Investigating the de nitions of metabolic syndrome among urban high-school students in Taipei City in Taiwan and the optimal cutoff points of relevant risk factors


 Background: A comparison of different definitions of metabolic syndrome (MetS) on its prevalence among a sample of urban high-school students in Taipei City in Taiwan was examined. The differences in the discriminatory power and the optimal cutoff points of relevant risk factors were analyzed in this study.Methods: A total of 45,756 health checkup data sets from 2011 to 2014 of high-school students aged between 15 to 17 years were sourced in Taipei city in Taiwan. The database included the students’ gender, age, height, weight, waist circumference (WC), systolic and diastolic blood pressure, as well as biochemical markers such as triglycerides (TG), high-density lipoprotein cholesterol, and fasting glucose (FG) levels. The receiver operating characteristic (ROC) curve statistical approach was used to analyze the discriminatory power and optimal cutoff points of the relevant MetS risk factors. Results: The prevalence of MetS among adolescents in Taipei City in Taiwan was 2.3% and 1.2%, according to the criteria of the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) respectively. The prevalence increased to 4.3% when this study’s criteria were used. Among the components of MetS analyzed, WC and TG had stronger discriminatory powers, while FG had the weakest. The optimal cutoff point for WC was approximately the 90th percentile, while that for the TG was similar to the criteria of the modified NCEP ATP III. About 44.6% of adolescents had at least one MetS component. Body mass index also had good discriminatory power.Conclusions: The prevalence of MetS differs depending on the diagnostic criteria used. Redefining the cutoff points for the components of MetS in adolescents in different regions, as well as further screening and intervention, is crucial to prevent cardiovascular disease and type 2 diabetes mellitus in adulthood.


Introduction
Childhood and adolescent overweight and obesity are major concerns in developed countries [1]. According to the 2010-2011 Nutrition and Health Survey in Taiwan (NAHSIT), the prevalence among Taiwanese adolescents aged between 11 and 18 years of overweight and obesity was 12.4% and 16.8%, respectively [2]. With the number of overweight and obese adolescents on the rise, the prevalence of metabolic syndrome (MetS) has also escalated, and has a positive correlation with obesity [3]. From 1988 to 1994, the prevalence of MetS among American adolescents aged 12 to 19 years was 28.7% in overweight subjects (BMI ≥ 95th percentile), which was signi cantly higher than the prevalence of 6.8% and 0.1% in subjects with a BMI in the 85th to 95th percentile and low-risk subjects (BMI < 85 th percentile), respectively [3]. Research has shown that cardiometabolic risk factors identi ed in childhood and adolescence are associated with subclinical atherosclerosis in adulthood [4]. The presence of MetS during childhood exacerbates the risk of having adulthood MetS, cardiovascular disease (CVD), and type 2 diabetes mellitus (T2DM) [5,6]. Therefore, screening of MetS and obesity during childhood and adolescence, as well as further interventions (especially changes in diet and increase physical activity), are important factors to improve the future health of the adult population [7].
MetS comprises of the risk factors for CVD and T2DM [8]. It represents the association between obesity, insulin resistance, hypertension, dyslipidemia, T2DM, and CVD [9]. In 1988, Reaven rst proposed the notion of insulin resistance (IR), and named the cluster of risk factors for CVD and diabetes as "Syndrome X" [10]. In 1998, the World Health Organization (WHO) formally named the syndrome as MetS and de ned its criteria [11]. Afterwards, various de nitions were proposed, such as that of the European Group for the Study of Insulin Resistance (EGIR) in 1999 [12]; the National Cholesterol Education Program Adult Treatment Panel III(NCEP ATP III) in 2001 [13]; the International Diabetes Federation (IDF) [14] and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) [15] in 2005. Early studies suggested IR as the primary cause of MetS [16], but subsequent studies deduced that the interaction between obesity, IR, and in ammation plays a crucial role in the development of MetS [17]. Moreover, MetS is in uenced by other metabolic and pathological factors such as in ammatory factors, adipocytokines, cortisol, oxidative stress, vascular factors, inheritance, and lifestyle factors [9].. The uni ed criteria for diagnosing MetS in adults have been determined [8] and successfully applied in clinical practice and research [9]. However, due to the growing concern about MetS in children and adolescents, many studies have attempted to de ne MetS in these groups [9]. At present, as there are no uni ed diagnostic criteria, the di culty in de ning the condition may be associated with physiological changes during growth, racial differences, lack of CVD cases, and lack of clinical trials [18]. Consequently, the discrepancies in the prevalence of MetS in children and adolescents is remarkably large as there is no uni ed diagnostic criteria. Many studies have modi ed the NCEP ATP III's de nition of MetS in adults [19], while recent studies commonly adopt the modi ed NCEP ATP III criteria and the 2007 IDF criteria [20]. Based on the modi ed NCEP ATP III criteria, the prevalence of MetS in American, Korean, and Chinese adolescents was 8.6% (2001)(2002)(2003)(2004)(2005)(2006) [21], 5.7% (2010-2012) [22], and 3.7% (2008) [23], respectively. It must be noted, however, that cutoff points for abnormal MetS factors had different sources in these three studies. Based on the IDF criteria, the prevalence of MetS in Taiwanese, Korean, and American adolescents was 3% (2010-2011) [24], 2.1% (2010-2012) [22], and 4.24% (2011-2016) [25], respectively.
This study aimed to examine the performance of selected existing MetS de nitions and a new set of criteria of MetS on its prevalence among a sample of urban high-school students in Taipei City in Taiwan. Also, optimal cutoff points of relevant risk factors of MetS components were examined. Findings from this study may serve as a reference to accurately estimate MetS prevalence among Taiwanese adolescence.

