Biomedical subjects

Dorit Carmelli

Publications and source records attributed to Dorit Carmelli.

At least 19 recordsLinked to original sources

PubMed2006

Longitudinal genetic analysis of executive function in elderly men.

The objective of this study was to characterize the relative contribution of genetic and environmental influences to individual differences in longitudinal performance and decline of executive function (EF) using a population-based prospective study of male, WWII veteran twins (NHLBI twin study). Three tests of EF were administered when the twins were 59-70 years old, with 9- and 13-year follow-up. APOE epsilon4 allele status was incorporated in the genetic models to determine its contribution to longitudinal genetic variability. Mean EF performance significantly worsened over time. EF performance was highly genetically correlated across repeat assessment. There were significant genetic influences on 9- and 13-year decline in digit symbol performance. For all tasks decline over the last 4-year follow-up was influenced by individual-specific environmental effects. Controlling for APOE epsilon4 allele presence did not appreciably change the magnitude of genetic effects. These results suggest that common genetic factors underlie longitudinal EF task performance. Genetic influences on EF decline, however, appear to be evident at longer time intervals between assessments.

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PubMed2005

Heritability of plasma sex hormones and hormone binding globulin in adult male twins.

Plasma sex hormone concentrations have been used as biomarkers in epidemiological studies of many conditions including cancer, obesity, bone density, and coronary heart disease. The objective of this analysis was to estimate genetic and nongenetic influences on endogenous sex hormones (testosterone, estradiol, estrone, and SHBG) in a large sample of 532 adult white male twins (134 monozygotic and 132 dizygotic twin pairs) from the National Heart, Lung, and Blood Institute Twin Study. Participants were aged 59-70 yr at the time of plasma collection, and hormone concentrations were determined with RIA. Genetic models were fitted by the method of maximum likelihood. Testosterone and SHBG concentrations have substantial genetic variation, with additive genetic factors accounting for 57 and 68% of the total phenotypic variation, respectively. In contrast, variation in estrone (37% shared environmental and 63% individual specific environmental effects) and estradiol concentrations (25% genetic effect, 44% shared environmental effects, and 31% individual specific environmental effects) were largely influenced by nongenetic factors. Assessment of the relative contribution of genetic and nongenetic influences on hormone concentrations may help in the search for genes underlying variation and covariation in complex traits affected by plasma sex hormone concentrations.

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PubMed2005

Apolipoprotein E epsilon4 and change in cognitive functioning in community-dwelling older adults.

The relationship between apolipoprotein E (APOE) epsilon4 and change in cognition was examined in older men (n = 247; age = 75.0 +/- 3.5 years) and women (n = 79; age = 70.8 +/- 4.9 years) free of history of stroke. Participants were examined again 4.0 +/- 0.5 years later. Exclusion criteria were (1) initial scores on the Mini-Mental State Examination of 23 or less or (2) the presence of the APOE 2/4 genotype. Men with epsilon4 showed greater decline in some measures of executive function and verbal memory compared to those without epsilon4; women with epsilon4 showed greater decline in Trail Making test performance relative to women without the allele. A significant gender x APOE epsilon4 interaction was seen for change in performance on short delay cued recall. These results suggest that APOE epsilon4 is associated with cognitive decline differently in older adult men and women.

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PubMed2004

Genetic and environmental influences in sleep-disordered breathing in older male twins.

