FNOA: Assessment of Overweight/Obesity (2012)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To examine the associations among cardiorespiratory fitness, adiposity, and mortality in older adults ages 60 years and older, after a 12-year follow-up.

Inclusion Criteria:
  • Men and women aged 60 years and older
  • Maximal treadmill exercise test at baseline where they achieved at least 85% of their age-predicted maximal heart rate (220 minus age in years).
Exclusion Criteria:
  • BMI less than 18.5kg/m2 at baseline
  • Younger than age 60 at baseline. 
Description of Study Protocol:

Recruitment

Subjects were sent by their employers for the examination, referred by their physicians, or self-referred. 

Design

Prospective cohort study

Subjects completed a baseline clinical examination during 1979-2001 which included: self-reported personal and family health histories, a standardized medical examination by a physician, fasting blood chemistries, weight, height, percent body fat, fat mass, fat free mass, waist circumference, blood pressure, smoking habits, physical activity habits, a maximal treadmill exercise, and a modified-Balke protocol to determine fitness. Subjects were followed for 12 years during which time they came to the clinic for periodic preventive health exams and for counseling regarding diet, exercise, and other lifestyle factors. Mortality was determined using the National Death Index and using death certificates from states in which participant deaths occurred. Causes of death were determined using the International Classification of Diseases, Ninth Revision (ICD-9), and Tenth Revision (ICD-10) codes. 

Blinding used

Not applicable 

Intervention

Not applicable 

Statistical Analysis

  • Descriptive statistics were used to summarize baseline characteristics by survival status and by fitness levels  
  • Groups were compared using t-tests, Chi-squared tests, and F tests  
  • Correlations among adiposity measures and exercise duration were assessed by Pearson coefficients after fisher's Z transformation  
  • Hazard ratios (HRs) and 95% confidence intervals (CIs) of mortality according to fitness, adiposity, age, smoking status, abnormal exercise ECG and baseline medical condition were determined using Cox proportional hazard models  
  • Six baseline covariates were included in multivariate analyses: age (years), sex, examination year, current smoker, abnormal exercise ECG responses, and chronic medical conditions [CVD (myocardial infarction or stroke), hypertension, diabetes or hypercholesterolemia]  
  • Due to the small sample size (516) and number of deaths (52) in women, a meaningful analysis on women alone was not able to be performed  
  • The pattern of associations between fitness, adiposity measurements and all-cause mortality in men was similar to that of men and women combined  
  • There were no significant interactions with sex and other covariates in the Cox regression model. Therefore all analyses were conducted with combined data from men and women.  
  • Statistical tests were two-sided; P<0.05 indicated statistical significance.
Data Collection Summary:

Timing of Measurements

All independent variables were measured at baseline (between the years of 1979-2001). Subjects were followed until death (dependent variable) or until December 31, 2003.

Dependent Variables

  • Mortality, determined using:
    • The National Death Index
    • Death certificates from states in which participant deaths occurred
    • Causes of death were determined using the International Classification of Diseases, Ninth Revision (ICD-9), and Tenth Revision (ICD-10) codes.

Independent Variables

  • Fasting blood chemistries; total cholesterol measured in the Cooper Clinic clinical chemistry laboratory
  • Weight
  • Height
  • Percent body fat; assessed by hydrostatic weighing
  • Fat mass; weight (kg) x (percent body fat / 100)
  • Fat free mass; weight (kg)-fat mass (kg)
  • Waist circumference; measured at the umbilicus
  • Blood pressure; measured with standard auscultatory methods
  • Physical activity habits; as reported on a standardized questionnaire
  • A maximal treadmill exercise; endpoint was volitional exhaustion or termination by the physician for medical reasons
  • Modified-Balke protocol.

Control Variables

The following variables were included as covariates in the multivariate analyses:

  • Age (years)
  • Sex
  • Examination year
  • Current smoker; as reported on a standardized questionnaire
  • Abnormal exercise ECG responses; included rhythm and conduction disturbances and ischemic ST-T wave abnormalities
  • Chronic medical conditions [CVD (myocardial infarction or stroke), hypertension, diabetes, or hypercholesterolemia]; defined as a history of physician diagnosis, measured phenotypes that met clinical thresholds, or the combination of both methods when appropriate.

