bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of disease risk under bivariate models of multifactorial inheritance
Authors: Moldin Steven O. , Rice John P. , Van Eerdewegh Paul , Gottesman Irving I. , Erlenmeyer‐Kimling L. , Risch Neil J. 
Published: June 2005

AbstractAdjunct consideration of both qualitative (affection status) and quantitative (correlated liability indicator) information to define a bivariate phenotype can increase considerably the accuracy and efficiency of disease risk estimation. A general approach for calculating morbid risks to offspring on the basis of parental affection status and an offspring quantitative trait is presented. We also describe two different bivariate models of multifactorial inheritance, as implemented in the computer programs POINTER and YPOINT, and make explicit their assumptions/constraints when estimating the within‐person and parent–offspring correlations necessary for calculation of morbid risks. We use psychometric family data on schizophrenia from the New York High‐Risk Project to estimate these correlations and illustrate our methods. Our results show that even when a trait is only moderately correlated with liability, incorporation of quantitative trait information can lead to resolution of a range of risk to offspring that is not possible through reliance on parental affection status alone. Bivariate models provide a useful methodology for incorporating quantitative indicators of liability in the investigation of genetically complex diseases.
A time‐dependent logistic hazard function for modeling variable age of onset in analysis of familial diseases
Authors: Abel Laurent , Bonney George Ebow , Rao D. C. 
Published: June 2005

AbstractThe paper presents an extension of the regressive logistic models proposed by Bonney [Biometrics42:611–625, 1986], to address the problems of variable age‐of‐onset and time‐dependent covariates in analysis of familial diseases. This goal is achieved by using failure time data analysis methods, and partitioning the time of follow up inKmutually exclusive intervals. The conditional probability of being affected within thekth interval (k= 1…K) given not affected before represents the hazard function in this discrete formulation. A logistic model is used to specify a regression relationship between this hazard function and a set of explanatory variables including genotype, phenotypes of ancestors, and other covariates which can be time dependent. The probability that a given person either becomes affected within thekth interval (i.e., intervalkincludes age of onset of the person) or remains unaffected by the end of thekth interval (i.e., intervalkincludes age at examination of the person) are derived from the general results of failure time data analysis and used for the likelihood formulation. This proposed approach can be used in any genetic segregation and linkage analysis in which a penetrance function needs to be defined. Application of the method to familial leprosy data leads to results consistent with our previous analysis performed using the unified mixed model [Abel and Demenais,Am J Hum Genet42:256–266, 1988], i.e., the presence of a recessive major gene controlling susceptibility to leprosy. Furthermore, a simulation study shows the capability of the new model to detect major gene effects and to provide accurate parameter estimates in a situation of complete ascertainment.
On the asymmetry of biological frequency distributions
Authors: Schork Nicholas J. , Weder Alan B. , Schork M. Anthony , Rao D. C. 
Published: June 2005

AbstractThe long‐standing problem of determining whether the skewness in a sample frequency distribution is the manifestation of the intermixing of disparate groups characterizable by a normal mixture distribution or the manifestation of non‐mixture, skew‐producing determinants is discussed. Biometrical tools for modeling and quantifying the significance of the skewness in a trait of interest that invite interpretations other than those formed in mixtures or “subgroups” are elaborated. Statistical methods for testing whether a normal mixture distribution better characterizes a set of data than the proposed (or any other) skewed, single‐population‐oriented models are offered. The power of these tests is examined through Monte Carlo experimentation. A brief application in hypertension research demonstrates some of the problems and methods discussed in the paper.
Investigating the HLA component in rheumatoid arthritis: An additive (dominant) mode of inheritance is rejected, a recessive mode is preferred
Authors: Rigby Alan S. , Silman Alan J. , Voelm Lianne , Gregory Julie C. , Ollier William E. R. , Khan Muhammad A. , Nepom Gerald T. , Thomson Glenys , Vogler G. P. 
Published: June 2005

