Yongling Xiao

Intra-abdominal adiposity and individual components of the metabolic syndrome in adolescence: sex differences and underlying mechanisms.

OBJECTIVEnTo investigate the association between intra-abdominal adiposity and individual components of the metabolic syndrome (MS) in adolescent males and females.nnnDESIGNnCross-sectional study of a population-based cohort.nnnSETTINGnSaguenay Youth Study, Quebec, Canada.nnnPARTICIPANTSnA total of 324 adolescents, aged 12 to 18 years.nnnINTERVENTIONnMeasures were compared between males and females with high or low intra-abdominal fat (IAF).nnnMAIN OUTCOME MEASURESnIntra-abdominal fat was quantified with magnetic resonance imaging. Primary outcome measures were blood pressure (BP) and fasting serum glucose, insulin, lipids, and C-reactive protein levels. Secondary mechanistic measures were cardiovascular variability indexes of autonomic nervous system function, pubertal development, and serum levels of cortisol, leptin, and sex hormones.nnnRESULTSnThe MS was completely absent in adolescents with low IAF and was present in 13.8% of males and 8.3% of females with high IAF. Excess IAF was associated with a higher homeostasis model assessment index (0.5 [95% confidence interval (CI), 0.3 to 0.8]; P < .001) and triglycerides level (17.7 mg/dL [to convert to millimoles per liter, multiply by 0.0113] [95% CI, 9.7 to 25.7 mg/dL]; P < .001), lower high-density lipoprotein cholesterol level (-3.9 mg/dL [to convert to millimoles per liter, multiply by 0.0259] [95% CI, -6.2 to -1.5 mg/dL]; P = .003), and higher C-reactive protein level (0.03 mg/L [to convert to nanomoles per liter, multiply by 9.524] [95% CI, 0.01 to 0.05 mg/L]; P = .003). High IAF was associated with elevations of BP and sympathetic activity in males only (higher systolic BP, 6 mm Hg [95% CI, 1 to 11 mm Hg]; P = .02 and low-frequency power of diastolic BP, 629 mm Hg2 [95% CI, 37 to 1222 mm Hg2]; P = .04).nnnCONCLUSIONSnOur results suggest that, already in adolescence, accumulation of IAF may promote development of the MS, affecting the metabolic and inflammatory components similarly in both sexes but influencing BP adversely only in males. The latter may be attributed, in part, to the augmentation of sympathetic activity also seen only in males.

A Common Variant of the FTO Gene Is Associated With Not Only Increased Adiposity but Also Elevated Blood Pressure in French Canadians

Background—FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. Methods and Results—The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. Conclusions—These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

Accuracy of Conventional and Marginal Structural Cox Model Estimators: A Simulation Study

Marginal structural models (MSM) provide a powerful tool to control for confounding by a time-dependent covariate without inappropriately adjusting for its role as a variable affected by treatment (Hernán et al., 2000). In this paper, we demonstrate that it is possible to fit a marginal structural Cox model directly, rather than the typical approach of using pooled logistic regression, using the weighted Cox proportional hazards function that has been implemented in standard software. To evaluate the performance of the marginal structural Cox model directly via inverse probability of treatment weighting, we conducted several simulation studies based on two data-generating models: one which replicates the simulations of Young et al. (2009) and an additional, more clinically plausible approach which mimics survival data with time-dependent confounders and time-varying treatment. Using the simulations, we illustrate the limitations of the conventional time-dependent Cox model and the MSM fitted via pooled logistic regression. Furthermore, we propose two novel normalized weights with the goal of reducing the MSM estimators variability. The performance of the normalized weights is evaluated alongside the usual unstabilized and stabilized weights.

A Common Variant of the FTO Gene Is Associated Not Only With Increased Adiposity But Also Elevated Blood Pressure in French-Canadians

Background—FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone. Methods and Results—The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP. Conclusions—These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

Effect of Cumulating Exposure to Abacavir on the Risk of Cardiovascular Disease Events in Patients From the Swiss HIV Cohort Study.