Study population and data collection
This study was approved by the institutional review board of the Taipei City Hospital (TCHIRB-10811003-E). The personal health data of urban high-school students aged between 15 to 17 years who underwent health checkups at a district hospital from 2011 to 2014 was sourced from the hospital's database. There were 50,280 sets of data. After omitting those with missing information, a total of 45,756 sets of data were included in this study.
The database of this study included the subjects' gender, age, height, weight, systolic blood pressure (SBP), diastolic blood pressure (DBP), and waist circumference (WC), as well as biochemical markers such as triglycerides (TG), highdensity lipoprotein cholesterol (HDL-C), and fasting glucose (FG) levels.
Height and weight were measured using automatic height and weight scale(HW-3050; Kongho Instruments Co.,Ltd., Taipei, Taiwan), and measured height (in cm) and weight(in kg) were rounded to the rst decimal place. To measure blood pressure (BP), a subject was told to sit in a relaxed manner, and their BP was measured by placing their left arm into a tunnel-type electronic sphygmomanometer(ES-P2000; TERUMO, Japan). The recorded BP was taken as the mean of two measurements. To measure WC, a measuring tape was kept parallel to the ground and was wrapped around a subject's waist, starting from a point midway between the upper iliac crest margin and the lower rib margin. The recorded WC was taken after the subject had breathed out. A subject's body mass index (BMI) was taken as their weight in kilograms divided by the square of their height in meters. Blood samples were drawn from the antecubital vein for biochemical analysis after at least 8 hours of fasting. Plasma was separated from the blood within 3 hours and then stored in a refrigerator. Blood samples were examined within 24 hours after transfer to the examination center. Plasma FG, TG and HDL-C levels were analyzed in plasma using an automatic analyzer (cobas c 702; Roche Diagnostics GmbH, Mannheim, Germany).

De nition of MetS
In this study, three de nitions for the prevalence of MetS were compared: the modi ed NCEP ATP III proposed by Ford et al. [26]; the 2007 IDF [20]; and the new criteria based on the cutoff points of this study's receiver operating characteristic (ROC) curves. All of these diagnostic criteria include the ve components of WC, TG, HDL-C, BP, and FG. The modi ed NCEP ATP III served as a baseline for the criteria of this study, in which the optimal cutoff point of each MetS component with an area under the ROC curve (AUC) greater than 0.8 were taken as new components (modi ed WC, TG, and HDL-C). The components of BP and FG remained unchanged (see Table 1).

Statistics
The statistical approaches used to analyze the discriminatory power and optimal cutoff points of relevant MetS risk factors in this study included descriptive statistics, chi-squared tests, independent sample t-tests, and ROC curves.

