bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular risk factors in a french canadian population: Resolution of genetic and familial environmental effects on blood pressure using twins, adoptees, and extensive information on environmental correlates
Authors: Rice Treva , Vogler George P. , Pérusse Louis , Bouchard Claude , Rao D. C. , Williams Roger R.
Published: June 2005

Genetic and environmental influences on systolic (SBP), diastolic (DBP), and mean arterial (MBP) blood pressure were examined using an expanded version of a path model in which parents and their singleton, twin, and adopted offspring were incorporated, and which also included an environmental index as an estimate of the underlying familial environmental component. Estimates of genetic heritability are lower in parents (10–15%) than in offspring (40–50%). Cultural heritability was significant for SBP (0.31) and MBP (0.40), and an intergenerational effect was found for DBP, with higher estimates in parents (0.42) than in offspring (0.21). Marital resemblance was significant, and no support was found for differential maternal and paternal cultural transmission. Two novel results arising from this study are 1) gender‐specific sibling effects, with greater female than male resemblance for SBP and MBP and the opposite pattern for DBP, and 2) the suggestion of extra twin resemblance arising on account of additional shared environments and resulting in greater like‐sex than opposite‐sex twin resemblance. The major conclusions drawn from this study are that 1) parameter estimates are stable with or without the use of extensive environmental indices, and 2) the addition of twins and adoptees did not significantly impact the results, with the exception of a possible influence of the adoptees in estimates of cultural heritability for DBP. Combining both these features (i.e., extended relatives and environmental indices) enables testing for additional sources of familial aggregation, which is not possible using the traditional nuclear family approach and results in a more accurate assessment of the relative roles of heredity and environment on blood pressure than has been previously possible.
Criteria for onset critically influence the estimation of familial risk in Alzheimer's disease
Authors: Breitner John C. S. , Magruder‐Habib Kathryn M. , Rao D. C. , Voglera G. P.
Published: June 2005

The rare early‐onset variant of Alzheimer's disease (AD) appears to be transmitted as an autosomal dominant genetic trait. More typical late‐onset AD also shows familial aggregation, but possible genetic mechanisms are difficult to examine because the phenotypic expression of the putative AD genotype is often censored by prior death from competing causes. Lifetable methods have been used to examine the age‐specific risk of dementia among relatives, and thus to test the hypothesis of genetic transmission of late‐onset AD. These methods require the ascertainment of affected relatives and the determination of their age at onset. The latter determination is somewhat arbitrary, since symptoms of AD evolve and develop in a continuous and progressive fashion, and different workers may thus use differing criteria for “onset.” This paper demonstrates that the use of divergent thresholds for “caseness” (typically, progressive dementia of several years' duration) and onset (e.g., the first appearance of mild cognitive symptoms, or the first clear evidence of dementia) can introduce substantial bias toward underestimation of risk among relatives. Depending on the definition of onset, familial risk may be underestimated, with apparent cumulative incidence decreased to only 60% of values otherwise expected. We suggest that this problem can be avoided by the use of identical threshold criteria for caseness and for onset.
On the measurement of susceptibility to genetic factors
Authors: Khoury Muin J. , Flanders W. Dana , Rao D. C. , Vogler George P.
Published: June 2005

Geneticists usually measure the phenotypic effects of a single gene trait in terms of penetrance and recurrence risks in relatives of affected individuals, while epidemiologists usually compute measures of relative and attributable risks. These concepts can be merged to measure the proportion of individuals “susceptible” to a genetic factor. In the context of a sufficient cause model, susceptibility can be defined as the underling factor(s) sufficient to make a person develop disease because of the genetic factor in the absence of other causes. The proportion of susceptibles to the genetic factor in the population differs conceptually and often arithmetically from the penetrance of the genotype especially for common diseases with etiologic heterogeneity. For a wide range of disease and allele frequencies, it can be shown that the proportion of susceptibles can be approximated by the risk difference measure (i.e., difference between penetrance with the genotype and penetrance without the genotype). We also apply the concept of susceptibility to estimate familial recurrence of disease due to a genetic factor. This measure of familial recurrence differs conceptually from simple recurrence risk and can be approximated by the familial risk difference measure (i.e., difference between recurrence risks in relatives of cases and relatives of controls) for a wide range of disease and allele frequencies.
Genetic linkage and complex diseases, with special reference to psychiatric disorders
Authors: Risch Neil , Rao D. C.
Published: June 2005

Recent linkage findings for psychiatric disorders, in particular schizophrenia, manic‐depression, and Alzheimer disease, have raised a number of important conceptual issues regarding the genetic etiology of these diseases, as well as the appropriate interpretation of linkage results in studying complex diseases. Perspectives on mode of inheritance, genetic heterogeneity, and phenotypic variation are given.
Transmission of a psychometric indicator for liability to schizophrenia in normal families
Authors: Moldin Steven O. , Rice John P. , Gottesman Irving I. , Erlenmeyer‐Kimling L. , Sing C. F.
Published: June 2005

