bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complex segregation analysis for a three‐allele locus: Experience from an analysis of acid phosphatase activity
Authors: Iselius L. , Evans D. A. P. , Eze L. C. , Tweedie M. C. K. , Bullen M. F. , Wren P. J. J. , Rao D. C. 
Published: June 2005

AbstractA complex segregation analysis of acid phosphatase activity in 50 British families showed that the essential features of the acid phosphatase polymorphism, i.e., a major gene with three alleles, is retrieved by using the biallelic mixed model. The estimates of gene frequency and displacement obtained from segregation analysis were in agreement with those obtained from electrophoretic studies. In addition, there was evidence for a multifactorial component.
Test of genetic heterogeneity of cleft lip with or without cleft palate as related to race and severity
Authors: Chung C. S. , Beechert A. M. , Lew R. E. , Vogler G. P. , Rao D. C. 
Published: June 2005

AbstractThe question of possible heterogeneity among population groups and phenotypic groups on the role of major gene in the etiology of cleft lip with or without cleft palate [CL(P)] was examined using the uniformly collected data in Hawaii. Complex segregation analysis was used to analyze patterns of family resemblance under the mixed model incorporating the effects of major gene and multifactorial inheritance. Analysis of the entire data showed superior fit of the mixed model including the effects of both major gene and multifactorial inheritance over the model of major gene alone or multifactorial inheritance alone. No significant heterogeneity could be detected between the high‐incidence group (Oriental or Japanese) and the low‐incidence group (non‐Oriental) in the underlying general model, although higher heritability was observed in general. When families were classified into “severe” and “mild” phenotypes based on cleft lip vs. cleft lip and palate or unilateral vs. bilateral cleft in the proband, no significant differences could be detected between the two types in the underlying genetic model.
Commingling and segregation analyses: Comparison of results from a simulation study of a quantitative trait
Authors: Kwon Jennifer M. , Boehnke Michael , Burns Trudy L. , Moll Patricia P. , Vogler G. P. , Rao D. C. 
Published: June 2005

AbstractCommingling analysis is commonly used to provide preliminary evidence for a single genetic locus with a major effect on the quantitative trait of interest. In this paper, the effectiveness of commingling analysis as a screening technique to identify samples for segregation analysis is assessed by applying both commingling and segregation analyses to samples of simulated pedigree data in which a major locus is segregating in the presence of polygenes and an individual‐specific environmental effect. Under the circumstances simulated here, there is evidence for a single locus from segregation analysis but not from commingling analysis in at least 20% of the samples. No more than 2% of the samples provided evidence for commingling but not for segregation of a single locus. Comparisons of the samples that give evidence for both commingling and segregation, evidence for one but not the other, and no evidence for either show that evidence for commingling depends on the distributional characteristics of the trait in the sample, while support for the single locus from segregation analysis depends on both the distributional characteristics as well as the transmission of the rarer allele from parents to offspring. Since lack of commingling does not rule out the existence of a single locus in the realistic situations considered here, commingling analysis has limited usefulness as a screening technique for the presence for a single locus. In contrast, evidence for commingling does suggest the possibility that a single locus has a major effect on the trait and commingling analysis can provide guidance in the choice of initial parameter estimates for segregation analysis.
Linkage disequilibrium between DNA markers at the low‐density lipoprotein receptor gene
Authors: Hegele Robert A. , Plaetke Rosemarie , Lalouel Jean‐Marc , Vogler G. P. , Rao D. C. 
Published: June 2005

