bluuebunny/crossref_metadata_2025_split huggingface dataset:
Segregation analysis of quantitative traits in nuclear families: Comparison of three program packages
Authors: Konigsberg Lyle W. , Kammerer Candace M. , MacCluer Jean W. , Rao D. C. , Vogler G. P. 
Published: June 2005

AbstractSegregation analysis frequently is used to test for the presence of major gene effects and to estimate the various genetic and environmental components contributing to diseases. Recent advances in both theoretical models and computational algorithms have provided a number of new programs for performing segregation analyses. We compared two newer programs: REGC (part of the package “SAGE”) and FISHER/MENDEL with an older established program (PAP) to determine relative accuracy in recovering parameter values and asymptotic standard errors, ability to discriminate between alternative transmission models, and execution speeds. Each program was applied to a set of computer simulations of a quantitative trait generated under a variety of genetic models. The results of these comparisons indicated that all the programs provided very similar parameter estimates, but that they differed in their abilities to identify the correct mode of transmission. In our simulations, PAP more often led to the selection of the correct transmission model, whereas REGC frequently indicated the presence of a major gene in simulations of purely polygenic transmission. Relative speeds for the programs differed, and their rank ordering varied with the complexity of the model being fitted. Although REGC was the fastest program for fitting a major gene or mixed model, it was by far the slowest program for estimating parameters in a sporadic or polygenic model.
Using factor scores to detect G × E Interactive Origin of “pure” genetic or environmental factors obtained in genetic covariance structure analysis
Authors: Molenaar P. C. M. , Boomsma D. I. , Neeleman D. , Dolan C. V. , Rao D. C. , Vogler G. P. 
Published: June 2005

AbstractMoment expressions for individual factor scores can serve as simple tests for the presence of a particular class of interaction factors that are disguised as pure genetic and/or environmental factors. That is, individual genetic and environmental factor scores may be used to construct fourth‐order moments of these factors in order to test whether a common genetic or environmental factor in the multivariate genetic factor model is in fact of the interactive origin concerned. Expected fourth‐order moments are derived for cases with and without interaction. Application of fourth‐order moments of factor scores to detect interactive origin of common factors is illustrated with simulated twin data.
Biochemical intermediates in α1‐antitrypsin deficiency: Residual family resemblance for total α1‐antitrypsin, oxidized α1‐antitrypsin, and immunoglobulin E after adjustment for the effect of the Pi locus
Authors: Silverman E. K. , Province M. A. , Campbell E. J. , Pierce J. A. , Rao D. C. , Martin N. G. 
Published: June 2005

Abstractα1‐antitrypsin (α1AT) deficiency is variably associated with the development of pulmonary emphysema. To gain insight into the process which begins the Z point mutation at the Protease Inhibitor (Pi) locus and results in the variable development of emphysema, three quantitative phenotypes, including total α1AT, oxidized α1AT, and total immunoglobulin E (IgE), were measured in sera from α1‐antitrypsin‐deficient individuals and their families.The mean and variance effects of the Pi locus on these biochemical phenotypes were removed, and path analysis of the residual phenotypes was performed by using a TAU model to investigate whether there was any additional multifactorial transmission. Significant transmission was demonstrated for total serum IgE and serum‐oxidized α1AT, which could be due to major genes other than the Pi locus, polygenes, or familial environment.Segregation analysis of the residual phenotypes was performed to determine whether additional major gene effects, other than the Pi effect, influence these quantitative phenotypes. Convincing evidence for an additional major gene was not found for oxidized α1AT, total α1AT, or IgE.
Genetic epidemiology of differences in low‐density lipoprotein (LDL) cholesterol concentration: Possible involvement of variation at the apolipoprotein B gene locus in LDL kinetics
Authors: Houlston R. S. , Turner P. R. , Lewis B. , Humphries S. E. , Rao D. C. 
Published: June 2005

