Cardiovascular Disease Risk Factors Two-Township Research Articles

Central obesity and elevated blood pressure in middle life are associated with physical and cognitive impairment in later life: A retrospective design with repeated measures

Background and aimsPhysical and cognitive function decline indicates the prestage of disability and is associated with mortality among older adults. We investigated the association of metabolic disorders in midlife with physical and cognitive function decline in later life in a retrospective cohort. Material and methodsA total of 618 older adults aged ≥60 years in wave-6 (2014–2017) were enrolled in the Cardiovascular Disease Risk Factor Two-Township Study to evaluate physical (hand grip strength and 4-m walking speed) and cognitive function (Mine–Mental State Examination [MMSE] score). Repeated metabolic disorder measures in wave-2, wave-3, and wave-5 were obtained to identify three trajectory pattern groups according to each metabolic disorder through group-based trajectory modeling. Linear and logistic regressions were conducted to investigate the association of metabolic disorders in middle life with physical and cognitive function decline in later life. ResultsThe prevalence rates of a weak hand grip (<28 kg for men and <18 kg for women), slow walking speed (<0.8 m/s), and poor cognitive function (MMSE <25) were 24.43 %, 16.83 % and 10.5 %, respectively, among the older adults. In the retrospective cohort with 15-year follow-up, those with a waist circumference of ≥95 cm for men and ≥85 cm for women in middle life exhibited a significantly weak hand grip (odds ratio: 2.78 [95 % confidence interval: 1.26, 6.11]) and slow walking speed (2.26 [1.15, 4.43]) in later life compared with those with a smaller waist circumference (<85 cm for men and <75 cm for women). Elevated blood pressure (systolic blood pressure [BP] ≥130 mmHg or diastolic BP ≥80 mmHg) was significantly associated with a higher risk of cognitive function decline in later life. Furthermore, the high-trajectory and middle-trajectory groups' body mass index (3.17 [1.25, 8.04] and 2.27 [1.28, 4.00], respectively) and waist circumference (4.39 [2.07, 9.31] and 2.54 [1.39, 4.67], respectively) were significantly associated with a weak hand grip and slow walking speed, respectively, compared with those of the low-trajectory group. The high-trajectory diastolic BP group was significantly associated with a higher risk of cognitive function decline compared with the low-trajectory diastolic BP group. ConclusionWaist circumference and BP in middle life were associated with physical function decline and poor cognitive function in later life. The management of central obesity and BP in midlife may slow the decline of physical and cognitive function in later life.

Causal link between milk consumption and obesity? A 10-year longitudinal study and a Mendelian randomization study

Background: Obesity control and prevention remains challenging. Randomized controlled trials in western countries have demonstrated efficacy of dairy supplementation on fat mass reduction and lean mass increase, when combined with energy restriction protocols. However, there is scanty information on this issue among the East Asian population.&#x0D; Objective: The aim of this study is to investigate the association between milk consumption and weight status in Asian.&#x0D; Design: First, we studied the association between milk intake and body mass index (BMI) changes in a 10-year longitudinal study of Cardiovascular Disease Risk Factor Two-township Study (CVDFACTS) with 1,644 adults. Second, taking advantage of the genetic and phenotype data of 10,000 participants collected by Taiwan Biobank (TWB), we carried out a Mendelian randomization (MR) study to investigate the causal relationship between milk intake and BMI. A lactase persistence genetic marker (rs4954490) was used as the instrumental variable.&#x0D; Results: We found in the longitudinal study that higher baseline milk consumption level was associated with lower odds of increasing BMI or maintaining overweight/obesity status. In the MR study, we found that G allele of the rs4954490, a surrogate of greater milk intake, was associated with lower odds of being obese (BMI &gt; 27 kg/m2); the odds ratio (OR) for the GG versus AA is 0.85 (P = 0.037), and the OR for the GA versus AA is 0.84 (P = 0.032).&#x0D; Conclusions: These findings support current food guide in Asian countries to include dairy group as one of the six food groups for nutrition recommendation.

Is Hyperuricemia, an Early-Onset Metabolic Disorder, Causally Associated with Cardiovascular Disease Events in Han Chinese?

