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org - Comparison of Screening Tools

Comparison of Screening Tools

Key Points
WHO and EGIR clinical criteria rely mainly on insulin resistance. IDF criteria rely on abdominal
obesity, while NCEP-ATP III gives equal weight to each clinical criterion of the metabolic syndrome.

The IDF and NCEP-ATP III approaches use the same cut-off values for lipids, fasting glucose, and
blood pressure. However, the IDF has proposed ethnic-specific cut-offs for waist circumference. Waist
circumference is also a mandatory IDF criterion.

A few prospective studies have compared metabolic syndrome criteria in assessing CVD risk.
Although most criteria have a similar relationship to CVD risk, NCEP-ATP III criteria seem to have
the strongest ties to CVD.

Independent of the clinical criteria studied, the metabolic syndrome better predicts type 2 diabetes risk
than CVD risk.

Further studies are needed to compare various metabolic syndrome clinical criteria using different
statistical models and in all populations of the world.

How Are Screening Tools Different?

Although the metabolic syndrome clinical criteria proposed by major organizations are similar, some of them
put special emphasis on certain variables by using different cut-off values. Most organizations have criteria
for obesity (mostly abdominal), insulin resistance, dyslipidemia, and blood pressure. The proposals put
forward by the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and
treatment of high blood cholesterol in adults (Adult Treatment Panel III or ATP III) and the International
Diabetes Federations (IDF) use virtually the same criteria and cut-off values. The exception is waist
circumference, for which the IDF cut-off value is lower. The IDF has also proposed different waist
circumference cut-offs for various regions of the world in order to address the question of ethnicity. In
addition, the IDF makes waist circumference a mandatory criterion. To be diagnosed with the metabolic
syndrome, one should have a waist circumference above the proposed IDF waist cut-off plus two other
components of the metabolic syndrome. Consequently, in a given population, metabolic syndrome
prevalence can be expected to be higher when IDF criteria are applied. Moreover, since the American
Association of Clinical Endocrinologists (AACE) did not propose a working definition, its criteria can hardly
be tested in population studies unless investigators decide to specify their criteria/cut-offs in advance.
Therefore, when comparing the criteria for the metabolic syndrome and incident cardiovascular disease
(CVD) or diabetes, investigators can choose from the clinical criteria of NCEP-ATP III, IDF, World Health
Organization (WHO), European Group for the Study of Insulin Resistance (EGIR), and hypertriglyceridemic
waist.

The Insulin Resistance Atherosclerosis Study

One of the few prospective population studies to compare NCEP-ATP III, IDF, WHO, and
hypertriglyceridemic waist criteria is the Insulin Resistance Atherosclerosis Study (IRAS) (1). This study
followed 822 subjects 40 to 69 years of age without diabetes for 5.2 years. A total of 148 individuals
developed type 2 diabetes over the follow-up period. The best predictor of incident diabetes was impaired
glucose tolerance. The prevalence of the metabolic syndrome was 27.5%, 34.4%, 39.5%, and 18.4% with
NCEP-ATP III, WHO, IDF, and hypertriglyceridemic waist criteria, respectively. This study is valuable in
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that it used many statistical models to evaluate the association between metabolic syndrome criteria and
incidence of diabetes. NCEP-ATP III criteria showed the strongest association with incident diabetes with an
odds ratio (OR) of 4.14 (95% CI, 2.79-6.16). The ORs were 3.68 (95% CI, 2.48-5.45), 3.40 (95% CI, 2.28-
5.06), and 2.51 (95% CI, 1.68-3.75) for WHO, IDF, and hypertriglyceridemic waist clinical criteria,
respectively. The area under the receiver operating characteristics curve (AROC), which plots the true-
positive rate vs. the false positive rate graphically, was also higher with NCEP-ATP III criteria (0.69). The
AROC was 0.68 for both WHO and IDF criteria and 0.64 for hypertriglyceridemic waist. The population
attributable risk (PAR), which is an estimate of the proportion of CVD in a population attributable to the
metabolic syndrome, was very similar between NCEP-ATP III, WHO, and IDF (46.3%, 48.0%, and 48.7%,
respectively) criteria and lower with hypertriglyceridemic waist criteria (21.7%). The authors of the IRAS
study concluded that IDF and NCEP-ATP III criteria predicted diabetes at least as well as WHO criteria,
suggesting that measuring insulin sensitivity with clamp techniques and measuring microalbuminuria are not
necessary to predict diabetes from a clinical diagnosis of the metabolic syndrome.