Results
The results of this study are shown in Among metabolic components, WC SBP TG and FG were signi cantly higher, while DBP and HDL-C were signi cantly lower, in males than in females(p < 0.001). There are already signi cant differences in height and weight between boys and girls, and compared with other indicators, we need to pay more attention to BMI. BMI, a reference value of overweight and obesity, was signi cantly higher in males than in females (p < 0.001). a Independent sample t-tests used for data analysis; **: p < 0.01 , *** p < 0.001.
The relevant MetS risk factors of high-school students have different discriminatory powers toward the diagnosis of MetS ( Fig. 1 and Table 3). Table 3    The prevalence of MetS among urban high-school students in Taipei City in Taiwan was 2.3%, 1.2%, and 4.3% according to the criteria of the modi ed NCEP ATP III, the IDF, and this study, respectively (

Discussion
MetS in adolescents and the prevalence of its components At present, there are no uni ed criteria for diagnosing MetS in adolescents, which makes it di cult to compare between studies in the literature. The prevalence of MetS differs across studies, which could be associated with differences in diagnostic criteria, age (especially IR in adolescents), gender, regions, and races [7]. In this study, the prevalence of MetS as measured using the modi ed NCEP ATP III and IDF criteria was 2.3% and 1.2% respectively, and increase to 4.3% by using this study's criteria. Low prevalence of MetS was also found among adolescents(mainly in urban area) in southern Brazil(1.9% to 5.0% by using different criteria) and in many studies(1.6% to 6.3% by using the IDF criteria) [27].
Differences in the percentage of abnormal measures of MetS components are a result of different diagnostic criteria.
According to this study's criteria, 10.7% of high-school students had a slightly large WC, 10.8% had high TG, and 21.2% had low HDL-C. The study population had a higher percentage of individuals with abnormal measures for these three components than for the other two components (elevated BP and elevated FG).
The criteria developed in this study identi ed a signi cantly higher percentage of subjects with low HDL-C (21.2%), compared to that seen using the modi ed NCEP ATP III (4.2%) and the IDF (5.1%). A possible explanation could be that a uni ed criterion (< 40 mg/dL) was used in the modi ed NCEP ATP III (in which subjects were 12 to 19 years old) and the IDF (in which subjects were below 16 years old), which gender differences were not adjusted for in the cutoff values, which resulted in a low prevalence among females. This has also been observed in another study [24].
Differences were observed between the results from the modi ed NCEP ATP III and IDF in the percentage of individuals with abnormal measures for TG (9.7% vs. 2.9%) and BP (18.6% vs. 15.7%). This may be because the modi ed NCEP ATP III criteria de ne elevated BP as ≧ 90 th percentile after adjusting for age, gender, and height, while high TG are de ned as ≧ 110 mg/dL after adjusting for age [3], whereas the IDF criteria de ne elevated BP in adults as ≧ 130/85 mmHg and high TG as ≧ 150mg/dL.
Compared with the modi ed NCEP ATP III criteria adjusted by Ford et al. [26], the percentage of subjects identi ed as having a large WC in this study(10.6%) was similar to that in a Korean population (9.7%) [22], but lower than that in an American population (19.1%) [21]; the percentage of subjects with elevated BP in this study(18.6%) was also similar to that in a Korean population (20.4%), but higher than that in an American population (6.9%). These differences could due to differences in the populations, which indicates the importance of establishing a large database on the WC and BP of people in different regions. The percentage of subjects with high TG in this study(9.7%) was lower than that in studies conducted in Korea (21.2%) and the USA (25.6%); the percentage of subjects with low HDL-C in this study(4.2%) was lower than that in Korea (11.6%) and the USA (19.3%); and the percentage of subjects with elevated FG was 2.9%, which is signi cantly lower than that in the USA (14%) and Korea (11.4%) [21,22]. The components of MetS in adolescents must be adjusted for racial and regional differences. This highlights the importance of the results of this study.
Moreover, according to the criteria of the modi ed NCEP ATP III, the IDF, and this study, about 34.4%, 28.3%, and 44.6% of adolescents, respectively, had at least one MetS component. The fewer of these components that are present during childhood, the lower the cardiovascular risk in the future [28]. Some researchers [29] have emphasized that the effects of metabolic risk factor clustering are more important than diagnosing MetS in children. Based on these arguments, it is not only crucial to detect MetS in adolescents, but those present with MetS components despite not yet reaching the diagnostic criteria should receive attention as well, to provide prompt intervention and prevention [7,28].

