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Biomedical subjects

R C Elston

Publications and source records attributed to R C Elston.

At least 109 records · Page 6Linked to original sources
PubMed1996

Segregation analysis of physician-diagnosed asthma in Hispanic and non-Hispanic white families. A recessive component?

The inheritance of asthma, evident from its high family concordance, is not well understood. To investigate whether asthma may be inherited through a major gene with two alleles, segregation analyses were conducted in 3,369 individuals from 906 nuclear families enrolled, without selection, in a longitudinal study of respiratory health in Tucson, Arizona. Physician-diagnosed asthma and its age of onset were ascertained for each family member when children were at a mean age of 7 yr. Age of asthma diagnosis was allowed for in analyses, and the impact of the covariate total serum IgE level on age of onset was examined. Segregation analyses were conducted with and without residual family effects, with and without the covariate IgE. The hypothesis of a single two-allele locus for asthma was rejected. However, depending on the method of assessment of the residual familial effects, either a polygenic/multifactorial mode of inheritance alone, or an oligogenic model with some evidence of a recessive component present in the population with the high frequency of 0.67, were compatible with the data. Results were unchanged with the addition of the covariate IgE.

Adult↗
PubMed1995

Statistical validity for testing associations between genetic markers and quantitative traits in family data.

In genetic analysis it is often of interest to analyze associations between traits of unknown genetic etiology and genetic markers from pedigree data. Statistical methods that assume independence of pedigree members cannot be used because they disregard the statistical dependencies of members in a pedigree. For quantitative traits, a regression model proposed by George and Elston [Genet Epidemiol 4:193-201, 1987] uses an asymptotic likelihood ratio test and incorporates a correlation structure that allows for statistical dependence among the pedigree members. The statistical validity of this test is assessed for finite samples by measuring the discrepancy between the empirical and theoretical chi-square distributions. The variance of the mean of the dependent variable is determined to be related to this discrepancy and can be used to determine whether a pedigree structure is large enough for making valid statistical inferences on the basis of the asymptotic test. A multi-generational pedigree of 200 or so individuals should in many cases be sufficient for valid results when using the asymptotic likelihood ratio test for the association between markers and continuous traits.

Family↗
PubMed1995

Model-free association analysis of a rare disease.

Model-free methods of testing for association of a disease with alleles at a marker locus were used to analyze simulated data for a rare disease locus and 360 marker loci distributed at 2 cM intervals along six chromosomes. After adjustment for multiple tests, there was no evidence of significant heterogeneity of parental allele frequencies between a sample of parents with at least one affected child and a sample of parents with no affected children. Several significant deviations from Hardy-Weinberg equilibrium were detected after Bonferroni correction but these were Type I errors. After adjusting for multiple tests, the model-free test for association detected significant associations of alleles at two loci with the disease. These associations were in fact part of the generating model for the simulated data. However, these methods were unable to detect two other major loci contributing to the disease since these loci were not associated with any of the marker loci.

Alleles↗
PubMed1995

Effects of marker information on sib-pair linkage analysis of a rare disease.

Model-free sib-pair linkage analysis was used to screen the GAW9-Problem 1 data set for evidence of linkage of a rare disease to any of 360 highly polymorphic marker loci. Negative regressions nominally significant at the alpha = 0.05 level were obtained for 44 markers; however all of these proved to be Type I errors. None of the four disease loci were detected by sib-pair linkage, which was not surprising, given the particular model and sampling scheme used to generate these data. Neither deleting parental marker genotypic information nor misspecifying marker allele frequency estimates substantially increased the Type I error rate. A two-stage testing procedure using a 10 or 20 cM map and a liberal first stage significance level gave the same overall results as a one-stage 2 cM map but required only about 42% or 22% as many markers, respectively.

Alleles↗
PubMed1995

Linkage analysis with an alternative formulation for the mixed model of inheritance: the finite polygenic mixed model.

This paper presents an extension of the finite polygenic mixed model of Fernando et al. (1994) to linkage analysis. The finite polygenic mixed model, extended for linkage analysis, leads to a likelihood that can be calculated using efficient algorithms developed for oligogenic models. For comparison, linkage analysis of 5 simulated 4021-member pedigrees was performed using the usual mixed model of inheritance, approximated by Hasstedt (1982), and the finite polygenic mixed model extended for linkage analysis presented here. Maximum likelihood estimates of the finite polygenic mixed model could be inferred to be closer to the simulated values in these pedigrees.