 

Description of Actual Data Sample:
  • Initial N: 2,603
    • 2,087 men
    • 516 women
  • Attrition (final N): As above
  • Age: All participants: 64.4±4.8 years (mean ± SD)
    • Survivors: (n=2,153) 64.2
    • Decedents: (n=450) 65.7
  • Ethnicity: Not quantified in this study but based the standard medical history the authors report "the majority of the study participants were white, well-educated and from middle to upper socioeconomic strata"
  • Other relevant demographics: None
  • Anthropometrics: BMI, waist circumference, percent body fat, fat free mass, fat mass and BMI were not different between survivors and decedents
  • Location: Cooper Clinic, Dallas, Texas.
Summary of Results:

Key Findings

Risk of All-cause Mortality According to Cardiorespiratory Fitness (Fitness) Categories

Fitness Quintiles HR
(95% CI)*

HR
(95% CI)
+

HR
(95% CI)
^

HR
(95% CI)^^
HR
(95% CI)#
Q1 1.00 1.00 1.00 1.00 1.00
Q2

0.53
(0.40-0.70) 

0.51
(0.39-0.68)

0.52
(0.40-0.69) 

0.53
(0.40-0.71)
0.54 (0.41-0.72)
Q3 0.44
(0.33-0.58)
0.42
(0.31-0.56)

0.43
(0.32-0.57) 

0.43
(0.32-0.57)
0.44 (0.33-0.59)
Q4 0.43
(0.32-0.58)
0.40
(0.30-0.55)
0.42
(0.31-0.56)
0.41
(0.31-0.56)
0.44 (0.33-0.59)
Q5 0.30
(0.22-0.42)
0.27
(0.19-0.42)
0.29
(0.21-0.40)
0.27
(0.19-0.39)
0.31 (0.22-0.43)
P for linear trend <0.001 <0.001 <0.001 <0.001 <0.001

*adjusted for covariables: Age, sex, examination year, smoking status, abnormal exercise electrocardiogram responses, and baseline health conditions (CVD, hypertension, diabetes, hypercholesterolemia, present or not for each)

+adjusted for covariables plus body mass index

^adjusted for covariables plus waist circumference

^^adjusted for covariables plus percent body fat

# adjusted for covariables plus fat free mass

Risk of All-cause Mortality According to Adiposity Measures

Adiposity Measures HR (95% CI)* HR (95% CI)+
Body Mass Index    
Normal Weight 1.00 1.00
Overweight 0.88 (0.70-1.07) (0.72 (0.58-0.89)
Obese I 1.00 (0.80-1.53) 0.76 (0.54-1.07)
Obese II 1.98 (1.09-3.61) 1.11 (0.61-2.05)
P for quadratic trend 0.004 0.005
WC     
Normal 1.00  1.00 
Abdominal Obesity 1.25 (1.00-1.56)  0.99 (0.79-1.25) 
P for difference 0.05  0.95 
Percent Body Fat    
Normal  1.00  1.00 
Obese  1.03 (0.85-1.25)  0.83 (0.67-1.01) 
P for difference  0.78  0.07 
Fat free mass quintiles    
Q1  1.00  1.00 
Q2  1.04 (0.70-1.53)  1.01 (0.69-1.49) 
Q3  0.92 (0.61-1.38)  0.86 (0.57-1.28) 
Q4  1.01 (0.66-1.54)  0.90 (0.59-1.37) 
Q5  1.21 (0.79-1.86)  1.02 (0.66-1.57) 
P for linear trend 0.36  0.91 

*adjusted for covariables: Age, sex, examination year, smoking status, abnormal exercise electrocardiogram responses, and baseline health conditions (CVD, hypertension, diabetes, hypercholesterolemia, present or not for each)

+adjusted for covariables plus cardiorespiratory fitness

Joint Associations of Cardiorespiratory fitness (Fitness) and Adiposity Exposures with All-cause Mortality*