Background: Serum uric acid (SUA) has gradually been recognized as a potential risk factor for cardiovascular disease (CVD). However, whether the relationship is causal remains controversial. Methods: We employed two methods to demonstrate the importance of SUA in CVD development. First, we examined the onset sequence of hyperuricemia in relation to five cardiometabolic (CM) diseases. Second, we conducted a Mendelian randomization (MR) study to causally infer the relationship between SUA and CVD. The information collected from the Cardiovascular Disease Risk Factors Two-Township Study (CVDFACTS) and Taiwan Biobank was used, respectively. Results: The onset sequence study showed that hyperuricemia and hypo-alpha-lipoproteinemia (low HDL-C) have earlier ages of onset than other CM diseases. For the MR analysis, the high weighted genetic risk score (WGRS) group had a significantly increased cumulative lifetime risk of CVD compared with the low WGRS group (OR = 1.62, (1.17−2.23), P = 0.003). Sensitivity analysis using the WGRS derived from other populations’ SUA-influential SNPs revealed similar results. Conclusions: We showed that hyperuricemia is an earlier-onset metabolic disorder than hypertension, hypertriglyceridemia, and diabetes mellitus, indicating that high SUA plays an upstream role in CM development. Moreover, our MR study results support the idea that hyperuricemia may play a causal role in CVD development. Further validation studies in more populations are needed.

Semiparametric regression analysis for left-truncated and interval-censored data without or with a cure fraction

Interval censoring and truncation arise often in cohort studies, longitudinal and sociological research. In this article, we formulate the effects of covariates on left-truncated and mixed case interval-censored (LTIC) data without or with a cure fraction through a general class of semiparametric transformation models. We propose the conditional likelihood approach for statistical inference. For data without a cure fraction, we propose a computationally efficient EM algorithm, facilitated by a novel data augmentation method, to obtain the conditional maximum likelihood estimator (cMLE). For data with a cure fraction, we consider a semiparametric mixture cure model, which combines a logistic regression formula for the uncured probability with the class of transformation models for the failure time of uncured individuals. To overcome the computational complexity due to the presence of a cure fraction, by reparameterization of cure rate in the conditional likelihood function, we propose a computationally stable EM algorithm for obtaining the cMLE. We show that the cMLEs for the regression parameters are consistent and asymptotically normal. Based on the profile likelihood, we apply an EM-aided numerical differentiation method to compute the asymptotic variance estimates. We demonstrate the performance of our procedures through intensive simulation studies and application to the datasets from the Cardiovascular Disease Risk Factors Two-Township Study.

Ages at Onset of 5 Cardiometabolic Diseases Adjusting for Nonsusceptibility: Implications for the Pathogenesis of Metabolic Syndrome.

To shed light on the etiology of metabolic syndrome development, it is important to understand whether its 5 component disorders follow certain onset sequences. To explore disease progression of the syndrome, we studied the ages at onset of 5 cardiometabolic diseases: abdominal obesity, diabetes, hypertension, hypertriglyceridemia, and hypo-α-lipoproteinemia. In analyzing longitudinal data from the Cardiovascular Disease Risk Factors Two-Township Study (1989-2002) in Taiwan, we adjusted for nonsusceptibility, utilizing the logistic-accelerated failure time location-scale mixture regression models for left-truncated and interval-censored data to simultaneously estimate the associations of township and sex with the susceptibility probability and the age-at-onset distribution of susceptible individuals for each disease. We then validated the onset sequences of 5 cardiometabolic diseases by comparing the overall probability density curves across township-sex strata. Visualization of these curves indicates that women tended to have onsets of abdominal obesity and hypo-α-lipoproteinemia in young adulthood, hypertension and hypertriglyceridemia in middle age, and diabetes later; men tended to have onsets of abdominal obesity, hypo-α-lipoproteinemia, and hypertriglyceridemia in young adulthood, hypertension in middle age, and diabetes later. Different onset patterns of abdominal obesity, hypo-α-lipoproteinemia, and male hypertension were identified between townships. Our proposed method provides a novel strategy for investigating both pathogenesis and preventive measures of complex syndromes.