STUDY OBJECTIVES: To estimate the extent to which genetic factors contribute to the variation in several indices of sleep-disordered breathing in elderly male twins. DESIGN AND SETTING: A biometric genetic study based on data from unattended Edentrace recordings in a sample of elderly male twins. PARTICIPANTS: 122 World War II male veteran twin pairs, including 68 monozygotic pairs aged 78.9 (+/- 2.7) years and 54 dizygotic pairs aged 78.4 (+/- 2.4) years. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The average (+/- SD) respiratory disturbance index for this sample was 17.2 +/- 14.5, the average (+/- SD) oxygen desaturation index was 18.8 +/- 16.4, and the average (+/- SD) minimum SaO2 level was 79.6 +/- 8.1%. Intraclass twin-pair correlations for log-transformed respiratory disturbance index were 0.59 in monozygotic pairs and 0.36 in dizygotic pairs. For oxygen desaturation index, intraclass correlations were 0.44 in monozygotic pairs and 0.24 in dizygotic pairs. For minimum SaO2, intraclass correlations were 0.38 and 0.11, respectively. Maximum likelihood estimates of heritability with associated 95% confidence intervals were 37% [22%, 52%] for respiratory disturbance index, 36% [19%, 53%] for oxygen desaturation index, and 10% [0%, 30%] for minimum SaO2. Adjustments of sleep-disordered breathing measures for age, body mass index, and waist and neck circumference had minimal effect on estimates of heritability. CONCLUSIONS: The present data indicate that sleep-disordered breathing, even in old age, is determined, in part, by genetic factors.

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PubMed2004

Prospective assessment after pediatric cardiac ablation: recurrence at 1 year after initially successful ablation of supraventricular tachycardia.

OBJECTIVES: A multicenter prospective study was performed to assess the results and risks associated with radiofrequency ablation in children. This report focuses on recurrences following initially successful ablation. METHODS: Patients recruited for the study were aged 0 to 16 years and had supraventricular tachycardia due to accessory pathways or atrioventricular nodal reentrant tachycardia (AVNRT), excluding patients with more than trivial congenital heart disease. A total of 481 patients were recruited into the prospective cohort and were followed at 2, 6, and 12 months following ablation. RESULTS: There were 517 successfully ablated substrates out of 540 attempted (95.7%). Loss to follow-up for individual substrates was 3.3%, 10.6%, and 21.2% at 2, 6, and 12 months, respectively. Recurrence was observed in 7.0%, 9.2%, and 10.7% of these substrates at 2, 6, and 12 months, respectively (adjusted for loss to follow-up as an independent source of data censoring). Recurrence rate varied by substrate location (24.6% for right septal, 15.8% for right free wall, 9.3% for left free wall, and 4.8% for left septal), as well as for AVNRT versus all others (4.8% vs 12.9%) at 12 months. The recurrence rate was higher for substrates ablated using power control but was not a function of whether isoproterenol was used for postablation testing. CONCLUSIONS: Recurrence after initially successful ablation occurs commonly in children. It is least common after AVNRT ablation and most common following ablation of right-sided pathways. These results serve as a benchmark for the time course of recurrence following initially successful ablation of supraventricular tachycardia in children.

Adolescent↗

PubMed2004

Morphological changes in aging brain structures are differentially affected by time-linked environmental influences despite strong genetic stability.

This longitudinal study used the full twin model to estimate change and stability of genetic contributions to morphology of two brain structures, the corpus callosum and lateral ventricles. The 142 subjects were 34 monozygotic (MZ) and 37 dizygotic (DZ) elderly male twin pairs from the National Heart, Lung, and Blood Institute (NHLBI) Twin Study who underwent brain magnetic resonance imaging twice, separated by a 4-year interval. Genetic factors accounted for a substantial portion of individual differences in the size of the corpus callosum and its substructures and of lateral ventricular size. Longitudinal genetic analyses revealed no significant change in the heritability of these structures and no evidence for new genetic variance at Time 2 not present at Time 1. However, both the callosal and ventricular measures showed evidence for new environmental variance at Time 2 not present at Time 1. Confirming a previously posed hypothesis, the phenotypic correlation between absolute change in height of the corpus callosum and absolute change in ventricular volume was significant. Bivariate genetic analysis estimated a significant genetic correlation between the changes in these two structures and the genetic variance in the change of callosal height was entirely due to genes involved in the expansion of ventricles. Genetic stability was present even in old age when brain and other morphological changes can be rapid and highly variable across individuals, inconsistent with an hypothesis that random DNA damage is the cause of aging.

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PubMed2004

Prospective assessment after pediatric cardiac ablation: demographics, medical profiles, and initial outcomes.