The genetic analysis of schizophrenia would be facilitated by identification of a heritable correlate of liability. Deviance on an index of Minnesota Multiphasic Personality Inventory (MMPI) signs is associated with the disease phenotype; the familial aggregation and mode of transmission of this continuous psychometric indicator have yet to be established. In this paper, we examine the indicator through commingling analysis and segregation analysis with both the mixed and unified models on 65 nuclear families containing 211 normal individuals. Evidence for a high degree of familiality is found. Analysis of untransformed data under a conditional likelihood provides evidence for Mendelian transmission of a major gene with commingling of two distributions. The frequency of the “high index score” allele is 0.15, with the gene accounting for 31% of the total population variance; such a locus would be relevant to the study of psychopathology as 28% of the population would carry at least one deviant allele. When power‐transformed scores are used to eliminate skewness, there is evidence for one distribution and it is not possible to distinguish single gene from multifactorial (polygenic or cultural) inheritance. While our findings regarding mode of transmission must be interpreted cautiously and confirmation of a single locus requires further study, demonstration of familiality warrants continued investigation of the index as an indicator of liability for schizophrenia.
Structure of ischemic heart disease risk factors in the North Khanty population of Western Siberia
Authors: Puzyrev V. P. , Lemza S. V. , Rao D. C.
Published: June 2005

The relationships between serum lipids, blood pressures, anthropometric traits, age, and ischemic changes of the electrocardiogram (ECG) in the North Khanty population were studied. To this end, eight morphophysiological variables—presumably risk factors for ischemic heart disease—have been subjected to a principal components analysis. Two principal components were extracted. The first revealed age dependency of the traits not associated with ischemic changes of myocardium in both sexes. A comparative analysis of the second component has shown that the chosen traits correlated with ischemic heart disease in males but not in females. Interpretation is given of the components obtained.
Twin concordance for a binary trait: III. A bivariate analysis of hay fever and asthma
Authors: Hopper John L. , Hannah Murray C. , Macaskill Gregory T. , Mathews John D. , Rao D. C.
Published: June 2005

Self‐reported histories of hay fever and asthma were obtained from 3,808 pairs of adult twins 18 years and over registered with the Australian National Health Medical Research Council Twin Registry (1232 MZF, 567 MZM, 751 DZF, 352 DZM, 906 DZO). The prevalence of hay fever and asthma was 0.32 and 0.13, respectively, with little variation with zygosity, sex, and age. The associations between twin pairs for these two traits were analysed, under the assumption of constant prevalences, as a special case of a log‐linear model for binary traits in pedigrees using the statistical package GLIM. The model assumption that there are no secondor higher‐order interactions was tested in the 2 × 2 × 2 × 2 table of twin by disease outcomes without revealing strong evidence of departure, even in this large data set. The log‐linear modelling showed that only three first‐order interactions, namely 1) between hay fever in a twin pair, 2) asthma in a twin pair, and 3) hay fever and asthma in the same twin, were necessary to describe the data. The first two interaction terms were significantly larger in identical pairs; the third was independent of zygosity. Under this parsimonious model, there was a significant difference between identical and fraternal pairs in marginal correlation, both in asthma and hay fever, and in the cross‐correlation between hay fever in one twin and asthma in the other. This suggests that genetic factors are implicated in both hay fever and asthma and that some of these genetic factors are common (at least among a subgroup of individuals) to both traits.
Estimating familial effects on age at onset and liability to schizophrenia. II. Adjustment for censored data
Authors: MacLean Charles J. , Neale Michael C. , Meyer Joanne M. , Kendler Kenneth S. , Rao D. C.
Published: June 2005

Genetic studies of disorders with adult onset often contain individuals who have not completed their age at risk when last observed. Without correction for such censoring, correlation in ages at onset among relatives is substantially underestimated. Moreover, without correction for the effect of correlated ages at onset, the relationship between age at onset in the proband and liability in relatives is substantially overestimated. The present paper describes methods for correcting the effects of censoring on these estimates. In a companion paper [Kendler and MacLean,Genet Epidemiol7:409–417, 1990] these methods are applied to a large family study of schizophrenia.
Heritability of blood pressure in 7‐ to 12‐year‐old Chinese twins, with special reference to body size effects
Authors: Wang Zhiqiang , Ouyang Zhen , Wang Dongmei , Tang Xilin , Rao D. C.
Published: June 2005

Systolic and diastolic blood pressures and body‐size indices such as body height, body weight, sitting height, chest circumference, skinfold thickness, and body mass index (BMI) were assessed in 110 pairs of like‐sex Chinese twins (75 monozygotic and 35 dizygotic) aged 7–12 years. Significant correlations of blood pressure with body‐size indices were found. Prior to adjusting for body‐size effects, three twin methods yielded low heritability estimates for both systolic (0.32–0.41) and diastolic (0.32–0.51) pressures. Adjusting systolic pressure for body height and BMI via multiple regression nearly halved heritability estimates, but adjusting diastolic pressure for body height and skinfold thickness only changed the estimates slightly.
Evidence for a dominant gene mechanism underlying coeliac disease in the West of Ireland
Authors: Hernández Jaime L. , Michalski Joseph P. , McCombs Candace C. , McCarthy Ciaran F. , Stevens Fiona M. , Elston Robert C. , Vogler G. P. , Rao D. C.
Published: June 2005

