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Important Food Sources of Fructose-Containing Sugars and Incident Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

ABSTRACT: Background Sugar-sweetened beverages are associated with hypertension. We assessed the relation of important food sources of fructose-containing sugars with incident hypertension using a systematic review and meta-analysis of prospective cohort studies. Methods and Results We searched MEDLINE, EMBASE, and Cochrane (through December week 2, 2018) for eligible studies. For each food source, natural log-transformed risk ratios (RRs) for incident hypertension were pooled using pair-wise meta-analysis and linear and nonlinear dose-response meta-analyses. Certainty in our evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. We identified 26 reports, including 15 prospective cohorts (930 677 participants; 363 459 cases). Sugar-sweetened beverages showed harmful (RRper-355-mL, 1.10 [95% CI, 1.08, 1.12]) whereas fruit (RRper-240-g, 0.94 [95% CI, 0.96, 0.99]) and yogurt showed protective associations (RRper-125-g, 0.95 [95% CI, 0.94, 0.97]) with incident hypertension throughout the dose range. One hundred percent fruit juice showed a protective association only at moderate doses (RRat-100-mL, 0.97 [95% CI, 0.94, 0.99]). The pair-wise protective association of dairy desserts was not supported by linear dose-response analysis. Fruit drinks or sweet snacks were not associated with hypertension. Certainty of the evidence was "low" for sugar-sweetened beverages, 100% fruit juice, fruit, and yogurt and "very low" for fruit drinks, sweet snacks, and dairy desserts. Conclusions The harmful association between sugar-sweetened beverages and hypertension does not extend to other important food sources of fructose-containing sugars. Further research is needed to improve our estimates and better understand the dose-response relationship between food sources of fructose-containing sugars and hypertension. Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02702375.

SUBMITTER: Liu Q

PROVIDER: S-EPMC6951071 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Important Food Sources of Fructose-Containing Sugars and Incident Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

Liu Qi Q Ayoub-Charette Sabrina S Khan Tauseef Ahmad TA Au-Yeung Fei F Blanco Mejia Sonia S de Souza Russell J RJ Wolever Thomas M S TMS Leiter Lawrence A LA Kendall Cyril W C CWC Sievenpiper John L JL

Journal of the American Heart Association 20191212 24

Background Sugar-sweetened beverages are associated with hypertension. We assessed the relation of important food sources of fructose-containing sugars with incident hypertension using a systematic review and meta-analysis of prospective cohort studies. Methods and Results We searched MEDLINE, EMBASE, and Cochrane (through December week 2, 2018) for eligible studies. For each food source, natural log-transformed risk ratios (RRs) for incident hypertension were pooled using pair-wise meta-analysi ...[more]

PMID: 31826724

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Project description:ObjectiveSugar-sweetened beverages (SSBs) are associated with hyperuricaemia and gout. Whether other important food sources of fructose-containing sugars share this association is unclear.DesignTo assess the relation of important food sources of fructose-containing sugars with incident gout and hyperuricaemia, we conducted a systematic review and meta-analysis of prospective cohort studies.MethodsWe searched MEDLINE, Embase and the Cochrane Library (through 13 September 2017). We included prospective cohort studies that investigated the relationship between food sources of sugar and incident gout or hyperuricaemia. Two independent reviewers extracted relevant data and assessed the risk of bias. We pooled natural-log transformed risk ratios (RRs) using the generic inverse variance method with random effects model and expressed as RR with 95% confidence intervals (CIs). The overall certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system.ResultsWe identified three studies (1 54 289 participants, 1761 cases of gout), comparing the highest with the lowest level of exposure for SSBs, fruit juices and fruits. No reports were found reporting incident hyperuricaemia. Fruit juice and SSB intake showed an adverse association (fruit juice: RR=1.77, 95% CI 1.20 to 2.61; SSB: RR=2.08, 95% CI 1.40 to 3.08), when comparing the highest to lowest intake of the most adjusted models. There was no significant association between fruit intake and gout (RR 0.85, 95% CI 0.63 to 1.14). The strongest evidence was for the adverse association with SSB intake (moderate certainty), and the weakest evidence was for the adverse association with fruit juice intake (very low certainty) and lack of association with fruit intake (very low certainty).ConclusionThere is an adverse association of SSB and fruit juice intake with incident gout, which does not appear to extend to fruit intake. Further research is needed to improve our estimates.Trial registration numberNCT02702375; Results.

