Search PubMed⌕ Search

Biomedical subjects

T H Beaty

Publications and source records attributed to T H Beaty.

At least 109 records · Page 6Linked to original sources
PubMed1991

Measuring familial aggregation by using odds-ratio regression models.

Detection of familial aggregation of a disease is important for studying possible genetic and environmental factors contributing to disease etiology. Accurate quantification of familial aggregation can provide guidance for subsequent, more sophisticated genetic studies. This article presents a statistical model and method for detecting both inter- and intra-class aggregation of a binary trait with family data. The method used here is based on the logistic regression model which incorporates effects of individual covariates while measuring familial aggregation of risk as the odds ratios among classes of relatives. An estimation equation approach is presented where the joint distribution of binary traits among family members need not be fully specified. Data from a genetic epidemiologic study on liver cancer in Shanghai are analyzed for illustration, and reveal strong aggregation of risk even after adjusting for covariates. Effects of non-random sampling and ascertainment bias are also discussed.

Adolescent↗
PubMed1991

Familial risk factors for prostate cancer.

This chapter describes the application of the genetic epidemiological approach to the study of human prostate cancer. We review the evidence for the familial clustering of prostate cancer and the Mendelian nature of this aggregation. The nature of this clustering is such that the closer genetically a man is to an affected relative and the greater number of relatives affected in a man's family, the greater his risk of prostate cancer. A complex segregation analysis of the 691 prostate cancer families showed that prostate cancer clustering can be explained by Mendelian inheritance of a rare autosomal gene producing prostate cancer at an early age. A model of inherited prostate cancer in the setting of multistep carcinogenesis is presented. The implications of these data for clinicians who diagnose and treat prostate cancer are also discussed.

Aged↗
PubMed1990

Family history and the risk of prostate cancer.

A case-control study was performed to estimate the relative risk of developing prostate cancer for men with a positive family history. Extensive cancer pedigrees were obtained on 691 men with prostate cancer and 640 spouse controls. Fifteen percent of the cases but only 8% of the controls had a father or brother affected with prostate cancer (P less than .001). Men with a father or brother affected were twice as likely to develop prostate cancer as men with no relatives affected. In addition, there was a trend of increasing risk with increasing number of affected family members such that men with two or three first degree relatives affected had a five and 11-fold increased risk of developing prostate cancer. Recognizing that 9-10% of U.S. men will develop prostate cancer in their lifetime, men with a family history of prostate cancer should be advised of their significantly increased prostate cancer risk and should undergo appropriate screening measures for this disease.

Case-Control Studies↗
PubMed1990

Major genetic mechanisms in pulmonary function.

Regressive models were used to search for possible major gene effects on pulmonary function in two groups of families: one ascertained through patients with chronic obstructive pulmonary disease [COPD defined as forced expiratory volume in one second (FEV1) less than 70% forced vital capacity (FVC)] and the other ascertained through patients with non-pulmonary disorders. There were 85 COPD families with data on 270 individuals and 56 non-pulmonary families with data on 199 individuals. The analysis was done on residuals obtained from a regression of FEV1 on age, sex, race, height, and ascertainment group. Smoking status was incorporated directly as a covariate in the regressive models. Data on probands were excluded in this analysis as a partial correction for ascertainment bias. The best fitting model for the 85 COPD families included a major gene effect with sex specific variances, but no residual familial correlation. The best fitting model for the non-pulmonary families was one with no major gene effect and no residual familial correlation. Cigarette smoking was a significant covariate in both groups of families. Testing for heterogeneity showed a significant difference in the control of pulmonary function among these COPD and non-pulmonary families (X2 = 20.12 on 6 df; p = 0.0026). Major gene effects appear to be limited to these COPD families, while there was no evidence for major gene effects in the non-pulmonary families.

Adult↗
PubMed1990

Path analysis of familial resemblance of pulmonary function and cigarette smoking.