AbstractWe determined pairwise linkage disequilibria between 12 restriction fragment length polymorphism (RFLP) markers at or near the low‐density lipoprotein receptor (LDLR) locus on chromosome 19p13.2‐13.1 in 92 unrelated individuals. Of these 12 RFLPs, two were newly identified under a cosmid‐based strategy designed to screen for RFLPs. We estimated linkage disequilibrium by determining three different measurements: D (the maximum likelihood estimate of linkage disequilibrium), D' (Lewontin's normalized estimate of D), and r (an index of gametic correlation). When r was used as the estimate of linkage disequilibrium, five of the 66 comparisons were significant according to a level of significance adjusted by the Bonferroni‐Holm correction. Only four pairs of RFLPs within a 100 kb region that included the LDLR gene itself were in significant linkage disequilibrium. Although we were able to detect strong linkage disequilibrium between some pairs of RFLPs in this sample, most RFLPs at the LDLR locus were not in strong linkage disequilibrium despite their physical proximity.
A family study of panic disorder: Reanalysis using a regressive logistic model that incorporates a sibship environment
Authors: Hopper John L. , Judd Fiona K. , Derrick Peter L. , Macaskill Greg T. , Burrows Graham D. , Rao D. C. 
Published: June 2005

AbstractPrevious analysis of affection status in parents and siblings of 117 probands with panic disorder by a log‐linear model for binary pedigree data found a common concordance across biological first‐degree relatives and no spouse association [Hopper JL, Judd FK, Derrick PL, Burrows GD: Genet Epidemiol 4:33–41, 1987]. In this paper the data were reanalyzed using a regressive logistic model that modelled both vertical transmission and a shared sibship environment. Ascertainment correction was made by a) an “ascertainment assumption‐free” procedure, following Ewens and Shute [Theor Pop Biol 30:388–412, 1986] and compared with b) complete ascertainment and c) single ascertainment. Under every scheme there was evidence for vertical transmission from parents to offspring. Inclusion of a sibship environment gave an improved fit, suggesting that vertical transmission alone may not be sufficient to explain the familial aggregation observed in these families. The effects of an affected parent, of the postulated environmental factor (present for all siblings if it was present for one sibling), and of the prevalence of the rare environmental factor were estimated and found to be roughly similar under the different schemes. Model predictions of lifetime prevalence were consistent with other population‐based studies. Under the same assumption‐free method, standard errors approximately doubled and computation time increased compared with the other ascertainment schemes that made specific, although not necessarily correct, assumptions. The regressive logistic model used less computation time and gave greater insight into the pattern of familial aggregation than did the previous modelling.
Familial resemblance of plasma apolipoprotein B: The Nancy study
Authors: Tiret Laurence , Steinmetz Josianne , Herbeth Bernard , Visvikis Sophia , Rakotovao Roger , Ducimetiere Pierre , Cambien Francois , Borecki I. B. , Rao D. C. 
Published: June 2005

AbstractThe familial resemblance of plasma apolipoprotein B (apo b) was investigated in a sample of 102 families including 419 members who volunteered for a free health checkup in the Preventive Center of Vandoeuvre‐lès‐Nancy, France. The mean levels (±SD) of apo B were 141.0 (±32.6), 121.8 (±27.7), and 98.6 (±22.6) mg/dl in fathers, mothers, and offspring, respectively. The familial correlations were 0.04, 0.13, 0.21 (P < .01), and 0.47 (P < .001) between spouses, father‐offspring, mother‐offspring, and siblings, respectively, after adjustment on age, body mass index, and sex. A genetic analysis was performed using the approach proposed by Bonney, which indicated that a recessive and a dominant major‐locus model appeared nearly equally supported by the data. Under the recessive model, the frequency q of the most common allele was estimated as 0.825, with a mean difference of 60.4 mg/dl between high and low homozygotes. Under the dominant model, q was estimated as 0.875, with a mean increase of 34.2 mg/dl in heterozygotes and high homozygotes. However, the hypothesis of Mendelian transmission and the environmental hypothesis could not be formally tested because of great numeric difficulties encountered in the estimation of the three transmission probabilities. Given these analytical restrictions, we cannot conclude in favor of a major locus influencing apo B level in our population, even though the evidence is suggestive. The genetic heterogeneity underlying the familial aggregation of apo B level, suggested by several recent publications, might explain the difficulty in discerning a single major locus in a population sample of small nuclear families, not ascertained through patients enriching the sample in high values of apo B. These findings call into question the relevance of the approach through “healthy” populations in the search for major loci influencing biological traits.
Power of the linkage test for a heterogeneous disorder due to two independent inherited causes: A simulation study
Authors: Martinez Maria , Goldin Lynn R. , Rao D. C. 
Published: June 2005