  Fit Unfit  
  No. of deaths Rates+ HR
(95% CI)
++
No. of deaths Rates+ HR (95% CI)++ value

BMI, kg/m2

             
18.5-24.9 158 1.2 1.00 (referent) 34 4.9 3.63 (2.47-5.32) <0.001
25.0-29.9 152 1.2 0.88 (0.70-1.11) 44 2.7 1.74 (1.23-2.46) <0.001
30.0-34.9 32 1.6 1.12 (0.76-1.66) 18 2.5 1.68 (1.02-2.78) 0.46
≥35.0 2 1.2

0.86 

90.21-3.50)

10 4.8 3.35 (1.74-6.44) 0.05
WC, cm              
<88.0 (women); <102.0 (men) 274 5.1 1.00 (referent) 61 14.5 2.84 (2.15-3.75) <0.001
≥88.0 (women); ≥ 102.0 (men) 70 6.2 1.21 (0.93-1.58) 45 13.5 2.65 (1.93-3.63) <0.001
Percent body fat              
<30.0 (women); <25.0 (men) 151 9.1 1.00 (referent) 29 26.8 2.94 (1.97-4.38) <0.001
≥30.0 (women); ≥25.0 (men) 190 8.7 0.96 (0.78-1.19) 72 21.8 2.39 (1.81-3.16) <0.001

*Cross-product tests of interaction between Fitness and adiposity exposures were not statistically significant: Fitness-BMI (df=1, X2=0.05, P=0.82); Fitness-WC (df=1, X2=1.38, P=0.24); Fitness-percent fat (df=a, X2=0.04, P=0.84)

+All-cause death rates per 1,000 person-years adjusted for age, sex, and examination year

++Adjusted for age, sex, examination year, smoking status, abnormal exercise electrocardiogram responses, and baseline health conditions (CVD, hypertension, diabetes, hypercholesterolemia, present or not for each)

Other Findings

Baseline Characteristics by Vital Status in 2603 Older Adults- Aerobics Center Longitudinal Study, 1979-2003.

  All (n=2603) Survivors (n=2153) Decedents (n=450)
Female, No. (percent) 516 (19.8) 464 (21.6) 52 (11.6)*
Age, mean (SD), years 64.4 (4.8) 64.2 (4.7) 65.7 (5.0)*
BMI, mean (SD), kg/m2 26.3 (3.7) 26.4 (3.7) 26.2 (3.9)
Waist circumference, mean (SD), cm 90.3 (19.9) 90.4 (19.3)  90.3 (22.6) 
Percent body fat+, mean (SD)

26.5 (5.4)

26.5 (5.4)  26.6 (5.6) 
Fat free mass+, mean (SD), kg 58.4 (9.4) 58.4 (9.5) 58.5 (8.7) 
Fat mass+, mean (SD), kg 21.6 (7.2) 21.5 (7.1) 21.8 (7.8) 
Treadmill time, mean (SD), minutes 12.6 (4.8) 12.9 (4.7) 11.0 (4.8)* 
Maximal METs, mean (SD) 9.1 (2.2)  9.3 (2.2)  8.4 (2.2)* 
BMI-defined weight groups, No. (percent)   
18.5-24.9 1,020 (39.2) 828 (38.5)  192 (42.7) 
25.0-29.9 1,206 (46.3) 1,010 (46.9)  196 (43.6) 
30.0-34.9 316 (12.1) 266 (12.4)  50 (11.1) 

≥35

61 (2.3) 49 (2.3)  12 (2.7) 
Waist circumference≥88 cm for women; ≥102 cm for men, No. (percent)

643 (24.7)

