with equivalent energy from PUFA and MUFA was associated with estimated reductions in total mortality of 27% (HR, 0.73; 95% CI, 0.70-0.77) and 13% (HR, 0.87; 95% CI, 0.82-0.93), respectively. The HR for total mortality comparing extreme quintiles of ω-6 PUFA intake was 0.85 (95% CI, 0.81-0.89; P < .001 for trend). Intake of ω-6 PUFA, especially linoleic acid, was inversely associated with mortality owing to most major causes, whereas marine ω-3 PUFA intake was associated with a modestly lower total mortality (HR comparing extreme quintiles, 0.96; 95% CI, 0.93-1.00; P = .002 for trend).

Conclusions and Relevance  Different types of dietary fats have divergent associations with total and cause-specific mortality. These findings support current dietary recommendations to replace saturated fat and trans-fat with unsaturated fats.

Health effects of different types of dietary fats have been a long-standing research topic of interest for decades.¹ Vast literature clearly indicates that specific types of dietary fat have distinct effects on the risk for cardiovascular disease (CVD), and replacing saturated fats with unsaturated fats and avoidance of trans-fat is widely recommended.^1-4 However, a recent meta-analysis⁵ concluded that dietary polyunsaturated fatty acids (PUFAs) or saturated fatty acids (SFAs) had no significant associations with the risk for coronary heart disease (CHD), but failed to specify the macronutrient to which saturated fat was compared; by default this component consists largely of refined starch and sugar in Western diets.^6,7 In addition, existing evidence, especially from relatively small clinical trials, regarding the effects of ω-3 PUFAs on total and cause-specific mortality remains inconsistent.^8,9 The health benefits of ω-6 PUFA intake are still contentious; concern has been raised over the hypothesized proinflammatory and prothrombotic effects of ω-6 PUFA.¹⁰ The evidence of an association of industrially produced trans-fatty acids (TFAs) and the risk for CHD is well established,¹¹ although little data are available on TFA intake and mortality.

Numerous controlled metabolic trials have documented the effects of dietary fatty acids on blood lipid levels.^3,12 However, these fatty acids also influence other mechanistic pathways such as insulin resistance, endothelial function, electrophysiologic phenomena, carcinogenesis, and systemic inflammation.^9,13,14 In addition to CVD, various dietary fatty acids have been associated with incidence of other major chronic diseases, including type 2 diabetes, cancer, multiple sclerosis, and respiratory diseases, in prospective cohort studies.^15-18 To address the role of dietary fats in overall health, analysis of total and cause-specific mortality as outcomes would be informative. Therefore, we prospectively examined the associations of specific dietary fats with total and cause-specific mortality in 2 large ongoing prospective cohort studies, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). The many repeated dietary assessments in the cohorts provided a unique assessment of diet during multiple decades. Also, these assessments allowed us to estimate the consequences of isocalorically replacing one type of fat with another, thus describing the choices we make on a daily basis and providing a basis for dietary guidelines.

Box Section Ref ID

Quiz Ref IDThe NHS is a prospective cohort study of 121 700 registered female nurses aged 30 to 55 years in 1976; 92 468 participants responded to the semiquantitative food frequency questionnaire (SFFQ) in 1980. The HPFS is a prospective cohort study of 51 529 male health care professionals aged 40 to 75 years in 1986. The baseline of this analysis was defined as 1980 for the NHS and 1986 for the HPFS. Both cohorts have been followed up via biennial mailed questionnaires that inquire about lifestyle risk factors and other exposures of interest, as well as newly diagnosed diseases. We also collected information on race, marital status, and family history of major chronic diseases. The cumulative follow-up of both cohorts exceeds 90% of potential person-time. The study was approved by the human research committees at the Harvard T. H. Chan School of Public Health and the Brigham and Women’s Hospital. The study protocol was approved by the institutional review boards of Brigham and Women’s Hospital and the Harvard School of Public Health, with participants’ consent implied by the return of the questionnaires.

We excluded participants who had a history of diabetes, CVD, or cancer; who did not provide information on dietary fat intake; or who reported implausible SFFQ data (total energy intake <800 or >4200 kcal/d for men and <600 or >3500 kcal/d for women) at baseline (eTable 1 in the Supplement). After exclusions, the analytical population consisted of 83 349 women and 42 884 men.