The techniques of path analysis were utilized to assess the relative importance of genetic factors, personal smoking behavior, and shared environment in the resemblance of pulmonary function among relatives using both cross-sectional and longitudinal data from nuclear families. Data on 1-s forced expiratory volume, FEV1 (adjusted for age, sex, race, height, and ascertainment group) and the number of cigarettes smoked per day were available on 978 individuals in 384 nuclear families residing in the Baltimore metropolitan area. All these individuals were seen twice between 1971 and 1981, with an average of 5 yr between visits. The direct effect of an individual's own smoking explained 10 and 3% of variation in adjusted FEV1 among parents and offspring, respectively. Shared environmental factors influencing personal smoking behavior accounted for 5% of the parent-offspring correlation in adjusted FEV1 and 3% of the sibling correlation in adjusted FEV1 in this sample. Undefined environmental factors that influenced an individual's smoking habits and could be shared among relatives were found to explain 19% of the familial correlations in smoking. Genetic heritability estimates ranged between 36 and 40%, with no evidence of intergenerational differences in the expression of apparent genetic control of pulmonary function.

Adult↗
PubMed1989

Predicting intrauterine growth retardation in sibships while considering maternal and infant covariates.

Data on 6,210 full-term sibships (gestational age greater than 36 weeks) reconstructed from birth certificates registered in Maryland between 1980 and 1984 were used to study sibship aggregation and recurrence risk of intrauterine growth retardation (IUGR) while considering maternal and infant covariates. In this study, IUGR was defined as being below the 10th percentile for race-, sex-, and gestational-age-specific birth weight based on all births registered in Maryland during 1984. Maternal factors (race, age at delivery, marital status, amount of prenatal care, concurrent illnesses, and complications during pregnancy) and infant factors (congenital malformations and first born child or not) were used as covariates in a modified logistic regression model which allowed correlation among sibs. First-time mothers who were under age 30 years, unmarried, received too little prenatal care, or had any reported pregnancy complications were at high risk of delivering an infant with IUGR. Even given the effects of these risk factors, however, there was a significant correlation in risk among full sibs (r = .237 +/- .028), which, combined with information on risk factors, can be used to estimate sibling recurrence risk for IUGR.

Adult↗
PubMed1989

Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations.

Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study, regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group, the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects, right heart defects, and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However, when race was included as a covariate in these genetic models, there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD, while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.

Blood Vessels↗
PubMed1989

Genetic analysis of total cholesterol and triglycerides in a pedigree of St. Thomas rabbits.

A pedigree consisting of 103 New Zealand White hyperlipidemic and normal rabbits was used in a genetic analysis of total cholesterol and triglyceride levels to test for Mendelian control of hyperlipidemia. The founder male of this pedigree was identified through hypercholesterolemia and evidence suggested vertical transmission of a hypercholesterolemic phenotype in this pedigree, although a combined hyperlipidemia phenotype (elevated cholesterol and triglycerides) also occurred in many descendents of the original founders. Segregation analysis of quantitative measures of total cholesterol and triglycerides in this pedigree was employed to test hypotheses about Mendelian control in the presence of substantial inbreeding. A simple Mendelian model was the best explanation for triglycerides in these animals. This best fitting model was essentially co-dominant with genotypic specific variances, where the heterozygote was hypertriglyceridemic and the mutant homozygote showed even more extreme values. The observed distribution of total cholesterol was also compatible with a mixture of distinct genotypic distributions, but there was evidence of non-Mendelian transmission in this pedigree. The observed hypertriglyceridemia in these animals may reflect an abnormality of very low density lipoprotein metabolism described previously. Further studies will be required to elucidate the genetic control of hypercholesterolemia and the associated combined hyperlipidemia in these rabbits.

Animals↗
PubMed1988

Penetrance in the presence of genetic susceptibility to environmental factors.