AbstractWe have conducted a simulation study in small pedigrees to investigate the power to detect linkage and heterogeneity for a disorder due to either one of two independent disease loci. We have considered a highly polymorphic marker locus (PIC = 70%) linked to one disease locus and unlinked to the second. The power to detect linkage has been examined by using the admixture test. We have varied the mode of transmission of each disease locus, the ascertainment of families and the proportion of cases in the population due to the linked disease locus. Generally, for the multiplex ascertainments we have considered, the power to detect linkage is greater when the linked disease locus has a high penetrance, when the unlinked disease locus has a low penetrance, and when pedigrees with multiple affected are selected. When selecting families with multiple affected, the rate of “mixed” families (i.e., those segregating for both disease loci) increases. However, for the pedigree structure we have considered, the power of the linkage test is more affected by a decrease in the rate of “linked” families than by an increase in the rate of “mixed” families. Finally, the present study shows that detection of linkage in presence of heterogeneity is feasible with a realistic sample size of small pedigrees as long as the linked disease locus accounts for more than 25% of the cases.
Measuring the inflation of the lod score due to its maximization over model parameter values in human linkage analysis
Authors: Weeks Daniel E. , Lehner Thomas , Squires‐Wheeler Elizabeth , Kaufmann Charles , Ott Jurg , Rao D. C. 
Published: June 2005

AbstractA computer‐simulation method is presented for determining and correcting for the effect of maximizing the lod score over disease definitions, penetrance values, and perhaps other model parameters. The method consists of simulating the complete analysis using marker genotypes randomly generated under the assumption of free recombination. It is applicable as a “post‐treatment” to linkage analyses of any trait with an uncertain mode of inheritance and/or disease definition. When the method is applied to a linkage analysis of schizophrenia versus chromosome 5 markers, we find that, in this specific case, the P‐value associated with a maximum lod score of 3 is equal to 0.0003. We also find that a lod score of 3.0 should be “deflated” by approximately 0.3 to 1 units, and, by tentative extrapolation, the observed lod score of 6.5 should be “deflated” by 0.7 to 1.5 units.
Familial factors associated with malignant gliomas
Authors: Wrensch Margaret R. , Barger Geoffrey R. , Rao D. C. 
Published: June 2005

AbstractFamily histories of male patients with histologically confirmed malignant gliomas were compared to family histories of controls (wives). Included were 77 case families with 892 relatives and 77 control families with 719 relatives. Cases had significantly more siblings than controls (P = 0.02), although cases were not preferentially the oldest or the youngest sibs. Odds ratios of two or more were found for mental retardation, Parkinson's disease, and meningitis for the relatives of cases versus controls, but none were statistically significant. The excesses of Parkinson's disease and meningitis were explained by the family of one particularly interesting case containing three relatives with meningitis and two relatives with Parkinson's disease. Noteworthy age‐adjusted odds ratios for cancer among relatives of cases compared to relatives of controls were 1.6 (95% confidence interval (CI) = 1.0–2.3) for cancer of any site, 2.4 (95% CI = 0.8–6.1) for breast cancer, and 4.0 (95% CI = 0.6–10.7) for lung cancer. Only the odds ratio for cancer of any site was statistically significant. Overall, 6 of 77 (8%) of cases came from families that included two or more relatives with breast or lung cancer in addition to the proband with malignant glioma. These three cancer sites may form familial clusters worthy of further evaluation in future studies by pedigree and genetic linkage analyses.
Sib‐pair linkage tests for disease susceptibility loci: Common tests vs. the asymptotically most powerful test
Authors: Schaid Daniel J. , Nick Todd G. , Rao D. C. 
Published: June 2005