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.
Genetic epidemiological study of schizophrenia: Two modes of sampling
Authors: Ritsner Michail S. , Karas Sergei I. , Drigalenko Evgenii I. , Gottesman Irving I. , Vogler G. P.
Published: June 2005

The ascertainment of probands according to place of residence in hospitals or in the community has enabled our sampling to be representative of whole subpopulations of patients. Probands from psychiatric hospitals are characterized by biased clinical parameters. Our sampling procedure provides important preliminary results which appear to be contradictory to those produced by conventional sampling methods.
Genetic and nongenetic determinants of blood pressure in a Southern Brazilian sample
Authors: Robinson Wanyce M. , Borges‐Osório Maria Regina , Callegari‐Jacques Sidia M. , Achutti Aloyzio C. , da Silveira Lúcia G. , Klein Carlos H. , Costa Eduardo A. , Rao D. C. , Vogler G. P.
Published: June 2005

A probabilistic sample representative of the adult population of Rio Grande do Sul, Brazil, was studied to estimate the genetic and nongenetic determinants of blood pressure. Four thousand five hundred and sixty‐five individuals, 20 to 74 years old, from 2050 households, were examined. The genetic determination of the SBP (systolic blood pressure) and DBP (diastolic blood pressure) was evaluated in 557 families extracted from this sample. The analysis was performed first with no adjustments for other influencing factors, and then adjusting for the effects of the two significant covariates, age and Quetelel's index, identified through a multiple stepwise regression analysis with nine independent variables. Higher heritability estimates were obtained for DBP (raw data: 0.40; residuals: 0.45) than for SBP (raw data: 0.22; residuals: 0.26). The significant correlation coefficients varied from 0.13 (for father–offspring raw data, total sample), to 0.36 (for siblings, adjusted data, untreated sample). Slight differences were observed between the total and pharmacologically untreated samples in relation to correlation and heritability estimates.
Consanguinity and multiple sclerosis in Orkney
Authors: Roberts D. F. , Vogler G. P.
Published: June 2005

For all patients with multiple sclerosis in Orkney who were alive in 1974 or who had died during 1958 to 1974, pedigree data were analysed. The relationship between their parents, expressed by kinship coefficients, was compared with that between parents of matched controls. The closer relationship between parents of patients suggests that it is the genes that are shared by a patient's parents, and that he inherits from both, that influence his susceptibility to multiple sclerosis.
Statistical analysis of outcomes from repeated pregnancies: Effects of HLA sharing on fetal loss rates
Authors: Hauck Walter W. , Ober Carole , Rao D. C. , Vogler G. P.
Published: June 2005

As part of our ongoing studies of genetic markers of reproductive outcome in the Hutterites, we have been analyzing potential risk factors for pregnancy outcomes. In particular, we are interested in the effects of HLA sharing between parents on fetal loss rates. Pregnancy outcome data such as these have two characteristics that create statistical challenges, i.e., repeated observations per couple and between‐couple heterogeneity in risk. We critically examine four approaches based on the logistic model for the analysis of this and similar data: 1) unconditional likelihood analysis with and without fixed cluster effects; 2) conditional likelihood analysis; 3) mixed‐effects analysis with random cluster effects; and 4) the robust generalized estimating equation (GEE) procedure. Of these approaches, the GEE method of Liang and Zeger would be best suited for the analysis of our data when the question of interest concerns a variable that is constant over all pregnancies, such as HLA sharing. If the question concerns a couple's risk associated with a changing variable such as maternal age, the mixed‐effects analysis is the more appropriate.
Inheritance of human plasma dopamine‐β‐hydroxylase thermal stability
Authors: Vuchetich John P. , Dunnette Joel , Lunetta Kathryn L. , Weinshilboum Richard M. , Price R. Arlen , Vogler G. P.
Published: June 2005

Although the structural gene for human dopamine‐β‐hydroxylase (DBH) has been cloned, the mechanism by which DBH physical properties and activity are regulated is not well understood. Previous reports have suggested that three‐allele or two‐locus models may account for the genetic regulation of these traits in human blood. It is an interesting challenge to determine the extent to which quantitative analyses will complement or guide molecular genetic studies. In this study we analyzed data on the physical property of DBH thermal stability and DBH activity in 230 individuals in 53 families in an attempt to clarify genetic mechanisms for the inheritance of these traits. Commingling and segregation analyses of the thermal stability data provided the first clear evidence of a major gene polymorphism for DBH thermal stability analyzed as a quantitative trait. Major gene transmission was supported within a mixed model (χ = 13.39, P < .004). In keeping with earlier findings, similar analyses of DBH activity provided strong evidence of genetic transmission. However, in our data support for a major gene polymorphism was equivocal (χ = 2.99, P = .22).
Power and validity of methods to identify variability genes
Authors: Elashoff Janet D. , Cantor Rita M. , Shain Sara , Vogler G. P.
Published: June 2005

