Biomedical subjects

T H Beaty

Publications and source records attributed to T H Beaty.

143 records · Page 8Linked to original sources

PubMed1986

Genetic analysis of plasma sitosterol, apoprotein B, and lipoproteins in a large Amish pedigree with sitosterolemia.

We previously reported the finding of phytosterolemia, xanthomatosis, and hyperapobetalipoproteinemia (hyperapoB) in five siblings in a large Amish pedigree ascertained through a 13-year-old boy who died suddenly from advanced coronary atherosclerosis. Here, we present further analyses of the plasma levels of the plant sterol, sitosterol, of low density (beta) lipoprotein (LDL) sterol, and of LDL B protein. Of 254 relatives and spouses of the proband, 90.5% were examined. A series of genetic models were explored using a pedigree analysis where parameters reflecting frequency, transmission, and penetrance of putative genotypes were examined simultaneously using a maximum likelihood approach. Segregation analysis of the sitosterol levels showed that the phenotype of sitosterolemia was controlled by a rare autosomal recessive gene. There was also significant familial correlation in plasma sitosterol levels that was attributed to a polygenic component under a mixed model but could also be due to shared environments such as diets. The recessive model was supported by our finding that the plasma sitosterol levels in the parents and in six children born to three of the five sitosterolemics were less than 1 mg/dl, well within the normal range. The phenotype of hyperapoB is based on an elevated level of LDL B protein in the presence of a normal LDL cholesterol level (low LDL sterol to LDL B ratio). For both LDL sterol and LDL B, a polygenic model showed a slightly greater improvement in ln likelihood than did the Mendelian single locus model when both were compared to a sporadic model. Similar results were obtained for sterol levels of high density (alpha) lipoprotein (HDL) sterol. When segregation analysis was performed using the ratio of LDL sterol to LDL B, the Mendelian single locus model gave a slightly better fit to the data than did the polygenic model. While the analyses presented here provided unequivocal evidence for the recessive phenotype of phytosterolemia, we also identified a possible single gene factor that could account for the major portion of the strong familial aggregation in the ratio of LDL sterol to LDL B, and to a lesser extent LDL B. However, there is clear evidence of familial aggregation for these traits in this pedigree beyond that due to Mendelian components.

Adolescent↗

PubMed1985

Variance components analysis of forced expiration in families.

Familial aggregation of forced expiration (as measured by forced expiratory volume in 1 sec (FEV1) and the ratio of this to total forced vital capacity (FEV1/FVC) was analyzed in 439 adult members of 108 families ascertained through control patients who had participated in a genetic and epidemiologic study of chronic obstructive pulmonary disease. Residual values for both FEV1 and FEV1/FVC obtained from regression on age, sex, race, and cigarette smoking (and height for FEV1) were used in a variance components analysis to assess the relative importance of genetic and nongenetic factors influencing familial aggregation of pulmonary function among adults. For both residual FEV1 and residual FEV1/FVC, the "best" model among a series of genetic and nongenetic models was a simple additive genetic model. A modified score test, which is robust to the assumption of multivariate normality, was used to test the significance of these estimated components. Under the most parsimonious model, additive genetic variation accounted for 28% of the variation in residual FEV1 in 108 families and 24% of the variation in residual FEV1/FVC. After outlying individuals were identified by examining goodness-of-fit statistics, the simple genetic model still gave the best fit to these data. There was little indication of non-normality in FEV1 in these families; however, FEV1/FVC did show evidence of non-normality when examining goodness-of-fit statistics. This genetic component contributing to the distribution of forced expiration may be a factor in the familial aggregation of certain respiratory diseases.

Adult↗

PubMed1985

Familial aggregation in chronic obstructive pulmonary disease: use of the loglinear model to analyze intermediate environmental and genetic risk factors.