The Aerobics Center Longitudinal Study

In the Aerobics Center Longitudinal Study (ACLS), Katzmarzyk et al. (2) have
followed 20,789 non-Hispanic men 20 to 83 years of age for 11.4 years and
compared NCEP-ATP III and IDF criteria in predicting CVD mortality. At the
beginning of the follow-up, metabolic syndrome prevalence was 19.7% and
30%, respectively, when diagnosed using NCEP-ATP III and IDF screening
tools. During the follow-up period, 213 CVD deaths occurred. After adjusting
for age and year of examination, the relative risk (RR) for CVD mortality was
2.03 (95% CI, 1.54-2.69) with NCEP-ATP III criteria and 1.86 (95% CI, 1.42-
2.44) with IDF criteria. The AROCs for CVD mortality were 0.802 and 0.799 Figure: CVD death rates
for NCEP-ATP III and IDF criteria, respectively, which are very similar in the Aerobics Center
findings. Since the cut-off values for triglycerides, HDL cholesterol, glucose, Longitudinal Study
and blood pressure are the same in NCEP-ATP III and IDF criteria, the authors according to categories of
classified the cohort according to waist circumference thresholds (102cm) and waist circumference (WC)
further stratified subjects with the metabolic syndrome based on other risk and the presence or
factors (2 risk factors). As shown in the Figure, CVD death rates increased absence of two or more
among waist circumference thresholds and further increased with the presence other metabolic syndrome
of two or more risk factors in every category of waist circumference, risk factors
suggesting that lowering waist circumference thresholds may be an avenue to
consider. The authors concluded that the predictive ability of both NCEP-ATP
III and IDF criteria was similar and that the public health burden associated with the metabolic syndrome is
considerable, regardless which metabolic syndrome criteria are used.

The San Antonio Heart Study

Lorenzo et al. (3) used data from the San Antonio Heart Study to compare NCEP-ATP III, IDF, and WHO
screening tools in predicting CVD and diabetes incidence. The San Antonio Heart Study recruited 2,559
Mexican American and non-Hispanic white individuals and followed them for an average of 7.4 years.
Metabolic syndrome prevalence was higher when IDF criteria were used and lower when WHO criteria were
used. During the follow-up, 93 men and 63 women developed CVD events and 195 subjects developed
diabetes. NCEP-ATP III, IDF, and WHO clinical criteria yielded an OR for CVD events of 2.00 (95% CI,
1.33-3.01), 1.69 (95% CI, 1.13-2.54), and 1.73 (95% CI, 1.12-2.67), respectively. The various criteria
predicted CVD incidence independent of age, sex, ethnicity, type 2 diabetes, non-HDL cholesterol (VLDL +
IDL + LDL cholesterol fractions), smoking, and personal and family history of CVD. With respect to
diabetes risk, the respective ORs were 6.90 (95% CI, 4.97-9.58), 5.76 (95% CI, 4.11-9.07), and 6.67 (95%
CI, 4.75-9.35) for NCEP-ATP III, IDF, and WHO criteria. In subjects free of CVD at baseline, the ORs for
CVD and diabetes risk were similar with all three proposed screening tools, but the IDF tools showed greater
sensitivity and higher false positive rates. The authors explored whether the presence of the metabolic
syndrome enhanced risk prediction in addition to age. Selected age cut-off values were 45 years for men and
55 years for women. The authors found that the metabolic syndrome was better able to predict CVD in men
45 and over and in women 55 and over. They also suggested that, for both men and women, adding diagnosis
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of the metabolic syndrome to traditional risk factors included in the Framingham risk score could enhance
CVD prediction. The combination of traditional CVD risk markers and emerging markers could heighten
sensitivity, particularly in older individuals.

The Hoorn Study

The Hoorn Study is a population-based cohort study of diabetes that included 615 asymptomatic men and
749 asymptomatic women 50 to 75 years of age (4). The study investigated the incidence of fatal and
nonfatal CVD associated with metabolic syndrome clinical criteria proposed by NCEP-ATP III, WHO,
EGIR, and a modified version of AACE. The results of the Hoorn Study were published at the same time as
the proposed IDF criteria, and therefore the authors could not compare IDF criteria to the others. In men,
metabolic syndrome prevalence was 19%, 32%, 19%, and 41%, respectively, when NCEP-ATP III, WHO,
EGIR, and AACE criteria were used. In women, the respective prevalence of the metabolic syndrome was
26%, 26%, 17%, and 35%. The Hoorn Study was the first study to compare metabolic syndrome prevalence
between criteria using Cohen’s agreement test (κ). In men, the best coefficient of concordance was found
between WHO and EGIR criteria (both criteria relying mostly on insulin resistance) with κ=0.66 (95% CI,
0.59-0.72). The poorest coefficient of concordance was found between WHO and NCEP-ATP III criteria
with κ=0.37 (95% CI, 0.29-0.45). In women, the strongest coefficient of concordance was between NCEP-
ATP III and AACE criteria with κ=0.78 (95% CI, 0.73-0.82), while the poorest coefficient of concordance
was between EGIR and AACE criteria with κ=0.36 (95% CI, 0.29-0.43).