Dietary information was collected with SFFQs.^19,20 In each SFFQ, we asked how often, on average, the participant had consumed a specified portion size of each food during the preceding year. The number of listed foods was 61 in 1980 and was expanded to 116 to 150 in 1984 and thereafter; additional frequently used foods were reported in an open-ended section. We also collected detailed information on the type of fat or oil used in food preparation and the brand or type of margarines on the SFFQ. Fatty acid and other nutrient values were calculated based on the Harvard University Food Composition Table,²¹ which is updated regularly using external publications and direct analysis of fatty acids in commonly used margarines and processed foods to take into account changes in manufacturing. We calculated mean daily nutrient and total energy intakes by multiplying the frequency of consumption of each item by its nutrient content and summing the products across all foods, taking into account the specific brand and type of margarines and the types of fat used in food preparation. The assessment of specific types of fat has been validated by comparison with multiple weighed 1-week dietary records and with fatty acid measurements in adipose tissue and plasma.^19,20,22-24

The correlations between energy-adjusted intakes assessed by the 1986 questionnaire and the mean of diet records collected in 1980 and 1986, corrected for variation in the records, were 0.67 for total fat, 0.70 for SFAs, 0.69 for monounsaturated fatty acids (MUFAs), and 0.64 for PUFAs.^19,20 Correlations increased when the mean of 3 SFFQs (1980, 1984, and 1986) was used; for example, for SFAs the correlation was 0.95.^19,20 The correlations between dietary fatty acid intake assessed by the SFFQ and the composition of fatty acids in adipose tissue were 0.51 for TFAs, 0.35 for linoleic acid, and 0.48 for marine ω-3 PUFAs in women,²² and 0.29 for TFAs, 0.48 for linoleic acid, and 0.47 for eicosapentaenoic acid in men. Alcohol intake was also estimated from the SFFQs.

In the NHS, dietary questionnaires used in this analysis were completed in 1980, 1984, 1986, and then every 4 years, for a total of 9 assessments. In the HPFS, dietary questionnaires were completed in 1986 and then every 4 years for a total of 7 assessments.

Quiz Ref IDWe performed systematic searches of the vital records of states and of the National Death Index, supplemented by reports from family members or postal authorities. More than 98% of the deaths in each cohort were identified.²⁵ A physician reviewed death certificates and medical records to classify the cause of death according to the International Classification of Diseases, Eighth Revision and Ninth Revision (eTable 2 in the Supplement).

Data were analyzed from September 18, 2014, to March 27, 2016. The percentages of energy intake from total fat and specific dietary fats were calculated as cumulative means to the start of each 2- or 4-year follow-up interval to best represent long-term dietary intake and dampen within-person variation. We categorized participants into quintiles of intake levels. Person-years of follow-up were calculated from baseline to the earliest of time of death, loss to or unavailability for follow-up, or the end of follow-up. The last date of follow-up was defined as June 30, 2012, for the NHS and January 31, 2012, for the HPFS.

Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and their 95% CIs of mortality by comparing participants in each quintile with those in the lowest quintile. To quantify a linear trend, we assigned the median within each quintile and modeled this variable continuously; the Wald test was used for statistical significance. In addition to including percentages of energy from total and specific fat as quintiles, we also included them as continuous terms in the multivariable models.

For multivariable analyses, we built isocaloric substitution models that simultaneously included energy intake, the percentages of energy derived from protein, and specific types of fat and other potentially confounding variables. The coefficients from these models can be interpreted as the estimated effect of substituting a certain percentage of energy from fat for equivalent energy from carbohydrates.

For repeatedly measured covariates, we included their updated values as time-varying variables in the model. To minimize missing covariates, we replaced missing data with the last valid values. The covariates had very few missing values after the replacement. In addition, we included missing indicators for the remaining missing covariates in the model.

To evaluate the effect of substituting specific types of fat for saturated fat, we treated intake as a continuous variable and calculated the difference in coefficients. Because we hypothesized that the effects of total and specific ω-3 PUFAs might be more acute, we conducted an additional analysis using the most recent data on ω-3 PUFAs at the beginning of each biennial follow-up.

We conducted sensitivity analyses to test the robustness of our findings. To address concern that chronic disease occurrence in the years that preceded diagnosis may influence dietary behavior, we conducted lagged analyses by excluding the first 4 years of follow-up data and adding a 4-year lag period between assessment of dietary fat intake and each follow-up period. To address the possibility that our findings may be explained by underlying overall dietary pattern, we further adjusted for overall dietary pattern score (the Alternate Healthy Eating Index–2010 score²⁶ minus component scores for fatty acids). To minimize the influence of hypertension and hypercholesterolemia on our results, we performed additional analysis by excluding participants who reported hypertension and hypercholesterolemia at baseline. An inverse-variance–weighted, fixed-effect meta-analysis was used to combine the results across the cohorts. All analyses were performed using SAS software (version 9.2; SAS Institute Inc), at a 2-tailed P value of .05.