To examine the contribution of environmental and genetic risk factors to familial aggregation in chronic obstructive pulmonary disease (COPD), 325 first-degree (1d) relatives and 56 spouses of 150 COPD patients were compared with 222 1d relatives and 49 spouses of 107 nonpulmonary patient controls for the prevalence of two clinical outcomes: 1) airways obstruction (AO; 1-sec forced expiratory volume less than 68% of forced vital capacity) and 2) chronic bronchitis (CB; cough and sputum for 3+ months per year for 2+ years). The loglinear model was used to study direct and indirect (ie, those mediated by other risk factors) components of familial aggregation. Three risk factors were found to be independently associated with CB and/or AO: alpha 1-antitrypsin deficiency (PiZ allele), personal cigarette smoking, and parental cigarette smoking. Because 1d relatives of COPD patients were more likely to have a PiZ allele, be heavy smokers (1+ packs per day), and be exposed to parental smoking than 1d relatives of controls, these three factors also constitute indirect components of familial aggregation. However, after controlling for the three factors, 1d relatives of COPD patients were more likely to have AO and CB than 1d relatives of controls (direct component). This direct component might have a genetic basis, because no such association was found when spouses instead of 1d relatives were compared. Thus, both shared environmental factors (personal and passive smoking) and shared genetic factors (alpha 1-antitrypsin and a possible direct genetic component) contribute to familial aggregation in COPD. The loglinear model provides a useful tool for analyzing familial aggregation in diseases of multifactorial etiology.

Biometry↗

PubMed1985

Effects of pulmonary function on mortality.

Survivorship data from a 24 year longitudinal study of 874 male volunteers in the Baltimore Longitudinal Study of Aging were used to assess the role of pulmonary function on total mortality. Even when age and smoking were considered, the ratio of forced expiratory volume in 1 sec to its predicted value was significantly associated with mortality from all causes. Individuals with poorer pulmonary function showed greater mortality during the follow-up period of this study. This relationship was also seen among never smokers in this sample, further supporting the hypothesis that impaired pulmonary function is itself a predictor of total mortality and may contribute to a number of disease processes.

Adolescent↗

PubMed1985

Use of robust variance components models to analyse triglyceride data in families.

A robust approach for analysis of variance components models is presented which does not rely on the assumption of multivariate normality for its validity. This approach uses the multivariated normal distribution as a 'working model' but obtains standard errors for the final estimators which do not depend on this underlying distribution. By using the observed variance in the first derivatives of the multivariate normal 'working model' to modify the conventional score test, hypotheses regarding specific components can also be tested without relying directly on the assumption of multivariate normality. A special case is presented where both the modified score test and the likelihood ratio test are equally robust, and simulated data are used to illustrate this situation. Measurements of triglyceride levels in 391 individuals in 60 families randomly selected from the membership of a health maintenance organization are used to illustrate this robust approach to variance components.

Genetic Variation↗

PubMed1985

Nitrogen washout and mortality.

We studied the association between different tests of pulmonary function and subsequent mortality. Subjects were drawn from an epidemiology study of chronic obstructive pulmonary disease. Between 1971 and 1976, 2,539 nonpatient adults had tests of forced expiration, diffusing capacity, and single-breath nitrogen washout. By 1981, 115 of those subjects had died, including 3 from known lung disease. In assessing the relationship between lung function and mortality, the following tests of pulmonary function were examined: forced expiratory volume in one second as a percentage of forced vital capacity, forced expiratory volume divided by height cubed, slope of phase III from the single-breath nitrogen test, closing capacity, diffusing capacity for CO, and the ratio of maximal flow at 75% to that at 25% vital capacity. When adjustments for age and smoking were made, slope of phase III was strongly associated with mortality, even more so than tests of forced expiration. There are two possible explanations for this striking relationship between these observed abnormalities of lung function and subsequent overall mortality (which is largely from nonpulmonary disease): the lungs may serve to protect other systems of the body and therefore poor pulmonary function may contribute to a number of diseases leading to death, or lung function may merely reflect existing disorders in other systems of the body, and the observed association between mortality and pulmonary function is a byproduct of nonpulmonary diseases.