Blood Pressure, Carotid Flow Pulsatility, and the Risk of Stroke: A Community-Based Study.

High blood pressure is a major cause of cardiovascular events, and carotid flow pulsatility may be associated with cardiovascular events. However, the combined effect of blood pressure and flow pulsatility on the development of stroke remains unclear. Therefore, we investigated the combined influence of central blood pressure and pulsatility index (PI) on the incidence of stroke. Baseline data from 2033 adults (≥30 years) without stroke history in the Cardiovascular Disease Risk Factor Two-Township Study were linked to incident stroke. Common carotid flow PI was calculated by peak systolic velocity, end-diastolic velocity, and mean vessel velocity, which were measured in the common carotid artery. Hazard ratios for the risk of total stroke resulting from high central systolic blood pressure (CSBP) and high PI were calculated with Cox proportional hazard models. Over a median follow-up of 9.81 years, 132 people incurred stroke events. The incidence rates of stroke were 1.3, 6.4, and 13.2 per 1000 person-years for tertile groups of CSBP (P for trend<0.05) and 4.3, 7.0, and 9.4 per 1000 person-years for tertile groups of PI (P for trend<0.05). Compared with the first tertile of CSBP, hazard ratios were 4.88 (95% confidence interval, 2.29-10.43) for the second tertile and 10.42 (5.05-21.53) for the third tertile. Hazard ratios of PI were 2.18 (1.39-3.42; third tertile) and 1.64 (1.02-2.63; second tertile) compared with the first tertile. The individuals with a high CSBP and high PI had a 13-fold higher stroke risk compared with those with low CSBP and low PI (13.2; 1.75-99.71) after adjusting for age, sex, and traditional cardiovascular risk. CSBP and common carotid PI jointly and independently predicted future stroke. Carotid flow pulsatility may play an important role in the development of stroke.

Prognostic significance of mechanical biomarkers derived from pulse wave analysis for predicting long-term cardiovascular mortality in two population-based cohorts

BackgroundNumerous mechanical biomarkers derived from pulse wave analysis (PWA) have been proposed to predict cardiovascular outcomes. However, whether these biomarkers carry independent prognostic value and clinical utility beyond traditional cardiovascular risk factors hasn't been systematically evaluated. We aimed to investigate the additive utility of PWA-derived biomarkers in two independent population-based cohorts. MethodsPWA on central arterial pressure waveforms obtained from subjects without a prior history of cardiovascular diseases of two studies was conducted based on the wave transmission and reservoir-wave theory: firstly in the Kinmen study (1272 individuals, a median follow-up of 19.8years); and then in the Cardiovascular Disease Risk Factors Two-Township Study (2221 individuals, median follow-up of 10years). The incremental value of the biomarkers was evaluated by net reclassification index (NRI). ResultsIn multivariate Cox analyses accounting for age, gender, body mass index, systolic blood pressure, fasting glucose, high-density- and low-density-lipoprotein cholesterol, and smoking, only systolic (SC) and diastolic rate constant (DC) of reservoir pressure could independently and consistently predict cardiovascular mortality in both cohorts and the combined cohort (SC: hazard ratio 1.18 [95% confidence interval 1.08–1.28, p<0.001; DC: 1.18 [1.09–1.28], p<0.001]. Risk prediction estimates in traditional risk prediction models were significantly more accurate when incorporating peak of reservoir pressure (NRI=0.049, p=0.0361), SC (NRI=0.043, p=0.0236) and DC (NRI=0.054, p=0.047). ConclusionsOf all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts.

