bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linkage and segregation analyses of apolipoproteins A1 and B, and lipoprotein cholesterol levels in a large pedigree with excess coronary heart disease: The Bogalusa heart study
Authors: Amos Christopher I. , Elston Robert C. , Srinivasan Sathanur R. , Wilson Alexander F. , Cresanta James L. , Ward Laura J. , Berenson Gerald S. , Rao D. C. 
Published: June 2005

AbstractRobust methods were employed, using data from a single large pedigree, to screen serum apolipoprotein A1 and B levels, serum lipoprotein cholesterol levels, and ratios of serum lipoprotein cholesterol fractions to apolipoprotein A1 and B levels for genetic linkage to 31 polymorphic markers. Segregation analyses were performed for each of the apolipoprotein and lipoprotein cholesterol fractions to obtain estimates for use in applying likelihood methods of linkage analysis. Trait‐marker combinations for which linkages were suggested from the robust methods were then reexamined for linkage using the likelihood (lod score) method. Results from the segregation analyses were consistent with major gene determination of apo B and HDL‐C levels, the HDL‐C to apo A1 ratio, the LDL‐C to apo B ratio, and a measure of relative content of cholesterol in HDL‐C and LDL‐C. Linkage between haptoglobin and the HDL‐C/apo A1 ratio was suggested, with a lod score of 1.72 at θ = 0.05.
A Monte Carlo evaluation of three statistical methods used in path analysis
Authors: McGue M. , Wette R. , Rao D. C. , MacCluer J. W. 
Published: June 2005

AbstractResults of a Monte Carlo study to investigate the properties of three statistical methods used extensively in path analysis of family data are presented. All three methods are based on the maximum likelihood principle and involve the assumptions of multivariate normality and large sample (asymptotic) statistical properties. The methods differ, however, in the specification of the likelihood function. Given a set of correlation estimates, method 1 maximizes the likelihood function under the stipulation that the estimates are independent. Method 2 differs from the former by allowing for covariances among the correlation estimators. Method 3 involves (direct) maximization of the likelihood function for the individual family observations assuming multivariate normality for the vector of family observations. The Monte Carlo study investigated validity of the test statistics and confidence intervals and evaluated the relative efficiency and bias of the parameter estimates based on 1,000 replications of each of several simulation conditions. The effects of violating the two basic assumptions, multivariate normality and asymptotic theory, were investigated by comparing results for non‐normally vs normally distributed family data and for small vs large sample sizes. It is shown that method 3 provides valid statistical inferences under multivariate normality and that it is generally robust against minor departures from normality. Method 2 is also robust against minor deviations from normality, but it is sensitive to small sample sizes. Method 1 yields highly conservative test statistics under all conditions studied.
Repeated‐measures model for the investigation of temporal trends using longitudinal family studies: Application to systolic blood pressure
Authors: Province M. A. , Tishler P. , Rao D. C. , Eaves Lindon J. 
Published: June 2005

AbstractA contemporary path model for the analysis of familial resemblance is extended to incorporate repeated measurements on the entire pedigree over time, in order to assess age‐related changes in familiality. The parameters of the model can be defined as arbitrary functions of the ages, age differences, or cohabitation times of the family members at the exact time of measurement. Tracking of the phenotypes is decomposed into a familial and a nonfamilial component, which vares with both the time span between measurements and the ages at measurement. Some of the family members may have data missing on one or more visits, and the visits may be unequally spaced both within and across families. The method incorporates all measurements available from all visits into a single model. The model is applied to longitudinal data on systolic blood pressure in 490 East Boston families measured two times at 3‐year intervals. Evidence for some nonfamilial tracking is found. Additionally, significant temporal trends are demonstrated in the familiality as a function of age, t2(A), which appears to be near zero at birth, grow to a maximum of about 40% at around age 30, and then appears to monotonically decrease again. No evidence was found for temporal trends in marital resemblance or residual sibling environmental effects. This model provides an objective method of investigating developmental changes in the correlational structure of families over time using repeated‐measures and of estimating continuous changes in familiality with age.
Path analysis under generalized marital resemblance: Evaluation of the assumptions underlying the mixed homogamy model by the Monte Carlo method
Authors: McGue M. , Wette R. , Rao D. C. , Elston Robert C. 
Published: June 2005