INTRODUCTION: A multicenter prospective study was designed and implemented to assess the short- and longer-term results and risks associated with radiofrequency (RF) ablation in children. METHODS AND RESULTS: Patients recruited for the study were aged 0 to 16 years with supraventricular tachycardia due to accessory pathways or AV nodal reentrant tachycardia (AVNRT), excluding patients with nontrivial congenital heart disease. A national registry also was established, and contributing centers were encouraged to enroll all pediatric patients, aged 0 to 21 years, undergoing ablation at their center. This report summarizes acute results of these procedures. For analysis, subjects were divided into three groups: the prospective cohort (n = 481), cohort-eligible registry participants (n = 504), and not cohort eligible registry participants (n = 1,776). Prospectively enrolled cohort patients were similar to cohort-eligible patients in terms of demographic and other patient characteristics. Overall success rates for RF ablation were high (95.7%), with higher success rates for left-sided and particularly left free-wall pathways (97.8%) than right free-wall pathways (90.8%). Complications of both electrophysiologic study and RF ablation were infrequent (4.2% and 4.0%, respectively), and there were no deaths. AV block was uncommon overall (1.2%) and was limited to ablation in AVNRT (2.1%) and septal accessory pathways (3.0%). CONCLUSION: Despite the multicenter and prospective design, the study demonstrates high success rates and low complication rates, which are comparable to prior single-center retrospective studies. These results may serve as the current best benchmark for expected results in the pediatric population, aged 0 to 16 years, both in terms of acute success rates and the occurrence of complications.

Adolescent↗

PubMed2004

Relationship of endogenous sex hormones to coronary heart disease: a twin study.

We examined the association between endogenous sex hormones (estradiol, estrone, testosterone, and SHBG) and coronary heart disease (CHD) in white male twins. Stored plasma samples were available for 566 participants of the National Heart, Lung, and Blood Institute Twin Study, a longitudinal study of cardiovascular disease in male twins. Twenty-eight of these individuals were lost to follow-up, and outcome data were missing. Of the remaining 538 participants, 78 had CHD at baseline, and 154 subsequently developed CHD over 20 yr of follow-up. We observed no differences in mean unadjusted or age- and body mass index-adjusted log-transformed sex hormone concentrations for participants with and without CHD (all P > 0.08). Quartile and median split analyses revealed no significant association between any of the sex hormones and either prevalent or incident CHD. The discordant monozygotic twins showed no significant case-control group difference in estradiol, estrone, testosterone, and SHBG (all P > 0.3). The positive and negative concordant twin pairs had similar values for each of the sex hormones (all P > 0.3). We observed no relationship between endogenous sex hormone concentrations and prevalent or incident CHD in this sample of male twins.

Adult↗

PubMed2003

A study of depressive symptoms and smoking behavior in adult male twins from the NHLBI twin study.

Self-report measures of depressive symptoms, such as the Center for Epidemiological Studies-Depression Scale (CES-D), correlate with current and lifetime smoking status. In one previous study of adult female twins, genetic factors accounted for the covariation of liability to a diagnosis of major depressive disorder and liability to lifetime smoking (Kendler, Neale, MacLean, Heath, Eaves, & Kessler, 1993b, Archives of General Psychiatry, 50, 36-43); however, it remained unclear whether genetic effects also account for the covariation between subclinical depressive symptomology and smoking behavior. In this study, we use twin structural equation modeling to explore whether genetic and/or environmental influences contribute to the covariation between depressive symptoms, as measured by the CES-D, and current and lifetime smoking status among 120 monozygotic and 114 dizygotic Caucasian male twin pairs (aged 59-69). In this sample, depressive symptoms showed small but significant correlations with current and lifetime smoking status. Univariate twin analyses indicated that additive genetic and non-shared environmental factors contributed significantly to liability to current and lifetime smoking. However, the majority of variance in CES-D scores was attributable to non-shared (individual) environment. In bivariate analyses, non-shared environmental factors accounted for the majority of covariation between liability to depressive symptoms (CES-D scores > or = 8; above the 75th percentile) and liability to current and lifetime smoking status. Taken together with the previous literature, these results suggest that the etiology of covariation among depressive symptoms and smoking behavior may vary by measurement and severity of depressive symptomology.