Logistic‐AFT location‐scale mixture regression models with nonsusceptibility for left‐truncated and general interval‐censored data

In conventional survival analysis there is an underlying assumption that all study subjects are susceptible to the event. In general, this assumption does not adequately hold when investigating the time to an event other than death. Owing to genetic and/or environmental etiology, study subjects may not be susceptible to the disease. Analyzing nonsusceptibility has become an important topic in biomedical, epidemiological, and sociological research, with recent statistical studies proposing several mixture models for right-censored data in regression analysis. In longitudinal studies, we often encounter left, interval, and right-censored data because of incomplete observations of the time endpoint, as well as possibly left-truncated data arising from the dissimilar entry ages of recruited healthy subjects. To analyze these kinds of incomplete data while accounting for nonsusceptibility and possible crossing hazards in the framework of mixture regression models, we utilize a logistic regression model to specify the probability of susceptibility, and a generalized gamma distribution, or a log-logistic distribution, in the accelerated failure time location-scale regression model to formulate the time to the event. Relative times of the conditional event time distribution for susceptible subjects are extended in the accelerated failure time location-scale submodel. We also construct graphical goodness-of-fit procedures on the basis of the Turnbull-Frydman estimator and newly proposed residuals. Simulation studies were conducted to demonstrate the validity of the proposed estimation procedure. The mixture regression models are illustrated with alcohol abuse data from the Taiwan Aboriginal Study Project and hypertriglyceridemia data from the Cardiovascular Disease Risk Factor Two-township Study in Taiwan.

C-reactive Protein Predicts Systolic Blood Pressure and Pulse Pressure but not Diastolic Blood Pressure: the Cardiovascular Disease Risk Factors Two-Township Study

Inflammation has been associated with cardiovascular events and mortality, using C-reactive protein (CRP) as a marker. We examined whether the baseline serum concentration of CRP can independently predict the development of hypertension or future systolic or diastolic blood pressure (BP) in a community-based population in Taiwan. A study population sample was recruited in cycle 2 (1990-1993) of the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS) and was followed to 1994-1997. A total of 2,113 nondiabetic adults with normal BP were enrolled for the study of incident hypertension. Hypertension was defined as a systolic blood pressure (SBP) ≥ 140 mm Hg, a diastolic blood pressure (DBP) ≥ 90 mm Hg, or the use of antihypertensive drugs. Cox regression and linear regression analyses were used to evaluate the association between baseline serum concentrations of CRP measured with a high-sensitivity assay and the development of hypertension and future SBP/DBP and pulse pressure (PP). During the follow-up period of a median of 3.27 years, 145 participants developed incident hypertension. The incidence rates of hypertension by tertile of increasing CRP were 9.3, 19.0, and 33.0 per 1,000 person-years (P for trend < 0.01). In the multivariate model adjusted for age, gender, and prehypertension, baseline CRP remained significantly predictive of incident hypertension. The concentration of CRP was associated with SBP and PP, but not with DBP. Inflammation is associated with future SBP in the Taiwanese population.

Lower intake of magnesium and dietary fiber increases the incidence of type 2 diabetes in Taiwanese

Several studies have indicated an inverse association between the incidence of diabetes mellitus and magnesium and dietary fiber intake. Few studies have examined both of these associations together, not to mention in Asian populations with prospective study design. We therefore aimed to study how dietary magnesium and fiber intake levels affect diabetes incidence separately or in combination, in a prospective study in Taiwan. The study subjects were recruited for a longitudinal study, CardioVascular Disease risk FACtor Two-township Study cycle 2 from November 1990. Data from complete baseline information on dietary and biochemical profile and at least one additional follow-up visit were gathered on a total of 1604 healthy subjects aged 30 years and over. Cox proportional hazard model was used to study the association between diabetes incidence and dietary magnesium and fiber intake level estimated from a food frequency questionnaire. A total of 141 diabetes mellitus events were identified and confirmed during the 4.6 years of follow-up (7365.1 person-years). A significantly higher diabetes risk was observed for people in the lowest quintile of total dietary fiber intake (hazard ratio = 2.04; 95% CI = 1.17-3.53) and magnesium intake (hazard ratio = 2.61; 95% CI = 1.42-4.79) compared with the highest quintile after adjusting for traditional cardiovascular disease risk factors. Similar inverse associations for total dietary fiber were also shown for vegetable fiber and fruit fiber. Lower magnesium, lower total dietary fiber intake, or lower intake of both was associated with higher risk of diabetes in the Taiwanese population. Clinical trials are required to confirm the protective effects of the adequate intake of fiber, magnesium, and/or their combination.

