Phenotypic discordance in a family with monozygotic twins and non-syndromic cleft lip and palate.
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Adult↗
Biomedical subjects
T H Beaty
Publications and source records attributed to T H Beaty.
Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search.
Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.
Adult↗
Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro-Caribbean and Caucasian populations.
To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) controlling asthma and the associated "high total IgE" trait.
Adolescent↗
Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts.
Oral clefts are common birth defects affecting approximately 1 every 1,000 caucasian newborns. While many syndromes with cleft lip with or without cleft palate (CL/P) or with cleft palate (CP) are recognized, the majority of oral clefts fall into the category of "nonsyndromic oral clefts" and the etiology of this group remains incompletely understood. Investigators agree that oral clefts are multifactorial in origin, with both genetic and environmental factors in their etiology. While animal models have identified several teratogens for oral clefts, their precise relevance for humans remains unclear. The goal of this work is to review literature on environmental exposures potentially associated with non-syndromic oral clefts.
Agriculture↗
Comparison of methods for survival analysis of dependent data.
Analysis of dependent survival data by conventional partial likelihood methods produces unbiased estimates of the regression coefficients but incorrectly estimates their variance. Here we compared the conventional partial likelihood methods with two alternative methods for analyzing dependent survival data. The first alternative method estimated the regression coefficient by the partial likelihood approach but adjusted the variance to account for clustering. The second alternative method used marginal likelihoods to estimate both the regression coefficient and its variance. We evaluated the performance of the three methods using simulated and actual data. Simulated data were used to examine bias, efficiency, type I errors, and power. An Old Order Amish genealogy was analyzed under these models to illustrate their performance on real data. The simulation study showed that all three methods provided unbiased estimates of the regression coefficient, but the efficiency of the estimated regression coefficient varied according to the simulation conditions. The standard partial likelihood method showed increasing type I error as the dependence increased within clusters. Both alternative methods had acceptable levels of type I errors at all dependence levels. In the analysis of genealogic data, the regression coefficient was similar in the three methods showing stable estimates of the regression coefficients. The variance estimates from the alternative methods were slightly different from the conventional method, suggesting a flow level of dependence. This study displays the effect of violating the independence assumption and provides guidelines for using alternative statistical methods.
Analysis of Variance↗
Determining linkage and mode of inheritance: mode scores and other methods.
The lod score method remains a popular approach for detecting linkage and estimating the recombination fraction theta between a marker locus and a trait locus. However, its implementation requires knowledge of all parameters of the genetic mechanism, including the number of loci involved and the genotype specific penetrance, which could depend on factors such as age. When some of the penetrance parameters phi are unknown, several methods are available, and have been reviewed by Hodge and Elston [(1994) Genet Epidemiol 11:329-342]. These include the "wrod score" (lod score maximized over theta under a wrong value of phi) and "mod score" (lod score maximized over both theta and phi) methods for inference on theta. It has further been proposed that the mod score also be used for estimating phi. In this paper, we review and assess the adequacy of these two methods for inferences on both phi and theta. In particular, all of the methods can be seen as variations on likelihood inference, using the information in the conditional likelihood for the marker data, given the trait data. The loss of efficiency of the mod is compared to that of the full likelihood, which utilizes all information available in the trait data. We also propose an alternative, based on the pseudo-likelihood, where phi is estimated via the trait information and plugged into the conditional likelihood. This method is compared to the mod score method, and the advantages and disadvantages of each are elucidated. In particular, it is seen that the pseudo-likelihood method can be more efficient than the mod score method if the ascertainment scheme can be modeled. As examples, both a random sample and a multiplex ascertainment scheme are considered. In addition, the pseudo-likelihood method leads to likelihood ratio tests for detecting linkage with a simple, known asymptotic reference distribution, a feature not shared by the mod score. Finally, we discuss the advantages of using the pseudo-likelihood method over the full likelihood method, both of which are valid when the ascertainment scheme is known.
Genetic Linkage↗
Histopathologic characterization of hereditary benign prostatic hyperplasia.