AbstractWe examined the mode of inheritance of rheumatoid arthritis (RA) and estimated the genetic contribution of the HLA‐linked locus to the development of RA using data from 111 multiplex families (54 London, 57 Cleveland), and 43 randomly ascertained patients (Seattle). HLA‐DR4 was present in 78 multiplex probands (70%); a further 16 probands who were negative for DR4 were positive for DR1. Both DR4 and DR1 were significantly in excess when compared to control population frequencies (P < 0.001); an additional finding was an excess of DR7, although the numbers of probands with DR7 were small. Despite the well‐established HLA association with RA, neither recessive nor additive (dominant) modes of inheritance, nor any intermediate models have been ruled out using affected sib‐pair and antigen genotype frequency among patients (AGFAP) methods. However, in our study the AGFAP data for HLA‐DR4 and DR1 were close to recessive expectations (P = ns) while an additive (dominant) mode of inheritance was rejected (P < 0.001). The same results were obtained by an independent method which considered HLA‐DR transmission from affected parents to their affected children. The affected sib‐pair haplotype sharing method showed deviation from random expectations but did not allow discrimination between recessive and additive (dominant) modes. The effect of the HLA‐linked locus on familiarity accounted for only a 1.61‐fold increased risk to sibs over the population prevalence, compared to an observed value of 3.90. This indicated that there could be at least one other non‐HLA locus predisposing to RA with a weight that is slightly greater than that of HLA.
Association of incident lung cancer with family history of female reproductive cancers: The Iowa women's health study
Authors: Sellers Thomas A. , Potter John D. , Folsom Aaron R. , Vogler G. P. 
Published: June 2005

AbstractA number of studies have documented the familial aggregation of lung cancer; there is at least one report that female reproductive cancers are also increased in these families. To determine if the risk exists for all reproductive cancer sites, we conducted a nested case‐control study of lung cancer incidence in a cohort of 41,837 women ages 55–69 years. Women were recruited by mail and asked to provide information on education, occupation, smoking habits, physical activity, and family history of specific cancer sites among female relatives. Four year follow‐up for cancer incidence was conducted using a state‐wide tumor registry. Compared to random controls (n = 1900), cases (n = 152) were more likely to have reported at baseline a sister affected with cancer of the uterus [crude odds ratio (OR) = 3.4, 95% Cl = 1.7–7.0, P < 0.01], cervix (OR = 3.2, 95% Cl 1.2–8.6, P < 0.05), or cancer at any site (OR = 1.6, 95% Cl 1.1–2.4, P < 0.05). A family history of an affected mother with a female reproductive cancer was also more common among the cases, but not statistically significant. Cases were less educated, more likely to work in a technical/industrial setting, less physically active, more likely to smoke, and to smoke for a longer period of time than the controls (all P < 0.01). These differences reduced the magnitude of the family history risk indicators; only the combined category of reproductive cancer at all sites among sisters remained statistically significant. Additional family studies should be done to assess environmental factors in the relatives of the cases and controls to disentangle the influence of shared genes and shared environmental factors in these associations.
A temporary increase of down syndrome among births of young mothers in Norway: An effect of risk unrelated to maternal age?
Authors: Lie Rolv Terje , Heuch Ivar , Irgens Lorentz M. 
Published: June 2005

AbstractThe Medical Birth Registry of Norway carries out a population‐based surveillance of birth defects on a routine basis. An increased proportion of newborn with Down syndrome was seen among children of young mothers during 1985–1986. Three alternative explanations were considered: a first representing a maternal age specific effect, a second based on a general increase in a subgroup of cases caused by factors not related to maternal age, and a third based on the assumption that a particular birth cohort of young women was carrying a high risk. As 1987 and 1988 showed very low proportions in all age groups, the last explanation was considered less likely. Statistical modeling was used to explore which of the two remaining explanations of the temporary increase was the more likely. The observed changes were compatible with a change in the occurrence of a group of maternal age‐independent Down syndrome cases, from 4.59 per 10,000 in 1973–1984 and again in 1987–1988 to a temporary high of 7.68 per 10,000 in 1985–1986. However, the possibility of an age specific change only among young mothers could not be ruled out.
Linkage analysis of low‐density lipoprotein subclass phenotypes and the apolipoprotein B gene
Authors: LaBelle Michael , Austin Melissa A. , Rubin Edward , Krauss Ronald M. , Vogler G. P. 
Published: June 2005