Is Ischemic Stroke Risk Related to Folate Status or Other Nutrients Correlated With Folate Intake?

Folate status was inversely associated with plasma homocysteine concentration, a potential risk factor of cardiovascular disease. However, it is uncertain whether folate is causally associated with risk of ischemic stroke (IS). We aimed to examine the association between IS incidence and folate intake, biochemical folate status, and folate associated nutrients. Information on baseline characteristics and food frequency questionnaire was collected in 1990 to 1993 and included for analyses data from 1772 adults over 40 years, who were free of stroke and cancer at baseline from the CardioVascular Disease risk FACtor Two-township Study. Multivariate Cox proportional hazard model was used to relate baseline nutrient status with IS event. Over an average of 10.6 years of follow-up, 132 incident IS events were documented. Low folate intake (1st and 2nd quartiles) was significantly and independently associated with increased IS risk (HR=1.61; 95% CI: 1.04 to 2.48 and HR=1.82; 95% CI: 1.20 to 2.76) compared with those in the 3rd and 4th quartile combined, whereas no association was observed for plasma folate concentration. On the other hand, several nutrients correlated with dietary folate: vitamin B2, potassium, iron, vitamin A of plant origin, calcium were also associated with IS risk in an inverse linear manner with HR ranging from 1.5 to 1.9 for the first quartile. The protective association of dietary folate on IS risk may be in part through that of other correlated nutrients or other dietary components.

Costs of metabolic syndrome‐related diseases induced by obesity in Taiwan

The objective of this paper is to estimate the cost of obesity's contribution to the metabolic syndrome diseases in Taiwan. We used individual data from the Cardiovascular Disease Risk Factors Two-Township Study survey and medical use and expenditures data from the Bureau of National Health Insurance (NHI) of Taiwan. By adopting the prevalence-based and population attributable risk (PAR) approaches, direct costs of obesity for six kinds of obesity related metabolic syndrome diseases have been estimated. Comorbidities used in our analysis included ischemic heart diseases, congestive heart failure, cerebrovascular disease accident, diabetes, hyper-cholesterolaemia and hypertension. The results indicate that overweight and obesity are associated with a higher prevalence and costs of the metabolic syndrome related diseases. PAR increases as the obese [body mass index (BMI)] prevalence increases. About 4-9% of the costs of those diseases can be attributed to overweight (24 < or = BMI < 27) and about 7-13% and 8-19% of such costs are attributable to the first and second degree obesity (27 < or = BMI < 30 and BMI > or = 30). The cost of obesity derived from the PAR and medical costs of metabolic syndrome diseases accounts for 2.9% of the national total healthcare expenditure. We therefore conclude that overweight and obesity have increased health costs and resulted in higher prevalence of and greater costs from metabolic syndrome related diseases in Taiwan. These findings provide important support for implementing obesity prevention programs in Taiwan.

Do centrally obese Chinese with normal BMI have increased risk of metabolic disorders?

Body mass index (BMI) and waist circumference are highly correlated. One or the other predicts the metabolic syndromes better, depending on characteristic of the population studied, such as age, gender, and ethnicity. We examined the impact of isolated central obesity, isolated BMI elevation, and the combined type of obesity on metabolic disorders, in order to shed lights on the strategy of obesity screening. The study subjects were Chinese aged 20 or above residing in Taiwan. Their data were derived from two large-scale studies: the Nutrition and Health Survey in Taiwan (NAHSIT 1993-1996) and the Cardiovascular Disease Risk Factor Two-township Study (CVDFACTS, 1994-1997). In evaluating the relations between obesity and health risks, the cut-points of BMI (> or =24 kg/m(2) for overweight) and waist circumference (> or =80 cm for women and > or =90 cm for men) recommended by Department of Health in Taiwan for Taiwanese people were used to define various types of obesity. We found that there was a small but nontrivial proportion (1.7% for men and 4.0% for women) of Taiwanese people for whom BMI was in the normal range but their waist circumferences were above normal. These people were at a higher risk of developing metabolic syndromes than those with isolated BMI elevation. Their risks were close to that of the combined type. In order to screen out high-risk obese individuals, isolated centrally obese subjects should not be overlooked. Therefore, we recommend to assess waist circumference in parallel to, not just sequential to the measurement of BMI in Chinese.

Associations between carotid atherosclerosis and high factor VIII activity, dyslipidemia, and hypertension.

A subsample of 147 Chinese subjects from a population-based study of cardiovascular diseases (Cardiovascular Disease Risk Factor Two-Township Study) participated in an ancillary study on extracranial carotid color duplex ultrasonography that aimed to assess the relations of coagulation factors to stroke and carotid atherosclerosis. Logistic models were used to study the associations between cardiovascular disease risk factors and stroke/carotid atherosclerosis, controlling for the effects of age and sex. Stroke was significantly associated with hypertension and high values of plasma glucose but not with fibrinogen, factor VIIc, or factor VIIIc. Carotid plaques identified in this study were mostly mild and moderate. The presence of these mild and moderate carotid plaques was significantly associated with high values of factor VIII activity, hypercholesterolemia, hypertriglyceridemia, and hypertension. The highest tertile of factor VIIIc (> 1.53) was associated with an odds ratio of 3.35 for carotid atherosclerosis when compared with the lowest tertile (< 1.20). A multiple logistic regression including all significant risk factors showed that the degree of association between factor VIIIc and atherosclerosis was attenuated to an odds ratio of 2.65 (P = .061). In the present study, the roles of hypertension, hypercholesterolemia, and hypertriglyceridemia have been implicated in the pathogenesis of carotid atherosclerosis, and roles for hypertension and hyperglycemia in stroke were indicated. A positive association between factor VIIIc and carotid atherosclerosis in this Chinese population was found. Whether this association is independent of the effect of other cardiovascular risk factors awaits further study.

Thrombophilia in patients with hypercholesterolemia

To investigate a possible interrelationship between hypercholesterolemia and the coagulation and fibrinolytic system, the Cardiovascular Disease Risk Factor Two-Township Study in Taiwan was undertaken as a longitudinal prospective study focusing on the evolution of cardiovascular disease risk factors, with an emphasis on hemostatic factors. Hemostatic parameters measured in this study included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, factor VIIc, factor VIIIc, antithrombin III, and plasminogen. Subjects of both sexes with hypercholesterolemia (> 6.2 mmol/L) also had significant elevations of diastolic blood pressure, plasma glucose, triglycerides, fibrinogen, and factor VIIc and reduced PT and APTT compared with subjects with lower cholesterol. The hypercholesterolemic women additionally had significant elevations of systolic blood pressure and factor VIIIc. Levels of the anticoagulant factors, antithrombin III and plasminogen, were also higher in both hypercholesterolemic men and women. In men, only factor VIIIc had no statistically significant elevation. In women, only PT showed no statistical difference. Established coronary risk factors such as fibrinogen and factor VIIc showed remarkable elevations in patients of both sexes. Using Pearson correlation and multiple regression, the most significant parameter related to cholesterol level was factor VIIc. The present results show that hemostatic abnormalities do exist in patients with hypercholesterolemia, and this thrombophilic phenomenon sheds further light on the study of higher cardiovascular mortality in these subjects.

Curvilinear Relations between Age and Hemostatic Parameters in Chinese

The role of hemostatic factors in the pathogenesis of cardiovascular disease has gained much attention recently. Information about hemostatic factors, and their age patterns is sparse for orientals. With the data collected in the Cardiovascular Disease Risk Factor Two-township Study in Taiwan, this study shows that, in general, the older the age, the stronger the tendency toward thrombosis. With advancing age, prothrombin time, activated partial thromboplastin time, and antithrombin-III level decreased steadily; but mean values of fibrinogen, factor VIIc, and factor VIIIc increased. Gender differences in the age patterns of the above factors are carefully described. Curvilinear relations between hemostatic factors and age were demonstrated for adults aged 18 and above for all hemostatic factors studied. This curvilinearity should be taken into consideration when adjusting for the effect of age in data analysis to avoid residual confounding, particularly when the age range of the study subjects is wide.