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Biomedical subjects

R C Elston

Publications and source records attributed to R C Elston.

At least 127 records · Page 7Linked to original sources
PubMed1994

Tuberculin reactivity in families of infants who failed to develop tuberculin reactivity after BCG immunization at birth.

SETTING: Some infants immunized with BCG in the newborn period fail to develop any measurable tuberculin reactivity despite a local reaction at the site of immunization. OBJECTIVE: We wished to determine the possibility of a genetic regulation of this phenomenon by comparing the tuberculin reactivity of BCG-immunized parents and siblings of infants who failed to respond to BCG, and of infants who developed tuberculin reactivity after immunization. DESIGN: We studied 65 parents and siblings of 33 nonresponder infants, and 35 parents and siblings of 14 infants who had developed tuberculin reactivity. Tuberculin reactivity was analyzed by multiple regression analysis considering the BCG immunization status of each individual, and the 2 groups were compared by analysis of covariance. RESULTS: 96 of these family members had one or more BCG scars. The percentages of tuberculin reactors and non-reactors among BCG-immunized family members of both index infant groups were not significantly different. CONCLUSION: These observations suggest that maturational differences among newborns, rather than genetic regulation, account for the lack of development of cellular immunity against tuberculin after BCG immunization in some infants.

Adult↗
PubMed1994

Testing specific hypotheses by fitting underlying distributions to categorical data.

The problem of estimating parameters and testing hypotheses pertaining to categorical data is well known in statistical analysis. Much of the literature on the subject specifies and fits linear models to multinomial data using methods such as weighted least squares. This article describes maximum-likelihood estimation and likelihood ratio tests for ordered categorical response variates with either discrete or continuous underlying probability distributions. Emphasis is on fitting and making inferences about parameters of mixture distributions, especially mixtures of normal distributions. Goodness-of-fit tests are given to check the adequacy of the fitted distributional models.

Data Interpretation, Statistical↗
PubMed1994

Evaluation of tuberculin reactivity in BCG-immunized siblings.

The purpose of the present study was to determine in BCG-immunized sibships < or = 14 yr of age whether the correlations of intensity of tuberculin reactivity support a genetic regulation of the response to BCG immunization. The study population consisted of 659 healthy children living in 265 households exposed to an adult with tuberculosis: 38 children did not have a BCG scar, 327 children had one BCG scar, and 294 had two BCG scars from vaccinations at birth and at 6 yr of age. There were 603 full siblings, 16 half-siblings, and 40 unrelated children. Tuberculin testing was performed by one trained nurse. Sibling correlations of the intensity of the tuberculin response were calculated after adjusting for various nongenetic covariates that could be important in predicting it. The sibling correlations were significant at the 1% significance level. There was no significant correlation of tuberculin reactivity among unrelated children in the same household. These results are consistent with genetic regulation of the development and persistence of tuberculin reactivity after BCG immunization.

Adolescent↗
PubMed1993

Genetic etiology of nuclear cataract: evidence for a major gene.

Sibling correlations and segregation analysis were used to examine the familial distribution of age-sex-adjusted measures of nuclear sclerosis in 1,247 individuals from 564 sibships in the Beaver Dam Eye Study. There are highly significant sibling correlations for all sibs, and separately for sister-sister, sister-brother, and brother-brother pairs. Two transformed normal distributions give the best fit to the data. The hypothesis of mendelian transmission of a major effect cannot be rejected, but the hypothesis of a random environmental major effect is rejected. The parameters of the tau AB free model showed close similarity to the values expected under a mendelian hypothesis. Our results suggest that a single major gene can account for 35% of the total variability of age-sex-adjusted measures of nuclear sclerosis.

Adult↗
PubMed1993

Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: analysis of a large pedigree from the Bogalusa Heart Study.