Adult↗

PubMed2003

More favorable midlife cardiovascular risk factor levels in male twins and mortality after 25 years of follow-up is related to longevity of their parents.

BACKGROUND: Genetic studies of life span in humans have used broad survival measures, most commonly longevity, which is moderately correlated between parents and offspring. We examined whether genetic cardiovascular disease risk factors in male twin offspring are related to longevity of their parents in the National Heart, Lung, and Blood Institute twin study. METHODS: Cholesterol levels, body mass index, blood pressures, and pulmonary function measured over the first three examinations (average subject age 48, 58, and 63 years, respectively) were compared with the twins' paternal, maternal, and parental mean longevity divided into upper versus lower quintiles. The presence of an apolipoprotein E epsilon 4 allele typed from DNA collected at Exam 3 and mortality in the twin cohort through 1997 were also examined in relation to parental longevity quintiles. RESULTS: Twins, particularly whose fathers died at younger ages, had significantly higher total cholesterol (p <.05), ratio of total cholesterol to high-density lipoprotein (p <.01), and blood pressures (p <.01) in middle age. This relationship decreased at the subsequent two examinations, but consistently, twins with longer-lived parents tended to have better risk factor profiles. A twin death (mean age 65) was significantly more common in families with mothers (p <.001) and, to a lesser extent, fathers who died early. An apolipoprotein epsilon 4 allele was more common in families with parents' age at death in the lowest quintile (p <.05). CONCLUSIONS: Systolic blood pressures, cholesterol levels, and the presence of the apolipoprotein E epsilon 4 allele likely contribute to the observed familial correlations in longevity that have been reported in the literature.

Apolipoproteins E↗

PubMed2003

Environmental and genetic determinants of tobacco use: methodology for a multidisciplinary, longitudinal family-based investigation.

This article describes the ongoing collaborative effort of six research teams to operationalize and execute an integrative approach to the study of gene x environment interactions in the development of tobacco dependence. At the core of the project is a longitudinal investigation of social and behavioral risk factors for tobacco use in individuals who were, on average, 13 years of age at intake and for whom smoking outcomes extending from early adolescence to young adulthood have been characterized previously (current average age of the cohort is 29 years). The conceptual framework for the integrative approach and the longitudinal investigation on which the study is based is presented. A description is also provided of the methods used to: (a) recruit participants and families to provide DNA samples and information on tobacco use; (b) assess participants for relevant tobacco-related phenotypes including smoking history, current use of tobacco, and nicotine metabolism; (c) assess the quality of the DNA samples collected from participants for genome-wide scanning and candidate gene analysis; (d) examine several research questions concerning the role of genetic and environmental factors in the onset and maintenance of tobacco use; and (e) ensure adherence to local and federal guidelines for ethical and legal investigations of genotypic associations with tobacco-related phenotypes in families. This investigation is unique among ongoing studies of the genetics of tobacco dependence in the extent to which equal importance has been assigned to both phenotypic and genotypic measurements.

Adolescent↗

PubMed2002

Heritability of lobar brain volumes in twins supports genetic models of cerebral laterality and handedness.