AbstractCirculating levels of low‐density lipoprotein (LDL) vary considerably within and between populations, paralleled by differing coronary heart disease (CHD) mortality rates. We have previously shown that variation in the apolipoprotein (apo) B gene as associated with certain restriction fragment length polymorphisms (RFLPs) influences the metabolism of LDL in the U.K. population. To investigate a possible genetic contribution to variation in LDL levels in differing populations we have extended this original study. RFLPs of the apo B gene were determined in samples of individuals from the United Kingdom, Finland, Italy, Spain, and Africa. Significant associations of LDL fractional catabolic rate with the apo B EcoRI and XbaI RFLP genotypes were detected only in the two North European populations. In the African population sample, the XbaI RFLP displayed a significant association with LDL apo B synthesis. The data suggest that variation in the apo B gene influences the metabolism of LDL and that it is different in individuals of different ethnic background.
Assessing the effect of multiple linkage tests in complex diseases
Authors: Clerget‐Darpoux Françoise , Babron Marie‐Claude , Bonaïti‐Pellié Catherine , Rao D. C. 
Published: June 2005

AbstractThe significance of a lod score value of 3 is very difficult to assess in linkage studies between a genetic marker and a complex disease. One reason is that multiple tests may have been performed, voluntarily or otherwise. For the same disease, linkage may be tested by different laboratories with several markers under various genetic models and diagnostic schemes for the disease. In such a case, we show that the probability of getting a lod score value of 3 under independent transmission of the disease and the marker may be not negligible.
Genetic variation at the apolipoprotein gene loci contribute to response of plasma lipids to dietary change
Authors: Xu C.‐F. , Boerwinkle E. , Tikkanen M. J. , Huttunen J. K. , Humphries S. E. , Talmud P. J. , Rao D. C. 
Published: June 2005

AbstractDietary intervention studies (from a low polyunsaturated/saturated fatty acid ratio P/S diet to a high P/S diet), carried out on a group of healthy individuals from North Karelia, Eastern Finland between 1981–1984, provided evidence that there may be a genetic component contributing to variation in response to dietary change. We have resampled blood from 107 individuals involved in the original studies and used Restriction Fragment Length Polymorphisms (RFLPs) to study the genetic contribution of variation at a number of candidate gene loci to the response to dietary change. The genes investigated in this study were the apolipoprotein (apo) genes: apo B, apo AII, apo E (protein polymorphism), apo AI‐CIII‐AIV gene cluster, and the LDL‐receptor gene.On the basal diet the major effect of genotype on lipid traits was due to variation at the apo E gene locus; this protein polymorphism explained 14.6% of the phenotypic variance in LDL cholesterol levels and 12.7% of the phenotypic variance in total cholesterol levels. When switched to low fat high P/S diet, these effects of variation at the apo E gene locus on the phenotypic variation of LDL and total cholesterol levels disappeared. The major effect on the response to dietary change, Δ, was seen on the difference in apo AI levels mediated by variation at the apo B gene locus (MspI RFLP) explaining 6.3% of the phenotypic variance in apo AI change. For the RFLPs of the apo AI‐CII‐AIV gene cluster, small but not significant differences on Δ were found. Our results indicate that within the limits of the candidate genes studied, the major effects in response to dietary change was on apo AI levels mediated through variation at the apo B gene locus.
Search for faster methods of fitting the regressive models to quantitative traits
Authors: Demenais Florence M. , Murigande Charles , Bonney George E. , Rao D. C. 
Published: June 2005

AbstractThe regressive models describe familial patterns of dependence of quantitative measures by specifying regression relationships among a person's phenotype and genotype and the phenotypes and genotypes of antecedents. When the number of sibs in the pattern of dependence increases, as in the class D regressive model, computation of the likelihood becomes time consuming, since the Elston‐Stewart algorithm cannot be used generally. On the other hand, the simpler class A regressive model, which imposes a restriction on the sib‐sib correlation, may lead to inference of a spurious major gene, as already observed in some instances. A simulation study is performed to explore the robustness of class A model with respect to false inference of a major gene and to search for faster methods of computing the likelihood under class D model. The class A model is not robust against the presence of a sib‐sib correlation exceeding that specified by the model, unless tests on transmission probabilities are performed carefully: false detection of a major gene is reduced from a number of 26–30 to between 0 and 4 data sets out of 30 replicates after testing both the Mendelian transmission and the absence of transmission of a major effect against the general transmission model. Among various approximations of the likelihood formulation of the class D model, approximations 6 and 8 are found to work appropriately in terms of both the estimation of all parameters and hypothesis testing, for each generating model. These approximations lessen the computer time by allowing use of the Elston‐Stewart algorithm.
Family history of ischemic heart disease with respect to mean twin‐pair cholesterol and subsequent ischemic heart disease in the NHLBI twin study
Authors: Reed Terry , Fabsitz Richard R. , Quiroga Jose 
Published: June 2005