During 32 years of follow-up in the NHS (2 464 852 person-years), we documented 20 314 deaths; during 26 years of follow-up in the HPFS (975 102 person-years), we documented 12 990 deaths (total, 33 304 deaths in 3 439 954 person-years of follow-up). Quiz Ref IDAt baseline, participants with higher SFA and MUFA intakes had higher body mass indexes and higher levels of total energy and dietary cholesterol intake, but were less likely to be physically active, to use multivitamin and vitamin E supplements, and to report histories of hypercholesterolemia and hypertension (Table 1). The prevalence of current smoking was higher among men with higher SFA and MUFA intakes. Women with higher intakes of SFA, PUFA, and MUFA were generally older.

Quiz Ref IDAlthough total fat intake was positively associated with total mortality in age-adjusted models, an inverse association became apparent after adjusting for other potential confounding variables (P < .001 for trend) (Table 2 and eTable 3 in the Supplement). When substituted for total carbohydrates, a higher intake of SFA was associated with a slightly higher total mortality (HR comparing extreme quintiles, 1.08; 95% CI, 1.03-1.14; P < .001 for trend). For TFA intake, a significant positive association with total mortality was observed (HR comparing extreme quintiles, 1.13; 95% CI, 1.07-1.18; P < .001 for trend). Intakes of PUFA and MUFA were inversely associated with total mortality (Figure 1 and eTable 4 in the Supplement); HRs comparing extreme quintiles were 0.81 (95% CI, 0.78-0.84) for PUFA and 0.89 (95% CI, 0.84-0.94) for MUFA (P < .001 for trend for both). The inverse association between total PUFA and mortality was mainly driven by linoleic acid, as illustrated by their high correlation (correlation coefficient, 0.99; eTable 5 in the Supplement). The corresponding HR for linoleic acid intake was 0.82 (95% CI, 0.79-0.86; P < .001 for trend) (Table 3 and eTable 6 in the Supplement). Intake of total ω-3 PUFA was associated with modestly lower total mortality, which was mainly driven by the inverse association of marine ω-3 PUFAs (docosahexaenoic acid and eicosapentaenoic acid) with total mortality. The HRs comparing extreme quintiles were 0.95 (95% CI, 0.91-0.99; P = .03 for trend) for total ω-3 PUFAs and 0.96 (95% CI, 0.93-1.00; P = .002 for trend) for marine ω-3 PUFAs. The inverse associations became stronger in continuous analyses and when recent intakes of total and marine ω-3 PUFAs were used (eTable 7 in the Supplement); HRs comparing extreme quintiles were 0.91 (95% CI, 0.87-0.95) and 0.90 (95% CI, 0.87-0.93; P < .001 for trend for both) for recent intakes of total and marine ω-3 PUFAs, respectively. The ω-6:ω-3 ratio was not significantly associated with total mortality (P = .29 for trend). The associations for total and specific types of fat remained largely unchanged in sensitivity analyses (eTables 8-10 in the Supplement).

Intake of SFA, when substituted for total carbohydrates, was not significantly associated with CVD mortality (P = .17 for trend across quintiles; eTable 11 in the Supplement), whereas TFA intake was associated with a 20% higher CVD mortality across quintiles (HR, 1.20; 95% CI, 1.08-1.33; P < .001 for trend). Intake of PUFA was inversely associated with CVD mortality (P < .001 for trend). We observed an inverse association, primarily in women, between MUFA intake and CVD mortality (P = .01 for trend). Among specific PUFAs, linoleic acid intake was most strongly related to a lower risk for CVD mortality (P < .001 for trend) (eTable 12 in the Supplement).

Dietary intake of SFA, when substituted for total carbohydrates, was associated with slightly higher cancer mortality (HR comparing extreme quintiles, 1.07; 95% CI, 0.98-1.17; P = .02 for trend), whereas PUFA intake, especially linoleic acid intake, was associated with modestly lower cancer mortality (HR comparing extreme quintiles of PUFA intake, 0.93; 95% CI, 0.87-0.99; P = .02 for trend) (eTables 13 and 14 in the Supplement). Other major subclasses of dietary fat generally were not associated with cancer mortality except that α-linolenic acid intake was associated with a slightly elevated risk for cancer mortality (eTables 13 and 14 in the Supplement). However, this association was not significant when recent α-linolenic acid intake was analyzed (eTable 7 in the Supplement). We observed inverse associations of PUFA and MUFA intakes and strong positive associations of TFA intake with neurodegenerative (eTable 15 in the Supplement) and respiratory (eTable 16 in the Supplement) disease mortality. Higher SFA intake was associated with a substantial increase of mortality due to respiratory disease (HR comparing extreme quintiles, 1.56; 95% CI, 1.30-1.87; P < .001 for trend). Among major PUFAs, ω-3 PUFA intake, primarily α-linolenic acid, was inversely associated with neurodegenerative disease mortality (eTable 17 in the Supplement). Marine ω-3 PUFA intake was inversely associated with respiratory disease mortality (eTable 18 in the Supplement). Sensitivity analyses minimally changed these results for cause-specific mortality (eTables 8-10 in the Supplement).