A pedigree of a large family with high prevalence of heart disease is subjected to association and sib-pair linkage analysis to investigate the role of 5 candidate genes in the regulation of lipoprotein metabolism and the development of coronary artery disease. At the 5% nominal significance level, the apolipoprotein B locus (APOB) was found to be linked to high-density lipoprotein cholesterol level (HDL-C), low-density lipoprotein cholesterol level (LDL-C), the ratio HDL-C/LDL-C, and apolipoprotein AI level times this ratio (apoAI x LDL-C/HDL-C). APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004). No significant linkage results were found with cholesterol ester transfer protein (CETP). At the 1% nominal significance level, CETP [TaqI(B)] showed significant association with LDL-C, apoB, and HDL-C/LDL-C. There was significant linkage of lipoprotein lipase (LPL) with very-low-density lipoprotein cholesterol and the ratio apoAI/HDL-C, and strong association results between LPL (HindIII) and triglyceride levels (P = 0.005). At the 5% nominal significance level, haptoglobin (HPA) was associated with HDL-C, HDL-C/LDL-C, apoAI/HDL-C and apoAI x LDL-C/HDL-C. The apolipoprotein AI locus did not show any significant linkages or associations. The study thus indicated that genetic variation of APOB, LPL, CETP, and lecithin cholesterol acyl transferase (which is linked to HPA and CETP) may play an important role in the regulation of lipoprotein metabolism and could contribute to the risk of coronary artery disease.

Apolipoproteins↗
PubMed1993

Confidence limits based on the first occurrence of an event.

Confidence limits for population prevalence based on the first occurrence of an item in a medical database, or for incidence based on time to first occurrence, should be based on the geometric or exponential distributions, respectively. These intervals are presented and compared with the corresponding intervals based on the binomial and Poisson distributions. The lower confidence limits are shown to be the same, but the upper limits are smaller, hence leading to shorter intervals. Applications of these intervals are also presented.

Confidence Intervals↗
PubMed1993

Potential role of an additive genetic component in the cause of amyotrophic lateral sclerosis and parkinsonism-dementia in the western Pacific.

Amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) are neurological degenerative disorders that occur in three high incidence foci in the western Pacific: among the Chamorros of Guam and the Commonwealth of the Northern Marianas Islands, among Japanese on the Kii peninsula of Honshu Island, and among the Auyu and Jakai peoples of southern West New Guinea. Previous studies have implicated both genetic susceptibility and environmental risk factors in the causation and familial clustering of these disorders. The data analyzed consist of 2,026 individuals in nuclear families ascertained on Guam through two mechanisms: (1) nuclear families were included in the study if one or both parents in the family were affected with ALS or PD or both; and (2) a group of "controls" was selected by obtaining nuclear families where neither parent was affected and both had lived through the age of risk. Clinically, ALS and PD are two distinct disorders. However, preliminary analyses indicated that combining all three diagnoses into one affected diagnosis for genetic analyses (thereby assuming any genetic effect on susceptibility to the two disorders was due to the same genetic mechanism) was reasonable. An age, sex and birth cohort-specific liability was defined and segregation analysis was performed under both logistic and normal models for this liability at the time of disease onset. Under either model, purely environmental, Mendelian dominant and Mendelian recessive hypotheses could be rejected, but a two-allele additive major locus hypothesis could not be rejected.

Amyotrophic Lateral Sclerosis↗
PubMed1993

The HGAR1 familial hypercholesterolemia pedigree.

Data on 232 members of a single pedigree, descended from two pairs of original parents, were made available to the participants of Genetic Analysis Workshop 8 (GAW8). In addition to information concerning age and sex, measurements for 10 quantitative traits and genotypes at 22 polymorphic marker loci were also provided for a subset of 193 of these family members.

Adult↗
PubMed1993

Statistical validity of the Haseman-Elston sib-pair test in small samples.

Simulation experiments were used to determine the empiric type I error rate of the Haseman-Elston sib-pair test for linkage between a quantitative trait and a marker locus in samples with 60 or fewer sib pairs. The effect of different levels of marker-locus heterozygosity on statistical validity was also considered. The test was performed on the trait and each of five unlinked markers, and evaluated using two different degrees of freedom for the t-distribution. The number of degrees of freedom in the first evaluation was based on the number of sib pairs in each sibship, sigma s(i)(s(i) - 1)/2 - 2. In the second evaluation, the number of degrees freedom was based on the number of sibs minus 1 in each sibship, sigma (s(i) - 1) - 2. Empirically determined type I error rates using sigma s(i)(s(i) - 1)/2 - 2 degrees of freedom were slightly liberal. For sigma (s(i) - 1) - 2 degrees of freedom, the estimated empiric p-values were nearly identical to their respective nominal p-values. Decreasing levels of heterozygosity did not increase the empiric type I error rate when the sample size was small.