OBJECTIVES: Recent studies suggest the presence of a hereditary form of benign prostatic hyperplasia (H-BPH). This study was undertaken to characterize the histopathologic features of BPH in these men. METHODS: Because study subjects with H-BPH were young (mean age 59 years) and had a large prostate (mean prostate weight 61 g), we compared the histopathologic findings in these men with those in two different control groups: (1) age-matched control subjects (mean age 59 years; mean prostate weight 31 g), and (2) prostate weight-matched control subjects (mean age 70 years; mean prostate weight 61 g). Using a color video image analysis system, we morphometrically determined stromal/epithelial ratios in histologic sections taken from 12 men with H-BPH, 36 age-matched control subjects, and 36 prostate weight-matched control subjects. RESULTS: The stromal/epithelial ratio was 2.6 +/- 1.4 in the men with H-BPH, 2.7 +/- 1.7 in the age-matched control subjects, and 1.7 +/- 0.9 in the prostate weight-matched control subjects. Regression analysis, which controlled for the differences in prostate weight or patient age between men with H-BPH and age-matched and prostate weight-matched control subjects, respectively, revealed a significant difference between men with H-BPH and prostate weight-matched control subjects (P = 0.015) but no difference from age-matched control subjects (P = 0.36). CONCLUSIONS: The larger prostates in young men with H-BPH are characterized by a higher stromal/epithelial ratio than are similar-sized prostates in older men with sporadic BPH. This finding gives rise to speculation that H-BPH is associated with an increase in stromal elements.
Adult↗
Genetics of nonsyndromic oral clefts revisited.
Nonsyndromic oral clefts are among the most common birth defects, affecting approximately 1 in 1000 Caucasian newborns. In recent decades, many investigators have used genetic and epidemiologic methods to identify etiologic factors, but results have often been inconclusive or contradictory. Etiologic heterogeneity is undoubtedly a major component in these birth defects, and there may not be a single answer to this problem. Here, we describe the main features of published studies pointing out their strengths and limitations. Additionally, we give insight into current methods for detecting the presence of interaction between genetic markers and environmental exposures in the etiology of oral clefts.
Alleles↗
Risk of cancer in relatives of prostate cancer probands.
BACKGROUND: It is estimated that there will be more than 244,000 new prostate cancer cases diagnosed and that more than 40,000 men will die of this disease during 1995. Evidence exists for a hereditary predisposition to prostate cancer, but the proportion of cases attributable to the inheritance of a specific gene or genes is not large. Some hereditary cancer syndromes involve more than one tumor site, and some studies have reported a familial association between prostate cancer and other cancers. The presence of other cancers in prostate cancer families may indicate a specific type of hereditary predisposition. PURPOSE: We studied families that were selected because of the presence of prostate cancer to determine whether hereditary prostate cancer is associated with cancers at other sites and possibly with other heritable cancer syndromes. METHODS: Data from two distinct study populations were studied retrospectively. The first population consisted of 690 case patients undergoing radical prostatectomy who were not selected for family history of prostate cancer and 640 control subjects who were the spouses or female companions of the case patients. The second population consisted of 75 multiplex families (i.e., families with multiple cases of prostate cancer) referred because they fulfilled the criteria for hereditary prostate cancer. A comparison between case and control populations for the occurrence of 14 aggregated groups of cancer was performed. Data were analyzed using Poisson regression, and relative risks (RRs) and their 95% confidence intervals (CIs) were calculated. RESULTS: Brothers and fathers of prostate cancer probands have a statistically significant higher risk of prostate cancer than the male first-degree relatives of control subjects (RR = 1.76; 95% CI = 1.28-2.43). Therefore, the risk for prostate cancer is 76% higher among first-degree relatives of prostate cancer patients compared with first-degree relatives of control subjects. This higher risk was not modified by an occurrence of breast cancer in the pedigree. Also, a statistically significant higher risk was found for tumors of the central nervous system in hereditary families (RR = 3.02; 95% CI = 1.08-8.41). Statistically significant higher risks of cancer at other major sites, such as breast, ovary, or endometrium were not observed in these families. CONCLUSIONS: Even among families that were specifically selected because of the presence of prostate cancer, risks for cancer at other sites appeared not to be increased. Therefore, hereditary prostate cancer appears to be a relatively site-specific disease, and it does not seem to be a part of other hereditary cancer syndromes.