AbstractA common heritable phenotype has recently been identified which is characterized by a relative abundance of small, dense low‐density lipoproteins (LDL), and mild elevations of plasma triglycerides and reductions in plasma high‐density lipoproteins (HDL) cholesterol. This phenotype, designated LDL subclass phenotype B, has been associated with up to a three‐fold increase in coronary disease risk. Complex segregation analysis in two large family studies has demonstrated that LDL subclass phenotype B is influenced by an allele at a single genetic locus with a population frequency of 0.25–0.3, and autosomal dominant inheritance, but with full penetrance only in males age 20 and over and in postmenopausal women. Since apolipoprotein B (apoB) is the principal protein component of LDL, linkage analysis was used to investigate possible linkage between the phenotyope B phenotype and the apoB gene, using a variable number of tandem repeats site located 0.5 kb from the 3′ end of the apoB gene. In 6 informative families including only family members in the penetrant classes, a total LOD score of −7.49 was found at a recombination fraction of 0.001. Thus, under the assumptions of the single gene model, it is unlikely that the apoB locus controls LDL subclass phenotype B.
Estimating effects of probands' characteristics on familial risk: I. Adjustment for censoring and correlated ages at onset
Authors: Liang Kung‐Yee , Vogler G. P. 
Published: June 2005

AbstractFamily studies with age at onset of the disease as the endpoint face two important problems: censoring and correlation of age at onset among relatives. We present a multivariate survival model for ages at onset of relatives which incorporates the problems cited above. The interpretations of regression coefficients and association parameter in the context of family studies are emphasized. The present paper describes a statistical method for estimating these parameters. In a companion paper [Pulver and Liang,Genet Epidemiol8:339–350, 1991] this model is applied to a genetic epidemiologic study of schizophrenia.
Estimating effects of proband characteristics on familial risk: II. The association between age at onset and familial risk in the Maryland schizophrenia sample
Authors: Pulver Ann E. , Liang Kung‐Yee , Vogler G. P. 
Published: June 2005

AbstractIn this report we apply methods outlined in the companion paper [Liang,Genet Epidemiol8:329–338, 1991] to study the association between proband age at onset and familial risk among first‐degree relatives of 374 schizophrenic probands. The analyses take into consideration the potential problems of censoring and correlation of age at onset within families. All analyses were done by gender of the proband; age at onset was dichotomized. The results of the analyses of the male probands suggest that there is an increased risk of schizophrenia among the relatives of male probands who have an onset prior to age 17 when compared to relatives of male probands who have an onset later than 16. We did not find an association between age at onset and familial risk among the female probands, but this may be due to the smaller number of female probands and the lower power associated with the analyses.
Genetics of total serum IgE levels: A regressive model approach to segregation analysis
Authors: Meyers Deborah A. , Beaty Terri H. , Colyer Claudia R. , Marsh David G. , Vogler G. P. , Rao D. C. 
Published: June 2005

AbstractThe genetics of basal total serum IgE levels was investigated in 278 individuals from 42 randomly ascertained nuclear families. The data were analyzed using the regressive model approach to segregation analysis with age, sex, and a measure of skin test responsiveness as covariates in the Class D models. The best fitting model was that of recessive inheritance of high IgE levels with a gene frequency of 0.99 for the “high” allele. Only 3 families showed evidence for segregation of the rare “low” allele, and, if extended further, these families could be useful for molecular genetic linkage studies. These results suggest that there may be a rare allele for very low total serum IgE levels that can be detected even after a measurement of allergic responsiveness (skin test results) is considered as a covariate. Therefore, this major gene for IgE levels appears independent of any similar locus controlling atopy.
Effects of selective return on estimates of heritability for body mass index in the national heart, lung, and blood institute twin study
Authors: Selby Joseph V. , Reed Terry , Newman Beth , Fabsitz Richard R. , Carmelli Dorit , Vogler G. P. , Rao D. C. 
Published: June 2005