A variability gene model [Magnus et al., Clin Genet 19:67–70, 1981] hypothesizes that environmental influences on the expression of additive genes for a quantitative trait such as cholesterol are under the control of alleles at a separate nonadditive locus. They suggest identifying such genes using an analysis of variance to compare absolute intrapair monozygotic twin trait differences between the genotypes of the postulated variability locus. However, quantitative traits such as cholesterol often have skewed distributions with a long right tail; what are the effects of such nonnormality on the procedure suggested by Magnus et al. [1981]? We show that their method is a special case of the Levene tests, robust tests for variability differences. We introduce a statistical model representing sources of variability in twin pair differences and demonstrate with simulation studies that although the Levene tests have robust Type I error, power is enhanced when nonnormal data are transformed before analysis, and the apparent presence and degree of variability differences are dependent on the scale of analysis. These findings indicate the importance of appropriate transformation of the trait before analysis. Analysis of a well‐characterized twin data set illustrates these conclusions.
Adequacy of single‐locus approximations for linkage analyses of oligogenic traits
Authors: Vieland Veronica J. , Hodge Susan E. , Greenberg David A. , Vogler G. P.
Published: June 2005

When a disease is controlled by two or more mendelian loci acting epistatically, it can be modeled in a linkage analysis as a single‐locus mendelian disease with reduced penetrance. However, the reliability of such an approximation has not yet been demonstrated. This study evaluates the adequacy of such single‐locus approximations, when the disease under investigation is determined by two loci, one of which is tightly linked to a genetic marker.

A wide range of two‐locus models were simulated, and analyzed under both the correct two‐locus model and under a single‐locus approximation to that model. In general, the single‐locus approximations yielded lod scores very close to the correct ones, but estimates of θ tended to be upwardly biased. We conclude that a single‐locus linkage analysis will, in general, provided an excellent approximation to a correct (two‐locus) linkage analysis of epistatic two‐locus diseases. This enables researchers to continue to use single‐locus linkage analyses when two‐locus disease transmission is a possibility, and it validates linkage findings already obtained under single‐locus analysis, even if the disease under in vestigation proves ultimately to be governed by two mendelian loci. We also examine alternative methods for obtaining parameter estimates for the single‐locus approximations, and we discuss both generalizations and limitations of our findings. © 1992 Wiley‐Liss, Inc.
An analytical method for assessing patterns of familial aggregation in case‐control studies
Authors: Zhao L. P. , Le Marchand L. , Chakrawarti Aravinda
Published: June 2005

This paper describes an analytical method that is used to assess patterns of disease aggregation within family based on family history information collected in case control studies. In such a study, cases and controls are thought of as probands whose relatives are identified, and relatives' phenotypes and other covariates such as age, sex, and genealogical relationship with the probands are recorded. By modeling the dependence of relatives' phenotypes on case‐control status and other covariates, this method yields adjusted odds ratios that quantify familial aggregation. The estimated standard errors are obtained for statistical inference since the method acknowledges the potential correlations between relatives' phenotypes by using the estimating equations technique. In population‐based case‐control studies, the estimates and statistical inferences are generalizable to the general population. To illustrate this method, we analyzed a case‐control study of colorectal cancer involving 5,190 relatives of 792 cases and 4,478 relatives of 680 population‐based controls conducted in Hawaii. Although detailed results will be presented elsewhere, the colorectal cancer was found to aggregate within family with an odds ratio of 2.74 (95% confidence interval (CI): 1.78–4.21). Among parents, the odds ratio for familial aggregation was 2.38 (95% CI: 1.25–4.54). The corresponding value for siblings was 3.09 (95% CI: 1.87–5.11). It was also found that the odds ratio increases from about 2.00 for relatives of the probands who were 50 years or older to 7.66 and 12.84 for relatives of the probands who were between 40 and 50 years and under 40 years, respectively, suggesting that the familial aggregation of colorectal cancer decreases as probands' age increases. © 1992 Wiley‐Liss, Inc.
Familial analysis of eosinophilia caused by helminthic parasites
Authors: Moro‐furlani A. M. , Krieger H. , Vogler G. P.
Published: June 2005

A highly significant familial aggregation of eosinophil levels (X2/3 = 38.00) was detected in a sample from three Brazilian populations with a high incidence of helminthic parasitism. The data were unable to resolve genetic or common environment causation due to the lack of environmental concomitant variables. Results of path analysis indicate that the familial cause accounts for about 58% of the total variability of eosinophil levels among parasite‐infected individuals. © 1992 Wiley‐Liss, Inc.
Do bilineal pedigrees represent a problem for linkage analysis? basic principles and simulation results for single‐gene diseases with no heterogeneity
Authors: Hodge Susan E. , Mulvihill J. J.
Published: June 2005