Genetic Linkage↗
PubMed1995

T cell receptor gamma gene polymorphisms and class II human lymphocyte antigen genotypes in patients with celiac disease from the west of Ireland.

Although celiac disease has one of the strongest human lymphocyte antigen (HLA) class II associations of any human illness, it is clear that at least one gene that is not linked to the HLA region also is required for its pathogenesis. The occurrence of large numbers of gamma delta T cells in the bowel mucosa of patients and the recent description of T cell receptor (TCR) gamma chain polymorphic variants identified by restriction fragment length polymorphism analysis led the authors to examine TCR gamma genotypes in relation to HLA-DR, DQ genotypes in 89 patients with celiac disease and 55 control subjects from the West of Ireland. The overall frequency of TCR gamma genotypes in patients and control subjects was comparable. However, most of the patients had 1 of 3 HLA-DR3 genotypes (DR3/15, 3/7, or 3/3), and there was a significant alteration of the expected frequency of TCR gamma genotypes among patients with these three genotypes. The major differences were an increased association of HLA-DR3 homozygosity, with TCR gamma genotypes having a 16.0 kb fragment and an increased frequency of DR3/7 heterozygosity and decreased frequency of DR3/15 heterozygosity, respectively, in association with the TCR gamma 13.0/11.3 kb genotype. Based on their results, there is the possibility that an interaction between the products of two polymorphic and unlinked gene regions contributes to the pathogenesis of celiac disease.

Celiac Disease↗
PubMed1995

Linkage and association to genetic markers.

Genetic markers that are sufficiently polymorphic (as measured by their heterozygosities) can be used in linkage and association analyses to detect Mendelian segregation underlying disease phenotypes. Each type of analysis can either be based on a specific genetic model or not make any assumptions about the mode of inheritance of the disease. Principles underlying these methods are reviewed, and the assumptions underlying them stressed. Association analyses are more powerful, provided there is linkage disequilibrium between the marker and disease loci; however, only linkage analyses have power in the absence of such disequilibrium. For this reason, models that allow for both kinds of tests are preferred, and such models must adequately approximate the complexity of the disease being studied.

Chromosome Mapping↗
PubMed1995

Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect.

Non-insulin-dependent diabetes mellitus (NIDDM) has a high prevalence in Pima Indians. The disorder is familial, but the extent to which genetic factors are involved in its etiology is largely unknown. Segregation analysis was used to determine whether familial aggregation of NIDDM in this population could reflect the action of a single major gene. The analysis included 2,697 subjects from 653 nuclear families in which both parents and at least one offspring had been examined in the course of a longitudinal epidemiological study. The REGTL program of the SAGE package was used to fit models in which age at onset of NIDDM is transmitted from parent to offspring under the unified model for segregation analysis. Likelihood-ratio tests were used to test hypotheses related to genetic transmission. The hypothesis of no major effect was strongly rejected (P < .01), as was that of no transmission of the major effect (P < .01). Mendelian transmission was not rejected (P = .91). Similar results were obtained when covariates for obesity and birth cohort were added to the models and when a power transformation of age at onset was estimated. A strong effect of birth cohort with earlier age at onset in the later born cohorts was observed (P < .01). The findings are consistent with the hypothesis that a major gene influences the risk for NIDDM in Pima Indians by affecting age at onset. The expression of this gene may depend on environmental factors that have become more prevalent in recent-birth cohorts.

Adolescent↗
PubMed1995

Familial anticardiolipin antibodies and C4 deficiency genotypes that coexist with MHC DQB1 risk factors.

OBJECTIVE: To investigate the familial basis of antiphospholipid antibodies by studying putative risk factors at the C4 and MHC class II loci. METHODS: Autoimmune diseases, anticardiolipin (aCL) and other autoantibodies were studied in 38 first and 2nd degree family members of 3 index cases selected for primary antiphospholipid syndrome (APS) and 33 controls. C4 protein phenotyping and restriction fragment length polymorphism analysis of C4 and MHC class II loci were performed. RESULTS: Nineteen family members (46%) had autoimmune diseases or autoantibodies; aCL were present in 10 family members, 4 of whom had primary APS. Each family had 2 or more subjects with aCL. Among 22 independent haplotypes in family members, there was a high frequency of C4A and C4B deficiency alleles (0.41 vs 0.18 in 66 controls, p = 0.03) and a strong trend toward an increase in MHC DQB1 putative risk factors that share the TRAELDT structural domain. This DQB1 structural domain was present in 4/5 different haplotypes that contained a C4B deficiency genotype; however, neither of 2 different haplotypes with a C4A deletion (one being a common ancestral haplotype) contained this DQB1 putative risk factor. Among the 10 family members who had aCL, 10/20 haplotypes contained a C4 deficiency genotype; moreover, the DQB1 putative risk factor was present in all 16 MHC haplotypes that did not contain a C4A deletion. CONCLUSION: In these families, expression of an autoimmunity trait as aCL antibody appears to be associated with the coexistence of C4 deficiency alleles with DQB1 alleles that contain the TRAELDT structural domain.