Adult↗

PubMed1984

Risk factors associated with longitudinal change in pulmonary function.

In a longitudinal study of pulmonary function, we investigated the relationship between loss of forced expiration over time and a series of potential risk factors, as well as 4 other measures of pulmonary function at initial visit. Data on 1,912 adults tested twice, with an average of 4.7 yr between visits, were used. Of the potential risk factors examined, only age and smoking were consistently associated with increased loss of forced expiratory function in both men and women. Statistically significant differences among ABO blood types and among Pi types were also seen in women, although the direction of these differences was unexpected in that non-Z Pi variant phenotypes showed less decline in pulmonary function than did the most common Pi M phenotypes. Similar patterns of differences were seen in men, although these were not statistically significant. Of 4 initial-visit pulmonary function measures examined, only closing capacity at initial visit was consistently associated with subsequent loss of forced expiratory volume in one second (delta FEV1) in both men and women. The final predictive model for delta FEV1 accounted for a modest proportion of the total variation seen in this sample, however, limiting its potential use for predicting decline in pulmonary function over a 5-yr span in individual subjects.

ABO Blood-Group System↗

PubMed1984

Risk of chronic obstructive pulmonary disease. Collaborative assessment of the validity of the Tecumseh index of risk.

Predictors of chronic obstructive pulmonary disease (COPD) have been identified in the prospective epidemiologic study of the population of Tecumseh, Michigan. Risk of developing COPD within 10 yr can be estimated from a profile that includes as risk factors age, sex, cigarette smoking habits, and forced expiratory volume in one second (FEV1). The index of risk placed 63% of male incidence cases and 64% of female incidence cases in the top 10% of the risk distribution and 81% of male and 86% of female COPD cases in the top 20% of the risk distribution for Tecumseh. The validity of the Tecumseh index of risk for other populations was determined in a collaborative investigation of data collected in longitudinal epidemiologic studies in Baltimore, Boston, Framingham, Louisiana, Staveley, and Tucson. The extent to which the risk model fitted these data sets was assessed by comparing predicted (or expected) onsets of COPD in each population with observations made in each study. The predictors of COPD identified in Tecumseh were shown to be the most important risk factors in the other populations as well. The goodness-of-fit of the index was satisfactory overall. In all populations, a high risk score was associated with an increased incidence of COPD, thus confirming the predictive ability of the risk index. The Tecumseh index of risk provides a practical method for developing a risk profile from answers to standard questions and simple tests of lung function. Risks are greatest for heavy cigarette smokers with reduced lung function, lower in smokers who stop smoking or reduce their cigarette consumption, and lowest of all in nonsmokers with above average lung function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

Risk factors, pulmonary function, and mortality.

In a genetic-epidemiologic study of obstructive airway disease (OAD), cross sectional and longitudinal data (4.7 year follow-up) were collected to investigate relationships among risk factors, pulmonary function, and mortality. In the cross sectional evaluation of 2539 non-patient adults, 11 potential risk factors were found to be significantly associated with airways obstruction. Most important among these were age and smoking. Others included: demographic variables (gender, SES, education); the intake of coffee and diet soda; genetic markers (protease inhibitor "Pi" type, ABO type, ABH secretor status); and familial pulmonary disease. Examination of combinations of risk factors in cross sectional data indicated that some of these factors were important risk factors in cigarette smokers but less evident in never smokers. For example, ABO type, familial component, coffee drinking and diet soda intake were related to marked differences in lung function in cigarette smokers, but had little impact in never smokers. Thus, interactions of factors must be considered when assessing risk of pulmonary dysfunction. In the longitudinal evaluation, 11 factors found to be significant on cross sectional study plus 4 tests of lung function (closing capacity, diffusing capacity, slope of Phase III, and flow volume curves) were examined for correlations with loss of forced expiratory volume. Consistently greater declines of lung function were noted in males, older subjects, smokers, whites, and individuals carrying the type A blood group allele. Increased initial visit closing capacity was also associated with increased deterioration. Together, however, these factors accounted for only a modest amount of observed variation in decline in lung function (17% in females and 12% in males). Initial visit characteristics were not only associated with deterioration of lung function in survivors, as described above, but with survivorship per se. Age, sex, race and cigarette smoking were associated with differences in mortality. In addition to these, pulmonary dysfunction itself at initial visit was an independent risk factor for increased mortality. For example, the mortality of unobstructed males in the 5th decade of life was 16 per thousand compared to 25 per thousand in obstructed males. For females, the mortality in the 5th decade of life was 7 per thousand if unobstructed and 12 per thousand if obstructed. We conclude: 1) In cross sectional evaluation, multiple factors are associated with airways obstruction. Of these, smoking appears to interact strongly with other factors.(ABSTRACT TRUNCATED AT 400 WORDS)