528 (24.5)  115 (25.6) 
Lipids, mean (SD), mmol/L   
Total cholesterol 5.6 (1.1) 5.6 (1.1)  5.7 (1.2) 
HDL-C 1.3 (0.4) 1.2 (0.4)  1.2 (0.4)* 
Triglycerides 1.5 (1.0) 1.5 (1.0)  1.6 (0.9) 
Fasting blood glucose, mean (SD), mmol/L 5.9 (1.4) 5.9 (1.3)  6.0 (1.6)
Physically inactive, No. (percent) 657 (25.2) 546 (25.4)  111 (24.7)
Current smoker, No. (percent) 235 (9.0) 175 (8.1)  60 (13.3)* 
Abnormal exercise ECG responses, No. (percent) 532 (20.4) 405 (18.8)  127 (28.2)* 
Metabolic syndrome++, No. (percent) 644 (24.7) 505 (23.5)  139 (30.9)* 
Chronic medical condition^, No. (percent)   
CVD 139 (5.3) 93 (4.3)  46 (10.2)* 
Diabetes 266 (10.2) 212 (9.9)  54 (12.0) 
Hypertension 1,241 (47.7) 993 (46.1)  248 (55.1)* 
Hypercholesterolemia 1,034 (39.7) 881 (40.9)  153 (34.0)* 

*Difference between survivors and decedents was statistically significant (P<0.05)

+Percent body fat, fat mass and fat free mass: n=2,584 (442 deaths)

++Defined as the presence of at least three of the five metabolic risk factors based on NCEP ATP-III criteria

^Chronic medical condition was defined as the presence of hypercholesterolemia (history of physician diagnosed high cholesterol or measured fasting total cholesterol ≥240mg/dL [6.20mmol/L]) or diabetes (history of physician diagnosis, or use of insulin or measured fasting glucose ≥126mg/dL [7.0mmol/L]); or hypertension (history of physician diagnosed or resting SBP≥140mmHg or DBP≥90 mmHg); or personal history of physician diagnosed CVD (MI or stroke).

Baseline Characteristics According to Cardiorespiratory Fitness Categories in 2603 Older Adults- Aerobics Center Longitudinal Study, 1979-2003*. 

Cardiorespiratory Fitness Quintile (minutes)
  Q1 (<8.7)

Q2
(8.7-11.3)

Q3 (11.3-13.7) Q4 (13.7-18.4) Q5 (≥18.4)
Female, No. (percent)  57 (11.1) 93 (18.0)  83 (16.1)  134 (26.0)  149 (28.9) 
Age, mean (SD), years  66.1 (5.0) 65.3 (5.0)  64.4 (4.8)  63.8 (3.9)  63.7 (5.0) 
BMI, mean (SD), kg/m2  29.0 (4.9) 27.3 (3.9)  27.0 (3.4)  26.0 (3.2)  24.3 (2.6) 
Waist circumference, mean (SD), cm  97.8 (23.5) 94.4 (18.0)  92.9 (19.8)  89.4 (18.9)  83.1 (18.1) 
Percent body fat+, mean (SD)  29.9 (5.2) 28.5 (4.8)  27.6 (4.7)  26.3 (4.8)  23.1 (5.3) 
Fat free mass+, mean (SD), kg  61.1 (10.5) 58.8 (9.8)  59.5 (9.0)  58.1 (8.9)  56.5 (9.0) 
Fat mass+, mean (SD), kg  26.8 (9.2) 23.9 (7.0)  23.1 (6.5)  20.9 (5.9)  17.1 (5.3) 
Treadmill time, mean (SD), minutes  5.4 (1.6) 8.7 (1.4)  11.3 (1.6)  13.7 (2.1)  18.4 (3.6) 
Maximal METs, mean (SD)  5.8 (0.7) 7.4 (0.6)  8.5 (0.7)  9.7 (1.0)  11.8 (1.7) 
BMI-defined weight groups, No. (percent)     
18.5-24.9  64 (6.3) 123 (12.1)  153 (15.0)  259 (25.4)  421 (41.3) 
25.0-29.9  121 (10.0) 225 (18.7)  293 (24.3)  348 (28.9)  219 (18.2) 
30.0-34.9  73 (23.1) 85 (26.9)  89 (28.2) 

58 (18.4) 

