Study design and participants
The BHS is a series of long-term studies begun in 1973 focusing on understanding the early natural history of CVD since childhood [12]. Between 1973 and 2016, 9 cross-sectional surveys of children aged 3 to 18 years and 11 surveys of adults aged 19 to 58 years, who had been previously examined as children were conducted in the semirural biracial (65% white and 35% black) community of Bogalusa, Louisiana. This panel design of repeated cross-sectional examinations conducted approximately every 3 to 4 years, resulted in serial observations from childhood to adulthood. Participants who had a baseline examination during childhood and underwent a follow-up examination as an adult were included in the present analysis. Children with underweight (BMI < 5th percentile), diabetes, or having a follow-up period < 5 years were excluded. A total of 3,351 children (2,126 whites and 1,225 blacks; 46.6% male; age 4–18 years at baseline) who had been examined for BMI, systolic/diastolic blood pressure (BP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and fasting plasma glucose (FPG) at least once in childhood (baseline) and at least once in adulthood (follow-up) were included in the analysis exploring the association of childhood obesity/metabolic phenotypes and shifts in obesity/metabolic phenotypes from childhood to adulthood with diabetes risk in adulthood. Among these participants, 1,639 adults (44.2% men; age 24–57 years at follow up) had echocardiography conducted to measure left ventricular hypertrophy (LVH) and thus were included in the analysis exploring the association of shifts in obesity/metabolic phenotypes from childhood to adulthood with LVH risk in adulthood. There was no difference in the baseline characteristics between children who had and did not have adult echocardiography measurements (data not shown).
Written informed consent was obtained from parents or guardians in childhood and from the participants themselves in adulthood. Study protocols were approved by the Institutional Review Board of the Tulane University Health Sciences Center in accordance with the principles of the Declaration of Helsinki as revised in 2008.
Clinical measurements
All participants in each survey were asked to complete a structured questionnaire which collected information on demographics, parental history of diabetes, medical history and use of medications, and smoking and drinking habits.
Standardized protocols were followed by trained and certified personnel across all surveys. Participants were instructed to fast for 12 hours before the screening. For each participant, replicate measurements of height and weight were obtained, and the mean values were used for analysis. BMI was calculated as weight in kilograms divided by height in meters squared. BP was measured between 8:00 AM and 10:00 AM on the right arm with appropriate cuff in a relaxed sitting position by 2 trained technicians (triplicate each), using calibrated mercury sphygmomanometers. The 6 readings were averaged. For both children and adults, the first Korotkoff phase was used for systolic BP; The fifth Korotkoff (K5) phase was used for diastolic BP. Diastolic BP at the fourth Korotkoff (K4) phase was also recorded for all children. For children with the K5 being very low (< 20 mm Hg), the K4 was used as diastolic BP [13].
Biochemical laboratory measurements
Between 1973 and 1986, total cholesterol (TC) and TG were determined with Technicon Auto Analyzer II (Technicon Instrument Corp, Tarrytown, NY) according to the laboratory manual of the Lipid Research Clinics Program. From 1987, these variables were measured using an Abbott VP instrument (Abbott Laboratories, Abbott Park, Ill) by enzymatic procedures. Both chemical and enzymatic procedures met the performance requirements of the Lipid Standardization Program of the Centers for Disease Control and Prevention (CDC). Measurements on CDC-assigned quality control samples showed no consistent bias over time within or between surveys. Serum lipoprotein cholesterols were analyzed by using a combination of heparin-calcium precipitation and agar-agarose gel electrophoresis procedures. Between 1978 and 1991, FPG was determined with a glucose oxidase method using a Beckman glucose analyzer (Beckman Instruments, Fullerton, CA). Since 1992, FPG has been measured enzymatically as part of a multi-chemistry profile.
Echocardiography
Left ventricular mass (LVM) was measured by 2-dimensional M-mode echocardiography with 2.25- and 3.5-MHz transducers following American Society of Echocardiography recommendations [14]. Parasternal long- and short-axis views were used for measuring LV end-diastolic and end-systolic measurements in duplicate, and the mean was calculated. LVM was calculated from a necropsy-validated formula on the basis of a thick-wall prolate ellipsoidal geometry [15]. The index of LVM to height2.7 (g/m 2.7) (LVMI) was used to adjust for body size.
Classification of adiposity and metabolic status in childhood and adulthood
For the definition of childhood weight status, BMI percentile for age and sex was calculated according to CDC reference charts. Children with BMI ≥ 85th but < 95th percentile were classified as overweight, and those ≥ 95th percentile as obese. Weight status in children were also defined using the BMI cut off points recommended by the World Health Organization (WHO). In adulthood, overweight was defined as BMI between 25 and 29.9 kg/m2 and obesity as BMI ≥ 30 kg/m2.
In the consensus criteria suggested by Damanhoury et al. [5]. childhood metabolic status (metabolically healthy, no risk factor, and metabolically unhealthy, one or more risk factors) was based on the following four cardiovascular risk factors: systolic/diastolic BP ≥ 90th percentile for sex, age, and height using the 2004 child BP Tables, TG ≥ 150 mg/dL, HDL-C < 40 mg/dL, and FPG ≥ 100 mg/dL. In the harmonized definition suggested by Lavie et al.[4]. adulthood metabolic status (metabolically healthy, no risk factor, and metabolically unhealthy, one or more risk factors) was based on the following four cardiovascular risk factors: systolic/diastolic BP ≥ 130/85 mmHg or using antihypertensive drugs, TG ≥ 150 mg/dL, HDL-C < 40 mg/dL in men and < 50 mg/dL in women, and FPG ≥ 100 mg/dL or using antidiabetic drugs.
According to their BMI and metabolic status, both children and adults were divided into four body size phenotypes according to harmonized definitions [4, 5]: MHNW defined as normal weight/overweight and heathy metabolic status, MUNW defined as normal weight/overweight and unhealthy metabolic status, MHO defined as obesity and heathy metabolic status, MAO defined as obesity and unhealthy metabolic status.
Definition of study outcomes
Diabetes in adulthood was defined based on FPG ≥ 7.0 mmol/L (126 mg/dL) or use of insulin or oral antidiabetic medications [16]. In a sensitivity analysis, diabetes was also defined based on FPG ≥ 7.0 mmol/l or HbA1c ≥ 6.5% (48mmol/mol) or use of insulin or oral antidiabetic medications [16]. LVH in adulthood was defined as LVMI > 46.7 g/m2.7 in women and > 49.2 g/m2.7 in men [17].
Statistical Analysis
All statistical analyses were performed with SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). The differences in baseline and follow-up variables between groups were tested using generalized linear models (for continuous) and χ2 or Fisher exact tests (for categorical). Bonferroni correction was applied to adjust P values for multiple comparisons. Poisson regression with robust errors variance were used to examine the associations of childhood body size phenotypes with adult cardiometabolic outcomes. Four models were applied: Model 1 was unadjusted; Model 2 was adjusted for baseline age, sex, race, and follow-up year; Model 3 was further adjusted for baseline LDL-cholesterol; Model 4 was additionally adjusted for parental history of diabetes, smoking and drinking status, and use of anti-diabetic, anti-hypertensive and lipid-lowering agents. We chose these covariates because of their significant correlations with body size phenotypes or as relevant factors associated with outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by using logistic regression models to examine the associations between child-adult body size phenotypes and cardiometabolic outcomes in adulthood. Significance was accepted at a two-tailed P < 0.05.