AbstractPath analysis of nuclear family data has been widely applied to resolve genetic and environmental sources of familial resemblance. Here we report the results of a systematic evaluation of the effects of departures from five modeling assumptions often made when analyzing nuclear family data; i) the observed environmental index is unaffected by the genotype, ii) the basis of marital resemblance is correctly specified in the model, iii) there are no intergenerational differences in either the genetic or cultural heritability, iv) there is no genetic dominance, and v) there is no genotype by family environment interaction. “Deterministic simulations” identified various situations where model misspecification could lead to substantial bias in the estimation of the heritabilities. For these situations, “stochastic simulations” were performed to determine whether the “goodness‐of‐fit” test used in path analysis would correctly reject the misspecified model. In samples of 500 nuclear families, each comprising two parents and two children, the goodness‐of‐fit test was found to be sensitive to misspecifications of the source of marital resemblance and the existence of intergenerational differences in heritabilities, although reduced power would make the test less sensitive in smaller samples. The test was largely insensitive to misspecifications of possible genetic effects on the environmental index, and to the existence of multiplicative interaction between the genotype and familial environment. When genetic effects on the index are ignored, the genetic heritability (h2) is understimated, the cultural heritability (c2) is overestimated, but h2 + c2 remains unchanged. Neglecting the interaction was found to result in an overestimate of h2.
Mixed model segregation analysis of LDL‐C concentration with genotype–covariate interaction
Authors: Konigsberg Lyle W. , Blangero John , Kammerer Candace M. , Mott Glen E. , Vogler G. P. 
Published: June 2005

AbstractMixed model complex segregation analyses have in the past ignored the possibility of genotype–covariate interaction. Only in the nonmixed model with polygenic heritability equal to zero have segregation analyses been performed that allowed for genotype specific regression of the phenotype on covariates. We present an extension of Hasstedt's [1982] mixed model likelihood approximation which does allow for genotype–covariate interaction in the mixed model. Following description of this approximation, we validate the likelihood calculation by a Monte Carlo procedure based on the actual pedigree and missing data structure used in a complex segregation analysis of low density plus very low density lipoprotein cholesterol (LDL‐C + VLDL‐C) in baboons. The observed averages of the bootstrap parameter estimates adequately recover the generating values, which included parameters specifying genotype–covariate interaction. We then applied both a traditional complex segregation analysis and an analysis with genotype–covariate interaction to test for the presence of a major locus affecting LDL‐C levels in baboons. The model including genotype–covariate interaction was significantly different from the model without interactions, and strongly supported the hypothesis that there is a segregating Mendelian locus as opposed to a random environmental factor. This major locus accounts for approximately 46% of the variance in LDL‐C levels, as compared to 40% explained by a locus with no genotype‐covariate interaction.
Clustering of hepatocellular carcinoma in Alaska Native families
Authors: Alberts Steven R. , Lanier Anne P. , McMahon Brian J. , Harpster Annette , Bulkow Lisa R. , Heyward William L. , Murray Christine , Vogler G. P. 
Published: June 2005

AbstractAlaska Natives have a high incidence of hepatocellular carcinoma (HCC), with regional, ethnic, village, and familial clustering. During 1969–1988, 15 of the 45 incident cases of HCC in Alaska Natives occurred in 5 families. This report presents epidemiologic, virologic, and immunogenetic data on these 5 families. The results of hepatitis B virus (HBV) serologic testing indicates that HBV infection was an important factor in 4 of the 5 families. Human lymphocyte antigen (HLA) testing was performed in 3 families. The HLA results are reviewed in relationship to the familial clustering of HCC.
Estimation of the frequency of isoform–genotype discrepancies at the apolipoprotein E locus in heterozygotes for the isoforms
Authors: Mailly F. , Moll P. , Kottke B. A. , Kamboh M. I. , Humphries S. E. , Ferrell R. E. , Chakravarti Aravinda 
Published: June 2005