11 (3.5) 
≥35  33 (54.1) 15 (24.6)  9 (14.8)  3 (4.9)  1 (1.6) 
Waist circumference ≥88 cm for women; ≥102 cm for men, No. (percent)  148 (23.0) 172 (26.8)  166 (25.8)  128 (19.9)  29 (4.5) 
Lipids, mean (SD), mmol/L     
Total cholesterol  5.8 (1.2) 5.6 (1.1)  5.7 (1.0)  5.6 (1.1)  5.5 (1.1) 
HDL-C  1.2 (0.3) 1.2 (0.4)  1.2 (0.4)  1.3 (0.4)  1.4 (0.4) 
Triglycerides  1.8 (1.1) 1.7 (1.0)  1.7 (1.1)  1.5 (0.9)  1.2 (0.6) 
Fasting blood glucose, mean (SD), mmol/L  6.6 (2.4) 6.1 (1.7)  5.9 (1.2)  5.8 (1.1)  5.6 (0.8) 
Physically inactive, No. (percent)  142 (48.8) 179 (40.0)  165 (30.3)  113 (16.9)  58 (8.9) 
Current smoker, No. (percent)  43 (18.3) 55 (23.4)  54 (23.0)  50 (21.3)  33 (14.0) 
Abnormal exercise ECG response, No. (percent)  90 (16.9) 122 (22.9)  116 (21.8)  116 (21.8)  88 (16.5) 
Metabolic syndrome++, No. (percent)  130 (20.2) 159 (24.7)  166 (25.8)  142 (22.1)  47 (7.3) 
Chronic medical condition^, No. (percent)     
CVD  30 (21.6) 35 (25.2)  38 (27.3)  20 (14.4)  16 (11.5) 
Diabetes  66 (24.8) 54 (20.3)  57 (21.4)  58 (21.8)  31 (11.7) 
Hypertension  167 (13.5) 245 (19.7)  278 (22.4)  305 (24.6)  246 (19.8) 
Hypercholesterolemia  128 (12.4) 174 (16.8)  229 (22.2)  286 (27.7)  217 (21.0) 

*All tests for linear trend across quintiles were significant (P<0.05)

+Percent body fat, fat mass and fat free mass: n=2,584 (442 deaths)

++Metabolic syndrome was defined as the presence of at least three of the five metabolic risk factors based on NCEP ATP-III criteria

^Chronic medical condition was defined as the presence of hypercholesterolemia (history of physician diagnosed high cholesterol or measured fasting total cholesterol ≥240mg/dL [6.20mmol/L]) or diabetes (history of physician diagnosis, or use of insulin or measured fasting glucose ≥126 mg/dL [7.0mmol/L]); or hypertension (history of physician diagnosed or resting SBP≥140mmHg or DBP≥90 mmHg); or personal history of physician diagnosed CVD (MI or stroke). 

Univariate Associations between Adiposity Measures and Treadmill Exercise Duration in 2603 Older Adults- Aerobics Center Longitudinal Study, 1979-2003

 

BMI

Pearson

Correlation

Coefficients*

WC 

Treadmill test duration 

 

 

Percent body fat

Fat mass

Fat free mass

 

 

BMI (kg/m2) 1.00 0.60 0.87 0.66 0.52 -0.30
Percent body fat   1.00 0.84 0.02 0.23 -0.50
Fat mass, kg     1.00 0.54 0.48 -0.37
Fat free mass, kg       1.00 0.55 -0.09
WC (cm)         1.00 -0.10
Treadmill test duration (minutes)           1.00

*P<0.001, except coefficient comparing percent body fat and fat free mass.

Risk of All-cause Mortality across Exposure Groups in 2603 Older Adults-Aerobics Center Longitudinal Study, 1979-2003.