Adult↗
Association study of transforming growth factor alpha (TGF alpha) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects.
In this study of infants with isolated birth defects, 69 cleft palate only cases, 114 cleft lip with or without cleft palate cases, and 284 controls with noncleft birth defects (all born in Maryland between 1984 and 1992) were examined to test for associations among maternal exposures, genetic markers, and oral clefts. A significantly higher frequency of positive family history of birth defects among both groups of oral cleft cases compared with controls was seen in these data. While there was a modest increase in the less common C2 allele at the TaqI site in the transforming growth factor alpha (TGF alpha) locus among cleft palate only infants compared with the birth defect controls, the association appeared to reflect an underlying interaction between maternal smoking and infant genotype. This apparent gene-environment interaction was also found among those reporting no family history of any birth defect. Infants carrying the rarer C2 allele who were exposed to maternal smoking of 10 or fewer cigarettes per day showed a 6.16-fold increase in risk for cleft palate only (95% confidence interval 1.09-34.7), while similar infants whose mothers smoked more than 10 cigarettes per day showed an 8.69-fold higher risk (95% confidence interval 1.57-47.8). However, the dose-response relation was not significant.
Adult↗
Detection of genotype-environment interaction in case-control studies of birth defects: how big a sample size?
Detecting interactions between risk factors in case-control studies of birth defects and other conditions usually requires increasing the sample size beyond that needed to detect marginal effects. A special case of such interaction is genotype-environment interaction in which the effects of an exposure on disease risk are modified by genetic susceptibility. When case-control studies are designed to detect marginal effects of an exposure (i.e., in the whole population), under many plausible interaction schemes, no additional case and control subjects are needed to detect genotype-environment interaction. On the contrary, inclusion of genotypic information generally can improve the statistical power of the original study. Using the example of oral clefts, maternal cigarette smoking, and genetic variation at the transforming growth factor alpha gene, we illustrate sample size and power issues in designing case-control studies when prior information is available on both the marginal effects of the exposure and the genetic factor.
Case-Control Studies↗
Total serum IgE levels and chromosome 5q.
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Adult↗
Segregation analysis of HDL3-C levels in families of patients undergoing coronary arteriography at an early age.
HDL cholesterol (HDL-C) level is a risk factor for coronary heart disease. Studies have shown a strong genetic influence on HDL-C levels in addition to environmental influences, but no definite major gene control has been demonstrated. Since HDL subfractions may better reflect the actions of distinct metabolic alterations than total HDL2 we tested the hypothesis that the amount of cholesterol in the denser HDL3 subfraction (HDL3-C) is under the control of a major gene. The study population included 676 family members of 116 probands who underwent coronary arteriography at an early age (men < or = 50 and women < or = 60 years). HDL3-C level was measured by using enzymatic methods after preparative ultracentrifugation at a density of 1.125 g/mL. HDL3-C was adjusted for age, gender, alcohol consumption, and smoking, which combined accounted for 3% of its variance. Segregation analysis was conducted on adjusted HDL3-C by using regressive models. The familial correlations for HDL3-C levels were spouse .03 +/- .08, parent-offspring .14 +/- .05, and sibling .24 +/- .05. The data strongly supported a codominant mendelian model, with the common allele coding for lower HDL3-C levels and the rarer allele (frequency, 25%) coding for higher HDL3-C levels. This major gene explained 34% of the variation in HDL3-C levels and 9% of the variation in total HDL-C levels. These results suggest that HDL3-C levels exhibit clearer genetic control than total HDL-C and may therefore be a useful target for further genetic studies.
Adult↗
Minimum sample size estimation to detect gene-environment interaction in case-control designs.