AbstractSeveral statistical tests for linkage between a disease susceptibility locus and a marker locus for sib‐pair data are examined analytically. Two common statistics, a test based on the mean number of marker alleles shared identical by descent by sib‐pairs, and a test based on the proportion of sib‐pairs sharing exactly two marker alleles, are shown to be special cases of a more general statistic. We use this more general statistic to derive the asymptotically most powerful statistic for a given genetic alternative hypothesis, and then compare this statistic with the “mean” statistic and the “proportion” statistic. Results indicate that the “mean” statistic generally compares well with the most powerful statistic. However, in some instances the “mean” statistic may lose power, relative to the most powerful. To guard against this, a new statistic (the maximum of the “mean” and “proportions” statistics) is considered and its asymptotic distribution is derived. Results indicate that this new statistic performs well.
Estimating familial effects on age at onset and liability to schizophrenia. I. Results of a large sample family study
Authors: Kendler Kenneth S. , MacLean Charles J. , Rao D. C. 
Published: June 2005

AbstractPrevious analyses of age at onset in schizophrenia, which is highly variable and appears to be influenced by familial factors, have neglected to consider either (1) the impact of censoring on correlations in age at onset in affected relatives or (2) the impact of correlated ages at onset on the relationship between age at onset in the proband and risk in relatives. In this report, using methods outlined in the companion paper [MacLean et al., Genet Epidemiol 7:419–426, 1990] we examine these questions in the large family data set of schizophrenia collected by Lindelius [Acta Psychiat Scand (Suppl) 216:1–125, 1970]. Ages at onset are positively correlated in pairs of affected relatives (parent–offspring ≅ siblings > nieces/nephews) and these correlations are substantially higher after correction for censoring. Early age at onset is associated with higher risk of illness in siblings and nieces/nephews but not in children. These results are consistent with the hypothesis that age at onset in schizophrenia is influenced by familial factors which are probably genetic and which are mostly unrelated to factors influencing disease liability.
Genetic epidemiology of childhood brain tumors
Authors: Bondy Melissa L. , Lustbader Edward D. , Buffler Patricia A. , Schull William J. , Hardy Robert J. , Strong Louise C. , Vogler G. P. 
Published: June 2005

AbstractThe study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed before age 15, and residents of the United States or Canada. Family histories were obtained for all the probands' first degree relatives (parents, siblings, and offspring) and extended to include selected second degree relatives (aunts, uncles, grandparents) using sequential sampling. To determine if these CBT families exhibited excess cancer, we compared their cancer experience to age‐, race‐, sex‐, and calendar‐year specific rates from the Connecticut Tumor Registry. No cancer excess was observed among 1,099 first and second degree relatives [39 cancers observed (O) and 44 expected (E) for a standardized incidence ratio (SIR) of 0.88]. For colon cancer, although small numbers, five cases were observed among the probands' first degree relatives with 1.6 expected, for a significant SIR of 3.10. Segregation analysis demonstrated that chance alone could not account for the observed cancer distribution with a multifactorial model providing the best overall explanation of the data. Overall, heredity played a role in the etiology of CBT in 4% of the study families: four (1.7%) due to known hereditary syndromes (nevoid basal cell carcinoma syndrome and von Recklinghausens neurofibromatosis—NF‐1), four (1.7%) with multifactorial inheritance, and two additional families with cancers aggregating similar to the clinical criteria described for the Li–Fraumeni cancer family syndrome.
Multivariate segregation analysis using the mixed model
Authors: Blangero John , Konigsberg Lyle W. , Vogler G. P. 
Published: June 2005

