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T H Beaty

Publications and source records attributed to T H Beaty.

At least 91 records · Page 5Linked to original sources
PubMed1993

Segregation analysis of hypospadias: a reanalysis of published pedigree data.

Little is known about the cause of hypospadias, one of the most common urogenital anomalies in males. Familial clustering of hypospadias is well recognized, with heritability estimated to be about 70% under a simple multifactorial threshold model. Neither alternative genetic mechanisms nor shared environmental factors within families have been explored fully. To learn more about possible genetic mechanisms, we used 2 methods of segregation analysis to analyze a set of published family data. These analyses are based on the families of 103 probands with hypospadias, who were ascertained through surgery departments in Denmark [Sørensen, 1953]. Urogenital examinations were performed on 95% (n = 1,510) of available male relatives, and 2.2% were found to have hypospadias. Within the probands' nuclear families, 12% of nonproband sons of normal fathers were affected. Using the mixed model of inheritance, both the autosomal dominant (AD) and codominant models fit these data better than either autosomal recessive (AR) or multifactorial models. Using the regressive logistic models, both AD and AR models were equally likely, and a model of nonMendelian sibship clustering gave a better fit to these data. These inconsistent findings illustrate the difficulties commonly encountered in segregation analysis. Using 2 different statistical approaches, we found 2 different explanations, both of which differ from the autosomal recessive model originally suggested by Sørensen [1953]. Hypospadias in these families is almost certainly heterogeneous. Determining the cause of familial clustering of hypospadias will require careful delineation of persons with recognized syndromes from uncomplicated cases and detailed information on potential prenatal risk factors.

Female↗
PubMed1993

Inheritance of plasma apolipoprotein B levels in families of patients undergoing coronary arteriography at an early age.

An elevated plasma level of apolipoprotein B (apoB), the major protein of low density lipoproteins, is a risk factor for coronary artery disease. This study tested the hypothesis, suggested by previous studies, that the apoB level is strongly influenced by a major gene. The study population included 832 family members of 116 subjects who had undergone elective coronary arteriography at an early age. The apoB level was adjusted for age, gender, body mass index, alcohol consumption, and cigarette smoking (R2 = 20%). ApoB levels revealed strong familial aggregation with correlations among spouses of 0.23, parent-offspring of 0.16, and siblings of 0.21. Regressive models were used to examine inter-individual variation in adjusted apoB levels. In the total sample, familial aggregation of the apoB level was consistent with two models: (1) a major gene model and (2) a polygenic model with a mixture of non-transmitted "types". Comparison of these two models in each family showed that 57 families supported the first model over the second. Segregation analysis in these 57 families conclusively favored a major gene model with codominant transmission. Genotypic means were 124, 164, and 208 mg/dl with relative frequencies of 45%, 44%, and 11%. Linkage studies in these families can be used to clarify the molecular basis of apoB regulation. However, in the whole population the genetic control of apoB levels may be quite complex.

Apolipoproteins B↗
PubMed1993

Genotype at a major locus with large effects on apolipoprotein B levels predicts familial combined hyperlipidemia.

A sample enriched for familial combined hyperlipidemia (FCHL) was examined for evidence of an association between genotype at an apolipoprotein B (apoB) elevating locus defined by complex segregation analysis and FCHL. Complex segregation analysis detected a locus with a large effect on plasma apoB levels and was used to compute the most probable genotype of family members. None of the 35 normolipidemic adults carried a copy of the allele associated with elevated apoB levels, yet 58% of the 109 adults with FCHL carried 1 (29%) or 2 (28%) copies. Two of 28 (7%) normal children had 1 copy of this allele and none had 2 copies, while 88 of 182 (48%) children with FCHL had 1 (26%) or 2 (22%) copies. Further, 41 of 48 (85%) individuals classified as having hyperapobetalipoproteinemia did not carry a copy of this "elevated apoB" allele. Therefore, the presence of the allele associated with elevation of apoB level is highly predictive of FCHL and this association cannot be explained solely by the presence of elevated apoB levels in FCHL, suggesting that the locus controlling apoB levels may play an etiologic role in FCHL.

Adolescent↗
PubMed1993

Scope and strategies of genetic epidemiology: analysis of articles published in Genetic Epidemiology, 1984-1991.