AbstractIn the National Heart, Lung, and Blood Institute Twin Study, body mass index (BMI) was studied at military induction and at three subsequent examinations spanning five decades in a cohort of white, male World War II veterans. At military induction (1940s) and again at the first clinical examination of this study (1969–1973), there was close agreement of three commonly used estimates of heritability (range 0.72 to 0.80), and no evidence of a difference in total variance of BMI between the zygosities. However, at the last two examinations (1980s), the total variance in dizygotic (DZ) twins was significantly greater than that of monozygotic (MZ) twins (P<0.01) and these same heritability estimates varied widely. The among‐pair estimate of heritability fell to unrealistic negative values, the within‐pair estimate rose to values of 1.0 or greater, and the intraclass correlation coefficient estimate was slightly lower than in the entire cohort at baseline. The cause of the unequal zygosity total variance appears to have been nonparticipation at later examinations of MZ twins with extreme values of BMI, with no evidence of a similar selection process influencing DZ twins. This selection process biased the three estimates of heritability, making it difficult to determine which estimate is the most appropriate. Despite these biases, it remains clear that genetic factors contribute substantially to BMI in this population.
Testing for association in SLE families
Authors: Seuchter Susanne A. , Knapp Michael , Hartung Klaus , Coldewey Rolf , Kalden Joachim R. , Lakomek Heinz J. , Peter Hans H. , Deicher Helmuth , Baur Max P. , Vogler G. P. 
Published: June 2005

AbstractSystemic lupus erythematosus (SLE) is a complex disease which is partly determined by genetic factors which influence susceptibility to the disease phenotype. In this association study we try to define the high risk haplotypes which are responsible for this disease, together with other environmental factors. In many other association studies a set of SLE patients is compared to a set of controls. The basic assumption about the underlying population is that the disease and control sample should originate from the same genetic population, which is not always completely satisfied in many studies. Therefore, we analyse our family data by applying the Haplotype Frequency Difference (HFD) Method, which constructs its internal control group from those haplotypes not transmitted to the affected individual. Results partially conform with other studies, showing that the haplotypes B8 DR3 as well as B7 DR2 have a high positive association with SLE. When the DR locus was analyzed alone, we found besides the alleles DR2 and DR3 a negative association for DR1, DR5, and DR6.
Linkage studies of schizophrenia: A simulation study of statistical power
Authors: Chen Wei J. , Faraone Stephen V. , Tsuang Ming T. , Vogler G. P. 
Published: June 2005

AbstractIn planning for a linkage study, it is important to determine the number of pedigrees needed to show linkage. Our study overcomes some of the limitations of previous power studies by simulating multigeneration pedigrees to be compatible with the demographic and genetic epidemiological features of schizophrenia; these are variable age at onset, reduced fertility, and increased mortality after onset. We evaluate the power of these pedigrees by first simulating an ascertainment rule requiring at least three ill family members per pedigree and then simulating the trait and marker genotypes according to a single gene model known to fit epidemiological family study data. Our analysis allows for incomplete and age‐dependent penetrance, phenocopies, and interpedigree heterogeneity. We present the power to detect linkage at several lod score thresholds since the multiple tests and phenotypic models required for complex diseases may necessitate using a lod score significance level greater than three. The sample size needed to achieve sufficient power is feasible if 50% of the pedigrees are linked to the marker under test. It may not be feasible to detect linkage if only 25% of the pedigrees are linked, even if a very closely linked marker is used. Our results indicate that to be certain of adequate statistical power, linkage analyses of schizophrenia will require very large samples that do not have a marked degree of genetic heterogeneity. © 1992 Wiley‐Liss, Inc.
Detection of genetic heterogeneity for complex quantitative phenotypes
Authors: Schork Nicholas J. , Chakravarti Aravinda 
Published: June 2005