AbstractThis study examines the independent and interactive effects of family history scores (FHxS) for the prevalence of ischemic heart disease with plasma lipids and subsequent morbidity and mortality from ischemic heart disease. FHxS were calculated for 514 sets of middle aged male twins who participated in the entry examination of the NHLBI Veteran twin study in 1969–1973. Comparison of the FHxS with the level of plasma total cholesterol and HDL cholesterol (HDLc) paralleled earlier reported findings in young adults; individuals with high total cholesterol in two exams 8–12 years apart had significantly (P < .01) higher FHxS. The same relationship was noted when using the mean twin‐pair cholesterol level at the initial exam when the twins were in their 40s. Using the pair means over two exams as the cotwins aged into their 50s, the association of FHxS with total cholesterol declined and pairs with HDLc persistently in the highest quintile at both exams had significantly (P < .01) lower FHxS. The changes in the pattern of association of lipid fractions with FHxS with age parallel the reported age decline of total cholesterol as a risk factor for heart disease. Assessment of ischemic heart disease events up to January 1988 revealed a highly significant association (P < .0001) of later ischemic heart disease events with FHxS. At each level of lipid categorization pairs who later had events had higher FHxS than those without any subsequent heart disease; these differences were significant in all but the low risk lipid groups (low total cholesterol, high HDLc, and low total cholesterol/HDLc ratio). We conclude that FHxS is related to total cholesterol and HDLc but also is an independent predictor of subsequent ischemic heart disease after 14–18 years of follow‐up.
Linkage analysis assuming a single‐locus mode of inheritance for traits determined by two loci: Inferring mode of inheritance and estimating penetrance
Authors: Greenberg David A. , Rao D. C. 
Published: June 2005

AbstractWhat happens to the results of linkage analysis when one assumes that a disease results from a single genetic locus with reduced penetrance when the actual cause is two epistatically interacting loci? We wanted to (1) determine whether assuming the correct mode of inheritance at the linked locus leads to a higher lod score than assuming the incorrect mode of inheritance irrespective of penetrance assumptions and (2) determine whether it is possible to estimate the apparent penetrance due to the second, unlinked locus from the linkage data. Linkage data were simulated under three different two‐locus models. Different “penetrances” were simulated by using different disease allele frequencies at the unlinked locus. Data were then analyzed assuming a single locus with reduced penetrance. The maximum lod score was maximized with respect to penetrance (LVP curves).We found that if there were enough data, assuming the correct (i.e., generating) mode of inheritance at the linked locus always led to a higher lod score than assuming the incorrect mode of inheritance no matter what the penetrance assumption. In contrast to the case where reduced penetrance is due to random factors, the estimate of the apparent penetrance (the “penetrance” due to the second locus) was biased, thus making any estimation of the gene frequency at the second locus doubtful. The ability to detect linkage was apparently not affected when the effects of the second locus were treated as random reduced penetrance. The results suggest that analyzing the data under the assumption of a single‐locus model with reduced penetrance rather than a two‐locus model will not substantially decrease the ability to establish linkage nor will it affect determining the mode of inheritance at the linked locus from the linkage data.
Efficient computation of patterned covariance matrix mixed models in quantitative segregation analysis
Authors: Schork Nicholas , Vogler G. P. , Rao D. C. 
Published: June 2005