Genetic epidemiology is a relatively new discipline that seeks to unravel the role of genetic factors and their interactions with environmental factors in the etiology of diseases, using population and family study approaches. To characterize the overall direction and emphasis of research strategies used in this field, we reviewed original research articles published in the journal Genetic Epidemiology since its inception in 1984 until the end of 1991. Of 259 published original articles, 92 (35%) focused primarily on methodologic/statistical developments, most commonly in the area of linkage analysis/gene mapping, and 167 (65%) articles were applied or data-derived. Only 42 articles (16%) were population studies, and 217 (84%) were family studies. Most family studies dealt with genetic analysis of pedigree data using segregation and linkage analyses. Of the 137 applied family studies, 73 (53%) were drawn from well-defined populations, and only 40 (29%) considered specific environmental factors in their analyses. These findings clearly indicate a rapid growth in the methodologic and statistical aspects of genetic epidemiology, and in the emphasis on family-based studies and genetic analysis methods. Further developments in genetic epidemiology will require greater integration of epidemiologic approaches of study design and analyses into population and family studies of disease etiology.

Epidemiology↗
PubMed1993

Two-locus and bivariate segregation analysis of HDL-C and apo AI.

Two-locus and bivariate segregation analyses of HDL-C and apo AI were carried out using the GAW8 Berkeley data set. For HDL-C, results are ambiguous. Both the mixed environmental model and the mixed Mendelian model fit the data equally well. For apo AI, however, univariate one-locus segregation analysis suggests a Mendelian major gene controlling its levels. Moreover, two-locus analysis suggests a second major gene is involved. Bivariate segregation analysis indicates these data cannot resolve the question as to whether a single Mendelian major gene with pleiotropic effects controls levels of both HDL-C and apo AI in humans.

Apolipoprotein A-I↗
PubMed1993

Familial aggregation of periodontal indices.

Analysis of three measures of periodontal health (plaque index, gingival index, and attachment loss) was carried out on 178 individuals in 75 families examined as part of a family study of periodontal health. Original participants in this study were volunteers recruited from the University of Maryland Dental Clinic, and were selected independently of any specific dental disease or condition. Relatives were invited to participate in the family study so that the extent of familial aggregation of indices of periodontal health could be assessed. By means of an analysis of variance model for persons nested within families, evidence for familial aggregation of plaque index was found both before and after adjustment for covariates such as age, gender, race, and reported oral hygiene habits. While a substantial fraction of variance in gingival index and attachment loss was also due to differences among families, neither attained statistical significance in these data. Examination of familial correlations (e.g., parent-offspring, sib-sib, spouse correlations) confirmed that plaque index showed greater familial resemblance compared with other measures of periodontal health. Both mean gingival index and mean attachment loss showed a stronger correlation between mothers and offspring compared with fathers and offspring. This suggests that further analysis of models for separating genetic and environmental effects may be appropriate for plaque index, but complete analysis of other periodontal indices will require more flexible statistical models for separation of genetic and cultural inheritance while considering gender-specific expression and transmission, as well as incorporation of information from covariates.

Adolescent↗
PubMed1992

Predictions of a 2-locus model for disease heterogeneity: application to adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked disorder that exhibits a wide range of phenotypic variability within individuals in a single family carrying the mutant allele. A 2-locus epistatic model has been proposed to explain the inheritance of the severe childhood form of ALD and the milder adult-onset adrenomyloneuropathy (AMN). Under a dominant epistatic model, a single M allele at an autosomal modifier locus ameliorates the most severe effects of the disease allele leading to the milder AMN phenotype; only males with genotype mm would have ALD. Under a recessive epistatic model, 2 copies of the M allele would be necessary to have the milder AMN phenotype. Here, we show that recurrence risks for a second affected male depend on the frequency of the protective allele at this modifier locus. Whereas it is most likely that 2 affected brothers will be concordant for their disease phenotypes, discordant pairs of affected brothers are possible at all frequencies of M. Within a narrow range of modifier allele frequencies, the predicted distribution of affected sib pairs (over all families) is consistent with empiric data from a large clinic population. Here we suggest sampling discordant affected sib pairs as a strategy for detecting linkage between a polymorphic DNA marker and a possible modifier gene. Since both epistatic models predict that discordant affected pairs should not share 2 alleles at the modifier locus, we expect that departures from the null distribution could be detected with relatively small numbers of sib pairs.

Adrenoleukodystrophy↗
PubMed1992

Genetic-epidemiologic study of omphalocele and gastroschisis: evidence for heterogeneity.