As genetic markers become more available, case-control studies will be increasingly important in defining the role of genetic factors in disease causality. The authors estimate the minimum sample size needed to assure adequate statistical power to detect gene-environment interaction. One assumption is made: the prevalence of exposure is independent of marker genotypes among controls. Given the assumption, six parameters (three odds ratios, the prevalence of exposure, the proportion of those with the susceptible genotype, and the ratio of controls to cases) dictate the expected cell sizes in a 2 x 2 x 2 table contrasting genetic susceptibility, exposure, and disease. The three odds ratios reflect the association between disease and 1) exposure among non-susceptibles; 2) susceptible genotypes among nonexposed individuals; and 3) the gene-environment interaction itself, respectively. Given these parameters, the number of cases and controls needed to assure any particular Type I and Type II error rates can be estimated. Results presented here demonstrate that case-control designs can be used to detect gene-environment interaction when there is both a common exposure and a highly polymorphic marker of susceptibility.
Case-Control Studies↗
Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations.
Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.
Adolescent↗
Comparative epidemiology of selected midline congenital abnormalities.
We present comparative epidemiologic characteristics of five congenital abnormalities that have been suggested to result from midline abnormal developmental disturbances: esophageal atresia with or without tracheoesophageal fistula (EA/TEF), imperforate anus with or without fistula (IA/F), omphalocele (OM), bladder exstrophy (BE), and diaphragmatic hernia (DH). The purpose was to assess the extent of epidemiologic similarities among these five defects. Data were collected as part of a population-based case-control study of infants with these defects born to mothers residing in Maryland, Washington, D.C., or Northern Virginia from 1980 through 1987. The estimated annual birth prevalences (per 10,000 live births) and 95% confidence intervals (CI) of these five defects were 0.40 (0.26-0.61) for BE, 1.34 (1.08-1.67) for OM, 1.59 (1.29-1.95) for DH, 2.11 (1.76-2.53) for EA/TEF, and 2.97 (2.55-3.46) for IA/F. The birth prevalence of IA/F and DH increased between 1980 and 1987. In contrast to the other four defects, DH showed a significant male preponderance (rate ratio 1.57, 95% CI 1.03-2.47), a significant white excess (rate ratio white:other, 1.56, 95% CI 1.00-2.48), and a lower proportion of multiple associated defects (30% vs. 46-61%). We concluded from this study that the descriptive epidemiology of diaphragmatic hernia is different from that of the other four defects. This finding may imply differences in etiologic and pathogenetic mechanisms underlying DH.
Abnormalities, Multiple↗
Genetic susceptibility of benign prostatic hyperplasia.
In an effort to provide new insight into the etiology of benign prostatic hyperplasia (BPH), an evaluation of genetic factors was performed. Recognizing that early age of onset is a marker for hereditary disease, we performed a case-control study of men with early onset of significant BPH. Men in the youngest quartile (less than 64 years old) with a large prostate (greater than 37 gm. resected tissue) who underwent surgery for BPH were identified as case probands from 909 consecutive prostatectomies for BPH. Control probands, selected because of the ability to distinguish treatment for benign prostate disease from treatment for malignant prostate disease, were women whose spouses underwent radical prostatectomy during the same interval. Male relatives of men with early onset of BPH had a 66% cumulative lifetime risk of prostatectomy for BPH, compared to a 17% cumulative risk among control relatives (p = 0.001). A 4-fold increase in age-specific risk of prostatectomy for BPH was present among relatives of men who had undergone prostatectomy for BPH (p = 0.0003), while brothers of these affected cases had a 6-fold increase in risk (p = 0.0089) compared to controls. To determine the likelihood that genetic factors account for this familial aggregation of BPH, segregation analysis was done. Although the small sample size prevented rigorous exclusion of nongenetic models, direct comparison of mendelian and nongenetic models showed that mendelian transmission provided the best overall explanation of the observed familial aggregation. The optimal model suggested mendelian dominant inheritance of a gene associated with early age at onset of BPH. These findings identify family history of BPH as a risk factor for clinical BPH and suggest the presence of a predisposing gene in patients with early onset BPH. Evidence of dominant mendelian transmission of this allele provides a framework for genetic studies to characterize this gene and elucidate the development of BPH in general.
Aged↗
Applications of the case-control method in genetic epidemiology.
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Case-Control Studies↗