During the follow-up, 132 men and 95 women developed fatal or nonfatal CVD. In men, the hazard ratios
(HR) for incident fatal or nonfatal CVD were 1.91 (95% CI, 1.31-2.79), 1.45 (95% CI, 1.02-2.05), 1.49 (95%
CI, 1.01-2.21), and 1.30 (95% CI, 0.92-1.83) for NCEP-ATP III, WHO, EGIR, and AACE clinical criteria,
respectively. Only the AACE screening tool yielded a non-significant HR for incident CVD. As for women,
the HRs for incident CVD were 1.68 (95% CI, 1.11-2.55), 1.31 (0.85-2.00), 1.34 (95% CI, 0.85-2.14), and
1.84 (95% CI, 1.22-2.78) for NCEP-ATP III, WHO, EGIR, and AACE, respectively. In women, both WHO
and EGIR criteria, two tools with insulin resistance as a central component, were not significantly associated
with incident CVD. The authors also sought to determine whether the control for traditional risk factors
included in the Framingham risk score would affect the HR for metabolic syndrome-related incident CVD. In
men, all HRs decreased slightly after this adjustment was made. NCEP-ATP III and WHO criteria remained
significant, while EGIR and AACE criteria did not. After adjusting for traditional risk factors, HRs were no
longer significant in women, regardless of the screening tools used. Although sensitivity and specificity were
not calculated, NCEP-ATP III clinical criteria seemed to yield more significant HRs than other available
criteria.

The DECODE Study

The Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study
compared the ability of NCEP-ATP III, WHO, and IDF criteria to predict CVD deaths (5). The DECODE
cohort included pooled data from European epidemiological studies on diabetes and impairment of glucose
regulation in which oral glucose tolerance tests were performed. A total of 4,715 men and 5,554 women 30
to 89 years of age were followed for a period ranging from 7 to 16 years. Using WHO criteria, metabolic
syndrome prevalence was 27.0% in men and 19.7% in women. Using NCEP-ATP III criteria, metabolic
syndrome prevalence was 32.2% in men and 28.5% in women. Using IDF criteria, these figures were 35.9%
in men and 34.1% in women. With respect to CVD deaths, the HRs for WHO clinical criteria were 2.09
(95% CI, 1.59-2.76) in men and 1.60 (95% CI, 1.01-2.51) in women. With NCEP-ATP III criteria, the
corresponding HRs were 1.72 (95% CI, 1.31-2.26) and 1.09 (95% CI, 0.70-1.69), and the HRs were 1.51
(95% CI, 1.15-1.99) and 1.53 (95% CI, 0.99-2.36) using IDF criteria. Paired homogeneity tests were
performed to compare proposed criteria and CVD death risk. In men, there was no difference between
NCEP-ATP III and WHO criteria in predicting CVD death, while risk was lower in women with NCEP-ATP
III criteria. Compared to IDF criteria, NCEP-ATP III criteria predicted risk similarly in both men and
women. With WHO and IDF criteria, risk prediction was similar in women, while in men, risk prediction
was stronger with WHO criteria. In the DECODE study, WHO clinical criteria seemed to predict CVD death
risk best, and this association was generally stronger in men than in women.

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The Prospective Epidemiological Study of Myocardial Infarction

WHO, NCEP-ATP III, and IDF screening criteria were compared in another very large population-based
study of 10,592 men 50 to 59 years of age from France and Belfast (Southern and Northern Europe) followed
for 5 years (6). Entitled the prospective epidemiological study of myocardial infarction-étude PRospective de
l’Infarctus du MyocardE (PRIME), it involved a nested case-control study cohort that matched 296 cases of
coronary heart disease (CHD) to 540 CHD-free controls according to age, recruitment centre, and date.
Metabolic syndrome prevalence was 36%, 30%, and 39% in cases and 29%, 23%, and 32% in controls
according to WHO, NCEP-ATP III, and IDF clinical criteria, respectively. The corresponding ORs for future
CHD were 1.40 (95% CI, 1.01-1.94), 1.46 (95% CI, 1.04-2.04), and 1.41 (95% CI, 1.02-1.95).