Project description:Abstract Objectives Sugars have been implicated in the epidemic of obesity. It is unclear whether food sources of fructose-containing sugars other than sugar-sweetened beverages (SSBs) are associated with increased risk of obesity. To assess the evidence of the relation of food sources of fructose-containing sugars with incident overweight or obesity, we undertook a systematic review and meta-analysis of prospective cohort studies. Methods We searched MEDLINE, EMBASE and Cochrane Library through Aug 2019. We included prospective cohort studies of ≥1 year. Two reviewers extracted data and assessed the risk of bias. The primary outcome was incident overweight/obesity. Data were pooled using generic-inverse variance method (random effects) and expressed as relative risks (RR) for incident outcomes and ß-coefficients for WC with 95% confidence intervals (CI). GRADE assessed the certainty of evidence Results We included 12 and 8 prospective cohorts involving 181,295 adults and 31,717 children, respectively. Four food sources of fructose-containing sugars were identified: SSBs, 100% fruit juice, fruit and yogurt. There was no data available in children for yogurt or WC. SSBs were associated with increased incident overweight/obesity in children (RR, 1.22 [95% CI, 1.03 to 1.44] but not in adults and increased incident abdominal obesity in both children (3.78 [1.08 to 13.25]) and adults (1.51 [1.11 to 2.06]), but there was no association with change in WC in adults. Fruit juice was associated with increased incident overweight/obesity in children (1.28 [1.07 to 1.53]) but not in adults, and there was no association with incident abdominal obesity in either children or adults or WC in adults. Fruit was associated with decreased incident overweight/obesity (0.87 [0.82 to 0.92]) and decreased WC (ß, −0.23 cm [−0.33 to −0.13]) in adults. Yogurt was associated with decreased incident abdominal obesity (0.65 [0.47 to 0.90]) in adults with no data available on WC. The certainty of the evidence was graded as “very low” to “moderate”. Conclusions Current evidence indicates that the relation between fructose-containing sugars and obesity outcomes differs by food sources. More research of more food sources of sugars is needed to improve our certainty in the evidence. (ClinicalTrials.gov, NCT02558920) Funding Sources ASN, Diabetes Canada, Banting and Best Diabetes Centre.

Project description:Abstract Objectives Sugars have been implicated in the epidemic of obesity. It is unclear whether food sources of fructose-containing sugars other than sugar-sweetened beverages (SSBs) are associated with increased risk of obesity. To assess the evidence of the relation of food sources of fructose-containing sugars with incident overweight or obesity, we undertook a systematic review and meta-analysis of prospective cohort studies. Methods We searched MEDLINE, EMBASE and Cochrane Library through Oct 2018. We included prospective cohort studies of ≥1 year. Two reviewers extracted data and assessed the risk of bias (Newcastle-Ottawa Scale). The primary outcome was incident overweight/obesity. Data were pooled using generic-inverse variance method with random effects model and expressed as relative risks (RR) with 95% confidence intervals (CI). GRADE assessed the certainty of evidence. Results We included 20 prospective cohort studies: 9 (n = 25,422; 2614 events) and 6 (n = 119,137; 24,123 events) of incident overweight/obesity and 1 (n = 424; 47 events) and 7 (n = 29,166; 4255 events) of incident abdominal obesity in children and adults, respectively. Three food sources of fructose-containing sugars were identified: SSBs, fruit juice, and yogurt. SSBs were associated with increased incident overweight/obesity in children (RR, 1.22 [95% CI, 1.03 to 1.44] but not in adults and increased incident abdominal obesity in both children (3.78 [1.08 to 13.25]) and adults (1.51 [1.11 to 2.06]). Fruit juice was associated with increased incident overweight/obesity in children (1.28 [1.07 to 1.53]) but not in adults, and there was no association with incident abdominal obesity in either children or adults. Yogurt was associated with decreased incident abdominal obesity (0.65 [0.47 to 0.90]) in adults with no data available for any outcome in children. The certainty of the evidence was graded as very low to low. Conclusions Current evidence indicates that the relation between fructose-containing sugars and obesity outcomes differs by food sources. Further research of different food sources of sugars is needed to improve our certainty in the evidence. (ClinicalTrials.gov, NCT02558920) Funding Sources American Society for Nutrition Foundation (commissioned and funded), Diabetes Canada.

Project description:ImportanceSugar-sweetened beverages (SSBs) are associated with increased risk of metabolic syndrome (MetS). However, the role of other important food sources of fructose-containing sugars in the development of MetS remains unclear.ObjectiveTo examine the association of major food sources of fructose-containing sugars with incident MetS.Data sourcesMEDLINE, Embase, and Cochrane Library were searched from database inception to March 24, 2020, in addition to manual searches of reference lists from included studies using the following search terms: sugar-sweetened beverages, fruit drink, yogurt, metabolic syndrome, and prospective study.Study selectionInclusion criteria included prospective cohort studies of 1 year or longer that investigated the association of important food sources of fructose-containing sugars with incident MetS in participants free of MetS at the start of the study.Data extraction and synthesisStudy quality was assessed using the Newcastle-Ottawa Scale. Extreme quantile risk estimates for each food source with MetS incidence were pooled using a random-effects meta-analysis. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). Dose-response analyses were performed using a 1-stage linear mixed-effects model. The certainty of the evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Results were reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines.Main outcomes and measuresPooled risk ratio (RR) of incident MetS (pairwise and dose response).ResultsThirteen prospective cohort studies (49 591 participants [median age, 51 years; range, 6-90 years]; 14 205 with MetS) that assessed 8 fructose-containing foods and MetS were included. An adverse linear dose-response association for SSBs (RR for 355 mL/d, 1.14; 95% CI, 1.05-1.23) and an L-shaped protective dose-response association for yogurt (RR for 85 g/d, 0.66; 95% CI, 0.58-0.76) and fruit (RR for 80 g/d, 0.82; 95% CI, 0.78-0.86) was found. Fruit juices (mixed and 100%) had a U-shaped dose-response association with protection at moderate doses (mixed fruit juice: RR for 125 mL/d, 0.58; 95% CI, 0.42-0.79; 100% fruit juice: RR for 125 mL/d, 0.77; 95% CI, 0.61-0.97). Honey, ice cream, and confectionary had no association with MetS incidence. The certainty of the evidence was moderate for SSBs, yogurt, fruit, mixed fruit juice, and 100% fruit juice and very low for all other food sources.Conclusions and relevanceThe findings of this meta-analysis suggest that the adverse association of SSBs with MetS does not extend to other food sources of fructose-containing sugars, with a protective association for yogurt and fruit throughout the dose range and for 100% fruit juice and mixed fruit juices at moderate doses. Therefore, current policies and guidelines on the need to limit sources of free sugars may need to be reexamined.