Adolescent↗
PubMed1995

Evidence for a major gene for cortical cataract.

PURPOSE: To examine the possible presence of a major gene determining susceptibility to cortical cataract. METHODS: The percentage of the lens area involved with cortical opacity, summed over both eyes, was evaluated in 1275 individuals from the Beaver Dam Eye Study. After adjusting for the effects of age and sex, these measures of cortical cataract were subjected to sibling correlational analysis, commingling analysis, and segregation analysis. The Box and Cox power transformation was applied to the data for the commingling and segregation analyses. Using regressive models, four modes of transmission were examined, and under each mode three hypotheses and a general model were fitted by maximum likelihood and compared. RESULTS: Sister-sister and brother-brother correlations of the adjusted measures of cortical cataract are significant and similar; the brother-sister correlation is not significantly different either from these correlations or from zero. Two commingled distributions give the best fit to the data, especially after power transformation. Under each of four modes of transmission, the hypothesis that best fits the data is one in which there are only two distributions (and, hence, dominance under mendelian transmission), the power transformation parameter is fixed at the estimate obtained from commingling analysis, and there is residual sibling correlation. The data thus suggest the existence of a major effect for cortical cataract. Random environmental influences can be rejected as a cause of this major effect. Our analysis indicates the existence of a significant effect of sex on the residual variance. Allowing for this, the data suggest transmission of a single major gene, though this may not be the sole cause of the commingled distributions. CONCLUSIONS: Assuming a common variance for the two sexes, a single major gene can account for 58% of the variability of age- and sex-adjusted measures of cortical cataract. With the variance sex dependent, a major gene can account for 75% and 45% of the total variability among males and females, respectively.

Adult↗
PubMed1994

Segregation analysis of smoking-associated malignancies: evidence for Mendelian inheritance.

Tobacco consumption is an established risk factor for cancer at a number of sites: oral cavity, esophagus, nasopharynx, lung, larynx, pancreas, bladder, kidney, and uterine cervix. These sites also demonstrate familial aggregation. To determine if evidence exists for a major gene controlling susceptibility to smoking-associated cancers, maximum likelihood segregation analyses were performed on 337 families (3,276 individuals) ascertained through a deceased lung cancer proband. Models were fitted that allowed for personal tobacco use and variable age of onset. The hypotheses of environmental transmission and no major gene were rejected (P < 0.005), but none of the Mendelian models could be distinguished. According to Akaike's Information Criterion, Mendelian dominant inheritance of an allele that produces cancer at an earlier age of onset provided the best fit to the data. The model suggests that 62% of the population are susceptible, and that the mean age-of-onset differs for men and women: at the mean level of tobacco exposure, female gene carriers are affected, on average, 24 years earlier than non-carriers (77 vs. 101), while in males the difference was 20 years (71 vs. 91). These findings extend our earlier observations on the genetic epidemiology of lung cancer and suggest that Mendelian factors may influence the risk of cancers that are known to be smoking associated.

Environment↗
PubMed1994

Combining two-point genetic linkage analyses using mapping functions.

A likelihood ratio statistic is proposed for combining two-point genetic linkage analyses when the two-point analyses are between a trait and a well-defined map of markers. It is assumed that the two-point analyses are independent, as in the case of choosing only the most informative marker per family. The asymptotic distribution of the likelihood ratio statistic is derived under the null hypothesis of no linkage of the trait with a map of 2 markers, with intermarker genetic distance delta. This distribution is shown to be a chi-square mixture distribution with mixing probability depending on delta and the assumed mapping function. We use this asymptotic result to approximate the distribution of the likelihood ratio statistic for the more general case of more than 2 markers. Simulation results indicate that this may be reasonable. Power is evaluated by simulations and results indicate that this approach, which constrains the intermarker distances to their known values, tends to be more powerful than other methods proposed in the literature.