Some investigators have expressed concern—specially for psychiatric disorders—that bilineal pedigrees should not be included in linkage studies. This study compares the ‘informativeness’ of bilineal and unilineal families for a homogeneous single‐gene disorder. Three approaches were used: (1) simulation studies of three‐generation pedigrees, ( 2 ) calculation of expected lod scores (ELODs) in nuclear families, and ( 3 ) calculation of Fisher's information number I(θ) in nuclear families. The simulation studies in (1) permitted a realistic comparison between bilineal datasets and purely unilineal ones. The calculations in nuclear families in ( 2 ) and (3) then made it possible to analyze the sources of information loss in bilineal families.

Overall, in datasets of five three‐generation pedigrees each, the drop in mean maximum lod score was approximately 50% from purely unilineal datasets to extremely bilineal ones. In less‐extreme bilineal datasets, which are closer to most real data than the extremely bilineal ones, the drops in lod score were very small—less than 10% in some, and practically zero in others. The details will vary, depending on size and structure of the pedigree, genetic model, true value of the recombination fraction, and informativeness of the marker. However, these results imply that the information loss due to bilineality is not necessarily very great.

The nuclear‐family calculations showed that for phase‐known matings there is relatively little information loss in bilineal families, but for phase‐unknown matings the loss is much greater.

In conclusion, for single‐gene disorders with no genetic heterogeneity, whereas bilineal families can be less informative than comparable unilineal families, they are not so much less informative that they should automatically be discarded from linkage datasets. The implications of bilineal pedigrees for linkage studies of heterogeneous disorders are also discussed. © 1992 Wiley‐Liss, Inc.
Epidemiologic analysis of gene‐environment interaction in twins
Authors: Ottman Ruth
Published: June 2005

Our aim was to develop a simple method for testing gene‐environment interaction in twin data ascertained through affected twins (probands), with known exposure status of both cotwins. To this end we derived formulae for two epidemiologic measures, as a function of prevalence of an exposure and genotype, and disease risk conditional on exposure and genotype: (1) relative risk of disease in exposed vs. unexposed cotwins, stratified by zygosity and proband exposure status (RRE), and (2) relative risk of disease in MZ vs. DZ cotwins, stratified by exposure status of proband and cotwin (RRZ). Then we investigated the behavior of these two measures under different assumptions about the relations between exposure and genotype in terms of their effect on disease risk. If an exposure has a different effect in the presence vs. absence of the genotype, RRE differs between MZ and DZ cotwins. Similarly, if a genotype has a different effect in exposed vs. unexposed persons, RRZ differs between exposed and unexposed cotwins. However, large differences in RRE between MZ and DZ cotwins, or large differences in RRZ between exposed and unexposed cotwins, do not occur except under very extreme conditions, such as a genotype that increases disease risk in exposed individuals, and has a protective effect in unexposed individuals. These results suggest that power to detect gene‐environment interaction is limited with this approach. Conversely, if large differences in RRE or RRZ are observed, they are likely to reflect strong gene‐environment interaction. © 1994 Wiley‐Liss, Inc.
Censored survival models for genetic epidemiology: A gibbs sampling approach
Authors: Gauderman W. James , Thomas Duncan C.
Published: June 2005

Methods are proposed for the analysis of diseases with variable age at onset. The Cox proportional hazards model, widely used for epidemiologic analysis, is modified to include both measured (environmental) covariates and latent (genetic) variables, as well as their interactions. A Monte Carlo technique known as Gibbs sampling is utilized to generate observations from the posterior distributions of all model parameters. A correction to account for single ascertainment of pedigrees is also described. Simulation studies show that parameter estimation is nearly unbiased for a wide variety of models, and that moderate gene‐environment interaction effects can be detected. © 1994 Wiley‐Liss, Inc.
Extended latent class approach to the study of familial/sporadic forms of a disease: Its application to the study of the heterogeneity of schizophrenia
Authors: Melton Beth , Liang Kung‐Yee , Pulver Ann E.
Published: June 2005

When no method exists for detecting genetic forms of a disorder, epidemiologists classify probands according to the presence or absence of an affected relative (familial or sporadic). Not only is this a surrogate measure but if the risk for the disorder is associated with characteristics such as age and gender, then probands with varied distributions of these characteristics among their relatives are subject to misclassification. A latent class approach is presented which explicitly models the relationship between the affected status of the relatives and the unobservable familial/sporadic status of the proband in order to adjust for these characteristics. Lastly, an approach is introduced to correct for attenuation in measures of association between familial/sporadic status and other variables that could result if probands are misclassified. This approach incorporates the latent class probabilities directly into the regression model without classifying probands. These methods are applied to a study of theheterogeneity of schizophrenia.
Familial risks for Alzheimer disease from a population‐based series
Authors: Hirst C. , Yee I. M. L. , Sadovnick A. D.
Published: June 2005