Project description:Abstract Objectives Overconsumption of fructose-containing sugars may increase blood pressure. Whether this effect is mediated by the food matrix is unclear. We conducted a systematic review and meta-analysis of controlled feeding trials of the effect of food sources of fructose-containing sugars at different levels of energy control on blood pressure (NCT02716870). Methods We searched MEDLINE, Embase and the Cochrane Library through January, 2020 for controlled trials ≥7d. Trial designs were prespecified based on energy control: substitution (energy matched replacement of sugars in the diet); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced in the diet) trials. Outcomes were systolic blood pressure (SBP) and diastolic blood pressure (DBP). Independent reviewers extracted data and assessed risk of bias. Certainty of evidence was assessed by GRADE. Results We included 76 trials (121 trial comparisons, N = 4 302) assessing 9 food sources (sugar-sweetened beverages [SSBs], sweetened dairy alternatives, 100% fruit juice, fruit, dried fruit, sweets, added nutritive sweetener, sweetened cereal grains/bars, and mixed sources) across the 4 levels of energy control. Total fructose-containing sugars decreased SBP (mean difference, −2.76 mmHg [95% CI, −4.36, −1.16], P = 0.001) and DBP (−1.26 mmHg [−2.29, −0.23], P = 0.016) in addition trials and the removal of these sugars decreased SBP (−1.79 mmHg [−3.36, −0.21], P = 0.026) in subtraction trials. There was evidence of interaction by food source with fruit decreasing and sweets and mixed sources increasing SBP and DBP in addition trials and the removal of SSBs decreased SBP in subtraction trials. The certainty of evidence was generally moderate to low for all food source-outcome relationships, except for the decreasing-effect of fruit on DBP in addition trials (high). Conclusions Food source and energy control appear to mediate the effect of fructose-containing sugars on blood pressure. The evidence provides a good indication that fruit decreases while excess calories from SSBs, sweets and mixed sources increase blood pressure. More high-quality trials of different food sources are needed to improve our estimates. Funding Sources Diabetes Canada.

Project description:Abstract Objectives Fructose providing excess calories has been shown to increase postprandial triglycerides (TAG). Whether this effect holds for different food sources of fructose-containing sugars is unclear. We conducted a systematic review and meta-analysis of controlled feeding trials on the effect of different food sources of fructose-containing sugars at different levels of energy control on postprandial blood lipids (NCT02716870). Methods MEDLINE, EMBASE, and Cochrane Library were searched through June 1st, 2020 for controlled feeding trials ≥7-days assessing the effect of food sources of fructose-containing sugars on postprandial lipids. Trial designs were prespecified based on energy control: substitution (energy matched replacement of sugars by other macronutrients); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients) trials. Independent reviewers extracted data and assessed risk of bias. Outcomes were postprandial TAG and apoB48. Certainty of evidence was assessed using GRADE. Results We included 29 trials (60 trial comparisons, N = 943) assessing 5 food sources (SSBs, fruit, sweets and desserts, added caloric sweetener and mixed sources) across 4 levels of energy control. Total fructose-containing sugars increased postprandial TAG in substitution (MD: 0.17 mmol/L [95% CI: 0.05, 0.30], P = 0.007), addition (0.38 mmol/L [0.13, 0.62], P = 0.003), and ad libitum (0.17 mmol/L [0.02, 0.31], P = 0.024) trials and increased apoB48 in addition trials (0.12 g/L [0.07, 0.18], P < 0.001).There was evidence of interaction by food source with SSBs increasing postprandial TAG and apoB48 in addition trials and mixed sources increasing postprandial TAG in ad libitum trials. The certainty of the evidence was “moderate” for SSBs increasing TAG in addition trials and mixed sources increasing TAG in ad libitum trials and “low” for all other comparisons. Conclusions Food source more than energy control appears to mediate fructose-containing sugars on postprandial lipids. Good evidence suggests that SSBs and mixed sources increase postprandial lipids while evidence is less certain for the lack of effect of other food sources. More high-quality trials of different food sources are needed. Funding Sources Primary: Diabetes Canada.