Figure 2 shows that replacing 5% of energy from SFAs with the same energy from PUFAs and MUFAs was associated with an estimated reduction in total mortality of 27% (HR, 0.73; 95% CI, 0.70-0.77) and 13% (HR, 0.87; 95% CI, 0.82-0.93), respectively (eTable 19 in the Supplement). Replacing SFAs with the same energy from PUFAs was associated with a lower risk for mortality due to CVD, cancer, and neurodegenerative disease. Replacement of 5% of energy from SFAs with 5% of energy from MUFAs was associated with a 29% estimated reduction in neurodegenerative disease mortality (HR, 0.71; 95% CI, 0.57-0.88) (eTable 19 in the Supplement).

Quiz Ref IDIn 2 large cohorts with many repeated measures of diet and a long duration of follow-up, we found that higher intakes of PUFA and MUFA were associated with lower mortality, whereas higher intakes of SFA and TFA were associated with increased mortality. Although the modest positive association between SFA intake and mortality suggests small health benefits of replacing SFAs with total carbohydrates, replacing SFAs with MUFAs and/or PUFAs was associated with a significantly lower risk for total and cause-specific mortality due to several major chronic diseases. Dietary intake of total fat, compared with total carbohydrates, was inversely associated with total mortality. However, the association between total fat intake and mortality largely depends on specific types of fat. Intake of linoleic acid, the most abundant ω-6 PUFA, showed strong inverse associations with total and most cause-specific mortality, without any evidence of detrimental effects. A higher ω-6:ω-3 PUFA ratio was not associated with increased mortality, but with a slightly lower CVD and cancer mortality.

Previous data on the associations between different types of ω-6 PUFA intake and total mortality have been limited. Concordant with our findings, 2 prospective cohort studies using circulating biomarkers^27,28 found a lower total mortality associated with higher serum concentrations of ω-6 PUFA. Evidence from clinical trials also supported a protective effect of soybean oil with a higher ω-6:ω-3 PUFA ratio on CHD risk.^29,30 Contrary to our findings, a recent reanalysis of the Sydney Diet Heart Study,³¹ a secondary prevention trial, reported a significant increase in total mortality in participants assigned to an intervention consisting of higher ω-6 PUFA intake. However, that study was very small (n = 221) and of short duration (39 months) and included only individuals with existing CVD, and the intervention likely reduced ω-3 PUFA intake. In addition, the results may have been confounded by trans-fat in the special margarines used for the intervention that were high in linoleic acid levels.⁶

We observed a modest inverse association between marine ω-3 PUFA intake and total mortality. Previously, prospective cohorts in generally healthy populations yielded mixed results,^32-36 whereas most randomized clinical trials found nonsignificant effects of fish oil supplementation on total mortality.^9,37 The significant inverse association between intake of ω-3 PUFAs and death due to neurodegenerative diseases has not, to our knowledge, been previously reported.

We found a significant inverse association between MUFA intake and total mortality. In contrast, previous studies^2,38,39 generally reported nonsignificant or even positive associations with MUFA. This discordance might be owing to the strong correlations between MUFA and SFA, because animal fats are major sources of both types of fats in most Western diets, and between MUFA and TFA, because partial hydrogenation produces both. In our 2 cohorts, the correlation between MUFA and SFA decreased during the follow-up, and the major food sources of MUFA have shifted from animal-sourced to plant-sourced foods over time (eTable 20 in the Supplement); thus we had greater power to differentiate the association of MUFA with mortality. Consistent with our analysis, the major source of MUFA in Mediterranean populations, olive oil, has been associated with a substantially lower total mortality.³⁸ Important benefits of MUFA from plant sources have also been supported by the Prevención con Dieta Mediterránea (PREDIMED) trial,^40,41 in which the addition of olive oil and nuts, also high in MUFA levels, reduced the incidence of CVD and diabetes.

Compared with overall carbohydrates, higher SFA intake was associated with a slight increase in total mortality, but not significantly associated with CVD mortality. The lack of the association with CVD is expected because the major sources of carbohydrates in a typical Western diet are highly processed foods with large amounts of refined starch and sugar, providing a high glycemic load that can increase CVD risk independent of SFA.^7,42,43 In our substitution analyses, replacing SFA with unsaturated fatty acids was associated with a substantially lower risk for total and CVD mortality. These findings were generally consistent with evidence from previous studies.^2,44-46 However, a recent meta-analysis⁵ concluded that specific types of fat, including saturated, monounsaturated, or polyunsaturated, had no significant effect on the risk for CHD. Another meta-analysis⁴⁷ also reported nonsignificant associations of SFA intake with total and CVD mortality and CHD incidence. However, most studies included in these meta-analyses did not explicitly model the effects of macronutrient substitution and did not specify the comparison source of energy for the type of fat under scrutiny, which limits the interpretations of these findings.^6,44 Our analyses provide strong evidence that using PUFAs and/or MUFAs as the replacement nutrients for SFAs can confer substantial health benefits, whereas replacing SFAs with total carbohydrates has little effect on CVD mortality. However, the effects of replacement by carbohydrates may depend in part on the quality of the carbohydrates.⁷

Data on specific types of dietary fat and non-CVD mortality are sparse. We observed no major effects of most types of dietary fat on cancer mortality, although a modest inverse association with linoleic acid was observed. Our findings of an inverse association between a higher intake of PUFAs, primarily α-linolenic acid, and lower mortality due to neurodegenerative diseases are consistent with limited evidence on the incidence of major neurodegenerative diseases, including Alzheimer disease,⁴⁸ amyotrophic lateral sclerosis,¹⁵ and Parkinson disease,⁴⁹ in prospective cohorts. Finally, we observed a positive association between saturated and trans-fat intakes and respiratory disease mortality, but an inverse association with PUFAs. These findings are novel and therefore require confirmation in further studies.

Our results have several limitations. First, reverse causation is a possible explanation for our findings, because people with chronic disease and poor health might change their habitual diet. However, we excluded participants with known major chronic diseases at baseline. Also, those persons concerned about a serious illness might change toward a diet generally perceived to be healthier, which would not explain our findings. In addition, our findings remained largely unchanged when we excluded the first 4 years of follow-up or added a 4-year lag period between dietary assessment and each follow-up period. Second, because our study was observational in nature, causality cannot be established. However, our results were largely consistent with results from existing observational studies and randomized clinical trials on diet and CVD-related outcomes. Third, although we adjusted for many potential confounders, residual confounding could not be ruled out. Fourth, measurement errors are inevitable in estimates of food and nutrient intakes. However, our adjustment for energy intake and use of prospectively collected, cumulative mean intake using many repeated dietary assessments reduced the impact of measurement errors.^19,20 The strengths of the present study include the large sample size, high rates of follow-up, and repeated assessments of dietary and lifestyle variables during a long period.

We found that different types of dietary fats have divergent associations with total and cause-specific mortality. Replacement of saturated fats with unsaturated fats can confer substantial health benefits and should continue to be a key message in dietary recommendations. These findings also support the elimination of partially hydrogenated vegetable oils, the primary source of trans-fatty acids.

Corresponding Author: Frank B. Hu, MD, PhD, Department of Nutrition, Harvard T. H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 02115 (nhbfh@channing.harvard.edu).

Accepted for Publication: March 28, 2016.

Published Online: July 5, 2016. doi:10.1001/jamainternmed.2016.2417.

Author Contributions: Drs Willett and Hu had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wang, Hu.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wang, Willett.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wang, Li.

Obtained funding: Manson, Rimm, Hu.

Administrative, technical, or material support: Stampfer, Manson, Willett, Hu.

Study supervision: Stampfer, Willett, Hu.

Conflict of Interest Disclosures: Dr Hu reported receiving research support from the California Walnut Commission and Metagenics. No other disclosures were reported.

Funding/Support: This study was supported by research grants UM1 CA186107, P01 CA87969, R01 HL034594, R01 HL088521, UM1 CA167552, R01 HL35464, R01 HL60712, and P30 DK46200 from the National Institutes of Health.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are indebted to the participants in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) for their continuing outstanding level of cooperation; to the state cancer registries of Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Nebraska, New Hampshire, New Jersey, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Virginia, Washington, and Wyoming for their kind help; and to the staff of the NHS and HPFS for their valuable contributions. Alberto Ascherio, MD, DrPH, and Kathryn C. Fitzgerald, ScD, Departments of Nutrition and Epidemiology, Harvard School of Public Health, provided helpful comments. Lisa Li, MD, ScM, Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, assisted with programming. None of these contributors were compensated for their roles.