AbstractMost major genes involved in the etiology of complex diseases are likely to have pleiotropic effects on a number of intervening quantitative traits. Methods of segregation analysis that incorporate the additional information from such multiple traits will exhibit greater power for detecting the effects of major genes and allow explicit tests of major locus pleiotropy hypotheses. In this study, we present a new method for multivariate segregation analysis that utilizes a multivariate generalization of Hasstedt's [1982] technique for calculating approximate mixed model likelihoods on pedigrees. The method is based on a simplification of the multivariate conditional likelihood via a transformation that simultaneously orthogonalizes the residual additive genetic and environmental covariance matrices. This transformation allows the multivariate conditional likelihood to be factored into the product of independent univariate conditional likelihoods. Resulting computations are relatively fast, making it feasible to analyze multiple traits in extended pedigrees. We demonstrate our method with a bivariate analysis of high‐density lipoprotein cholesterol (HDL‐C) and apolipoprotein AI (apo AI) serum levels in 585 pedigreed baboons.
Affected kin‐pair IBD methods: Genetic models
Authors: Motro Uzi , Thomson Glenys , Vogler G. P. 
Published: June 2005

AbstractCases of interest using affected sib‐pair methods to distinguish between recessive and additive (dominant) modes of inheritance of a disease‐predisposing gene involve goodness‐of‐fit tests with a small expected number in the “share‐zero parental haplotypes” category, as well as an unknown parameter, the frequency of the disease‐predisposing allele. Our simulations demonstrate that the real significance level of the chi‐square test using the three‐haplotype‐sharing IBD values (share 2, 1, and 0 parental haplotypes) is close to the assumed (.05) level in these cases, so that the haplotype‐sharing classes do not have to be lumped, which would leave no degrees of freedom for a statistical test. The validity of the chi‐square approximation in cases of small expected freqencies has previously been described, but the situations that have been considered do not cover the very small values in the share‐zero category that are often expected in the affected sib‐pair analysis, nor do they involve estimation of an unknown parameter. Although including IBD values from affected kin pairs other than sibs can be a very powerful tool in demonstrating linkage of a marker and disease, these pairs do not add power, in fact they reduce the power, of the chi‐square tests of goodness‐of‐fit of modes of inheritance.
Measuring familial aggregation by using odds‐ratio regression models
Authors: Liang Kung‐Yee , Beaty Terri H. , Vogler G. P. 
Published: June 2005

AbstractDetection 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.
Apolipoprotein B‐gene DNA polymorphisms (Xbal and EcoRI), serum lipids, and apolipoproteins in healthy Chinese
Authors: Saha N. , Tay J. S. H. , Humphries S. E. , Vogler G. P. 
Published: June 2005

AbstractThe frequency of restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene, detected by XbaI and EcoRI, and their influence on serum lipids and apolipoproteins were studied in healthy Chinese of both sexes in Singapore. A total of 221 subjects (150 males, 71 females) were investigated for the XbaI and 159 subjects for the EcoRI polymorphisms, while serum lipids and apolipoprotein levels were available for 196 subjects. The frequency of the X2 allele was found to be significantly lower in the Chinese than that reported in Caucasians from the United Kingdom (0.09 vs. 0.51, P < 0.001). The haplotype frequencies were also significantly different between the Chinese and Caucasians with a higher frequency of XlRl in the former compared to the latter (0.85 vs. 0.34, P <0.0001). The distribution of RFLP genotypes at both of the restriction sites was at Hardy‐Weinberg equilibrium in all groups. The influence of the apo B RFLPs on serum lipids and apolipoprotein levels (apo AI, AII, and B) was studied by both residual and multiple regression analyses considering age, sex, body mass index (BMI), and genotypes as independent variables in all possible combinations. No association was observed between the apo B genotypes and serum lipids or apolipoprotein levels except for high density lipoprotein cholesterol (HDLC), apo AI and AII, with the X2 being associated with significantly lower levels of HDLC as well as apo AI and AII, the effect being stronger in males. These data raise the possibility that the mechanism of reported association between apo B polymorphism and coronary artery disease may be through effects on HDLC. © 1992 Wiley‐Liss, Inc.