Trudy L. Burns

Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: The muscatine study

OBJECTIVES This study was designed to estimate the prevalence of coronary artery calcification in young adult men and women and to examine the association between the presence of coronary artery calcification and coronary risk factors measured in childhood and young adult life. BACKGROUND Electron beam computed tomography is a sensitive, noninvasive method for detecting coronary artery calcification, a marker of the atherosclerotic process. Coronary artery calcification is associated with coronary risk factors in older adults. METHODS Subjects (197 men, 187 women) had coronary risk factors measured in childhood (mean age 15 years) and twice during young adult life (mean ages 27 and 33 years). Each underwent an electron beam computed tomographic study at their second young adult examination. RESULTS The prevalence of coronary artery calcification was 31% in men and 10% in women. Increased body size, increased blood pressure and decreased high density lipoprotein (HDL) cholesterol levels were the coronary risk factors that showed the strongest association with coronary artery calcification. Significant odds ratios for coronary artery calcification, using standardized risk factor measurements at a mean age of 33 years in men and women, respectively, were 6.4 and 13.6 for the highest decile of body mass index, 6.4 and 6.4 for the highest decile of systolic blood pressure and 4.3 and 4.7 for the lowest decile of HDL cholesterol. CONCLUSIONS Coronary artery calcification is more prevalent in men in this young adult population. Coronary risk factors measured in children and young adults are associated with the early development of coronary artery calcification. Increased body mass index measured during childhood and young adult life and increased blood pressure and decreased HDL cholesterol levels measured during young adult life are associated with the presence of coronary artery calcification in young adults.

Automated 3-D Intraretinal Layer Segmentation of Macular Spectral-Domain Optical Coherence Tomography Images

With the introduction of spectral-domain optical coherence tomography (OCT), much larger image datasets are routinely acquired compared to what was possible using the previous generation of time-domain OCT. Thus, the need for 3-D segmentation methods for processing such data is becoming increasingly important. We report a graph-theoretic segmentation method for the simultaneous segmentation of multiple 3-D surfaces that is guaranteed to be optimal with respect to the cost function and that is directly applicable to the segmentation of 3-D spectral OCT image data. We present two extensions to the general layered graph segmentation method: the ability to incorporate varying feasibility constraints and the ability to incorporate true regional information. Appropriate feasibility constraints and cost functions were learned from a training set of 13 spectral-domain OCT images from 13 subjects. After training, our approach was tested on a test set of 28 images from 14 subjects. An overall mean unsigned border positioning error of 5.69 plusmn 2.41 mum was achieved when segmenting seven surfaces (six layers) and using the average of the manual tracings of two ophthalmologists as the reference standard. This result is very comparable to the measured interobserver variability of 5.71 plusmn 1.98 mum.

Bone Mineral Density and Its Change in White Women: Estrogen and Vitamin D Receptor Genotypes and Their Interaction

Low bone mineral density (BMD) is a major risk factor for development of osteoporosis; increasing evidence suggests that attainment and maintenance of peak bone mass as well as bone turnover and bone loss have strong genetic determinants. We examined the association of BMD levels and their change over a 3‐year period, and polymorphisms of the estrogen receptor (ER), vitamin D receptor (VDR), type I collagen, osteonectin, osteopontin, and osteocalcin genes in pre‐ and perimenopausal women who were part of the Michigan Bone Health Study, a population‐based longitudinal study of BMD. Body composition measurements, reproductive hormone profiles, bone‐related serum protein measurements, and life‐style characteristics were also available on each woman. Based on evaluation of women, ER genotypes (identified by PvuII [n = 253] and XbaI [n = 248]) were significantly predictive of both lumbar spine (p < 0.05) and total body BMD level, but not their change over the 3‐year period examined. The VDR BsmI restriction fragment length polymorphism was not associated with baseline BMD, change in BMD over time, or any of the bone‐related serum and body composition measurements in the 372 women in whom it was evaluated. Likewise, none of the other polymorphic markers was associated with BMD measurements. However, we identified a significant gene × gene interaction effect (p < 0.05) for the VDR locus and PvuII (p < 0.005) and XbaI (p < 0.05) polymorphisms, which impacted BMD levels. Women who had the (−/−) PvuII ER and bb VDR genotype combination had a very high average BMD, while individuals with the (−/−) PvuII ER and BB VDR genotype had significantly lower BMD levels. This contrast was not explained by differences in serum levels of osteocalcin, parathyroid hormone, 1,25‐dihydroxyvitamin D, or 25‐dihydroxyvitamin D. These data suggest that genetic variation at the ER locus, singly and in relation to the vitamin D receptor gene, influences attainment and maintenance of peak bone mass in younger women, which in turn may render some individuals more susceptible to osteoporosis than others.