Project description:Abstract Objectives Excess calories as fructose may initiate pathways increasing biomarkers of inflammation. Whether this effect is mediated by the food matrix at different energy levels is unknown. We conducted a systematic review and meta-analysis of controlled feeding trials of the effect of food sources of fructose-containing sugars at different energy control levels on biomarkers of inflammation (NCT02716870). Methods We searched MEDLINE, Embase, and the Cochrane Library through January 15 2020 for controlled trials ≥7d. Trial designs were prespecified based on energy control: substitution (energy-matched replacement of sugar in the diet); addition (excess energy from sugar added to diets); subtraction (energy from sugar subtracted from diets); ad libitum (energy from sugar freely replaced in the diet). The primary outcome was C-reactive protein (CRP). Secondary outcomes were tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). Independent reviewers extracted data and assessed the risk of bias. Certainty of evidence was assessed by GRADE. Results We included 48 trials (109 trial comparisons, n = 2108) assessing the effect of 10 food sources (SSBs, sweetened dairy, sweetened dairy alternatives (soy), fruit, 100% fruit juice, dried fruit, sweetened cereal grains/bars, sweets, added nutritive sweetener, and mixed sources) across the 4 levels of energy control. Total fructose-containing sugars had no effect on any outcome in any level of energy control. There was evidence of interaction by food source; in substitution trials, sweetened dairy alternative (soy) decreased CRP. In addition trials, fruit decreased while added nutritive sweetener increased TNF-α. The certainty of evidence was low for the effect of sweetened dairy alternative (soy) on CRP in substitution trials, and generally moderate for all other comparisons. Conclusions Food source more than energy control appears to mediate the effect of fructose-containing sugars on inflammation. The evidence provides some indication that sweetened dairy alternatives (soy) and fruit decrease and added nutritive sweeteners increase biomarkers of inflammation. More high-quality randomized trials of different fructose containing food sources are needed to improve our estimates. Funding Sources Diabetes Canada.

Project description:Background: Fructose providing excess calories in the form of sugar sweetened beverages (SSBs) increases markers of non-alcoholic fatty liver disease (NAFLD). Whether this effect holds for other important food sources of fructose-containing sugars is unclear. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials of the effect of fructose-containing sugars by food source at different levels of energy control on non-alcoholic fatty liver disease (NAFLD) markers. Methods and Findings: MEDLINE, Embase, and the Cochrane Library were searched through 7 January 2022 for controlled trials ≥7-days. Four trial designs were prespecified: substitution (energy-matched substitution of sugars for other macronutrients); addition (excess energy from sugars added to diets); subtraction (excess energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients). The primary outcome was intrahepatocellular lipid (IHCL). Secondary outcomes were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE. We included 51 trials (75 trial comparisons, n = 2059) of 10 food sources (sugar-sweetened beverages (SSBs); sweetened dairy alternative; 100% fruit juice; fruit; dried fruit; mixed fruit sources; sweets and desserts; added nutritive sweetener; honey; and mixed sources (with SSBs)) in predominantly healthy mixed weight or overweight/obese younger adults. Total fructose-containing sugars increased IHCL (standardized mean difference = 1.72 [95% CI, 1.08 to 2.36], p < 0.001) in addition trials and decreased AST in subtraction trials with no effect on any outcome in substitution or ad libitum trials. There was evidence of influence by food source with SSBs increasing IHCL and ALT in addition trials and mixed sources (with SSBs) decreasing AST in subtraction trials. The certainty of evidence was high for the effect on IHCL and moderate for the effect on ALT for SSBs in addition trials, low for the effect on AST for the removal of energy from mixed sources (with SSBs) in subtraction trials, and generally low to moderate for all other comparisons. Conclusions: Energy control and food source appear to mediate the effect of fructose-containing sugars on NAFLD markers. The evidence provides a good indication that the addition of excess energy from SSBs leads to large increases in liver fat and small important increases in ALT while there is less of an indication that the removal of energy from mixed sources (with SSBs) leads to moderate reductions in AST. Varying uncertainty remains for the lack of effect of other important food sources of fructose-containing sugars at different levels of energy control.