AbstractThe use of patterned covariance matrices in forming pedigree‐based mixed models for quantitative traits is discussed. It is suggested that patterned covariance matrix models provide intuitive, theoretically appealing, and flexible genetic modeling devices for pedigree data. It is suggested further that the very great computational burden assumed in the implementation of covariance matrix‐dependent mixed models can be overcome through the use of recent architectural breakthroughs in computing machinery. A brief and nontechnical overview of these architectures is offered, as are numerical and timing studies on various aspects of their use in evaluating mixed models. As the kinds of computers discussed in this paper are becoming more prevalent and easier to access and use, it is emphasized that it behooves geneticists to consider their use to combat needless approximation and time constraints necessitated by smaller, scalar computation oriented, machines.
Power of the admixture test to detect genetic heterogeneity
Authors: Narod Steven A. , Vogler G. P. 
Published: June 2005

AbstractSeveral dominant genetic diseases which appear to be homogeneous are the expression of genetic mutations at several loci. The power to detect linkage by likelihood methods is diminished for heterogeneous, as compared to genetically homogeneous, disorders. Using a simulation approach and two pedigrees typical of those available for the study of a dominant disease (with expected lod scores of 0.43 and 1.00 at θ = 0.05 and PIC = .59), I have evaluated the power to detect genetic heterogeneity by using the admixture test. Linkage power was determined by varying the number of families available for study, the recombination fraction (θ), the informativity of the hypothetical marker, and the proportion of linked families, α. For moderate and small values of α it is feasible to detect genetic heterogeneity once linkage has been established; rarely will it be possible to detect linkage and heterogeneity simultaneously given a limited number of small or moderate pedigrees.
Informativeness of twin‐nuclear family and nuclear family designs for segregation analysis
Authors: Duffy David L. , Eaves Lindon J. , Vogler G. P. 
Published: June 2005

AbstractThis brief note examines the precision of segregation parameter estimates from both twin‐nuclear family and conventional nuclear family designs. The program MENDEL was used to derive expected frequencies of different family patterns of affectation (with fixed sibship size) under various single gene models, and then to estimate the standard errors (and information) associated with gene frequency and penetrance values at given sample sizes. As might be expected, a 2‐ to 5‐fold increase in relative efficiency was found for the same family size if families included an MZ twin pair among their offspring. The methods used allow convenient calculation of expected informativeness of a given study design.
Lack of evidence for linkage between low‐density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia
Authors: Austin Melissa A. , Wijsman Ellen , Guo Sunwei , Krauss Ronald M. , Brunzell John D. , Deeb Samir , Vogler G. P. 
Published: June 2005

AbstractLow‐density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, appears to be a genetically influenced risk factor for coronary heart disease. Phenotype B, as determined by gradient gel electrophoresis, appears to be inherited in a manner consistent with the presence of a single major genetic locus, based on complex segregation analysis. Familial combined hyperlipidemia (FCHL) is a disorder characterized by elevations in total plasma cholesterol and/or triglyceride levels in probands and family members, variable lipoprotein phenotypes over time, and elevations in apolipoprotein B levels. Because apo B is the primary protein component of LDL particles, the present study was undertaken to determine whether LDL subclass phenotypes are controlled by the APOB locus in FCHL families. The evidence against linkage was very strong based on lod score analyses (total lod = −13.3), under assumptions that LDL subclass phenotypes are influenced by a major genetic locus and that the mode of inheritance and penetrance functions are known. Other methods requiring fewer assumptions also provided evidence against linkage, although the strength of this evidence was weaker. Thus the results demonstrate that the proposed gene responsible for LDL subclass phenotypes is unlikely to be the APOB gene in families with FCHL.
Apolipoprotein E polymorphism and plasma lipid, lipoprotein, and apolipoprotein levels in Italian children
Authors: Xu Chun‐Fang , Talmud Philippa J. , Angelico Francesco , Ben Maria Del , Savill John , Humphries Steve E. , Vogler G. P. 
Published: June 2005