AbstractEstimates of the impact of apolipoprotein E (apo E) alleles coding for the three common isoforms on plasma lipid levels assume genetic homogeneity among the genotype classes. To test this assumption, we have determined the apo E genotype at the two common polymorphic sites (amino acids 112 and 158) by DNA amplification and hybridisation with allele‐specific oligoprobes, in 195 unrelated Caucasian participants of the Rochester Family Heart Study previously classified as heterozygotes by isoelectric focusing (IEF). Fourteen discordant samples were initially detected. Repeat typing of these samples by both methods resolved nine discrepancies and analysis of additional blood samples from the remaining five individuals eliminated a further four discrepancies. The only truly discordant allele was found in a female subject who had an E3 isoform with the common E2 (Cys112, Cys158) genotype. Transmission of this allele from the mother was demonstrated. From these results, we estimate the frequency of discrepancies between isoforms and common genotypes to be 0.25% in this population. Allele misclassification was caused by poor amplification of the DNA in six samples and superimposition of glycosylated and nonglycosylated apo E isoforms on isoelectric focusing gels in five samples. We conclude that the assumption of genetic homogeneity among genotype classes is valid and that misclassification due to technical difficulties is more frequent than true discordancies. © 1992 Wiley‐Liss, Inc.
Preliminary ordering of multiple linked loci using pairwise linkage data
Authors: Falk C. T. , Chakravarti Aravinda 
Published: June 2005

AbstractA method is presented for the preliminary ordering of loci on a chromosome using pairwise linkage data. The method is based on the biologically reasonable assumption that the ‘true’ order of a set of linked loci will be the one that minimizes the total length of the chromosome segment. Here the ‘length’ is defined as the sum of adjacent recombination fractions. The method searches for the optimal order, represented by a minimum distance map (MDMAP), even when it is not possible to examine the n!/2 possible distinct orders for n loci. A computerized approach, using the simulated annealing algorithm of Kirkpatrick et al. [1983], forms the basis of the method. It can be applied to data from radiation hybrid experiments as well as that from conventional family linkage studies. The technique is applied to several sets of published data to illustrate how it performs in practice. The advantages and the disadvantages of the method are discussed so that it will be clear under what conditions it is likely to work well. When data sets are ‘complete,’ in the sense that all possible pairwise recombination fractions have estimates, and when no large clusters of extremely tightly linked loci are present, the method produces ordered sets of loci that agree well with those generated by other, more complex methods. Any discrepancies that occur are likely to be with respect to the orientation of nearest‐neighbor loci, where relative order cannot be reliably established by any method. The method thus provides a simple, rapid means of obtaining a preliminary order for a set of loci known to be in the same linkage group. © 1992 Wiley‐Liss, Inc.
Molecular basis of a unique African Variant (A‐IV 5) of human apolipoprotein A‐IV and its significance in lipid metabolism
Authors: Ilyas Kamboh M. , Williams Edward R. , Law John C. , Aston Christopher E. , Bunker Clareann H. , Ferrell Robert E. , Pollitzer William S. 
Published: June 2005