Gender difference among prevalences of MetS and MetS components abnormalities
The prevalence of MetS was signi cantly higher in males than females in our study with the modi ed NCEP ATP III, IDF and our study's criteria separately(see Table 4, P < 0.001). However, previous studies showed inconclusive results.
Among all the MetS components, in our study, the prevalence of elevated BP, high TG, low HDL-C and elevated FG were signi cantly higher in males than females, while the prevalence of central abesity showed no statistically difference between gender when applying the modi ed NCEP ATP III and IDF criteria separately. Similar results were noted when applying our study's criteria except the prevalence of low HDL-C, which was higher in females(25.5%) than in males(18.3%), and increased signi cantly in both gender comparing with the modi ed NCEP ATP III and the IDF criteria(see Table 4). However, previous studies showed inconclusive results. In USA adolescents, the prevalence of high TG, low HDL-C and elevated FG were higher, while central obesity and elevated BP were lower, in males than in females(all within 95% CI) [21]. In Korean adolescents, there were no statistically signi cant between gender among MetS components in the modi ed NCEP ATP III criteria, and similar results were noted in the IDF criteria except for the prevalence of elevated BP, which was signi cantly higher in males than in females(males 3.4%, females 1.2%, P < 0.001) [22]. Furthermore, according to the IDF criteria, the prevalence of elevated BP was signi cantly higher in males (22.3%) than females (6.1%), which showed only mild difference according to the modi ed NCEP ATP III criteria(male: 19.3%, female: 17.7%) This could be because the IDF criteria use xed values(≥ 130 mmHg for SBP and/or ≥ 85 mmHg for DBP) to de ne elevated BP, instead of ≥90 th percentile by modi ed NCEP ATP III and our study(adjusted for age, gender, and height).
As stated above, the prevalence of MetS and MetS components abnormalities could differ due to the differences in race, region and diagnostic criteria.

The predictive power of MetS components
According to the results of this study, WC has the highest predictive power, sensitivity, and speci city, regardless of gender. This is in agreement with other studies which have suggested that WC is a good indicator for predicting MetS during adolescence [25,29,30] and adulthood [32]. A study on American adolescents between 12 and 19 years of age revealed that abdominal obesity was closely associated with MetS and other MetS components [25]. Another study on 15-year old Greek teenagers showed that a WC at the 75th percentile or higher is closely related to the phenotypes of MetS [30]; while a study on Chinese adolescents between 11 and 16 years old indicated that WC has the best predictive power toward MetS [31].
To determine the optimal cutoff point for WC, Cook et al. (2003) [3] took into account the differences between adolescents and adults, and de ned abdominal obesity as at the 90 th percentile or higher; in 2004, de Ferranti et al. [33] adopted a value at the 75 th percentile or higher as their standard; afterward, in 2007, the IDF study (in which subjects were below 16 years of age) [20] and numerous studies [21,22,26] adopted a WC at the 90 th percentile or higher as their standards. A Chinese study on children and adolescents between 7 and 18 years of age found that a WC at the 75 th percentile and the 90 th percentile was the optimal cutoff point for predicting the risk of cardiovascular risk [34].
The optimal cutoff point for WC speci ed in this study was 86.8 cm for males and 76.25 cm for females, which was around the 90 th percentile and similar to that of the previous studies.
In this study, TG level also had adequate predictive power, with an optimal cutoff point of 108 mg/dL for males and 104.05 mg/dL for females, similar to that of the modi ed NCEP ATP III criteria (< 110 mg/dL).
SBP, DBP, and FG had weaker predictive powers. In particular, FG had the weakest predictive power, which was also observed in other studies with adolescents [31] and adult [32] subjects.
In this study, the cutoff points for MetS components were rede ned based on the results of urban high-school students in Taipei City in Taiwan. This indicates that it is necessary to take into account regional differences when determining de nition criteria.
The predictive power of BMI Based on the results of this study, BMI also had good predictive power on MetS in adolescents, after that of WC and TG. The optimal cutoff point for males was between the 80 th to 85 th percentile (25.6 kg/m 2 ) for males and approximately the 90 th percentile (24.65 kg/m 2 ) for females.
The WC and BMI of adolescents are good predictive indicators of cardiovascular risk factors [35]. A longitudinal study highlighted the close association between BMI and many other cardiometabolic risk factors, while changes in WC mainly have a stronger correlation with FG [36]. A study on children and adolescents between 8 and 19 years of age [37] revealed that a high BMI has strong predictive power for cardiometabolic risk factors. In addition, the sensitivity of BMI is higher among obese adolescents while its speci city is higher among overweight adolescents [38].
The de nitions of overweight and obesity are currently based on a person's BMI, and their criteria differ for adolescents [37][38][39]. In 2007, the WHO de ned overweight as having a BMI between the 85 th and 95 th percentiles, while obesity is de ned as having a BMI greater than the 95 th percentile [38]; in 2012, the International Obesity Task Force (IOTF) deduced the cutoff points for BMI in adolescents and adults after mathematical adjustments based on the de nition of overweight and obesity in adults I [38,39]. One study [41] used the three aforementioned criteria (WHO; Conde and Monteiro; IOTF) to analyze Brazilian adolescents between 12 and 20 years old; it revealed that the IOTF criteria had the best predictive power for MetS (AUC = 0.75-0.89), with a sensitivity ranging from 59.4% to 84.2% and a speci city ranging from 88.2% to 93.6 . In contrast, according to this study's adjusted de nition of MetS, BMI had a better predictive power (AUC = 0.915-0.926) and sensitivity (0.817-0.9) for the high-school students. The differences between these results and those of the aforementioned studies could be due to the differences in the diagnostic criteria, age, region, and race in adolescents [7].