Bias↗
PubMed1994

Linkage between the APOB gene and serum ApoB levels in a large pedigree from the Bogalusa Heart Study.

Maximum likelihood linkage analyses were performed to test for linkage between serum apoB levels and several candidate gene markers including apolipoprotein B, lipoprotein lipase, hepatic lipase, cholesterol ester transfer protein, and apolipoprotein AI in a large pedigree. Parameters of general Mendelian inheritance derived from maximum likelihood segregation analysis of the serum apoB levels were used in the linkage analysis. The highest two-point lod score between the quantitative trait and a marker defined by a single restriction digest was 1.86 at recombination fraction (theta) = 0. This was observed for linkage between serum apoB levels and the presence or absence of a PvuII digestion site in the apoB gene. Linkage between serum apoB levels and polymorphisms of the apoB gene defined by the two restriction digests EcoR1 and PvuII was supported by a lod score of 3.30, while inclusion of VNTR typings led to a lod score of 2.33. None of the other candidate genes gave positive evidence of linkage.

Adolescent↗
PubMed1994

Sibling correlations and segregation analysis of age-related maculopathy: the Beaver Dam Eye Study.

Sibling correlations were evaluated and segregation analysis was performed on age-dependent maculopathy scores of the right and left eyes of individuals from 564 families in the Beaver Dam Eye study. There is evidence of significant sibling correlations. The data fit a mixture of two normal distributions, especially after undergoing the Box and Cox power transformation. In each eye, the hypothesis of mendelian transmission of a major effect cannot be rejected under the tau AB free model, but is rejected under the tau's free model. The hypothesis of a random environmental major effect is rejected. Similar major gene parameter estimates are found for both eyes. The results are consistent with a major effect accounting for 62% and 59%, in the right and left eyes, respectively, of the determination of age-related maculopathy scores. A single major gene can account for about 89% and 97% of this variability due to a major effect, or for about 55% and 57% of the total variability, in the right and left eyes, respectively.

Adult↗
PubMed1994

Lods, wrods, and mods: the interpretation of lod scores calculated under different models.

In this paper we examine the relationships among classical lod scores, "wrod" scores (lod scores calculated under the wrong genetic model), and "mod" scores (lod scores maximized over genetic model parameters). We compare the behavior of these scores when the state of nature is linkage to their behavior when the state of nature is no linkage. We describe sufficient conditions for mod scores to be valid and discuss their use to determine the correct genetic model. We show that lod scores represent a likelihood-ratio test for independence. We explain the "ascertainment-assumption-free" aspect of using mod scores to determine mode of inheritance and we set this aspect into a well-established statistical framework. Finally, we summarize practical guidelines for the use of mod scores.

Bias↗
PubMed1994

Tuberculin reactivity after newborn BCG immunization in mono- and dizygotic twins.

SETTING: Studies showing significantly higher concordance of tuberculosis among monozygotic twins than dizygotic twins have provided support for genetically determined susceptibility to tuberculosis. OBJECTIVE: We wished to explore whether the development of delayed type hypersensitivity to tuberculin after newborn BCG immunization of twins suggested genetic regulation of the response to BCG in humans. DESIGN: Our study population consisted of 17 monozygotic twin pairs, 18 dizygotic twin pairs, and 64 single infants 3-34 months of age from Santiago, Chile. All had a BCG scar and were tuberculin tested by one trained nurse. RESULTS: The mean birth weight of both groups of twins was significantly lower than that of singletons and the percentage of individuals who failed to respond to tuberculin was approximately twice as high in twins as in singletons. After adjustment for birth weight and age by regression analysis, it was found that the distribution of tuberculin reactivity in both monozygotic and dizygotic twins was not significantly different from that of singletons. Both twin pair correlations is adjusted tuberculin reactivity were significantly greater than zero (P < 0.01) and led to a heritability estimate of 0.28. However, the monozygotic twin correlation was not significantly larger than the dizygotic twin correlation so that heritability is poorly estimated. CONCLUSION: These results are consistent with a genetic regulation of the response to newborn BCG immunization in humans by a mechanism capable of producing similar responses in identical and nonidentical twins alike.

BCG Vaccine↗