AbstractWe have investigated the effect of apolipoprotein (apo) E polymorphism on serum lipid, lipoprotein, and apolipoprotein levels in a sample of 195 children, aged 8–11 years, from Sezze, Central Italy. The relative frequencies of e2, e3, and e4 alleles were 0.062, 0.867, and 0.072, respectively. Variation at the apo E gene locus explained 5.1% of the sample variance in serum total cholesterol levels, 7.6% in low‐density lipoprotein (LDL) cholesterol levels, 7.3% in apo B levels, and 14.1% in high‐density lipoprotein‐apo E (HDL‐E) levels. The effect of the e2 allele was to lower levels of total cholesterol, LDL‐cholesterol, and apo B and to raise levels of HDL‐E, while the effect of the e4 allele was the opposite. Variation at the apo E gene locus was not associated with differences in serum triglyceride, HDL‐cholesterol, or apo AI levels. The effects of common apo E polymorphisms and genetic variation associated with the PvuII RFLP of the apo B gene on serum apo B levels were additive, explaining 11.3% of the phenotypic variance in this sample. When the effect of apo E polymorphism on serum lipid traits was estimated in boys and girls separately, variation at the apo E gene locus explained 10.4, 13.3, 13.3, and 13.5% of the phenotypic variance in serum total cholesterol, LDL‐cholesterol, apo B, and HDL‐E levels, respectively, in boys, while in girls only the effect on HDL‐E levels (19.3%) reached statistical significance. This study has demonstrated that genetic variations at the apo E locus contribute to the determination of serum lipid, lipoprotein, and apolipoprotein levels in youths and that the effects are gender specific.
Extensions to methods of sib‐pair linkage analyses
Authors: Flanders W. Dana , Khoury Muin J. , Vogler G. P. 
Published: June 2005

AbstractSib‐pair methods provide simple, robust, easily implemented ways to screen for linkage between a marker locus and a suspected disease susceptibility locus. The basic analysis reflects the idea that, in the presence of linkage, siblings who share more alleles at the marker locus should also tend to be concordant for disease. Available sib‐pair methods do not lead directly to estimates of risk associated with nongenetic factors, may not account for a variable age‐at‐onset, or may require that the age‐at‐onset distribution be known. In this paper, we propose a method for sib‐pair linkage analyses that allows for a variable age‐at‐onset using a logistic model, easily allows modelling of nongenetic factors, reflects the correlation of sibs within a sibship, and allows for nonzero risk in those without the susceptibility genotype. Based on a limited number of simulations, the method has as good or better power than another recently described method that also allows for a variable age‐at‐onset.
Are offspring of women with hereditary hematologic disorders at increased risk of congenital cardiovascular malformations?
Authors: Khoury Muin J. , Waters Grady D. , Martin M. Louise , Edmonds Larry D. , Vogler G. P. 
Published: June 2005

AbstractHereditary hematologic disorders (HHD) have been reported in excess among infants and families of infants with congenital cardiovascular malformations (CCM) compared with controls, suggesting possible common pathogenetic mechanisms. It is plausible that hemodynamic changes during pregnancy associated with HHD could affect cardiac morphogenesis. To investigate whether offspring of women with selected HHD have an excess risk of CCM, the authors examined data from a nationwide birth defects monitoring program (BDMP) covering about 2.9 million births in the United States between 1982 and 1988. The system ascertains major birth defects diagnosed in the newborn period. An anonymous linkage procedure linked maternal obstetric records with newborn records using demographic, diagnostic, and geographic variables. A total of 1,239 mothers were identified with selected HHD (47 hereditary spherocytosis, 575 thalassemias, 310 sickle cell anemia, 88 other hereditary hemolytic anemias, 159 von Willebrand disease, and 60 other congenital coagulapathies). In all, 14 infants received a newborn discharge diagnosis of CCM (expected number based on population rates of CCM from the same hospitals and time period is 7.74; P = 0.0268). No single CCM entity accounted for this excess. In contrast, 8 infants had major non‐CCM defects (expected number 7.46; P = 0.466). These data suggest an excess risk of CCM among offspring of women with selected HHD. Further studies are needed to explore these findings and to evaluate the pathogenetic significance of this association.