Computer Simulation↗
PubMed1993

Evidence for a major gene effect in early-onset lung cancer.

Genetic segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer patient. Results indicated compatibility of the data with Mendelian codominant inheritance of a rare major autosomal gene that acts in concert with smoking to predispose carriers to lung cancer, by producing earlier onset of the cancer when controlling for equivalent smoking levels. Segregation at this locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60 respectively, but only 22% of all lung cancers in persons up to age 70. This decrease in the importance of the gene's contribution to overall lung cancer rates at later ages is most likely a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco. A significant cohort effect was found, most likely due to differing smoking patterns before and after World War I, but in both cohorts the effect of a major locus could not be rejected.

Data Collection↗
PubMed1992

Lung cancer detection and prevention: evidence for an interaction between smoking and genetic predisposition.

The initiation and promotion of cancer is thought to result from a series of genetic mutations, some of which may be inherited. Our analysis of 337 lung cancer families suggested that, after allowing for an individual's pack-years of tobacco use, the pattern of disease was best explained by Mendelian codominant inheritance of an allele that produced earlier age of onset. Since lung cancer rarely occurs in the absence of exposure to tobacco, differences in the prevalence of smoking across generations could have a profound influence on the fit of genetic models. In the present study, families were partitioned into two groups, based on the birth cohort of the proband, i.e., born before World War I (age at death, greater than or equal to 60 years) or born after World War I (age at death, less than 60 years). This partition was chosen because the year 1915 signaled the start of the dramatic rise in tobacco use in the United States. In younger proband families, in which parents were more likely to smoke, Mendelian codominant inheritance provided the best fit to the data. In older proband families, for whom smoking among parents was less prevalent, the "no major gene" and "environmental" hypotheses were rejected; however, no Mendelian models could be distinguished. If the results on the families with the most homogeneous exposure to tobacco across generations (born after World War I) reflect the true underlying biology, then the influence of genetic factors in the pathogenesis of lung has been underestimated; the cumulative probability of lung cancer at age 80 for a noncarrier of the gene, at the average level of tobacco consumption, is close to zero, implying that virtually all lung cancer occurs among gene carriers. Identification of this putative genetic factor has profound implications for the detection and prevention of lung cancer.

Aged↗
PubMed1992

Lung cancer histologic type and family history of cancer.

The authors studied 300 patients with pathologically confirmed cancer of the trachea, bronchus, or lung in a 16-parish (county) area of southern Louisiana. Squamous-cell carcinoma was observed most frequently among these patients (39.3%), with nearly equal numbers of adenocarcinoma (25.0%) and small cell varieties (25.5%). Patients with large cell cancer, the least frequent type (10.3%), were 4.6 years younger on average than those with small cell (P less than 0.05) or squamous cell (P less than 0.05) neoplasias. Squamous cell neoplasia was more frequent among men (45.5%) than women (22.0%) (P less than 0.05). To assess whether family history differed according to the histologic cell type of the index family member, 248 patients were interviewed with regard to a family history of neoplasia. Those with small cell cancer had the highest family-size adjusted mean number of lung cancers per family (0.28). This was 2.2 times greater than the mean number of affected persons among relatives of patients with adenocarcinoma and 1.5 times greater than the mean for the families of patients with large or squamous cell types. However, none of these differences was statistically significant. Similar results were obtained when the total number of cancers at all sites was tabulated. Probands with small cell neoplasia were again most likely to have a positive family history, but the differences between histologic types were small. Although these data suggest an association, a larger study sample is required to determine conclusively whether or not a family history of lung cancer differs according to histologic type.

Adult↗
PubMed1992

Effect of cohort differences in smoking prevalence on models of lung cancer susceptibility.