Kaplan‐Meier risks estimates are calculated and compared for two consecutive series (N1 = 840, N2 = 819) of first‐degree relatives of Alzheimer disease (AD) patients diagnosed as either “probable” or “autopsy‐confirmed” AD. The consistency of results increases confidence in estimates and suggests consistent case ascertainment over 8 years. Lifetime risk estimates to age 88 for the combined sample (23.4% ± 3.0%) do not approach the 50% risk compatible with an autosomal dominant model of transmission. These results support our previous finding and suggest that an autosomal dominant gene(s) is not responsible for all cases of AD.
Segregation analysis of human red blood cell thiopurine methyltransferase activity
Authors: Vuchetich John P. , Weinshilboum Richard M. , Price R. Arlen
Published: June 2005

Thiopurine methyltransferase (TPMT) catalyzes thiopurineS‐methylation, an important metabolic pathway for drugs such as 6‐mercaptopurine (6‐MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6‐MP and other thiopurine drugs. Variation of TPMT activity in the red blood cell (RBC) has been found to reflect activity differences in less accessible tissues. Previously reported qualitative analyses of inheritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present study we completed complex segregation analyses of RBC TPMT activity of 213 individuals in 49 families that were randomly ascertained through children in the Rochester, MN, public school system. We found clear evidence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gene with frequency of 0.94 for the allele conferring high enzyme activity. The genotype distributions of individuals who were homozygous for the low activity allele, heterozygous, and homozygous for the high activity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respectively, of the individuals in the sample. This major locus accounted for 66% of the total variance in untransformed RBC TPMT activity. Although there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect additional major locus or polygenic inheritance effects on the residual variance. © 1995 Wiley‐Liss, Inc.
Comparison of analysis of variance and maximum likelihood based path analysis of twin data: Partitioning genetic and environmental sources of covariance
Authors: Christian Joe C. , Norton James A. , Sorbel Jeffrey , Williams Christopher J.
Published: June 2005

In order to investigate currently used model fitting strategies for twin data, analysis of variance (ANOVA) and path‐maximum‐likelihood (PATH‐ML) methods of analyzing twin data were compared using simulation studies of 50 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs. Phenotypic covariance was partitioned into additive genetic effects (A), environmental effects common to cotwins (C), and environmental variance unique to individuals (E). ANOVA and PATH‐ML had identical power to detect total covariance. The PATH‐ML AE model was much more powerful than ANOVA comparisons of rMZ and rDZ to detect A. However, to be unbiased, the AE model requires the assumption that C = 0.0. To allow use of the AE model to estimate A, the null hypothesis C = 0.0 is tested by comparing the goodness of fit of the ACE and AE models. Simulation of 50 MZ and 50 DZ pairs revealed that C must be greater than 55% of total variance before the null hypothesis would be rejected (P < 0.05) 80% of the time. Several recent publications were reviewed in which the null hypothesis C = 0.0 was accepted and apparently upwardly biased estimates of A, containing C, were presented with unrealistic P values. It was concluded that use of the AE model to estimate A gives an inflated view of the power of relatively small twin studies. It was recommended that ANOVA or comparison of the ACE and CE PATH‐ML models be used to estimate and test the significance of A as neither requires that C = 0.0. © Wiley‐Liss, Inc.
Extended HLA profile of an inbred isolate: The Schmiedeleut Hutterites of South Dakota
Authors: Dawson Deborah V. , Ober Carole , Kostyu Donna D.
Published: June 2005

HLA‐A, ‐B, ‐C, ‐DR, and ‐DQ typings of the Schmiedeleut Hutterites of South Dakota were collected as part of an ongoing genetic‐epidemiologic study of HLA and fertility. A total of 1,082 individuals, including 852 married adults representative of the reproductive population of this isolate, were characterized for five‐locus HLA haplotypes. HLA‐A1, A2, A3, and A24 accounted for 75% of observed HLA‐A alleles and HLA‐B27, B35, B51, and B62 accounted for 55% of observed HLA‐B alleles. S‐leut Hutterites are derived from 68 or fewer ancestors. However, only 48 ancestral HLA haplotypes were observed and nine of these accounted for over 52% of the observed haplotypes. Measures of two‐locus linkage disequilibrium derived from these haplotypes indicated that one‐third to half of the observed HLA‐A/B, B/DR, and A/DR allele combinations exhibited highly statistically significant linkage disequilibrium. Allele and haplotype frequencies did not differ between males and females. Recombination rates of 0.004% and 0.005% between HLA‐A and ‐C and between HLA‐B and ‐DR, respectively, were observed. This HLA profile points out a paucity of HLA alleles and haplotypes in this population and marked linkage disequilibrium among the HLA alleles that are present. © Wiley‐Liss, Inc.
Detection of a recessive major gene for high IgE levels acting independently of specific response to allergens
Authors: Dizier M. H. , Hill M. , James A. , Faux J. , Ryan G. , le Souef P. , Lathrop M. , Musk A. W. , Demenais F. , Cookson W.
Published: June 2005