ABO Blood-Group System↗

PubMed1983

Assessment of variance components models on pedigrees using cholesterol, low-density, and high-density lipoprotein measurements.

Plasma total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) measurements on 402 individuals in 62 randomly selected families from the Columbia Medical Plan population were used to select the "best" model among a series of multifactorial models using the maximum likelihood method described by Lange et al [1976]. These models included both genetic and nongenetic components of variance. The most parsimonious model for each trait was selected and examined using a goodness-of-fit statistic designed by Hopper and Mathews [1982] to test the assumptions of this technique. A simple additive genetic model was the most plausible for all three measurements, suggesting a strong role for genetic factors in determining lipid and lipoprotein levels in these data. Goodness-of-fit statistics for these models were examined and showed little evidence of deviation from the assumption of multivariate normality within pedigrees. This approach of selecting the most parsimonious model among a series of competing models and then assessing its goodness-of-fit has many applications in studying familial aggregation of quantitative traits.

Adult↗

PubMed1983

The use of life tables and survival analysis in testing genetic hypotheses, with an application to Alzheimer's disease.

Because of the late onset of some neuropsychiatric disorders suspected to be under genetic influence, such as Alzheimer's disease, standard techniques for testing genetic hypotheses are difficult to apply to clinical data. The statistical aspects of life table methods and survival probability estimators which can be used to test such hypotheses have been neglected in the psychiatric literature. Two techniques of this kind, the Weinberg morbidity table and the Kaplan-Meier product limit estimator, are applied to real and simulated data. As estimators of lifetime incidence these methods yield roughly equivalent results for both types of data, although from a theoretical standpoint the original Weinberg estimator appears to suffer from logical defects. Parametric models may offer more definitive results, particularly when an estimator of segregation ratio is required. The clinical data in this report were gathered by interviewing relatives of Alzheimer's disease patients sampled through a nursing home survey in metropolitan Baltimore, Maryland during 1980.

Actuarial Analysis↗

PubMed1982

Identifying risk factors for diabetes in first degree relatives of non-insulin dependent diabetic patients.

Glucose tolerance test data on 794 first-degree relatives of diabetics in pedigrees ascertained through non-insulin dependent diabetes mellitus from southeastern Michigan were used to identify risk factors for diabetes. The general risk factors, age and obesity, were important in predicting diabetes at initial visit, although the predicted risk curves were very different from males and females. In predicting diabetes at initial visit, the number of affected sibs contributed more to the logistic regression than did the number of affected parents. Among a group of 393 individuals who were followed up for a mean of eight years, the initial glucose tolerance test response was the best single predictor of being diabetic on follow-up. These results suggest there may be a strong within-generational component which influences both the quantitative test response and the risk to diabetes. This component may reflect environmental factors influencing glucose tolerance among sibs and, as such, should be considered when studying the genetics of diabetes.

Adolescent↗

PubMed1982

Impaired pulmonary function as a risk factor for mortality.