Data on 337 lung cancer families were analyzed to determine if known cohort differences in parental cigarette consumption influence parameters from a segregation analysis. Previous results suggested that, after allowing for an individual's pack-years of tobacco exposure, Mendelian codominant inheritance of an allele that produced an earlier age of onset provided a good fit to the data. In the present study, the data were split into two groups of families: probands age 60 and over (born before WWI) and probands younger than age 60. This partition of the data by age of the proband was done to separate families in which there were parents who were less likely to smoke from those with parents more likely to smoke--predicated on the known increase of smoking prevalence after World War I. For the younger proband families (those with parents more likely to smoke), only Mendelian codominant inheritance adequately fit the data. The hypotheses of no major type, environmental transmission, and Mendelian dominant or recessive inheritance were rejected. In contrast to our earlier findings, the estimate of population susceptibility increased from 28% in the total data to 60% in this subset. In the older proband families (those with parents less likely to smoke), the no major type and environmental hypotheses were rejected; further, none of the Mendelian models could be distinguished. Our results demonstrate that cohort differences, probably in exposure to tobacco, can confound parameters of a segregation analysis, and suggest that the genetic component of lung cancer may be greater than previously estimated. It further suggests that susceptibility to lung cancer occurs as a function of susceptibility to the effects of tobacco smoking.

Adult↗
PubMed1992

Regression toward the mean in 2 x 2 crossover designs with baseline measurements.

Clinical trials often involve the study of patients whose values for some quantitative characteristic are in the extreme of the distribution for the normal population. Subsequent observation of the characteristic of interest will ordinarily tend to regress toward the mean of the distribution even in the absence of a treatment effect. We consider the impact of regression toward the mean in the analysis of data arising in 2 x 2 crossover trials with two baseline measurements. The usual summary statistics can be especially misleading in the presence of regression toward the mean.

Bias↗
PubMed1992

The Elston-Stewart algorithm for continuous genotypes and environmental factors.

The Elston-Stewart algorithm for a normally distributed trait under a polygenic model is explained in detail and extended to allow for other continuous environmental variables. This formulation is especially useful for large pedigrees, as it avoids the need to invert matrices. Whereas it may not be feasible by this method to estimate all the various components of previously suggested models for polygenic inheritance, it can allow for a reasonably flexible pedigree correlational structure under which valid tests can be performed for fixed effects that may affect the phenotype.

Algorithms↗
PubMed1992

Segregation and linkage analysis.

Computer programs are available in the software package SAGE to perform a variety of segregation and linkage analyses used by human geneticists. These methods are designed specifically to uncover major gene segregation in pedigree data coming from non-inbred populations. With the aid of a closely linked polymorphic marker, they can detect a locus that contributes as little as 10% to the variation of a quantitative trait in a pedigree sample of several hundred individuals.

Animals↗
PubMed1991

Evidence for a dominant gene mechanism underlying coeliac disease in the west of Ireland.

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus. To address this controversy, we examined the association of CD with HLA in 39 families from the West of Ireland. Previous studies have shown that the prevalence of CD and the frequencies of the HLA antigens associated with it are higher in this population than in most others. Analysis of the data revealed a significant excess of concordant sib-pairs with two HLA haplotypes in common and an excess of discordant pairs with no haplotype in common. Chi-square tests confirmed a highly significant association between HLA-B8 and CD. Both heterozygotes and homozygotes for B8 had a significantly increased risk of CD. The risk for homozygotes was slightly higher than for heterozygotes, although not significantly so. The segregation ratio for disease occurrence among sibs of probands was estimated to be 0.185 when neither parent is affected. We estimated a gene frequency of 0.003 for the disease allele (C) at the HLA-linked locus and of 0.648 for the disease allele (d) at the HLA-unlinked locus. Assuming that CCdd homozygotes are always affected and that only carriers of C who are homozygous dd can be affected, the disease was found to be completely penetrant in Ccdd heterozygotes. These results support dominance at the HLA-linked locus conferring susceptibility to CD. Possible reasons for the discrepancy between the West of Ireland and other populations are discussed.

Alleles↗