 

Person-years

Deaths

Rate*
(per 1,000)

HR (95% CI)*

BMI, kg/m2    
Normal weight (18.5-24.9) 13,168 192 13.9 1.00 (referent)
Overweight (25.0-29.9) 14,412 196 13.3 0.95
(0.78-1.17)
Obese I (30.0-34.9) 3,226 50 18.3 1.31
(0.96-1.80)

Obese II (≥35.0)

528 12 31.8 2.29
(1.27-4.12)
P-quadratic trend       0.01
Percent body fat    
Normal (<30.0 women; <25.0 men) 13,859 180 13.7 1.00 (referent)
Abnormal (≥30.0 women; ≥25.0 men) 17,227 262 14.6 1.07
(0.88-1.30)
P-difference       0.51
Fat free mass quintiles, kg    
<50.6 6,375 72 12.9 1.00 (referent)
50.6-57.0 6,729 111 14.0 1.08
(0.73-1.60)
57.0-61.2 6,612 95 12.7 0.99
(0.65-1.49)
61.2-66.0 5,998 83 14.3 1.10
(0.72-1.68)
≥66.0 5,366 81 17.9 1.38
(0.90-2.12)
P-Linear trend       0.10
Waist circumference, cm    
Normal (<88.0 women; <102.0 men) 24,402 335 13.3 1.00 (referent)
Abnormal (≥88.0 women; ≥102.0 men) 6,925 115 18.2 1.37
(1.11-1.70)
P-difference       0.004
Fitness quintiles+ based on treadmill time, minutes    
<8.7 3,381 106 32.6 1.00 (referent)
8.7-11.3 5,690 98 16.6 0.51
(0.39-0.67)
11.3-13.7 6,762 95 12.8 0.39
(0.30-0.52)
13.7-18.4 7,729 90 12.3 0.38
(0.29-0.50)
≥18.4 7,772 61 8.1 0.25
(0.18-0.34)
P-Linear trend       <0.001
Age, years        
60-70 28,095 358 12.4 1.00 (referent)
70-80 2,765 82 34.4 2.78
(2.18-3.54)
80+ 464 10 15.7 1.27
(0.67-2.38)
P-Linear trend       <0.001
Current smoker    
No 28,345 390 14.0 1.00 (referent)
Yes 2,977 60 17.9 1.28
(0.97-1.69)
P-difference       0.08
Abnormal exercise ECG responses    
No 22,789 272 12.1 1.00 (referent)
Yes 8,550 178 20.4 1.64
(1.33-2.01)
P-difference       <0.001
Chronic medical condition    
No 11,689 119 12.0 1.00 (referent)
Yes 19,645 279 17.7 1.48
(1.19-1.84)
P-difference       <0.001

* Rates per 1,000 person-years and HRs are adjusted for age, sex and examination year.

+ Quintiles of fitness were based on the distribution of treadmill exercise duration standardized to the 60+ year age group in the overall ACLS population of women and men. The tabulated values reflect the average value for the women and men included in this analysis. MET levels of fitness associated with each quintile were <7.4, 7.4-8.5, 8.5-9.7, 9.7-11.8, and ≥11.8.

Author Conclusion:

Fitness is a significant mortality predictor in older adults independent of overall or abdominal adiposity. Practitioners should consider the importance of preserving functional capacity, by recommending regular physical activity for older individuals, normal weight and overweight alike. 

Funding Source:
Government: NIH grants AG06945 and HL62508
Reviewer Comments:

In the study design the authors report that study participants came to the clinic for periodic preventive health examinations and for "counseling regarding diet, exercise, and other lifestyle factors associated with increased risk of chronic disease". It would have been helpful to know more about the counseling the subjects received as it could impact the subjects' exercise and/or diet habits and therefore the study outcomes. Also, while the survivors and decedents differed in important characteristics at baseline (i.e. age, smoking, and chronic medical conditions), the authors took these covariates into account during statistical analysis. Authors note the following limitations:

  • Participants were primarily white and well-educated, with middle to upper socioeconomic status, so the results may not apply to other groups of older adults
  • Residual confounding from undetected subclinical disease at baseline may exist
  • Physical activity based on self-report
  • Due to limited sample of women, men and women were combined for analysis
  • Only single baseline assessment on fitness, adiposity measurements, and other exposures, thus we cannot examine whether changes in any of these variables occurred during follow-up or whether this may have influenced the study results.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) N/A
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) N/A
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? No
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? No
3. Were study groups comparable? No
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? No
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes