Lisa Aronson Friedman

Metabolic Syndrome in Childhood Predicts Adult Metabolic Syndrome and Type 2 Diabetes Mellitus 25 to 30 Years Later

OBJECTIVE To prospectively assess the association of the metabolic syndrome in childhood with adult metabolic syndrome and type 2 diabetes mellitus (T2DM) 25 to 30 years later. STUDY DESIGN Data from the National Heart Lung and Blood Institute Lipid Research Clinics (LRC) Princeton Prevalence Study (1973-1976) and the Princeton Follow-up Study (PFS, 2000-2004) were used. Body mass index (BMI = kg/m(2)) was used as the obesity measure in childhood because waist circumference was not measured at the LRC. The adult T2DM status of participants and their parents was obtained by participant report or fasting blood glucose >/=126 mg/dL. A logistic analysis for clustered samples was used to predict adult metabolic syndrome and T2DM, taking into account sibling correlations in the cohort. Pediatric metabolic syndrome, age at PFS, sex, race, change in BMI percentile, parental history of diabetes, and the interaction of pediatric metabolic syndrome and parental diabetes were explanatory variables. RESULTS Ages ranged from 5 to 19 years in the LRC and from 30 to 48 years in the PFS. Pediatric metabolic syndrome, parental diabetes, age at follow-up, and change in age-specific BMI percentile were significant predictors of metabolic syndrome in adulthood, and pediatric metabolic syndrome, age at follow-up, black race, and parental diabetes were significant predictors of T2DM. CONCLUSIONS Evaluating 5- to 19-year-old children for metabolic syndrome and family history of diabetes could identify children at increased risk of adult metabolic syndrome and T2DM, allowing prospective primary prevention of these outcomes.

Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study.

OBJECTIVE. The goal was to assess the association of metabolic syndrome in childhood with adult cardiovascular disease 25 years later. METHODS. Data from the National Heart, Lung, and Blood Institute Lipid Research Clinics Princeton Prevalence Study (1973–1976) and the Princeton Follow-up Study (2000–2004) were used. BMI was used as the obesity measure in childhood, because waist circumference was not measured in the Lipid Research Clinics study. The adult cardiovascular disease status of participants and their parents was obtained through participant report. A logistic analysis was used to predict adult cardiovascular disease; pediatric metabolic syndrome, age at the Princeton Follow-up Study, gender, race, and parental history of cardiovascular disease were potential explanatory variables. RESULTS. Ages ranged from 6 to 19 years in the Lipid Research Clinics study and from 30 to 48 years in the Princeton Follow-up Study. There were 17 cases of cardiovascular disease in the analysis cohort in the Princeton Follow-up Study. Pediatric metabolic syndrome and age at follow-up assessment were significant predictors of cardiovascular disease. Pediatric metabolic syndrome and changes in age-specific BMI percentile from childhood to adulthood were significant predictors of adult metabolic syndrome. CONCLUSIONS. Evaluating children for metabolic syndrome could identify patients at increased risk of adult cardiovascular disease, making targeted interventions possible.

Measurement of steroid sex hormones in serum: a comparison of radioimmunoassay and mass spectrometry.

Concern has been raised about the adequacy of radioimmunoassays to measure steroid sex hormones in population studies. We compared steroid sex hormone measurements in serum by radioimmunoassay with mass spectrometry. Four male and four female serum pools with known relative concentrations of steroid sex hormones were measured multiple times by both methods. Because measurements are expected to increase linearly with concentration for each sex, we examined whether the linear regressions of hormone measurements on concentration were the same for radioimmunoassay and mass spectrometry. Estradiol, estrone, androstenedione, testosterone, and dehydroepiandrosterone sulfate were measured in female pools; testosterone, dihydrotestosterone, androstenedione, and dehydroepiandrosterone sulfate were measured in male pools. Regression slopes for radioimmunoassay and mass spectrometry measurements were comparable for all hormones except androstenedione, which had a steeper slope when measured by mass spectrometry (P < or = 0.02). Intercepts for radioimmunoassay and mass spectrometry were similar and close to zero for estradiol, androstenedione, dehydroepiandrosterone sulfate, and in male samples, testosterone. For testosterone in female samples, estrone, and dihydrotestosterone, radioimmunoassay and mass spectrometry intercepts differed significantly. Standard deviations of individual measurements by radioimmunoassay and mass spectrometry differed by hormone and serum concentration; neither method consistently measured hormone concentrations with less variability. Our findings suggest that although absolute concentrations may differ for some hormones, radioimmunoassay and mass spectrometry can yield similar estimates of between subject differences in serum concentrations of most steroid sex hormones commonly measured in population studies. Relative power of studies using radioimmunoassay and mass spectrometry will depend on the hormones measured and their serum concentrations.