Prospective follow-up information obtained between 1976 and 1981 on mortality among 2539 individuals showed that pulmonary function impairment is a risk factor for short-term mortality, even when risk factors such as age, sex, and smoking are considered. Predicted risk curves for impaired individuals (those with forced expiratory volume in one second less than 68% of forced vital capacity) are consistently higher among all race-sex categories over all ages. Survival analysis using the proportional hazards model shows a steeper decline in estimated survival among individuals with poor pulmonary function compared to those with good pulmonary function, adjusted for age, race, and smoking effects. These observations are consistent with the concept that impairment of pulmonary function is a risk factor for morbidity and mortality from several nonrespiratory as well as respiratory diseases and that it acts by contributing to various pathogenic mechanisms in different organ systems.

Adult↗

PubMed1982

Estimating genetic and non-genetic components of variance for fasting glucose levels in pedigrees ascertained through non-insulin dependent diabetes.

Fasting glucose levels measured on 337 individuals in 14 pedigrees ascertained through a proband with non-insulin dependent diabetes were used to estimate genetic and non-genetic components of variance under a multifactorial model of inheritance. In this sample genetic factors were important in controlling variation in basal carbohydrate metabolism, as represented by age-adjusted log-fasting glucose. There was no evidence that arbitrary sib common environments or arbitrary parent common environments accounted for significant portions of the variability in fasting glucose in these data. An arbitrary environment shared by parent and offspring, however, had a marginally significant impact on the likelihood. Parameter estimates obtained from multifactorial models analysed in this manner are sensitive to extreme phenotypic values, however, and caution must be exercised in estimating total genetic variation. While additive genetic factors did account for a significant proportion of the total variation in fasting glucose, a large proportion remained unexplained.

Adolescent↗

PubMed1980

Discriminating among single locus models using small pedigrees.

Simulated small pedigrees (2 parents, 4 offspring) were used to illustrate the applications and limitations of a "model choice" approach designed to detect genetic heterogeneity in familial diseases. While it is possible to identify groups of pedigrees which have different genetic causes for quanitative phenotypic trait(s), theoretical limitations on discriminating between 4 single locus models exist for certain pedigree structures. These limitations originate from the overlapping phenotypic predictions of the various genetic models. Such limitations must be carefully considered in the design of genetic studies. Studies aimed at detecting genetic heterogeneity in familial diseases should limit the different genetic models being considered and tailor the sampling strategy to avoid collecting pedigrees which are non-informative for certain comparisons.

Alleles↗

PubMedDate not supplied

No evidence of linkage for cleft lip with or without cleft palate to a marker near the transforming growth factor alpha locus in two populations.

Nonsyndromic cleft lip with or without cleft palate is a common birth defect, affecting approximately 1 in 1,000 Caucasian newborns. Thirty-five multiplex families from the mid-Atlantic region of the United States and 22 families from central Mexico with a nonsyndromic form of cleft lip with or without cleft palate were selected for a linkage analysis. A tetranucleotide repeat marker (D2S443) located on the same yeast artificial chromosome as the transforming growth factor alpha locus was tested for linkage to a putative susceptibility Mendelian locus under varying levels of pentrance. No evidence for linkage between D2S443 and a susceptibility locus for cleft lip with or without cleft palate was found. Insight is given to explain this outcome in spite of the statistically significant associations found by other investigators.

Chromosome Mapping↗

PubMedDate not supplied

Genetic basis of IgE responsiveness: relevance to the atopic diseases.

Genetic analysis of 170 subjects in 11 extended Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum IgE levels. No linkage was found between these markers and specific IgE antibody levels. Analysis of total IgE within a subset of 128 IgE-antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially IL4 (p = 4 x 10(-6)). These and other data suggest that IL4 or a nearby gene regulates IgE production in a non-antigen-specific (noncognate) fashion and provide evidence for a possible link between asthma and the IL4 gene.

Antibody Formation↗