AbstractHuman apolipoprotein A‐IV (apoA‐IV) exhibits a genetically determined structural polymorphism amenable to analysis by isoelectric focusing and immunoblotting techniques. We have determined the allele frequency and molecular basis of a unique ApoA‐IV*5 allele which is widely distributed among blacks but is absent in other populations. The frequency of the ApoA‐IV*5 allele in blacks (N = 308) was estimated to be 3.2%. In comparison to the common ApoA‐IV*1 allele, analysis of coding and non‐coding sequences of the ApoA‐IV*5 allele revealed an in‐frame insertion of 12 nucleotides near the carboxyl terminal region of the mature protein. The insertion involves an exact duplication of the second of the four repeats and codes for 4 amino acids glutamic acid (GAA), glutamine (CAG), glutamine (CAG), and glutamine (CAG) and is responsible for the charge shift of the the apoA‐IV 5 isoform slightly toward the anode as compared to the wild type apoA‐IV 1 isoform on the isoelectric focusing gel. This in‐frame insertion occurs in a region which is highly conserved among rat, mouse, and humans. In addition to the 12 nucleotide insertion, the four individuals sequenced for the ApoA‐IV*5 allele also revealed a same‐sense mutation by replacing G to T at the third position of codon 316. Our preliminary data suggest that this unqiue black allele marker may be of potentially significance in studies of human lipid metabolism and in microevolution. © 1992 Wiley‐Liss, Inc.
Longitudinal study of the association between ABO phenotype and total serum cholesterol level in a Japanese cohort
Authors: Lennie Wong F. , Kodama Kazunori , Sasaki Hideo , Yamada Michiko , Hamilton Howard B. 
Published: June 2005

AbstractThe relationship between ABO blood phenotype and total serum cholesterol (TC) level was examined in a Japanese population to determine whether an elevated TC level is associated with phenotype A, as has been demonstrated in many West European populations. Such studies in nonwhite populations are scarce, and findings generally failed to demonstrate the relationship. Inconsistent results from cross‐sectional studies of various racial groups with widely varying ages raised an age effect as a possible explanatory factor. It was also suggested that the ABO–TC association may not be apparent in populations with low fat intake or low mean cholesterol level. These hypotheses are addressed by examining long‐term TC data collected serially from the unexposed controls of the atomic bomb survivors in Hiroshima and Nagasaki who were participants of the Adult Health Study program at the Atomic Bomb Casualty Commission‐Radiation Effects Research Foundation between 1958 and 1986. The statistical method of growth curve analysis, through the mixed effect model of Laird and Ware [1982], was used to model age‐dependent changes in cholesterol levels within individuals. The effects of the ABO polymorphism in modifying the resultant growth curve are examined. We demonstrate that TC levels are elevated on average by about 4 mg/dl in phenotype A compared to non‐A in the Japanese (P < 0.00001), and that this relationship is maintained from early to late adulthood, independent of sex, body mass index, cohort status, or city of residence. Thus, phenotype A individuals may be more predisposed to cardiovascular disease through one of its major risk factors. This is the first study of the ABO–cholesterol association in the Japanese, and the first based on a cohort with longitudinally collected TC data. © 1992 Wiley‐Liss, Inc.
A form of sensorineural deafness is determined by a mitochondrial and an autosomal locus: Evidence from pedigree segregation analysis
Authors: Bu Xiangdong , Shohat Mordechai , Jaber Lutfi , Rotter Jerome I. 
Published: June 2005

AbstractWe have previously reported a large Israili‐Arab pedigree with sensorineural deafness possibly determined simultaneously by two loci‐one mitochondrial, and one autosomal recessive. This was analyzed by extending classic segregation analysis methods to the many nuclear families derived from the maternal line pedigree. Here we expand this pedigree and extend our analysis by using the regressive models for segregation analysis on the entire pedigree. The corresponding REGD computer program was utilized and the marrying‐in males' and paternal line members' affection statuses were assigned as unknown to accommodate the exclusive maternal transmission pattern. For the autosomal locus, a simple autosomal recessive (q = 0.52) model with a nearly complete penetrance (0.93) was found to be the regressive models to test the hypothesis of mitochondrial mutation occurred in a heteroplasmic distribution in the family members, this could not explain the familial aggregation in this pedigree, and an autosomal recessive locus is still required. These results provide further support for the concept that the sensorineural deafness occurring in this large Israeli‐Arab pedigree results from simultaneous involvement of two genes at two different loci, one mitochondrial and likely homoplasmic, and the other autosomal and recessive. © 1993 Wiley‐Liss. Inc.
Cigarette smoking and trisomy 21 at amniocentesis
Authors: Kline Jennie , Levin Bruce , Stein Zena , Warburton Dorothy , Hindin Rita 
Published: June 2005