Development of the metabolic syndrome in black and white adolescent girls : A longitudinal assessment

Background. The metabolic syndrome, associated with increased risk of type 2 diabetes mellitus and cardiovascular disease, begins to develop during adolescence. Objective. We sought to identify early predictors of the presence of the syndrome at the ages of 18 and 19 years in black and white girls. Methods. Using longitudinal data on participants from 2 centers in the National Heart, Lung, and Blood Institute Growth and Health Study, a 10-year cohort study, we applied cutoffs from the Adult Treatment Panel III to document changes in the prevalence of abnormal syndrome elements and the syndrome in girls aged 9 and 10 years, when cases were rare, and those aged 18 and 19 years, when prevalence had reached 3%. Longitudinal regression models identified early predictors for the presence of the syndrome. Results. Only 1 girl of each race had ≥3 factors at ages 9 and 10 (0.2%), but 20 black girls (3.5%) and 12 white girls (2.3%) had the syndrome 10 years later. Low high-density lipoprotein cholesterol was prevalent throughout the period in both black and white girls. The prevalence of other variables was low at enrollment but increased during follow-up, except for abnormal triglyceride levels in black girls, which remained low throughout follow-up. In multivariate models, early measures of waist circumference and triglyceride level were significant predictors for development of the syndrome. Conclusion. The strong association of central adiposity with the development of the metabolic syndrome suggests that early interventions aimed at managing preteen obesity could reduce risk of developing the syndrome.

Sensitivity and Specificity of Pediatric Lipid Determinations for Adult Lipid Status: Findings From the Princeton Lipid Research Clinics Prevalence Program Follow-up Study

OBJECTIVE. The goal was to determine the diagnostic utility of the National Cholesterol Education Program pediatric guidelines. METHODS. With the use of pediatric lipid data from the Cincinnati Clinic of the Lipid Research Clinics Prevalence Study and lipid and cardiovascular disease data collected for the same subjects as adults in the Princeton Follow-up Study, the sensitivity and specificity of the National Cholesterol Education Program pediatric guidelines were calculated overall and according to age. Furthermore, whether use of parental cardiovascular disease history during childhood influenced the sensitivity and specificity was assessed. RESULTS. Overall sensitivities were 43% to 46% and specificities were 82% to 86% for total and low-density lipoprotein cholesterol levels. There was considerable variation in sensitivities according to age, with the lowest sensitivities at ages 14 to 16 years and the highest sensitivities at ages 5 to 10 years and 17 to 19 years. Results were similar whether or not the population was restricted to children with a positive parental history of cardiovascular disease. CONCLUSIONS. Results of our analyses suggest that the sensitivity and specificity for evaluating total cholesterol or low-density lipoprotein cholesterol levels that are elevated in adulthood are not improved by selecting children with a positive parental history. These data also show the strong role that age (particularly the pubertal years between 10 and 15 years of age) plays in lipid measurements for children and adolescents. Continued prospective and longitudinal studies designed with age as well as other risk parameters are needed to determine the best guidelines for clinical screening in the future.

Children's Adaptations to a Fat-Reduced Diet: The Dietary Intervention Study in Children (DISC)

Background. Prevention of cardiovascular disease through diet and lifestyle change is strongly advocated in adults and is initiated preferably during childhood. The Dietary Intervention Study in Children (DISC) was a multicenter, collaborative, randomized trial in 663 preadolescent children (363 boys and 301 girls) with elevated low-density lipoprotein cholesterol, designed to test the efficacy and safety of a dietary intervention to lower saturated-fat and cholesterol intake while also advocating a healthy eating pattern. DISC results have been published extensively. This ancillary study reports new data regarding changes in eating patterns among this cohort. Objective. We set out to compare childrens self-selected eating patterns and approaches to achieving adherence to the DISC fat-reduced diet intervention with children in the usual-care group. Methods. An ancillary study was conducted to develop a detailed food-grouping system and report new analyses on dietary adherence to the recommended eating pattern. Every food in the nutrient database was ranked by its saturated-fat and cholesterol content and classified within its relevant food group as a “go” (less atherogenic) or “whoa” (more atherogenic) food. Results. At baseline, go foods contributed ∼57% of total energy intake and 12.4% to 13.1% total fat energy intake in both groups. At 3 years, go foods contributed 67.4% and 13.7% of total and fat energy intake, respectively, in the intervention group versus 56.8% and 12.8% in the usual-care group. Differences between the 2 treatment groups were significant for changes in consumption of dairy foods, desserts, and fats/oils, with the intervention group reporting a 0.2- to 0.3-serving-per-day greater increase in go foods than the usual-care group. The intervention group also reported a 0.2- to 0.8-serving-per-day greater decrease in whoa foods than the usual-care group for breads/grains, dairy, fats/oils, meat/fish/poultry, snacks, and vegetables. Overall, snack foods, desserts, and pizza contributed approximately one third of total daily energy intake in both groups at 3 years. Conclusions. Children in the intervention group reported consuming more servings per day of go grains, dairy, meats, and vegetable foods compared with children in the usual-care group, but intake of fruits and vegetables was low in both groups. Discovering that snacks, desserts, and pizza actively contribute so heavily to the diets of this age group, even among children who were part of this intervention, offers valuable insights regarding the need for more aggressive, innovative, and realistic approaches for additional dietary counseling.

Effects of Diet and Sexual Maturation on Low-Density Lipoprotein Cholesterol During Puberty The Dietary Intervention Study in Children (DISC)

BACKGROUND The Dietary Intervention Study in Children (DISC) is a multicenter, randomized, controlled clinical trial designed to examine the efficacy and safety of a dietary intervention to reduce serum LDL cholesterol (LDL-C) in children with elevated LDL-C. METHODS AND RESULTS The effects of dietary intake of fat and cholesterol and of sexual maturation and body mass index (BMI) on LDL-C were examined in a 3-year longitudinal study of 663 boys and girls (age 8 to 10 years at baseline) with elevated LDL-C levels. Multiple linear regression was used to predict LDL-C at 3 years. For boys, LDL-C decreased by 0.018 mmol/L for each 10 mg/4.2 MJ decrease in dietary cholesterol (P<.05). For girls, no single nutrient was significant in the model, but a treatment group effect was evident (P<.05). In both sexes, BMI at 3 years and LDL-C at baseline were significant and positive predictors of LDL-C levels. In boys, the average LDL-C level was 0.603 mmol/L lower at Tanner stage 4+ than at Tanner stage 1 (P<.01). In girls, the average LDL-C level was 0.274 mmol/L lower at Tanner stage 4+ than at Tanner stage 1 (P<.05). CONCLUSIONS In pubertal children, sexual maturation, BMI, dietary intervention (in girls), and dietary cholesterol (in boys) were significant in determining LDL-C. Sexual maturation was the factor associated with the greatest difference in LDL-C. Clinicians screening for dyslipidemia or following dyslipidemic children should be aware of the powerful effects of pubertal change on measurements of lipoproteins.

BP Control and Left Ventricular Hypertrophy Regression in Children with CKD

In adult patients with CKD, hypertension is linked to the development of left ventricular hypertrophy, but whether this association exists in children with CKD has not been determined conclusively. To assess the relationship between BP and left ventricular hypertrophy, we prospectively analyzed data from the Chronic Kidney Disease in Children cohort. In total, 478 subjects were enrolled, and 435, 321, and 142 subjects remained enrolled at years 1, 3, and 5, respectively. Echocardiograms were obtained 1 year after study entry and then every 2 years; BP was measured annually. A linear mixed model was used to assess the effect of BP on left ventricular mass index, which was measured at three different visits, and a mixed logistic model was used to assess left ventricular hypertrophy. These models were part of a joint longitudinal and survival model to adjust for informative dropout. Predictors of left ventricular mass index included systolic BP, anemia, and use of antihypertensive medications other than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Predictors of left ventricular hypertrophy included systolic BP, female sex, anemia, and use of other antihypertensive medications. Over 4 years, the adjusted prevalence of left ventricular hypertrophy decreased from 15.3% to 12.6% in a systolic BP model and from 15.1% to 12.6% in a diastolic BP model. These results indicate that a decline in BP may predict a decline in left ventricular hypertrophy in children with CKD and suggest additional factors that warrant additional investigation as predictors of left ventricular hypertrophy in these patients.

Muscle Weakness and 5-Year Survival in Acute Respiratory Distress Syndrome Survivors.

Objectives: To longitudinally evaluate the association of post-ICU muscle weakness and associated trajectories of weakness over time with 5-year survival. Design: Longitudinal prospective cohort study over 5 years of follow-up. Setting: Thirteen ICUs in four hospitals in Baltimore, MD. Patients: One hundred fifty-six acute respiratory distress syndrome survivors. Interventions: None. Measurements and Main Results: Strength was evaluated with standardized manual muscle testing using the Medical Research Council sum score (range, 0–60; higher is better), with post-ICU weakness defined as sum score less than 48. Muscle strength was assessed at hospital discharge and at 3, 6, 12, 24, 36, and 48 months after acute respiratory distress syndrome. At discharge, 38% of patients had muscle weakness. Every one point increase in sum score at discharge was associated with improved survival (hazard ratio [95% CI], 0.96 [0.94–0.98]), with similar findings longitudinally (0.95 [0.93–0.98]). Having weakness at discharge was associated with worse 5-year survival (1.75 [1.01–3.03]), but the association was attenuated (1.54 [0.82–2.89]) when evaluated longitudinally over follow-up. Persisting and resolving trajectories of muscle weakness, occurring in 50% of patients during follow-up, were associated with worse survival (3.01 [1.12-8.04]; and 3.14 [1.40-7.03], respectively) compared to a trajectory of maintaining no muscle weakness. Conclusions: At hospital discharge, greater than one third of acute respiratory distress syndrome survivors had muscle weakness. Greater strength at discharge and throughout follow-up was associated with improved 5-year survival. In patients with post-ICU weakness, both persisting and resolving trajectories were commonly experienced and associated with worse survival during follow-up.

Evaluating Physical Outcomes in Acute Respiratory Distress Syndrome Survivors: Validity, Responsiveness, and Minimal Important Difference of 4-Meter Gait Speed Test.

Objective:To examine the reliability, validity, responsiveness, and minimal important difference of the 4-m gait speed test in acute respiratory distress syndrome survivors. Design:Secondary analyses of data from two longitudinal follow-up studies of acute respiratory distress syndrome survivors. Test-retest and inter-rater reliability, construct validity (convergent, discriminant, and known group), predictive validity, and responsiveness were examined. The minimal important difference was estimated using anchor- and distribution-based approaches. Setting:A national multicenter prospective study (ARDSNet Long-Term Outcome Study) and a multisite prospective study in Baltimore, MD (Improving Care of Acute Lung Injury Patients). Patients:Acute respiratory distress syndrome survivors with 4-m gait speed assessment up to 60 months after acute respiratory distress syndrome (ARDSNet Long-Term Outcome Study, n = 184; Improving Care of Acute Lung Injury Patients, n = 122). Interventions:Not applicable. Measurements and Main Results:Four-meter gait speed was assessed at 6- and 12-month follow-up (ARDSNet Long-Term Outcome Study) and 36-, 48-, and 60-month follow-up (Improving Care of Acute Lung Injury Patients). Excellent test-retest (intraclass correlation, 0.89–0.99 across studies and follow-up) and inter-rater (intraclass correlation, 0.97) reliability were found. Convergent validity was supported by moderate-to-strong correlations (69% of 32 > 0.40) with other physical function measures. Discriminant validity was supported by weak correlations (86% of 28 < 0.30) with mental health measures. Survivors with impaired versus nonimpaired measures of muscle strength and pulmonary function had significantly slower 4-m gait speed (all but one p < 0.05). Furthermore, 4-m gait speed significantly predicted future hospitalization and health-related quality of life. Gait speed changes were consistent with reported changes in function, supporting responsiveness. The estimated 4-m gait speed minimal important difference was 0.03–0.06 m/s. Conclusions:The 4-m gait speed is a reliable, valid, and responsive measure of physical function in acute respiratory distress syndrome survivors. The estimated minimal important difference will facilitate sample size calculations for clinical studies evaluating the 4-m gait speed test in acute respiratory distress syndrome survivors.