On the basis of clinical manifestations, epidemiologic characteristics, and the presence of additional malformations, omphalocele (OM) and gastroschisis (GA) are considered casually and pathogenetically distinct abdominal wall defects. More than 50% of infants with OM have additional defects, but only about 15% of those with GA do. To evaluate whether there is heterogeneity between isolated and multiply affected cases of OM and GA, we analyzed epidemiologic characteristics and familial risks of major defects for 82 OM and 81 GA cases drawn from a population-based study in the Maryland-Washington, DC-Northern Virginia area and born from 1980 through June 1987. We examined year of birth, sex, race, and maternal age distributions after stratifying the infants into isolated and multiple defect groups. We found significant differences in maternal age between cases with isolated OM and GA, but not between cases with GA or OM who had other defects. Using regressive logistic models, we analyzed familial aggregation of birth defects among relatives of infants with OM and GA. An autosomal recessive model of inheritance was found to be the most parsimonious explanation for the families of infants with isolated OM or GA. However, for families of infants with multiple defects, a sporadic or nongenetic model fit best. These findings are not only useful for estimating familial risk of major birth defects, but they also suggest further heterogeneity of infants with OM and GA according to the presence of other malformations.

Abdominal Muscles↗
PubMed1992

Mendelian inheritance of familial prostate cancer.

Previous studies have demonstrated familial clustering of prostate cancer. To define the nature of this familial aggregation and to assess whether Mendelian inheritance can explain prostate cancer clustering, proportional hazards and segregation analyses were performed on 691 families ascertained through a single prostate cancer proband. The proportional hazards analyses revealed that two factors, early age at onset of disease in the proband and multiple affected family members, were important determinants of risk of prostate cancer in these families. Furthermore, segregation analyses revealed that this clustering can be best explained by autosomal dominant inheritance of a rare (q = 0.0030) high-risk allele leading to an early onset of prostate cancer. The estimated cumulative risk of prostate cancer for carriers revealed that the allele was highly penetrant: by age 85, 88% of carriers compared to only 5% of noncarriers are projected to be affected with prostate cancer. The best fitting autosomal dominant model further suggested that this inherited form of prostate cancer accounts for a significant proportion of early onset disease but overall is responsible for a small proportion of prostate cancer occurrence (9% by age 85). These data provide evidence that prostate cancer is inherited in Mendelian fashion in a subset of families and provide a foundation for gene mapping studies of heritable prostate cancer. Characterization of genes involved in inherited prostate cancer could provide important insight into the development of this disease in general.

Adult↗
PubMed1992

Estimating familial aggregation while adjusting for covariates. Application to pulmonary function data from black and white sibships.

Although crude correlations are useful in family studies, some adjustment for effects of risk factors that vary both within and among families if often needed. A linear model for estimating sibship correlations while simultaneously considering height, age, race, sex, ascertainment, and smoking status was used on pulmonary function data on 1-second forced expiratory volume (FEV1) and the natural logarithm of the ratio of FEV1 to forced vital capacity (lnFEV%) from 402 adults in 152 white sibships and 172 adults in 59 black sibships. Crude correlations of .271 +/- .048 (FEV1) and .342 +/- .047 (lnFEV%) decreased significantly to .206 +/- .048 and .231 +/- .048, respectively, after adjustment. For black and white sibs, adjusted intraclass correlations, although not statistically different, were .153 +/- .089 and .225 +/- .055 (FEV1), respectively, and were .103 +/- .088 and .275 +/- .054 (lnFEV%), respectively, suggesting that pulmonary function may aggregate more strongly among whites. This analysis illustrates how risk factor adjustment can be readily incorporated into familial correlation studies.

Adult↗
PubMed1992

A genetic model for control of hypertriglyceridemia and apolipoprotein B levels in the Johns Hopkins colony of St. Thomas Hospital rabbits.

The St. Thomas Hospital (STH) rabbit has been previously shown to have a Mendelian form of hypertriglyceridemia, accompanied by accelerated atherosclerosis, and these animals may serve as a useful model for human dyslipoproteinemia syndromes. Here we describe the establishment of a new colony of these STH animals, and present genetic analysis of triglyceride (TG) and apolipoprotein B (apoB) levels. Segregation analysis of TG in 39 STH animals and 24 controls gave evidence of Mendelian segregation for an allele leading to both elevated TG levels and increased variability in these levels. Predicted means from the most parsimonious model for the Johns Hopkins STH colony were quite similar to that seen in the original London colony, and this model accounted for 80% of the variation in TG seen in the sample. This hypertriglyceridemia locus indirectly influenced the mean apoB levels in these rabbits, and segregation analysis of mean apoB levels suggested a second locus controlling apoB levels. Analysis of residual apoB levels (adjusted for predicted effects of the hypertriglyceridemia locus) revealed clearer evidence for a second locus controlling mean apoB levels in this colony. Arguments for two distinct genetic mechanisms operating in these STH animals are presented.

