摘要:

AbstractOvert computational constraints in the formation of mixed models for the analysis of large extended‐pedigree quantitative trait data which allow one to reliably characterize and partition sources of variation resulting from a variety sources have proven difficult to overcome. The present paper suggests that by combining a restricted patterned covariance matrix approach to modeling and partitioning the variation arising from polygenic and environmental forces with an Elston–Stewart like algorithmic approach to modeling variation resulting from a single genetic locus with large phenotypic effects one can produce a model that is at once intuitively appealing, efficient computationally, and reliable numerically. Extensions and variations of this approach are also discussed, as are some simulation and timing studies carried out in an effort to validate the accuracy and computational efficiency of the proposed methodology. © 1992 Wiley‐Lis

ISSN:0741-0395    

DOI:10.1002/gepi.1370090202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAn accurate specification of the dimensionality and ordering of categorical multifactorial phenotypes (e.g., smoking status, including heavy, moderate, light, and nonsmokers) is an important prerequisite for the genetic analysis of these traits. Typically, phenotypic dimensionality and ordering are determined by comparing the relative fits of alternative parametric threshold models. Here, a method of analysis is described which addresses the same issue of trait dimensionality but does not require parametric assumptions. Specifically, we detail how nonmetric multidimensional scaling (MDS), applied to contingency tables which cross‐classify the phenotypes or responses of one relative with another, may be used to explore trait dimensionality. Scaling results from deterministic simulation studies indicate that the latent structure of categorical phenotypes can be recovered with nonmetric MDS. Results from stochastic simulations, however, indicate that the accuracy of recovery, as well as the rejection of models of incorrect dimensionality, are strongly dependent upon sample size and the latent liability correlation between relatives. As an application of the method, the dimensionality of a measure of smoking status in 1,656 pairs of monozygotic twins ascertained through the American Association of Retired Persons is considered. The MDS results indicate that the onset of the smoking habit and the quantity smoked in this aging population represent a unidimensional process. The implication this finding has for subsequent genetic analysis is discussed. © 1992 Wiley‐Liss,

ISSN:0741-0395    

DOI:10.1002/gepi.1370090203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractAn explanation for the consistently documented finding of higher levels of high density lipoprotein‐cholesterol in black men relative to white men was sought by comparing the frequency of restriction fragment length polymorphism markers present in blacks and in whites at the gene loci coding for the two major apolipoprotein constituents of high density lipoprotein, apolipoproteins AI and AII. The measurements were made in population‐based samples of 45 to 54‐year‐old black (n = 190) and white (n = 370) subjects from the Minnesota Heart Survey for whom lipoprotein levels were available. The mean high density lipoprotein‐cholesterol level for black men in the sample (47 ± 1.5 mg/dl) was higher (P<0.05) than that for white men (42 ± 0.9 mg/dl), while levels in women were not different between races. While theSacI andMspI markers at the apolipoprotein AI‐CIII‐AIV gene locus showed similar frequencies in blacks compared to whites, the degree of the linkage disequilibrium previously noted between these markers in white subjects was altered in blacks and the minor allele of thePstI marker at this locus was virtually absent in the black subjects (P<0.005 vs whites). For black men, there were significant associations of the M2 allele and the S2M2 haplotype at the apolipoprotein AI locus with lower high density lipoprotein‐cholesterol levels. The results are consistent with the hypothesis that DNA sequence variations in the vicinity of the apolipoprotein AI‐CIII‐AIV gene locus are associated with the difference in high density lipoprotein‐cholesterol levels between blacks and whites.

ISSN:0741-0395    

DOI:10.1002/gepi.1370090204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

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,

ISSN:0741-0395    

DOI:10.1002/gepi.1370090205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThis 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

ISSN:0741-0395    

DOI:10.1002/gepi.1370090206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

ISSN:0741-0395    

DOI:10.1002/gepi.1370090201

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY