Abstract

Importance Many claims have been made regarding the superiority of one diet or another for inducing weight loss. Which diet is best remains unclear.

Objective To determine weight loss outcomes for popular diets based on diet class (macronutrient composition) and named diet.

Data Sources Search of 6 electronic databases: AMED, CDSR, CENTRAL, CINAHL, EMBASE, and MEDLINE from inception of each database to April 2014.

Study Selection Overweight or obese adults (body mass index ≥25) randomized to a popular self-administered named diet and reporting weight or body mass index data at 3-month follow-up or longer.

Data Extraction and Synthesis Two reviewers independently extracted data on populations, interventions, outcomes, risk of bias, and quality of evidence. A Bayesian framework was used to perform a series of random-effects network meta-analyses with meta-regression to estimate the relative effectiveness of diet classes and programs for change in weight and body mass index from baseline. Our analyses adjusted for behavioral support and exercise.

Main Outcomes and Measures Weight loss and body mass index at 6- and 12-month follow-up (±3 months for both periods).

Results Among 59 eligible articles reporting 48 unique randomized trials (including 7286 individuals) and compared with no diet, the largest weight loss was associated with low-carbohydrate diets (8.73 kg [95% credible interval {CI}, 7.27 to 10.20 kg] at 6-month follow-up and 7.25 kg [95% CI, 5.33 to 9.25 kg] at 12-month follow-up) and low-fat diets (7.99 kg [95% CI, 6.01 to 9.92 kg] at 6-month follow-up and 7.27 kg [95% CI, 5.26 to 9.34 kg] at 12-month follow-up). Weight loss differences between individual diets were minimal. For example, the Atkins diet resulted in a 1.71 kg greater weight loss than the Zone diet at 6-month follow-up. Between 6- and 12-month follow-up, the influence of behavioral support (3.23 kg [95% CI, 2.23 to 4.23 kg] at 6-month follow-up vs 1.08 kg [95% CI, −1.82 to 3.96 kg] at 12-month follow-up) and exercise (0.64 kg [95% CI, −0.35 to 1.66 kg] vs 2.13 kg [95% CI, 0.43 to 3.85 kg], respectively) on weight loss differed.

Conclusions and Relevance Significant weight loss was observed with any low-carbohydrate or low-fat diet. Weight loss differences between individual named diets were small. This supports the practice of recommending any diet that a patient will adhere to in order to lose weight.

Introduction

Named or branded (trade-marked) weight loss programs are broadly available to the general public, providing structured dietary and lifestyle recommendations via popular books and in-person or online behavioral support. These programs represent a multibillion dollar industry.1 Debate regarding the relative merit of the diets is accompanied by advertising claiming which macronutrient composition is superior, such as a low-carbohydrate diet being better than a low-fat diet, and the benefits of accompanying lifestyle interventions. Establishing which of the major named diets is most effective is important because overweight and obese patients often want to know which diet results in the most effective weight loss.

Some physiological explanations regarding the merits of different macronutrient compositions, including variable genetic response to diets with different recommended dietary fat intake, make intuitive sense.2,3 Low-carbohydrate diets may drive weight loss due to a higher intake of protein, which may induce a stronger satiating effect than fats and carbohydrates.4

Quiz Ref IDDespite potential biological mechanisms explaining why some popular diets should be better than others, recent reviews suggest that most diets are equally effective,2,5,6 a message very different from what the public hears in advertisements or expert pronouncements. Only a few of the reviews of named diets have used rigorous meta-analytic techniques to provide quantitative estimates of how much better one diet is compared with another. They also relied on aggregating studies comparing one diet with another and did not have the ability to determine the relative performance of diets when they were not directly compared with one another in clinical trials. By not exploring the full range of potential comparisons in a statistically and methodologically rigorous fashion, these reviews could have missed important benefits of specific diets or their compositions.

Quiz Ref IDNetwork meta-analysis facilitates comparison of different diets using all available randomized clinical trial (RCT) data.7 In the absence of published head-to-head clinical trials of each diet against each other diet, network meta-analysis uses both direct and indirect clinical trial evidence to estimate their relative effects. Using a network meta-analytic approach, we assessed the relative effectiveness of different popular diets in improving weight loss.

Methods

Eligibility Criteria

As described in a protocol outlining our study methods,8 we included RCTs that assigned overweight (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared] of 25-29) or obese (BMI ≥30) adults (≥18 years of age) to a popular branded diet or an alternative. We included RCTs that reported weight loss or BMI reduction at 3-month follow-up or longer.

Named diets were identified through the explicit naming of the brand, the referencing of branded literature, or the naming of a brand as funders of an article reporting weight loss outcomes from the diet. The diet was labeled as brand-like when the diet met the definition of a branded diet, but failed to name or reference the brand in the article. For example, dietary programs that did not refer to Atkins but consisted of less than 40% of kilocalories from carbohydrates per day for the duration of study or were funded by Atkins were considered Atkins-like.9,10

We included dietary programs with recommendations for daily macronutrient, caloric intake, or both for a defined period (≥12 weeks) with or without exercise (eg, jogging, strength training) or behavioral support (eg, counseling, group support). Eligible programs included meal replacement products but had to consist primarily of whole foods and could not include pharmacological agents. Because it is impossible to provide a placebo diet in a clinical trial, eligible control diets included wait-listed controls, no specific assigned diet, or competing dietary programs. The characteristics of eligible branded dietary programs are reported in eTable 1 in the Supplement.

Outcomes and Effect Modifiers

The primary outcomes were weight loss at 6- and 12-month follow-up (±3 months for both periods). Secondary outcomes included BMI and adverse events. We considered 3 weight loss effect modifiers that were modeled as present or absent if they were included in an overall dietary program: calorie restriction, exercise, and behavioral support. Based on the lowest estimated caloric intake for sedentary adults, we defined calorie restriction as less than 1800 kcal/d.11

Exercise was defined as having explicit instructions for weekly physical activities and simply dichotomized when differences between varying degrees of exercise frequencies appeared to have negligible effects. Diets with at least 2 group or individual sessions per month for the first 3 months were considered as providing behavioral support.12

Search Strategy

We searched 6 electronic databases: AMED, CDSR, CENTRAL, CINAHL, EMBASE, and MEDLINE from inception of each database to April 2014. Search terms included extensive controlled vocabulary and keyword searches for (RCTs) AND (diets) AND (adults) AND (weight loss). The search strategy is available from the authors upon request.

We reviewed bibliographies of review articles and eligible trials, and searched the registries of ClinicalTrials.gov and the metaRegister of Controlled Trials. We contacted the named diet companies and individuals working in the field of obesity and weight management to identify additional or unpublished trials.

Study Selection

Reviewers, in pairs, independently screened titles and abstracts of articles and reviewed the full text of any title or abstract deemed potentially eligible by either reviewer. Reviewers resolved disagreements by discussion.

Risk of Bias Assessment of Individual Studies

Pairs of reviewers independently assessed the risk of bias associated with individual trials using the Cochrane Collaboration instrument.13 We assigned 1 of 2 summary assessments for each included study: low risk of bias for key domains, allocation concealment, and missing participant data or high risk of bias for key domains.14

Data Extraction

Pairs of reviewers independently, and in duplicate, extracted the following data items: study setting, type of trial (parallel or factorial), demographic information, experimental interventions, control interventions, exercise information, degree of calorie restriction, degree of behavioral support, and each of the outcomes of interest. We categorized dietary treatment groups in 2 ways: using diet classes (moderate macronutrient distribution, low carbohydrate, and low fat)15 and according to diet brands. Diet classes were established by macronutrient content (Table 1).

We considered the Lifestyle, Exercise, Attitudes, Relationships, and Nutrition (LEARN) diet akin to a usual care comparator because it is based on a popular program among health professionals, many of whom have been trained in or endorse the program because of it’s practicality, it’s emphasis on behavioral modification, and it’s adaptability to various dieters (eg, applied as either a low-fat or moderate macronutrient composition diet).16-18

Continuous outcomes were most often reported as mean change, but sometimes were reported as preintervention and postintervention measures or percentage change. In the latter cases, transformations were used to express weight loss and BMI as mean change. When available, we used P values for group differences to derive the standard deviation of change from baseline. Otherwise, we used the pre- and postintervention standard deviations along with a correlation estimated from studies that reported both change and pre- and postintervention results. In the case of percentage change, we assumed independence.

Data Synthesis and Analysis

Analyses were conducted using 6- and 12-month data, with a 3-month window (eg, if a study reported weight loss at 5 months, it was used in the 6-month analysis). The connectivity of each network meta-analysis was described using density, which was calculated as the ratio of the number of treatment pairs with head-to-head evidence over the total number of treatment pairs. Random-effects pairwise meta-analyses (using the method by DerSimonian and Laird19) were used to determine direct and indirect associated treatment effects for all network meta-analyses.

To determine weight loss outcomes between diets with all potential comparisons between them, we performed Bayesian network meta-analyses among 5 diet class nodes (no diet, moderate macronutrients, low carbohydrate, low fat, usual care) and each of the 11 eligible named diets.20 When P values were used, all tests were 2-sided with a significance level of .05. All analyses were conducted using WinBUGS version 1.4 (Medical Research Council Biostatistics Unit) and R version 3.0.1 (R Project for Statistical Computing) with the R2WinBUGS, xlsx, and the metafor packages. A detailed description of the statistical analysis appears in the eMethods in the Supplement.

Confidence in Estimates of Effect

For diet classes at 12-month follow-up, we assessed the quality of evidence associated with specific comparisons using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.21 For both direct and indirect comparisons, the starting point for confidence in estimates was high, but could be rated down to moderate, low, or very low based on risk of bias, imprecision, inconsistency, and indirectness.

Assessment of Publication Bias

For our branded diet analysis, we made a visual assessment of funnel plots for publication bias for direct comparisons that included 10 or more studies.

Results

Searches of 6 primary electronic databases identified 20 835 unique abstracts, titles, or both identified as original publications. The gray literature search identified 213 additional articles. Of the total, 889 proved potentially relevant for full-text review and 59 articles that reported 48 RCTs of 11 branded diets proved eligible (eFigure 1 in the Supplement).9,10,17,18,22-65

The 48 RCTs included 7286 individuals with a median age of 45.7 years (median SD, 9 years), median weight of 94.1 kg (median SD, 14.6 kg), and median BMI of 33.7 (median SD, 4.3). The median duration of the diet intervention across trials was 24 weeks (interquartile range, 16-52 weeks). The key characteristics of each included trial appear in Table 2. Forty-three trials (n = 5608) comprising 103 study groups reported weight loss at 6-month follow-up. The 6-month network meta-analyses were categorized according to diet class (eFigure 2 in the Supplement) and diet brand (eFigure 3).

Moderate macronutrient and low-carbohydrate diets were the most common diet classes; among these, Atkins, Weight Watchers, and Zone were the brands with the most comparisons. Twenty-five trials (n = 5386) with 67 groups reported weight loss at 12-month follow-up (eFigures 2 and 3 in the Supplement). The diet class network meta-analysis at both time points had a density of 1.0. Because these network meta-analyses were completely connected, all estimated effects were informed by both direct and indirect evidence. Aside from the 4 named diets that were only connected to a single node (Biggest Loser, Jenny Craig, Nutrisystem, and Volumetrics), the 6- and 12-month brand network meta-analyses were well connected with densities of 0.36 and 0.47, respectively.

Risk of Bias

Risk of bias of included studies was assessed by diet class and by diet brand (eTable 2 in the Supplement). Twenty-nine trials were at low risk of bias and 19 were at high risk of bias.

Weight Loss Diet Classes

In the analysis adjusted for diet class, all treatments were superior to no diet at 6-month follow-up (Figure 1). Compared with no diet, low-carbohydrate diets had a median difference in weight loss of 8.73 kg (95% credible interval [CI], 7.27-10.20 kg) and low-fat diets had similar estimated effects (7.99 kg [95% CI, 6.01-9.92 kg]). A low-carbohydrate diet resulted in increased weight loss compared with other diet classes (LEARN, moderate macronutrient distribution), but was not distinguishable from low-fat diets.

At 12-month follow-up, the estimated average weight losses of all diet classes compared with no diet were approximately 1 to 2 kg less than after 6-month follow-up. The diet classes of low fat (7.27 kg [95% CI, 5.26-9.34 kg]) and low carbohydrate (7.25 kg [95% CI, 5.33-9.25 kg) continued to have the largest estimated treatment effects. At 6-month follow-up, the low-carbohydrate diet class had the highest estimated probability of being superior to all other diet classes at 83%; however, at 12-month follow-up, the low-fat diet demonstrated the highest probability at 50% (Figure 1).

Meta-regression used to account for the use of exercise, calorie restriction, and the degree of behavioral support of each diet group at 6-month follow-up led to a model for weight loss with both exercise and behavioral support factors. Effect modification at 6-month follow-up differed from estimates at 12-month follow-up for behavioral support (3.23 kg [95% CI, 2.23 to 4.23 kg] vs 1.08 kg [95% CI, −1.82 to 3.96 kg], respectively) and exercise (0.64 kg [95% CI, −0.35 to 1.66 kg] vs 2.13 kg [95% CI, 0.43 to 3.85 kg]). Calorie restriction did not modify the effects.

Sensitivity Analysis

The findings of our sensitivity analyses in which populations with specific health problems (eg, breast cancer) were removed appear in eTable 3 in the Supplement. The findings were similar to the full analysis; low-carbohydrate diets demonstrated the most favorable estimates at 6-month follow-up, whereas low-fat diets were most favorable at 12-month follow-up.

Sensitivity analyses for low risk of bias, proportion lost to follow-up, baseline weights, and proportion female at 6- and 12-month follow-up also showed similar results (eTables 4-7 in the Supplement).

Individual Named Diets

In the adjusted named analysis, all diets demonstrated weight reduction at 6-month follow-up compared with no diet (Figure 2). The largest estimated effects at 6-month follow-up were found with the Atkins diet with a median difference in weight loss of 10.14 kg (95% CI, 8.19-12.12 kg), followed by the Volumetrics diet (9.87 kg [95% CI, 5.54-14.23 kg]) and the Ornish diet (9.03 kg [95% CI, 6.44-11.66 kg]). The estimated effect of behavioral support (3.67 kg [95% CI, 1.45-5.88 kg]) and exercise (1.15 kg [95% CI, 0.14-2.16 kg]) were similar to those obtained in the diet class network meta-analysis.

All diets except Jenny Craig slightly decreased in their estimated effects at 12-month follow-up compared with 6-month follow-up. The Ornish, Rosemary Conley, Jenny Craig, and Atkins diets were associated with the largest weight loss at this time point and all varied between 6.35 kg and 6.55 kg.

The findings of the sensitivity analyses for the named diets network meta-analysis in which populations with specific health problems and high risk of bias studies were removed appear in eTables 8 and 9 in the Supplement. In these analyses, some head-to-head comparisons from the primary analysis were no longer present, thus leaving the network meta-analysis sparser.

Our findings were not sensitive at 6- and 12-month follow-up to the removal of populations with additional health issues. Among studies at low risk of bias, the point estimates are smaller than our primary analysis; however, tests for interaction demonstrated no significant differences among trials at low vs high risk of bias.

For assessing publication bias, one comparison at 6-month follow-up and no comparisons at 12-month follow-up included 10 or more studies. Based on 15 studies comparing Atkins with moderate macronutrient diets, a funnel plot demonstrates asymmetry, suggesting publication bias (eFigure 4 in the Supplement).77

Confidence in Estimates

The overall quality of the evidence using GRADE methods for our direct, indirect, and overall network meta-analysis estimates appear in eTables 10-12 in the Supplement. We assessed the confidence in estimates of effect for weight loss at 12-month follow-up as moderate to low for all comparisons, suggesting that further research is likely to have an important effect on our confidence in the estimation of effect and may change the estimate (eTable 12 in the Supplement).

Body Mass Index

Due to a considerably lower number of studies reporting BMI measures, the associated network meta-analyses were sparse and do not permit trustworthy inferences (eFigures 5-6 and eTables 13-14 in the Supplement).

Adverse Events

Adverse events were reported in 5 included trials, all of which evaluated the Atkins diet.9,28,29,36,37 Although there were no significant differences in serious adverse events among treatment groups, the only trial to find significant differences in mild adverse events reported that they occurred more frequently in the low-carbohydrate diet group (n = 60) than in the low-fat diet group (n = 60), including constipation (68% vs 35%, respectively; P < .001), headache (60% vs 40%; P < .03), halitosis (38% vs 8%; P < .001), muscle cramps (35% vs 7%; P < .001), diarrhea (23% vs 7%; P < .02), general weakness (25% vs 8%; P < .01), and rash (13% vs 0%; P < .006).37

Discussion

Quiz Ref IDAmong the 48 original RCTs included in our network meta-analysis, evidence of low to moderate quality showed that both low-carbohydrate and low-fat diets were associated with an estimated 8-kg weight loss at 6-month follow-up compared with no diet. Approximately 1 to 2 kg of this effect was lost by 12-month follow-up. Although statistical differences existed among several of the diets, the differences were small and unlikely to be important to those seeking weight loss.

These findings support recent recommendations for weight loss in that most calorie-reducing diets result in clinically important weight loss as long as the diet is maintained.6 Network meta-analysis showed that although there are statistically significant differences between some of the named diets, these differences are small and likely to be unimportant to many seeking to lose weight. For example, the Atkins diet resulted in an estimated weight loss of only 1.71 kg (95% CI, 0.35-3.09 kg) more than the Zone diet at 6-month follow-up. Quiz Ref IDBecause different diets are variably tolerated by individuals, the ideal diet is the one that is best adhered to by individuals so that they can stay on the diet as long as possible.

Quiz Ref IDNetwork meta-analysis yielded larger weight loss estimates for diets compared with no dieting than the observed weight loss in the primary studies. This is explained by the effect of statistical adjustment for exercise that results in an apparent net weight gain for the no diet group. A similar effect is observed for behavioral support adjustment. The network meta-analysis estimates for trials that failed to include behavioral support were adjusted accordingly, leading to higher estimates than those originally reported.

The strengths of this review include our use of network meta-analyses that allowed for simultaneous direct and indirect comparisons of both dietary classes and individual named diets, a comprehensive literature search, an assessment of risk of bias, and application of the GRADE approach to rating confidence in estimates of effect of diet classes at 12-month follow-up. We also systematically addressed the potential harms of named diets; however, only 5 of 48 included trials reported information about adverse events.

To provide insight into the quality of the evidence, we applied GRADE methods to rate our confidence in the estimates of effect. To avoid redundancy, we only did so to the 12-month comparisons and not the 6-month comparisons for the diet classes (eTables 10-12 in the Supplement). However, the estimates at 12-month follow-up are the most relevant for individuals concerned about long-term weight loss. Furthermore, because there are considerably more trials reporting 6-month data, the network meta-analysis had increased density and the comparisons had more power, thus our confidence in the 6-month estimates is at least as great as those reported at 12-month follow-up using GRADE methods.

Our study has limitations related to the underlying evidence base for clinical trials on weight loss. For the 10 direct comparisons in which more than 1 study was available, 7 comparisons (eTable 10 in the Supplement) demonstrated substantial heterogeneity between studies, manifested by an I2 exceeding 70%, and visual inspection of forest plots confirming large inconsistencies between study results. Within our GRADE assessment, we rated the quality of evidence for our direct estimates for inconsistency as weaker inferences. Because we were unable to demonstrate that the differences in patients, interventions, or adherence influenced the magnitude of effect, we did not rate the quality of evidence down for indirect estimates across studies (eTable 11 in the Supplement).

Furthermore, 19 of 48 trials were at high risk of bias mostly as a result of missing participant outcome data, and the low and high risk of bias trials were not uniformly distributed across comparisons (eTable 2 in the Supplement). Nevertheless, we did not exclude studies because of risk of bias, primarily because the effect of treatment did not significantly vary after adjusting for missing participant outcome data and overall risk of bias (eTables 4-5 and eTable 9 in the Supplement). Our approach is consistent with the practices used in the systematic review methodological community.77,78

Our study also has limitations related to network meta-analysis connectivity, evaluation of effect modifiers, and assessment of publication bias. First, confidence in estimates is lower for individual brand-named diets (in particular for some comparisons) because they were poorly connected to the network meta-analysis, have small sample sizes, or both. In particular, Volumetrics (n = 97) and Jenny Craig (n = 516), which both fared well at 6- and 12-month follow-up, were only connected to a single other diet.

Second, although we accounted for the variability due to calorie restriction, exercise, and behavioral support using meta-regression, there were limitations in the explicit presentation of data regarding calorie restriction. Exercise and behavioral support were associated with increased weight loss, though we found no association with behavioral support at 12-month follow-up. This lack of effect at 12-month follow-up may be explained by our definition of behavioral support, which placed more importance on the intensity of support within the first 3 months of a diet.12

Third, a limitation of our review is that analyses were based on the original intended randomized design, not by adherence to the actual macronutrient composition (class) and caloric intake consumed.2 This means that although patients were randomized to various diets or controls, details on their actual adherence to the dietary program (eg, daily caloric intake, macronutrient consumption, and length and intensity of exercise was limited to the published reports) were not accounted for in the analyses.

Fourth, because there were fewer than 10 trials in all but 1 paired comparison, our assessment of publication bias was very limited.77

Although we used different methods, our study findings are similar to the review by the Joint Guidelines from the American Heart Association, the American College of Cardiology, and the Obesity Society, concluding that popular diets are roughly equally effective,6,79 and that evidence is inadequate to recommend any particular diet.80 Even though we found that low-carbohydrate (eg, Atkins) and low-fat (eg, Ornish) dietary programs are associated with the greatest weight loss, these differences were minor and likely unimportant to those interested in losing weight. The methodological differences between our analysis and the Joint Guidelines6 appear in eTable 15 in the Supplement.

We did not exclude studies based on any criteria beyond study design. There is concern within the clinical research community that excluding studies based on arbitrary thresholds for study quality may have an important influence on the study results of systematic reviews81 because subsequent evidence may demonstrate that assumed quality items have less effect than expected.82 Using the approach advocated by both the Cochrane Collaboration and the GRADE working group, we included all RCTs and considered rating down confidence in estimates because of risk of bias (eTables 4-5 and eTable 9 in the Supplement).77,78

We examined the relationship between estimated effect size, loss to follow-up, and overall risk of bias, and after finding no relationship, did not consider risk of bias an important effect modifier. As we have noted previously in this discussion, this approach is perhaps the most potentially controversial of our methodological decisions. There is a clear need for a better understanding between clinical trialists and guideline developers regarding the influence of loss to follow-up and other risk of bias issues. This issue is not limited to diets, but probably affects all fields of medicine.83

Similar to previous reviews, we found that weight loss decreased at 6-month follow-up,84,85 and began to regress to the baseline mean at 12-month follow-up, suggesting that future trials of dietary programs should focus on maintenance of long-term weight loss.86 Our findings should be reassuring to clinicians and the public that there is no need for a one-size-fits-all approach to dieting because many different diets appear to offer considerable weight loss benefits. This is important because many patients have difficulties adhering to strict diets that may be particularly associated with cravings or be culturally challenging (such as low-carbohydrate diets).2 Our findings suggest that patients may choose, among those associated with the largest weight loss, the diet that gives them the least challenges with adherence. Although our study did not examine switching between diets, such a strategy may offer patients greater choices as they attempt to adhere to diet and lifestyle changes.

Conclusions

Low-carbohydrate and low-fat dietary programs were associated with more weight loss than no dietary intervention over a 12-month period; behavioral support and exercise enhanced weight loss. The weight loss differences between indivdual named diets were small with likely little importance to those seeking weight loss. This supports the practice of recommending any diet that a patient will adhere to in order to lose weight.

Back to top Article Information

Corresponding Author: Edward J. Mills, PhD, MSc, Stanford University School of Medicine, 1265 Welch Rd, Stanford, CA 94305 (millsej@stanford.edu).

Author Contributions: Mr Kanters and Dr Mills had full access to all of 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: Johnston, Kanters, Siemieniuk, Ball, Busse, Thorlund, Mills.

Acquisition, analysis, or interpretation of data: Johnston, Kanters, Bandayrel, Wu, Naji, Siemieniuk, Busse, Thorlund, Guyatt, Jansen, Mills.

Drafting of the manuscript: Johnston, Kanters, Bandayrel, Naji, Ball, Thorlund, Mills.

Critical revision of the manuscript for important intellectual content: Johnston, Kanters, Wu, Siemieniuk, Busse, Thorlund, Guyatt, Jansen, Mills.

Statistical analysis: Johnston, Kanters, Thorlund, Mills.

Obtained funding: Johnston, Ball, Busse, Thorlund, Mills.

Administrative, technical, or material support: Johnston, Bandayrel, Wu, Naji, Mills.

Study supervision: Johnston, Thorlund, Guyatt, Mills.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by a Canadian Institute of Health research knowledge synthesis grant 201104 via the Public Health Agency of Canada. Dr Busse holds a Canadian Institute of Health Research new investigator award. Dr Mills holds a Canada Research Chair in global health.

Role of the Funders/Sponsors: The funding sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Additional Contributions: We thank Christopher Gardner, PhD (Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California), for his guidance and review of the manuscript. Dr Gardner did not receive any financial compensation for his guidance and review of the manuscript.