Influence of Age on Associations Between Childhood Risk Factors and Carotid Intima-Media Thickness in Adulthood The Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium

Background— Atherosclerosis has its roots in childhood. Therefore, defining the age when childhood risk exposure begins to relate to adult atherosclerosis may have implications for pediatric cardiovascular disease prevention and provide insights about the early determinants of atherosclerosis development. The aim of this study was to investigate the influence of age on the associations between childhood risk factors and carotid artery intima-media thickness, a marker of subclinical atherosclerosis. Methods and Results— We used data for 4380 members of 4 prospective cohorts—Cardiovascular Risk in Young Finns Study (Finland), Childhood Determinants of Adult Health study (Australia), Bogalusa Heart Study (United States), and Muscatine Study (United States)—that have collected cardiovascular risk factor data from childhood (age 3 to 18 years) and performed intima-media thickness measurements in adulthood (age 20 to 45 years). The number of childhood risk factors (high [highest quintile] total cholesterol, triglycerides, blood pressure, and body mass index) was predictive of elevated intima-media thickness (highest decile) on the basis of risk factors measured at age 9 years (odds ratio [95% confidence interval] 1.37 [1.16 to 1.61], P =0.0003), 12 years (1.48 [1.28 to 1.72], P <0.0001), 15 years (1.56 [1.36 to 1.78], P <0.0001), and 18 years (1.57 [1.31 to 1.87], P <0.0001). The associations with risk factors measured at age 3 years (1.17 [0.80 to 1.71], P =0.42) and 6 years (1.20 [0.96 to 1.51], P =0.13) were weaker and nonsignificant. Conclusions— Our analyses from 4 longitudinal cohorts showed that the strength of the associations between childhood risk factors and carotid intima-media thickness is dependent on childhood age. On the basis of these data, risk factor measurements obtained at or after 9 years of age are predictive of subclinical atherosclerosis in adulthood. # Clinical Perspective {#article-title-31}

Candidate genes for nonsyndromic cleft lip and palate and maternal cigarette smoking and alcohol consumption: evaluation of genotype-environment interactions from a population-based case-control study of orofacial clefts

Previous studies suggest that the relationship between genes and nonsyndromic cleft lip +/- cleft palate (CLP) or cleft palate only (CP) may be modified by the environment. Using data from a population-based case-control study, we examined allelic variants for three genes, i.e., transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), and Msh (Drosophila) homeobox homolog 1 (MSX1), and their interactions with two exposures during pregnancy (maternal cigarette smoking and alcohol consumption) as risk factors for CLP and CP. For each cleft phenotype, risk estimates associated with most allelic variants tended to be near unity. Risk estimates for maternal smoking (> or = 10 cigarettes/day) were significantly elevated for CP and were most elevated among infants with allelic variants at the TGFB3 or MSX1 sites. By comparison, risk estimates for maternal alcohol consumption (> or = 4 drinks/month) were significantly elevated for CLP and were most elevated among infants with allelic variants at the MSX1 site. Our results suggest that development of CLP and CP may be influenced independently by maternal exposures but more significantly by interaction of such exposures and specific allelic variants.

Urinary incontinence and Depression in middle-aged United States women

OBJECTIVE: To determine the correlates of incontinence in middle‐aged women and to test for an association between incontinence and depression. METHODS: This was a population‐based cross‐sectional study of 5701 women who were residents of the United States, aged 50‐69 years, and participated in the third interview of the Health and Retirement Study. The primary outcome measure was self‐reported urinary incontinence. Depression was ascertained based on criteria set by the Diagnostic and Statistical Manual of Mental Disorders, using a short form of the Composite International Diagnostic Interview. In addition, depressive symptoms were assessed using the revised Center for Epidemiologic Studies Depression Scale. Multivariable logistic regression models were constructed to determine the independent association between incontinence and depression, after adjusting for confounders. RESULTS: Approximately 16% reported either mild‐moderate or severe incontinence. Depression, race, age, body mass index, medical comorbidities, and limited activities of daily living were associated with incontinence. After adjusting for medical morbidity, functional status, and demographic variables, women with severe and mild‐moderate incontinence were 80% (odds ratio [OR] 1.82; 95% confidence interval [CI] 1.26, 2.63) and 40% (OR 1.41; 95% CI 1.06, 1.87) more likely, respectively, to have depression than continent women. The association did not hold for depressive symptoms measured by the revised Center for Epidemiologic Studies Depression Scale after adjusting for covariates. CONCLUSION: Depression and incontinence are associated in middle‐aged women. The strength of the association depends on the instrument used to classify depression. This reinforces the need to screen patients presenting for treatment of urinary incontinence for depression. (Obstet Gynecol 2003;101:149‐56.

Sustained Effect of Early Physical Activity on Body Fat Mass in Older Children

BACKGROUND Physical activity is assumed to reduce excessive fatness in children. This study examined whether the benefits of early childhood moderate-to-vigorous physical activity (MVPA) on fatness are sustained throughout childhood. METHODS MVPA minutes per day (min/d) and fat mass (kilograms; kg) were measured using accelerometry and dual-energy x-ray absorptiometry in 333 children aged 5, 8, and 11 years who were participating in the Iowa Bone Development Study. Mixed regression models were used to test whether MVPA at age 5 years had an effect on fat mass at age 8 years and age 11 years, after adjustment for concurrent height, weight, age, maturity, and MVPA. The analysis was repeated to control for fat mass at age 5 years. Using mixed-model least-squares means, adjusted means of fat mass at age 8 years and age 11 years were compared between the highest and lowest quartiles of MVPA at age 5 years. Data were collected between 1998 and 2006 and analyzed in 2008. RESULTS For boys and girls, MVPA at age 5 years was a predictor of adjusted fat mass at age 8 years and age 11 years (p<0.05). In girls, the effect of MVPA at age 5 years was not significant when fat mass at age 5 years was included. Boys and girls in the highest quartile of MVPA at age 5 years had a lower fat mass at age 8 years and age 11 years than children in the lowest MVPA quartile at age 5 years (p<0.05; mean difference 0.85 kg at age 8 years and 1.55 kg at age 11 years). CONCLUSIONS Some effects of early-childhood MVPA on fatness appear to persist throughout childhood. Results indicate the potential importance of increasing MVPA in young children as a strategy to reduce later fat gains.

Maternal alcohol use and risk of orofacial cleft birth defects

Maternal alcohol use during pregnancy is a known cause of birth defects associated with the fetal alcohol syndrome, but its role in more common, isolated, craniofacial birth defects is not well understood. A population-based, case-control study of orofacial clefts was conducted in Iowa using births during 1987-1991. Cases were identified by the Iowa Birth Defects Registry and classified as having a cleft lip with or without cleft palate (CLP) or cleft palate only (CP) and whether the cleft was isolated or occurred with other birth defects. Controls were selected from normal Iowa births. Maternal alcohol use during pregnancy was classified according to self-reported drinks consumed per month. Results are based on 302 controls and the following numbers in each case group: 118 isolated CLP, 56 isolated CP, 51 CLP with multiple defects, and 62 CP with multiple defects. Compared to women who did not drink alcohol during pregnancy, the relative odds of isolated CLP rose with increasing level of maternal drinking as follows: 1-3 drinks per months, 1.5; 4-10 drinks per month, 3.1; more than 10 drinks per month, 4.7 (chi-square test for trend, P = 0.003). Adjustment for maternal smoking, vitamin use, education, and household income did not substantially alter these results. No significant association was found between alcohol use and isolated cleft palate or clefts in children with multiple birth defects. Alcohol use during pregnancy may be a cause of isolated cleft lip with or without cleft palate.

Genetic Markers, Bone Mineral Density, and Serum Osteocalcin Levels

We evaluated five genetic markers for products that contribute to skeletal mineralization including the Sp1 polymorphism for type I collagen Ai (COLIA1), the vitamin D receptor (VDR) translation initiation site polymorphism, the promoter of the osteocalcin gene containing a C/T polymorphism, the estrogen receptor (ER) gene containing a TA repeat, and the polymorphic (AGC)n site in the androgen receptor. These markers were evaluated for their potential relationship with bone mineral density (BMD), measured by dual‐energy X‐ray densitometry, or its 3‐year change. Additionally, potential associations of these genotypes and with baseline osteocalcin concentration or its 3‐year change (assessed using radioimmunoassay) were evaluated. The study was conducted in 261 pre‐ and perimenopausal women of the Michigan Bone Health Study, a population‐based longitudinal study of musculoskeletal characteristics and diseases. The polymorphic (AGC)n site in the androgen receptor showed a strong association with BMD of the femoral neck (FN) and lumbar spine and remained highly significant after adjusting for body mass index (BMI), oophorectomy/hysterectomy, oral contraceptive (OC) use and hormone replacement use (p < 0.001). The TA repeat at the 5′ end of the ER gene was associated with total body calcium (p < 0.05) after adjusting for BMI, oophorectomy and hysterectomy, and OC use. The frequency of oophorectomy and hysterectomy within selected genotypes explained much of the statistically significant association of the ER genotypes with BMD of the FN and spine. There was no association of measures of BMD or bone turnover with the Sp1 polymorphism for COLIA1, the VDR translation initiation site polymorphism, or the C/T promoter polymorphism of the osteocalcin gene. These findings suggest that sex hormone genes may be important contributors to the variation in BMD among pre‐ and perimenopausal women.

Early Physical Activity Provides Sustained Bone Health Benefits Later in Childhood

PURPOSE This study examined the potential effect of early childhood moderate and vigorous physical activity (MVPA) on later bone health. METHODS Three hundred and thirty-three children, participating in the Iowa Bone Development Study, were studied at ages 5, 8, and 11 yr. MVPA (min x d(-1)) was measured using an accelerometry-based physical activity monitor. Bone mineral content (BMC; g) of the whole body, lumbar spine, and hip was measured using dual-energy x-ray absorptiometry. Mixed regression models were used to test whether MVPA at age 5 yr had an effect on BMC at ages 8 and 11 yr after adjustment for concurrent height, weight, age, maturity, and MVPA. The analysis was repeated to control for bone outcomes at age 5 yr. Mixed-model least-squares mean values at the person level of covariates for age group were used to compare the BMC at ages 8 and 11 yr of children in the highest and lowest quartiles of MVPA at age 5 yr. RESULTS For boys and girls, MVPA at age 5 yr predicted BMC adjusted for concurrent height, weight, age, maturity, and MVPA at ages 8 and 11 yr (P < 0.05). When the analysis was repeated to also control for BMC at age 5 yr, the effect of MVPA at age 5 yr was significant for boys but not for girls. Boys and girls in the highest quartile of MVPA at age 5 yr had 4%-14% more BMC at ages 8 and 11 yr than those in the lowest quartile of MVPA at age 5 yr (P < 0.05). CONCLUSIONS These results provide support for the benefits of early MVPA on sustained bone health during childhood especially for boys. Results indicate the importance of increasing MVPA as a strategy to improve BMC later in childhood.