Future aspect of establishing suitable criteria of MetS for adolescents in different region
First, we already know the difference of prevalence of MetS and MetS components abnormality in adolescents among different races and regions in previous studies [7,27]. In this study, urban high-school students in Taipei City in Taiwan, which are all Asians, were included for the purpose to specify race and region.
Second, there are many version of criteria published for metabolic syndrome in adolescents. However, Reuter et al. found low agreement between different criteria, and emphasized the importance to create speci c cutoff points of MetS components for adolescents in their region [27]. In this study, despite using current main criteria (modi ed NCEP ATP III, IDF), we establish new criteria for urban adolescents in Taipei City in Taiwan for comparison.
Third, previous studies have showed that presence of MetS in childhood increase the risk of CVD and T2DM in adulthood [5,6], there is still no exact MetS criteria for adolescents, which has proven to predict CVD and T2DM in adults. Therefore, the new criteria in this study is not only used to compare the differences between other current main MetS criteria for adolescents, but also can be used in future cohort study, to analyze which MetS criteria for adolescents can better predict CVD and T2DM in adulthood.

Limitations
The cross-sectional research design of this study hindered observations of the causal relationships in the data. Moreover, the subjects were adolescents from Taipei City, an urban region of northern Taiwan, which limited the extrapolation of results to adolescents in rural locations as well as those with special circumstances. However, the results of this study are still valuable and can serve as a reference to de ne MetS in urban adolescents in Taipei City in Taiwan. First, the sample size in this study is large enough, which can serve as the representatives for urban Taipei adolescents in Taiwan, which are all Asians. Seconds, this study analyzed the differences in the discriminatory power of relevant risk factors as well as their optimal cutoff points, which could provide markers for early interventions in the future. Subsequent research could include the potential confounders of MetS, such as the in uence of puberty and temporary IR during adolescence [7]; as well as taking into account more biochemical markers, and participating in cross-regional and cross-cultural cohort studies. A combination of these approaches would make the understanding of MetS in Taiwanese adolescents more comprehensive.

Conclusion
The prevalence of MetS in adolescents differs when measured using different criteria. In comparison to the results with the criteria of the modi ed NCEP ATP III and the IDF, the criteria de ned in this study found that the prevalence of MetS among urban adolescents in Taipei City in Taiwan was higher (4.3%). Of the MetS components, WC and TG had the strongest discriminatory power, sensitivity, and speci city, while FG had the weakest discriminatory power. The optimal cutoff point for WC was approximately at the 90 th percentile; while the optimal cutoff point for TG was similar to the criteria of the modi ed NCEP ATP III. Moreover, about 44.6% of adolescents had at least one MetS component.
The early detection of relevant risk factors during adolescence is a crucial issue as it provides vital information for prevention and intervention, to reducing the risk of CVD and T2DM in adulthood. For accurate detection, it is necessary to rede ne the cutoff points for MetS components speci c to adolescents in different regions, to establish suitable criteria for adolescents in Taiwan as a whole.