Animals↗
PubMed1992

Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients.

Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these two risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families.

Adolescent↗
PubMed1992

Pedigree and sib-pair linkage analysis suggest the apolipoprotein B gene is not the major gene influencing plasma apolipoprotein B levels.

Previous studies suggest that plasma apolipoprotein B-100 (apoB) level is strongly influenced by genetic factors. Characterizing alleles that influence plasma apoB level would help define genetic risk factors for coronary artery disease. This study examined the role of variability in the apolipoprotein B gene (APOB) in determining plasma apoB level. Twenty-three informative families from the Johns Hopkins Coronary Artery Disease Family Study were studied. Linkage analysis between three polymorphisms in the APOB gene (XbaI at codon 2488, MspI at codon 3611, and EcoRI at codon 4154) and a putative major gene with a codominant allele for elevated apoB levels gave evidence against linkage (LOD score of -7.9 at a recombination fraction of .001). None of the families had a LOD score greater than 0.5, while five families had a LOD score less than -0.5. Sib-pair analysis also showed no relationship between the proportion of genes identical by descent at the APOB locus and either crude or adjusted plasma apoB levels. Thus, in 23 informative families, there was no evidence for the presence, in APOB, of common alleles that influence plasma apoB levels. These results suggest that APOB is not the major locus influencing plasma apoB levels.

Apolipoproteins B↗
PubMed1991

Applications of the concept of attributable fraction in medical genetics.

Attributable fraction, the fraction of cases of a disease in a population attributed to a particular risk factor, is a useful measure in the design and interpretation of epidemiologic studies of disease etiology. We review here the applications of the concept of attributable fraction in medical genetics. Specifically, attributable fraction can be used 1) in studies of the association between genetic traits and specific diseases to quantitate the contribution of specific alleles to disease occurrence in a population; 2) in population studies of mutations and birth defects to estimate the impact of mutagens and teratogens; and 3) in genetic analyses of family data, to evaluate the contribution of putative single gene loci to disease etiology. In the latter context, the concept of attributable fraction can be contrasted with the more commonly used concept of heritability. Examples from the literature provide illustrations of the usefulness of attributable fraction in medical genetic studies.

Alleles↗
PubMed1991

Using log-linear models to test for associations among congenital malformations.

Log-linear models can be used to test for pairwise associations and higher order interactions among anatomically distinct birth defects or congenital malformations. A log-linear model, including terms for every possible pairwise association among seven severe and easily detectable congenital malformations, was examined using data on 16,217 infants registered in the Metropolitan Atlanta Congenital Defects Program between 1968 and 1986. The resulting model showed clear patterns of strong association between some congenital malformations and not others, and the presence of 3-way interaction terms where the association between two malformations depended on the presence of a third. Examining a more parsimonious log-linear model showed overlapping patterns of pairwise association involving anal-rectal atresia and omphalocele, anal-rectal atresia and limb deficiency, and anal-rectal atresia and tracheaesophageal fistula. A second common pattern involved a triangular cluster with a hierarchical relationship among the three malformations (where there was a strong association between the first and second malformations and between the first and third malformations, but the association between the second and third was only seen in the absence of the first). Three such overlapping triangular clusters were identified from these data: neural tube defects, oral clefts, and omphalocele; neural tube defects, oral clefts, and limb deficiency; and limb deficiency, diaphragmatic hernia, and neural tube defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Multiple↗
PubMed1991

Genetics of total serum IgE levels: a regressive model approach to segregation analysis.

The genetics of basal total serum IgE levels was investigated in 278 individuals from 42 randomly ascertained nuclear families. The data were analyzed using the regressive model approach to segregation analysis with age, sex, and a measure of skin test responsiveness as covariates in the Class D models. The best fitting model was that of recessive inheritance of high IgE levels with a gene frequency of 0.99 for the "high" allele. Only 3 families showed evidence for segregation of the rare "low" allele, and, if extended further, these families could be useful for molecular genetic linkage studies. These results suggest that there may be a rare allele for very low total serum IgE levels that can be detected even after a measurement of allergic responsiveness (skin test results) is considered as a covariate. Therefore, this major gene for IgE levels appears independent of any similar locus controlling atopy.

Adolescent↗