Background:Patients with HIV exposed to the antiretroviral drug abacavir may have an increased risk of cardiovascular disease (CVD). There is concern that this association arises because of a channeling bias. Even if exposure is a risk, it is not clear how that risk changes as exposure cumulates. Methods:We assess the effect of exposure to abacavir on the risk of CVD events in the Swiss HIV Cohort Study. We use a new marginal structural Cox model to estimate the effect of abacavir as a flexible function of past exposures while accounting for risk factors that potentially lie on a causal pathway between exposure to abacavir and CVD. Results:A total of 11,856 patients were followed for a median of 6.6 years; 365 patients had a CVD event (4.6 events per 1000 patient-years). In a conventional Cox model, recent—but not cumulative—exposure to abacavir increased the risk of a CVD event. In the new marginal structural Cox model, continued exposure to abacavir during the past 4 years increased the risk of a CVD event (hazard ratio = 2.06; 95% confidence interval: 1.43 to 2.98). The estimated function for the effect of past exposures suggests that exposure during the past 6–36 months caused the greatest increase in risk. Conclusions:Abacavir increases the risk of a CVD event: the effect of exposure is not immediate, rather the risk increases as exposure cumulates over the past few years. This gradual increase in risk is not consistent with a rapidly acting mechanism, such as acute inflammation.

Associations of education with 30 year life course blood pressure trajectories: Framingham Offspring Study

BackgroundEducation is inversely associated with cardiovascular disease incidence in developed countries. Blood pressure may be an explanatory biological mechanism. However few studies have investigated educational gradients in longitudinal blood pressure trajectories, particularly over substantial proportions of the life course. Study objectives were to determine whether low education was associated with increased blood pressure from multiple longitudinal assessments over 30 years. Furthermore, we aimed to separate antecedent effects of education, and other related factors, that might have caused baseline differences in blood pressure, from potential long-term effects of education on post-baseline blood pressure changes.MethodsThe study examined 3890 participants of the Framingham Offspring Study (mean age 36.7 years, 52.0% females at baseline) from 1971 through 2001 at up to 7 separate examinations using multivariable mixed linear models.ResultsMixed linear models demonstrated that mean systolic blood pressure (SBP) over 30 years was higher for participants with ≤12 vs. ≥17 years education after adjusting for age (3.26 mmHg, 95% CI: 1.46, 5.05 in females, 2.26 mmHg, 95% CI: 0.87, 3.66 in males). Further adjustment for conventional covariates (antihypertensive medication, smoking, body mass index and alcohol) reduced differences in females and males (2.86, 95% CI: 1.13, 4.59, and 1.25, 95% CI: -0.16, 2.66 mmHg, respectively). Additional analyses adjusted for baseline SBP, to evaluate if there may be educational contributions to post-baseline SBP. In analyses adjusted for age and baseline SBP, females with ≤12 years education had 2.69 (95% CI: 1.09, 4.30) mmHg higher SBP over follow-up compared with ≥17 years education. Further adjustment for aforementioned covariates slightly reduced effect strength (2.53 mmHg, 95% CI: 0.93, 4.14). Associations were weaker in males, where those with ≤12 years education had 1.20 (95% CI: -0.07, 2.46) mmHg higher SBP over follow-up compared to males with ≥17 years of education, after adjustment for age and baseline blood pressure; effects were substantially reduced after adjusting for aforementioned covariates (0.34 mmHg, 95% CI: -0.90, 1.68). Sex-by-education interaction was marginally significant (p = 0.046).ConclusionEducation was inversely associated with higher systolic blood pressure throughout a 30-year life course span, and associations may be stronger in females than males.

Flexible Marginal Structural Models for Estimating the Cumulative Effect of a Time-Dependent Treatment on the Hazard: Reassessing the Cardiovascular Risks of Didanosine Treatment in the Swiss HIV Cohort Study

The association between antiretroviral treatment and cardiovascular disease (CVD) risk in HIV-positive persons has been the subject of much debate since the Data collection on Adverse events of Anti-HIV Drugs (D:A:D) study reported that recent use of two antiretroviral drugs, abacavir (ABC) and didanosine (DDI), was associated with increased risk. We focus on the potential impact of DDI use, as this drug has not been as studied intensively as ABC. We propose a flexible marginal structural Cox model with weighted cumulative exposure modeling (Cox WCE MSM) to address two key challenges encountered when using observational longitudinal data to assess the adverse effects of medication: (1) the need to model the cumulative effect of a time-dependent treatment and (2) the need to control for time-dependent confounders that also act as mediators of the effect of past treatment. Simulations confirm that the Cox WCE MSM yields accurate estimates of the causal treatment effect given complex exposure effects and time-dependent confounding. We then use the new flexible Cox WCE MSM to assess the association between DDI use and CVD risk in the Swiss HIV Cohort Study. In contrast to the nonsignificant results obtained with conventional parametric Cox MSMs, our new Cox WCE MSM identifies a significant short-term risk increase due to DDI use in the previous year. Supplementary materials for this article are available online.