Project description:BackgroundFructose-containing sugars as sugar-sweetened beverages (SSBs) may increase inflammatory biomarkers. Whether this effect is mediated by the food matrix at different levels of energy is unknown. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials on the effect of different food sources of fructose-containing sugars on inflammatory markers at different levels of energy control.MethodsMEDLINE, Embase, and the Cochrane Library were searched through March 2022 for controlled feeding trials ≥ 7 days. Four trial designs were prespecified by energy control: substitution (energy matched replacement of sugars); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced). The primary outcome was C-reactive protein (CRP). Secondary outcomes were tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Independent reviewers extracted data and assessed risk of bias. GRADE assessed certainty of evidence.ResultsWe identified 64 controlled trials (91 trial comparisons, n = 4094) assessing 12 food sources (SSB; sweetened dairy; sweetened dairy alternative [soy]; 100% fruit juice; fruit; dried fruit; mixed fruit forms; sweetened cereal grains and bars; sweets and desserts; added nutritive [caloric] sweetener; mixed sources [with SSBs]; and mixed sources [without SSBs]) at 4 levels of energy control over a median 6-weeks in predominantly healthy mixed weight or overweight/obese adults. Total fructose-containing sugars decreased CRP in addition trials and had no effect in substitution, subtraction or ad libitum trials. No effect was observed on other outcomes at any level of energy control. There was evidence of interaction/influence by food source: substitution trials (sweetened dairy alternative (soy) and 100% fruit juice decreased, and mixed sources (with SSBs) increased CRP); and addition trials (fruit decreased CRP and TNF-α; sweets and desserts (dark chocolate) decreased IL-6). The certainty of evidence was moderate-to-low for the majority of analyses.ConclusionsFood source appears to mediate the effect of fructose-containing sugars on inflammatory markers over the short-to-medium term. The evidence provides good indication that mixed sources that contain SSBs increase CRP, while most other food sources have no effect with some sources (fruit, 100% fruit juice, sweetened soy beverage or dark chocolate) showing decreases, which may be dependent on energy control.Clinicaltrialsgov: (NCT02716870).

Project description:Abstract Objectives Fructose as a source of excess calories increases uric acid. Whether this effect is mediated by the food matrix at different levels of energy is unknown. We aim to conduct a systematic review and meta-analysis of controlled feeding trials on the effect of food sources of fructose-containing sugars at different energy levels on uric acid (NCT02716870). Methods MEDLINE, Embase and the Cochrane Library were searched through January 27, 2020 for controlled trials ≥7-days assessing the effect of food sources of fructose-containing sugars on uric acid. Trial designs were prespecified based on energy control: substitution (energy matched replacement of sugars by other macronutrients); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients) trials. Independent reviewers extracted data and assessed risk of bias. Certainty of evidence was assessed using the GRADE approach. Results Eligibility was met by 41 trials (72 trial comparisons, N = 2109) assessing the effect of 9 food sources (sugar-sweetened beverages [SSBs], sweetened dairy, fruit drink [lemonade], 100% fruit juice, fruit, dried fruit [raisins], baked goods desserts and sweets, added nutritive [caloric] sweetener and mixed sources) across the 4 energy levels. Total fructose-containing sugars increased uric acid in substitution trials (mean difference, 0.15 mg/dL [95% confidence interval, 0.03 to 0.27 mg/dL], P = 0.012) with no effect in addition, subtraction or ad libitum trials. There was evidence of interaction by food source with SSBs and baked goods, desserts and sweets increasing uric acid in substitution and SSBs increasing and 100% fruit juice decreasing uric acid in addition trials. The overall certainty of evidence was moderate for the increasing effect of SSBs in substitution and addition trials and low to very low for all other comparisons. Conclusions Food source more than energy control mediate the effect of fructose-containing sugars on uric acid. SSBs and baked goods, desserts and sweets appear to increase, and 100% fruit juice appear to decrease uric acid. More high-quality trials of different food sources of fructose-containing sugars are needed to improve our estimates. Funding Sources Diabetes Canada.

Dataset Information

Important Food Sources of Fructose-Containing Sugars and Incident Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

Publications

Important Food Sources of Fructose-Containing Sugars and Incident Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

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