The Strong Heart Study

In the 10 year longitudinal follow-up of the Strong Heart Study, de Simone et al. (7) compared the ability of
WHO, NCEP-ATP III, and IDF criteria to predict CVD events in 2,825 asymptomatic individuals (1,700
individuals had diabetes at the beginning of follow-up). In diabetic and non-diabetic men, metabolic
syndrome prevalence was 48%, 44%, and 59% using WHO, NCEP-ATP III, and IDF screening tools. In
women, the respective prevalence was 53%, 63%, and 73%. In participants without diabetes, the HRs for
incident CVD were 1.54 (95% CI, 1.32-1.80), 1.42 (95% CI, 1.22-1.66), and 1.37 (95% CI, 1.17-1.61) for
WHO, NCEP-ATP III, and IDF criteria, respectively. The HRs were definitely higher in participants with
diabetes, reaching 2.29 (95% CI, 1.97-2.67), 2.45 (95% CI, 2.12-2.84), and 2.59 (95% CI, 2.25-2.98).
Coefficients of concordance varied widely. The strongest coefficient of concordance was between NCEP-
ATP III and IDF criteria in women (κ=0.77), while the poorest coefficient of concordance was between IDF
and WHO criteria in men (κ=0.49).

Additional Evidence
Tankó et al. (8) sought to compare NCEP-ATP III criteria and the hypertriglyceridemic waist phenotype in
predicting accelerated atherogenesis and related cardiovascular mortality in 557 postmenopausal women
followed for 8.5±0.3 years. At baseline, hypertriglyceridemic waist prevalence was 15.8% and metabolic
syndrome prevalence was 17.6% with NCEP-ATP III criteria. After adjusting for age, smoking, and LDL
cholesterol levels, hypertriglyceridemic waist was associated with an HR of 4.7 (95% CI, 2.2-9.8, p<0.001),
while the corresponding HR was 3.2 (95% CI, 1.5-6.5, p<0.001) for NCEP-ATP III. Interestingly, the authors
found that women with hypertriglyceridemic waist who did not meet NCEP-ATP III criteria were
nevertheless at increased risk compared to women who did meet NCEP-ATP III criteria but did not have the
hypertriglyceridemic waist phenotype. The authors concluded that hypertriglyceridemic waist provides
greater, if not at least similar, sensitivity than NCEP-ATP III criteria at much lower cost to healthcare
systems.

In conclusion, the metabolic syndrome as diagnosed by any of the major organizations increases the risk of
developing CVD events and type 2 diabetes in particular. Generally, NCEP-ATP III clinical criteria predict
CVD risk better than other criteria. However, very few studies have compared the ability of clinical criteria
to predict diabetes risk. Since WHO criteria usually indicate a CVD risk that is similar to that of the other
screening tools, measuring microalbuminuria and insulin sensitivity with clamp techniques does not seem
necessary in order to diagnose the metabolic syndrome.

When comparing metabolic syndrome criteria, investigators mainly rely on ORs or HRs to assess the ability
of each approach to predict CVD risk. Additional studies should be conducted in various populations
worldwide and in all age groups in order to compare the proposed criteria using additional statistical models
and evaluate their sensitivities and false-positive rates. For now, most organizations agree that their criteria
for clinical diagnosis of the metabolic syndrome are not perfect (particularly regarding identification of
metabolic syndrome patients at increased risk of type 2 diabetes and CVD) and that further studies will refine
our ability to optimally diagnose the metabolic syndrome in clinical practice.

References
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1. Palaniappan L, Carnethon MR, Wang Y, et al. Predictors of the incident metabolic syndrome in adults:
the Insulin Resistance Atherosclerosis Study. Diabetes Care 2004; 27: 788-93.
2. Katzmarzyk PT, Church TS, Janssen I, et al. Metabolic syndrome, obesity, and mortality: impact of
cardiorespiratory fitness. Diabetes Care 2005; 28: 391-7.
3. Lorenzo C, Okoloise M, Williams K, et al. The metabolic syndrome as predictor of type 2 diabetes: the
San Antonio heart study. Diabetes Care 2003; 26: 3153-9.
4. Dekker JM, Girman C, Rhodes T, et al. Metabolic syndrome and 10-year cardiovascular disease risk in
the Hoorn Study. Circulation 2005; 112: 666-73.
5. Qiao Q. Comparison of different definitions of the metabolic syndrome in relation to cardiovascular
mortality in European men and women. Diabetologia 2006; 49: 2837-46.
6. Bataille V, Perret B, Dallongeville J, et al. Metabolic syndrome and coronary heart disease risk in a
population-based study of middle-aged men from France and Northern Ireland. A nested case-control
study from the PRIME cohort. Diabetes Metab 2006; 32: 475-9.
7. de Simone G, Devereux RB, Chinali M, et al. Prognostic impact of metabolic syndrome by different
definitions in a population with high prevalence of obesity and diabetes: the Strong Heart Study.
Diabetes Care 2007; 30: 1851-6.
8. Tanko LB, Bagger YZ, Qin G, et al. Enlarged waist combined with elevated triglycerides is a strong
predictor of accelerated atherogenesis and related cardiovascular mortality in postmenopausal women.
Circulation 2005; 111: 1883-90.

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