Although the left and right human cerebral hemispheres differ both functionally and anatomically, little is known about the environmental or genetic factors that govern central nervous system asymmetry. Nevertheless, cerebral asymmetry is strongly correlated with handedness, and handedness does have a significant genetic component. To explore the relative contribution of environmental and genetic influences on cerebral asymmetry, we examined the volumes of left and right cerebral cortex in a large cohort of aging identical and fraternal twins and explored their relationship to handedness. Cerebral lobar volumes had a major genetic component, indicating that genes play a large role in changes in brain volume that occur with aging. Shared environment, which likely represents in utero events, had about twice the effect on the left hemisphere as on the right, consistent with less genetic control over the left hemisphere. To test the major genetic models of handedness and cerebral asymmetry, twin pairs were divided into those with two right handers and those with at least one left hander (nonright handers). Genetic factors contributed twice the influence to left and right cerebral hemispheric volumes in right-handed twin pairs, suggesting a large decrement in genetic control of cerebral volumes in the nonright-handed twin pairs. This loss of genetic determination of the left and right cerebral hemispheres in the nonright-handed twin pairs is consistent with models postulating a right-hand/left-hemisphere-biasing genetic influence, a "right-shift" genotype that is lost in nonright handers, resulting in decreased cerebral asymmetry.

Aged↗

PubMed2002

Quantitative genetic modeling of regional brain volumes and cognitive performance in older male twins.

As part of an ongoing longitudinal twin study, data from both MRI brain scanning and from neuropsychological testing were obtained from 139 male-male twin pairs (72 monozygotic [MZ] and 67 dizygotic [DZ]), 69-80 years old at the time of examination. For descriptive purposes, we examined the MZ and DZ intraclass correlations (ICC) of four lobar brain volumes (frontal, temporal, parietal, and occipital), two cerebrospinal fluid (CSF) volumes (lateral ventricle and temporal horn of the lateral ventricles), and two measures of cognitive functioning (verbal memory and executive function). We found that for lobar brain and CSF space volumes, the MZ ICC were significantly greater than zero (r=0.37-0.77) and greater than the corresponding DZ correlations (r=0.02-0.49). Similarly, within-pair correlations for the two neuropsychological factors were statistically significant and significantly larger in MZ twin pairs than in DZ pairs, suggesting the presence of genetic variance. Bivariate genetic analysis revealed that while close to 60% of individual differences in neuropsychological performance were due to genetic influences, less than 50% of genetic effects were in common with those influencing brain volumes. These data may shed light on the genetic liability for brain diseases that affect the elderly.

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PubMed2002

Prospective assessment after pediatric cardiac ablation: design and implementation of the multicenter study.

A multicenter prospective study was designed and implemented as an activity of the Pediatric Electrophysiology Society to assess the risks associated with radiofrequency ablation in children. Patients (age 0-15 years) with supraventricular tachycardia due to accessory pathways or atrioventricular nodal reentry were enrolled and studied prior to ablation and periodically by clinical evaluation, electrocardiogram (ECG), Holter monitor, and echocardiogram. In addition, a national registry was established, to which the contributing centers report all pediatric patients undergoing ablation at their center. Initial electrophysiological study tracings and all noninvasive studies undergo blinded outside review for quality control. Clinical endpoints were death, recurrence, proarrhythmia, and echocardiographic abnormality. A pilot study demonstrated excellent agreement concerning diagnoses of previously reported ablation patients between the reporting center and the blinded reviewer (kappa = 0.938 +/- 0.062). A total of 317 patients were enrolled in the ongoing study from April 1, 1999 to December 31, 2000. The success rate of ablations was 96% with a complication rate of 4.3% for electrophysiological study and 2.9% for the ablation procedure. Comparison of the registry group versus the study group shows that the groups are comparable in terms of patient characteristics, diagnoses, and the results of ablation making it less likely that the sample of prospectively enrolled patients is biased.

Adolescent↗

PubMed2002

Evidence for genetic mediation of executive control: a study of aging male twins.

The objective of this study was to investigate the genetic and environmental influences on indexes of executive control in elderly male twins (members of the National Heart, Lung, and Blood Institute Twin Study). Multivariate genetic modeling was applied to performance on four tests: Digit Symbol Substitution, color--word interference, Trail Making B, and verbal fluency. After exclusion of individuals with a positive stroke history, data were available for 80 monozygotic and 78 dizygotic twin pairs of ages 69--80 years. Performance on all measures was adjusted for age and education. Significant genetic and environmental influences to performance on each measure of executive control were identified (range of heritability = 34%--68%). Multivariate analyses revealed that a model with a latent executive control factor most adequately fit the observed covariances on test performance, chi(2)(58, N = 316) = 69.7, p =.14. The shared executive control factor had a heritability of 79% and accounted for 10%--56% of the genetic variance in performance on each of the four tests. Of the 4 tests examined in this analysis, Digit Symbol Substitution appeared to be the marker of executive control with the largest genetic component, whereas verbal fluency stood out as displaying a pattern of genetic and environmental influences distinct from the other 3 measures.

Aged↗

PubMedDate not supplied

Influences of chorion type on measurements of the corpus callosum in adult monozygotic male twins?

MRI imaging was used to estimate volumes of corpus callosum structure in 45 pairs of identical (monozygotic, MZ) twins from the National Heart, Lung, and Blood Institute (NHLBI) twin study. Age range of the study subjects was from 68-78 years. Finger, palm, and footprint data (dermatoglyphics) collected at previous examinations of the NHLBI twin study were available for 39 pairs. The dermatoglyphics were scored for an index to retrospectively assess chorion type in MZ twin-pairs. The results indicated an association between variability in various structures of the corpus callosum with some of these dermatoglyphic traits, suggesting greater structural variation within pairs with dichorionic placentas. In contrast, total intracranial volume, which has similar heritability estimates as a result of shared genetic effects with the corpus callosum, was unrelated to the dermatoglyphic traits. The results provide indirect evidence that the intrauterine environment may influence twin-pair similarity of corpus callosum measures in adults.

Adult↗

PubMedDate not supplied

A bivariate genetic analysis of cerebral white matter hyperintensities and cognitive performance in elderly male twins.

White matter hyperintensities (WMHs) are frequently observed on MRI scans of elderly nondemented people and have been associated in the past with cognitive impairment and physical dysfunction. Individual differences in the prevalence and severity of WMHs have been documented and more recently we reported on the significant contribution of genetic influences to this variability. The objective of the present study was to further investigate, in the context of a behavioral genetic paradigm, the nature of the association between WMHs and cognitive and physical function. MRI brain scans and a battery of neuropsychological and physical function tests were given to 142 male-male twin pairs [72 monozygotic (MZ) and 70 dizygotic (DZ)], participants in the 4th exam of the NHLBI Twin Study. Biometric genetic modeling was used to estimate the genetic and/or environmental covariation between WMHs and cognitive and physical summary scores. The phenotypic association between WMHs and cognitive function in this sample of twins was modest but statistically significant. Genetic analyses of cognitive and physical function summary scores found that 55% to 70% of the observed variability was due to genetic influences. A further decomposition of the phenotypic association between WMHs and cognitive function found that 70% to 100% of the phenotypic covariation was due to common genetic effects. Similar results explained the association between WMHs and performance on two physical function tests. We conclude from these analyses that common genetic influences explain to a large extent previously observed phenotypic associations between large amounts of WMHs and poor cognitive and physical function in the elderly.

Aged↗

PubMedDate not supplied

Depressive symptoms and metabolic risk in adult male twins enrolled in the National Heart, Lung, and Blood Institute twin study.

OBJECTIVE: To determine the extent to which depressive symptoms are associated with metabolic risk factors and whether genetic or environmental factors account for this association. METHOD: Twin structural equation modeling was employed to estimate genetic and environmental contributions to the covariation of depressive symptoms, as indexed by the Centers for Epidemiological Studies-Depression Scale, and common variance among blood pressure, body mass index, waist-to-hip ratio, and serum triglycerides and glucose among 87 monozygotic and 86 dizygotic male twin pairs who participated in the NHLBI twin study. RESULTS: Depressive symptoms were associated with individual components of the metabolic syndrome and common variance among the risk factors. Twin structural equation modeling indicated that the associations were attributable to environmental (nongenetic) factors. CONCLUSIONS: These results support the hypothesis that depressive symptoms may increase risk for a pattern of physiological risk consistent with the metabolic syndrome.

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