Many single-gene disorders (especially dominant traits) are known to exhibit "incomplete penetrance," a term often criticized as reflecting our ignorance of genetic and environmental factors that may interact with the genotype to determine the ultimate phenotype of the individual. We explore the effects of an environmental factor on penetrance for a simple model of single gene-mediated susceptibility to environmental factors. We show that penetrance of the susceptible genotype increases with increasing frequency of exposure to the factor and the strength of interaction between the factor and the genotype (relative risk). For disorders with disease frequency of 0.001 or less (as seen with many congenital malformations), penetrance is generally low (less than 10%) if the exposure frequency is low (less than 10%) even in the face of strong gene-environment interaction. Such low penetrance can lead to low recurrence risks. Single-gene effects could easily be overlooked in genetic analysis unless specific environmental factors are considered.

Environment↗
PubMed1988

Effect of maternal and infant covariates on sibship correlation in birth weight.

Birth weight on 12,644 singleton infants from 6,196 sibships born in Maryland between 1980 and 1984 were used to estimate the effects of nine maternal and infant covariates on the sibship correlation in birth weight. Assuming a homogeneous correlation across all families, the estimated intraclass correlation was 0.4664 (+/- 0.0099). This high sibship correlation makes it possible to predict, with reasonable accuracy, the birth weight of a child given information on previous sibs, as well as covariates on the mother and/or infant pertinent to a given pregnancy. The reduction in variance associated with incorporating information on the nine covariates used here was approximately equal to that obtained by conditioning on a single previous sib. Testing for heterogeneity in correlation among different groups of families showed that a crude measure of parity (first live birth vs. other), time between births, mother's marital status, and maternal age at the birth of the last child significantly influenced the sibship correlation in birth weight.

Adult↗
PubMed1988

Assessing familial aggregation of congenital cardiovascular malformations in case-control studies.

Recent data indicate that the familial aggregation of congenital cardiovascular malformations (CCVM) varies with the type of defect in the index case. Using a logistic regression model that allows for dependence among family members, we calculated the risk of any CCVM to case relatives compared with relatives of controls. Data from 3,908 first-degree relatives of 570 matched cases and controls identified from 1981 through 1985 by the Baltimore-Washington Infant Study were used in the analyses. Overall risk for any CCVM in case relatives was increased four-fold over that of control relatives. While relatives of cases with flow lesions (including right and left heart defects, as well as perimembranous ventricular septal defect [VSD]) had a five-fold increase in risk, the risk to relatives of nonflow lesion cases did not differ significantly from the risk to relatives of controls. Sex, maternal age, miscarriage history in the mother, and birth order had no apparent effect on risk among siblings. However, there was an indication of increased risk in relatives of nonwhite cases with VSD compared to relatives of matched controls. However, with these data it was not possible to distinguish between environmental and genetic sources of this familial aggregation.

Black People↗
PubMed1988

Can familial aggregation of disease be explained by familial aggregation of environmental risk factors?

Although familial aggregation has been shown for many if not all diseases, it is often difficult to determine whether such aggregation is due to shared genes or shared environmental factors. The authors examine the effect of familial aggregation of environmental risk factors on familial aggregation of disease when there is no genetic susceptibility. An environmental risk factor with a relative risk (R) for disease and population exposure frequency (f) is assumed to be clustered among siblings with varying degrees of sibling correlation in exposure (c). The impact of varying R, f, and c is examined on two common measures of familial aggregation: the relative risk of disease for siblings of cases compared with siblings of controls, and the sibling recurrence risk. It can be shown that both measures increase with increasing R and c, but decrease at high levels of f. However, even in the face of complete correlation in exposure among siblings (c = 1), environmental risk factors that have values of R less than 10 lead to modest sibling relative risks (ranging from 1 to 2) and low recurrence risks. Similar findings are obtained when familial aggregation of two additive environmental factors is considered. Because many diseases show higher sibling relative risks and recurrence risks, this analysis suggests that simple familial clustering of environmental factors is unlikely to account entirely for familial aggregation of disease, and that genetic factors ought to play an important role in causing familial aggregation.

Environmental Exposure↗
PubMed1988

Problems of genetic model testing in early onset periodontitis.