Sex Differences in Blood Pressure and Its Relationship to Body Composition and Metabolism in Adolescence

OBJECTIVESnTo investigate during adolescence (1) sex differences in blood pressure (BP) and hemodynamic factors at rest and during physical and mental challenges and (2) whether these differences are mediated by body composition and glucose and lipid metabolism.nnnDESIGNnCross-sectional study of a population-based cohort.nnnSETTINGnSaguenay Youth Study, Quebec, Canada, from November 2003 to June 2007.nnnPARTICIPANTSnA total of 425 adolescents (225 girls aged 12-18 years).nnnOUTCOME MEASURESnSystolic and diastolic BP measured using a Finometer. Secondary outcome measures were (1) hemodynamic parameters also measured with a Finometer, (2) body composition assessed with magnetic resonance imaging, bioimpedance, and anthropometry, and (3) metabolic indices determined from a fasting blood sample.nnnRESULTSnGirls vs boys demonstrated lower systolic and diastolic BP at rest and during challenges, with the differences being greatest during a math-stress test (adjusted difference, 7 mm Hg; 95% confidence interval [CI], 4-10 mm Hg and adjusted difference, 6 mm Hg; 95% CI, 4-8 mm Hg, respectively). The differences were mainly due to girls vs boys having lower stroke volume while lying down, standing (adjusted difference, 4 mL; 95% CI, 1-7 mL), and sitting, and lower total peripheral resistance during the math-stress test (adjusted difference, 0.14 mm Hg . s/mL; 95% CI, 0.09-0.21 mm Hg . s/mL). Intra-abdominal fat was positively associated with BP, but less in girls than in boys, and fat-free mass, fat mass, and insulin resistance were also positively associated with BP, similarly in boys and girls.nnnCONCLUSIONSnIn adolescence, BP is lower in girls than boys, with the difference being determined mainly by lower stroke volume during physical challenges and by lower total peripheral resistance during mental challenges. Body composition and insulin resistance contribute to these differences.

Comparison of Approaches to Weight Truncation for Marginal Structural Cox Models

Abstract Marginal structural Cox Models (Cox MSMs) have been used to estimate the causal effect of a time-varying treatment on the hazard when there exist time-dependent confounders, which are themselves also affected by previous treatment. A Cox MSM can be estimated via the inverse-probability-of-treatment weighting (IPTW) estimator. However, IPTW estimators suffer from large variability if some observations are assigned extremely high weights. Weight truncation has been proposed as one simple solution to this problem, but truncation levels are typically chosen based on ad hoc criteria that have not been systematically evaluated. Bembom et al. proposed data-adaptive selection of the optimal truncation level using the estimated mean-squared error (MSE) of a truncated IPTW estimator for cross-sectional data. Based on a similar principle, we proposed data-adaptive approaches to select the truncation level that minimizes the expected MSE for time-to-event data with time-varying treatments. The expected MSE is approximated by using either observed statistics as a proxy for the true unknown parameter or using cross-validation. Simulations confirm that simple weight truncation at high percentiles such as the 99th or 99.5th of the distribution of weights improves the IPTW estimators in most scenarios we considered. Our newly proposed approaches exhibit similarly good performance and may be applied in a wide range of settings.

Consultation with cardiologists for persons with new-onset chronic heart failure: A population-based study

BACKGROUNDnIt is recommended that persons recently diagnosed with heart failure consult with a specialist in heart failure.nnnOBJECTIVESnTo determine whether patients who were diagnosed with new-onset chronic heart failure (CHF) by a noncardiologist consulted with a cardiologist, and identify the factors associated with delayed consultation.nnnMETHODSnPhysician reimbursement administrative data were obtained for all adults with suspected new-onset CHF in the year 2000 in Quebec, defined operationally as a physician visit for CHF (based on the International Classification of Diseases, 9th Revision diagnostic codes), with no previous physician visit code for CHF in the preceding three years. Among those first diagnosed by a noncardiologist, Cox regression modelling was used to identify patient and physician characteristics associated with time to cardiology consultation.nnnRESULTSnOf the 13,523 persons coded as having incident CHF, 54.9% consulted a cardiologist within the next 2.5 to 3.5 years, and 67.4% were seen by an internist or cardiologist. Older patients, women, and those with lower comorbidity and socioeconomic status had significantly longer times to cardiology consultation.nnnCONCLUSIONnThe data suggest that many patients with suspected new-onset CHF do not receive prompt cardiology care, as stipulated by current recommendations. Equity of access for women and those with lower socioeconomic status appears to be problematic.