The genetic control of the total IgE, the immunoglobulins E involved in allergy, remains still unclear. Although high IgE levels were found to be determined by a recessive major gene in several studies, other modes of inheritance were also reported. Moreover, at least two different genetic mechanisms controlling the IgE regulation have been suggested: one involved in the specific IgE response and the other one in the nonspecific response. To better understand the genetic mechanisms controlling IgE variation, we performed segregation analysis of IgE levels by ignoring or taking into account the specific response to allergens (SRA). Analyses were conducted using the class D regressive model, in a sample of 234 Australian nuclear families randomly selected during the winter months, when IgE levels are the lowest (basal). SRA, when included as a covariate in the model, was defined by one of the three following criteria: (1) raised specific IgE level for one or more allergens, (2) positive skin test for one or more allergens, and (3) at least one of the (1) or (2) criteria. When the presence of SRA is ignored, the familial transmission of total IgE level is compatible with the segregation of a recessive major gene and residual familial correlations. When the presence of SRA is accounted for in the analysis, whether defined by criteria (1), (2), or (3), there is still evidence for a recessive major gene controlling IgE levels but residual familial correlations are no longer significant. In addition, no interaction between this major gene and SRA is shown here. Our results suggest that this gene, which accounts for 28% of the variation of the trait, may be involved in the control of basal IgE production, independently of specific response to allergens. © Wiley‐Liss, Inc.
Use of robust statistical methods to determine the effect of fragile X on means and variance components of a quantitative trait
Authors: Huggins R. M. , Loesch D. Z.
Published: June 2005

Owing to the presence of outliers, an estimated 3.5% in the ridge breadth data and 1.7% in the height data, the effect of fragile X on height and ridge breadth was examined using robust statistical techniques for data collected from 54 families afflicted with this disorder. It is shown that fragile X affects ridge breadth and height in a different manner. Fragile X women had a greater mean ridge breadth than normal women, whereas there was a similar trend, but no significant difference, between normal and fragile X men. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. However, fragile X girls were shown to grow more quickly and to stop growing earlier than normal girls. An examination of the covariance between relatives classified according to fragile X status showed that for both traits the effect of fragile X was to reduce the covariance between parents and offspring, which produced the effect of departure from an additive polygenic model of inheritance. ©1995 Wiley‐Liss, Inc.
Method for calculating risk associated with family history of a disease
Authors: Kerber Richard A.
Published: June 2005

A method is described for estimating excess relative risks of a disease from familial factors. Beginning with population‐based series of cases and controls, a cohort of each subject's relatives is formed and checked for disease against a population based registry. The disease experience of the cohort formed from each subject's relatives is summarized as a kinship‐weighted familial standardized incidence ratio (FSIR). The FSIR's are used as exposure estimates in conditional linear excess relative risk models, which may be used not only to screen for significant familial disease aggregations, but also to estimate relative risks, population attributable risks, and gene‐environment interactions. The method is demonstrated on 4083 breast cancer cases from Utah and a set of matched controls. ©1995 Wiley‐Liss, Inc.
Population genetic study of the human dopamine transporter gene (DAT1)
Authors: Doucette‐Stamm Lynn A. , Blakely Derron J. , Tian Jingxiang , Mockus Sue , Mao Jen‐i
Published: June 2005

The human dopamine transporter gene, DAT1, acts to transport released dopamine into presynaptic terminals of the brain. The possibility that the DAT1 gene plays a role in genetic diseases of the brain has led to studies of DAT1 in several psychiatric and neurological disorders. Previous sequence analysis of DAT1 revealed a 40‐bp repeat in the 3′ end of the gene. In order to identify all potential alleles for this VNTR marker a population database was established. One thousand seventy‐four unrelated individuals were screened by PCR for the region containing the 40 bp repeat. Allele frequency differences were found between black Americans and Caucasians or Hispanics but no differences were observed between Caucasians and Hispanics. A previously unreported allele was detected in all three populations. Thus, we have shown that screening a large population identifies new alleles and generates more accurate allele frequencies. ©1995 Wiley‐Liss, Inc.
Dementia among elderly apolipoprotein E type 4/4 homozygotes: A prospective study
Authors: Ganguli Mary , Cauley Jane A. , Dekosky Steven T. , Kamboh M. Ilyas
Published: June 2005

The E*4 allele of the apolipoprotein E (APOE) gene on chromosome 19 has been shown to be an age‐ and dose‐related risk factor for Alzheimer's disease. Of 870 elderly women participating in an osteoporosis study, 13 were previously found to be homozygous for the APOE*4 allele; 1 was deceased and the rest were assessed for dementia in a “piggyback” study of dementia. One had moderate [clinical dementia rating (CDR) = 2], 2 had mild dementia (CDR = 1), and 2 had possible dementia (CDR = 0.5). All 3 women over 80 years were definitely demented (CDR ⩾ 1).