AbstractSeveral studies raise the possibility that smoking during pregnancy is associated with a slightly decreased odds of trisomy 21 at birth. If it is, associations may reflect decreased incidence at conception, increased intrauterine loss (at one or several times in gestation), or both. Women ( n = 13,729) undergoing prenatal diagnosis completed a questionnaire before learning karyotype results. For each women with a trisomy, up to 4 controls with chromosomally normal pregnancies, matched for age and hospital, were selected. Analyses drew on the 89 trisomy 21‐control matched m‐tuples in which diagnosis was by amniocentesis at 14‐26 weeks. We compared the odds of smoking at last menstrual period and in the past in cases and controls. The odds of current smoking versus never smoking were decreased [adjusted odds ratio = 0.8, 95% confidence interval (CI) 0.4‐1.6]; and the odds of exsmoking increased (adjusted odds ratio = 1.4, 95% CI 0.9‐2.4) in trisomy 21 cases. The association with current smoking was essentially unchanged when the unexposed reference group was defined as exsmokers and women who never smoked (adjusted odds ratio = 0.7, 95% CI 0.4‐1.4). These results for current smoking agree well with a summary estimate based on combined studies of births. One interpretation is that at amniocentesis, as has been reported for births, current smoking is associated with a slightly decreased odds of trisomy 21. If associations at amniocentesis and birth are of equal magnitude, the explanation that observations at birth reflect increased loss in the second half of pregnancy with current smoking is unlikely to be correct. However, the present amniocentesis evidence supports this interpretation weakly and is insufficient to rule out the null hypothesis that smoking is unrelated to trisomy 21. © 1993 Wiley‐Liss. Inc.
Estimating age at onset distributions: The bias from prevalent cases and its impact on risk estimation
Authors: Chen Wei J. , Faraone Stephen V. , John Orav E. , Tsuang Ming T. 
Published: June 2005

AbstractSince many disorders have a variable age at onset, knowing the age at onset distribution of a disease facilitates epidemiologic analyses in several ways. The age at onset distribution is commonly used to estimate morbidity risks or the recurrence risks in genetic counseling. Unfortunately, estimation of a disease's age at onset distribution is not straightforward. The observed age at onset distribution obtained from prevalent cases is usually used in these epidemiologic analyses. Through simulation studies, we show that, in certain situations, the observed age at onset distribution has a non‐negligible downward bias. This bias can lead to a substantial underestimation of the morbidity risk or the recurrence risk. The simulations also demonstrate that a non‐parametric approach for correcting the age at onset distribution works well even when mortality increases after onset. The results have implications for diseases that have adult onset and/or increased mortality after onset. We suggest that researchers should use corrected age at onset distributions, rather than relying on observed distributions, in the calculation of either morbidity risks or recurrence risks. © 1993 Wiley‐Liss. Inc.
Distribution of the admixture test for the detection of linkage under heterogeneity
Authors: Faraway Julian J. 
Published: June 2005

AbstractThe admixture test for the detection of linkage under heterogeneity is considered. We show that the null distribution of this test statistic has half its weight concentrated on zero and the other half on a complicated distribution that can be approximated by max (X1, X 2 ) where X1 and X2 are independent χ variables. We also investigate the stability of the size of the test for small samples. The power of this test to detect linkage, when heterogeneity is present, can be substantially greater than the standard test that assumes homogeneity. Even when heterogeneity is not present, the test is only slightly less powerful than the homogeneous test. This would suggest the use of the admixture test in preference to the homogeneous test if the presence of heterogeneity is at all suspected. © 1993 Wiley‐Liss. Inc.