Familial aggregation of early onset or juvenile periodontitis (JP), a disorder that varies in expression and age of onset, has been recognized for some time. Autosomal recessive and X-linked inheritance patterns have been suggested, and one large pedigree has demonstrated autosomal dominant inheritance. The variability and age limitations in clinical phenotypic diagnosis present several problems to genetic analysis, because information on members of the youngest and older generations may be lost to the analysis. The purpose of the present study was to elucidate the genetic basis of JP by formal pedigree analysis and comparison of competing genetic models. Twenty-eight families were included, with general and specific autosomal models, and an X-linked model being compared. The autosomal recessive model provided the most parsimonious explanation of the data, and its likelihood was not significantly different from the more general model. Likelihoods for the sporadic (nongenetic) and X-linked models were considerably lower than the autosomal models. While comparison of genetic models suggests recessive inheritance of JP, the serious complications to pedigree analysis posed by limitations warns against acceptance of this conclusion, without more exhaustive evaluation of: (1) a more extensive collection of family data, (2) more complete investigation of the effects of age limitations on comparisons among competing models, and (3) elucidation of the importance of diagnosis and phenotype assignment of adults through past dental records.

Adult↗
PubMed1987

Recurrence risks in the presence of single gene susceptibility to environmental agents.

Investigators often attribute the 2-5% sibling recurrence risks of common congenital malformations to a multifactional/threshold model (MFT) mechanism. However, most studies fail to address adequately the role of specific environmental factors and their interaction with genetic factors in recurrence risks. We consider the effects of a hypothetical environmental agent on recurrence risks in the presence of a single gene-mediated differential susceptibility. It can be shown that recurrence risks increase with increasing population exposure frequency to the agent and the strength of gene-environment interaction (relative risk among susceptible genotypes). However, they are usually much lower than expected on the basis of simple Mendelian segregation. Moreover, recurrence risks decline considerably between 1st, 2nd, and 3rd degree relatives, especially for recessive traits. Because single gene-mediated differential susceptibility can mimic the MFT model in many instances, family studies of malformations (and other common diseases) could be more rewarding if they incorporate in their design and analyses specific environmental exposures affecting disease risk.

Congenital Abnormalities↗
PubMed1987

Predicting recurrence risks under epistatic models.

We present the expected recurrence risks to a sib of an affected proband under 4 simple 2-locus epistatic models for various allele frequencies at both the disease locus and the epistatic locus. Four obvious epistatic models are considered: an autosomal recessive disease with both 1) dominant and 2) recessive masking by the epistatic locus, and an autosomal dominant disease again with both 3) dominant and 4) recessive masking. Expected recurrence risks to a sib of an affected proband and to a sib of an affected proband with another normal sib are presented in the absence of information on parental status. Similar risks are presented for the case where both parents are known to be phenotypically normal. These recurrence risks were calculated using a convenient matrix notation which allows sequential calculation of genotypic probabilities. In general, 2-locus epistatic models can give surprisingly low recurrence risks, and often these risks, especially for models of recessive diseases, fall into the range associated with a more general multifactorial model for liability.

Epistasis, Genetic↗
PubMed1987

Use of the G8 probe in predicting risk of Huntington disease.

Discovery of the linkage between the G8 probe and the gene for Huntington disease (HD) in families of varying ethnic origin, age-of-onset characteristics, and neurological symptomatology, makes it possible to use the G8 marker for presymptomatic testing of at-risk individuals. Risk estimates for such situations were calculated, using the program LIPED, with different G8 haplotype frequencies, different age-of-onset distributions, and varying amounts of family information. In the presence of untyped relatives, the resulting risk estimates can be extremely sensitive to G8 haplotype frequencies, and the higher risk was seen in individuals carrying rare haplotypes. Including haplotype information on distant relatives can also lead to greater variation in risk estimates. Changing the age-of-onset distribution had only a minimal effect on estimated risks; the largest effect was seen when informative at-risk sibs of the consultand were in their forties.

Adult↗