Typically, genetic studies of Alzheimer's and other dementias require the identification and diagnosis of large numbers of demented subjects, at considerable expense, followed by genotyping or phenotyping with a relatively low yield of individuals with rare alleles. We demonstrate a more cost‐effective approach in which the population is first phenotyped and then stratified by phenotype, so that diagnostic evaluation can be restricted to individuals with the phenotype of interest. ©1995 Wiley‐Liss, Inc.
Maximum‐likelihood estimation in linkage heterogeneity models including additional information via the EM algorithm
Authors: Houwing‐Duistermaat Jeanine J. , Sandkuijl Lodewijk A. , Bergen Arthur A. B. , van Houwelingen Hans C.
Published: June 2005

In linkage analysis, estimated recombination fractions between a disease gene and several markers are used to assign the disease gene to a a particular chromosome region. For rare diseases, locus heterogeneity leads to different recombination fractions in different families, and a set of pedigrees can be regarded as a mixture. Information which can help to classify the different families may be available and can be included in the model. This is demonstrated for a data set of X‐linked retinitis pigmentosa families. The joint distribution of the position of the disease gene and the additional information on the penetrance of tapetal reflex among obligate female carriers is studied. A model including the additional information is fitted to the data using the EM algorithm. The algorithm uses for every pedigree the lod score curve which can be obtained from a standard (multipoint) linkage analysis. ©1995 Wiley‐Liss, Inc.
Data simulation for GAW9 problems 1 and 2
Authors: Speer Marcy C. , Terwilliger Joseph D. , Ott Jurg
Published: June 2005

Herein we describe the methods utilized to simulate the genetic marker data for GAW9 Problems 1 and 2, as well as the pedigree and phenotype data for GAW9 Problem 1. ©1995 Wiley‐Liss, Inc.
Comparing the power of linkage detection by the transmission disequilibrium test and the identity‐by‐descent test
Authors: Clerget‐Darpoux Françoise , Babron Marie‐Claude , Bickeböller Heike
Published: June 2005

The aim of this study is to compare the power of the transmission disequilibrium test (TDT) to that of the identity‐by‐descent (IBD) distribution test. The relative powers of these tests depend both on the underlying genetic model and on the available family data. Families with two affected sibs are always more informative than those with one affected child and one unaffected child. The IBD test is always more powerful in the first situation and, contrary to the TDT, is independent of the presence of gametic disequilibrium. When there is strong linkage disequilibrium, the TDT can be more powerful than the IBD test. In that case, linkage can be detected by the TDT even in families with only one affected child. ©1995 Wiley‐Liss, Inc.
Two‐locus approach of segregation and linkage analysis in the study of complex traits
Authors: Xu Jianfeng , Taylor Eugene W. , Panhuysen Carolien I. M. , Prenger Valerie L. , Koskela Rebecca , Kiemeney Bart , LaBuda Michele C. , Maestri Nancy E. , Meyers Deborah A.
Published: June 2005

A two‐locus segregation and linkage‐analysis approach was used to characterize the genetic control of a complex trait (Q1) and to localize the genes that have detectable effects. The results suggested that a two‐locus Mendelian model fit the data significantly better than a one‐locus model. The linkage results based on the most parsimonious two‐locus model revealed linkage of Q1 to two areas (MG2 and MG3), while there was less evidence for linkage using one‐locus models. Results also suggested that the subphenotypes (Q2 and Q3) provided useful information for further analysis of Q1 using two‐locus models. © 1995 Wiley‐Liss, Inc.
Studies on the development of mouse embyros in vitro. II. The effect of energy source
Authors: Brinster Ralph L.
Published: June 2005

The effect of various possible energy sources on the development in vitro of two‐cell mouse ova into blastocysts was examined. Energy for development of two‐cell mouse ova could be supplied by lacatate, pyruvate, oxaloacetate, or phosphoenolpyruvate. Compounds such as glucose, fructose, ribose, glucose‐6‐phosphate, fructose‐1, 6‐phosphate, acetate, citrate, α‐ketoglutarate, succinate, fumarate, and malate could not provide energy for development of two‐cell mouse ova. The optimum concentrations at pH 7.38 for those compounds which would supply energy was 5.00 × 10−2 M lactate, 3.16 × 10−4 M oxaloacetate, and 1.00 × 10−2 M phosphoenolpyruvate.

The possibility that interactions existed between the effects of osmolarity, pH, and energy source was examined in several experiments. There was no interaction between the effects of osmolarity and pH or osmolarity and the four possible energy sources. However, there was a singnificant interaction between energy source and pH. The result of this is that an increase in pH of the medium results in an increase in the optimum concentration of the compound supplying energy to the developing ova.