AbstractStatistically characterizing factors responsible for quantitative phenotype expression (e.g., polygenes, major genes, shared household factors, etc.) through model selection strategies is a difficult task. A great deal of effort has been expended on refining mathematical and computational aspects of various segregation models used to characterize unique expressions of quantitative phenotypes in an effort to make these models easier to implement and evaluate for a given set of data. In this paper a slightly different angle is emphasized: namely, the explicit modeling of the potentially numerous heterogeneous genetic and environmental processes (i.e., segregation patterns, household aggregations, etiologic processes, etc.) that could contribute to the overall variation of a quantitative trait. As such, this paper describes tools for detecting quantitative trait heterogeneity that are meant to answer such questions as, ‘are there pedigress among a great many that show a pattern consistent with a possibly very specific single locus segregation pattern while the rest show compatibility with a polygenic or purely environmental pattern?’ Methods for determing the significance of such heterogeneity are also discussed, as are the results of numerous examples and simulation studies carried out in an effort to validate and further elaborate aspects of the proposed techniques. © 1992 Wiley‐Liss, Inc.
Variance components/major locus likelihood approximation for quantitative, polychotomous, and multivariate data
Authors: Hasstedt Sandra J. 
Published: June 2005

AbstractPearson [Philos Trans R Soc Lond [A] 200:1–66, 1903], Mendell and Elston [Biometrics 30:41–57, 1974], and Rice et al. [Biometrics 35:451–459, 1979] approximated the likelihood of the multifactorial model on a dichotomous phenotype by a procedure of successive univariate computation and conditioning. Hasstedt [Pap: Pedigree Analysis Package, Rev. 3. 1989] and Demenais [Am J Hum Genet 49:773–785, 1991] extended the algorithm to include a major locus. Here I extend the algorithm to polychotomous, quantitative, and multivariate phenotypes, add a major locus to the model, and describe and evaluate the accuracy of an approximation of the resulting variance components/major locus model. © 1993 Wiley‐Liss, Inc.
Inheritance of plasma apolipoprotein B levels in families of patients undergoing coronary arteriography at an early age
Authors: Coresh Josef , Beaty Terri H. , Kwiterovich Peter O. 
Published: June 2005

AbstractAn elevated plasma level of apolipoprotein B (apoB), the major protein of low density lipoproteins, is a risk factor for coronary artery disease. This study tested the hypothesis, suggested by previous studies, that the apoB level is strongly influenced by a major gene. The study population included 832 family members of 116 subjects who had undergone elective coronary arteriography at an early age. The apoB level was adjusted for age, gender, body mass index, alcohol consumption, and cigarette smoking (R2 = 20 %). ApoB levels revealed strong familial aggregation with correlations among spouses of 0.23, parent‐offspring of 0.16, and siblings of 0.21. Regressive models were used to examine inter‐individual variation in adjusted apoB levels. In the total sample, familial aggregation of the apoB level was consistent with two models: (1) a major gene model and (2) a polygenic model with a mixture of non‐transmitted “types.” Comparison of these two models in each family showed that 57 families supported the first model over the second. Segregation analysis in these 57 families conclusively favored a major gene model with codominant transmission. Genotypic means were 124, 164, and 208 mg/dl with relative frequencies of 45 %, 44 %, and 11 %. Linkage studies in these families can be used to clarify the molecular basis of apoB regulation. However, in the whole population the genetic control of apoB levels may be quite complex. © 1993 Wiley‐Liss, Inc.
Combining two‐point genetic linkage analyses using mapping functions
Authors: Schaid Daniel J. , Elston Robert C. 
Published: June 2005

AbstractA 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 δ. This distribution is shown to be a chi‐square mixture distribution with mixing probability depending on δ 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. © 1994 Wiley‐Liss, Inc.