Publications (23)101.51 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: A likelihood ratio statistic can be used to test whether a random sample is taken from a single normal distribution or from a mixture of two normal distributions with a common variance. The asymptotic distribution of the likelihood ratio test statistic G (minus twice the difference in the logc likelihoods) in this situation is often assumed to be χ with two degrees of freedom. In this study simulation is used to investigate the distribution of G for sample sizes up to 256,000. We determine several approximations to the empirical distribution for sample sizes between 50 and 500, including one that does not require the computation of a χ distribution with fractional degrees of freedom. We conclude that although the asymptotic distribution of G is not a χ with two degrees of freedom, this does appear to be a good approximation to the upper 15% of the distribution
- [Show abstract] [Hide abstract] ABSTRACT: Fitting a mixture of both two normal distributions and a single normal distribution to empiric data is necessary to construct the likelihood ratio statistic for testing the hypothesis of a mixture of two normals versus a single normal distribution. This problem is particularly troublesome because the iterative maximization methods necessary to compute the maximum likelihood often converge to a local rather than the global maximum. Simulation was used to explore two issues; 1) which maximization method (direct search or variable metric) is better at quickly finding the global maximum, and 2) how many sets of initial estimates are necessary to consistently find the global maximum. It was found that direct search is slow but accurate, whereas variable metric is fast but inaccurate. It was also found that at least three sets of initial estimates are needed to find the global maximum for more than 99percent of all samples. A hybrid method consisting of a few initial iterations of direct search followed by variable metric to convergence is almost as accurate as direct search and almost as fast as variable metric.
- [Show abstract] [Hide abstract] ABSTRACT: Robust sib-pair linkage analysis can be used as a screening tool in the search for the potential involvement of single-loci, multiple-loci, and pleiotropic effects of single loci underlying phenotypic variation. Four large families were each ascertained through one adult white male with essential hypertension. The robust sib-pair method was used to screen these families for evidence of linkage between 39 quantitative traits related to hypertension and 25 genetic marker loci. All traits were analyzed on the untransformed, square-root and log-transformed scales. Among other findings, there is a suggestion of linkage between the 6-phosphogluconate dehydrogenase locus on chromosome 1p36 and mean fifth-phase diastolic blood pressure. There may also be linkage between the following markers and traits: the adenylate kinase-1 marker and/or the Lewis blood group marker and the traits height, weight, and biacromial breadth; the glyoxylase I marker and the traits upper-arm circumference and suprailiac skinfold thickness; the ABO blood group and adenylate kinase-1 markers on chromosome 9q34 and the third component of complement marker on chromosome 19p13 and dopamine-beta-hydroxylase; and the P1 blood group and the traits weight and 1-h postload serum glucose level.
- [Show abstract] [Hide abstract] ABSTRACT: One of the long term goals of psychiatric research has been to identify distinct homogeneous disease entities not only from a clinical standpoint, but also from a biological, or genetic, standpoint as well. The identification of homogeneous disease entities can be facilitated with the use of genetic linkage analysis. Here we review twelve studies that present results of sib-pair and lod score linkage analyses of alcoholism and/or subclassifications of unipolar depression, and pool their results. The results reviewed here are striking in one respect. Of the ten studies that used a sib-pair method of analysis, six suggested evidence of linkage between the various unipolar affective disorders and markers in two linkage groups-the MNS-GC linkage group on chromosome 4q and the ABO-AK1-ORM linkage group on chromosome 9q. A seventh study had nominal significance levels of 0.06 and 0.07 with the GC and MNS loci, respectively. Of the eight studies that used lod score linkage analysis, four also suggested evidence of linkage (nominal p <= 0.05) with markers in either of these two linkage groups. Possible evidence of linkage or association to markers in either of these two linkage groups was found in seven of the nine independent sets of families involved. (C) Lippincott-Raven Publishers.
- [Show abstract] [Hide abstract] ABSTRACT: Segregation analyses that allowed for variable age of onset of lung cancer and smoking history were performed on 337 families, each ascertained through a lung cancer proband. Results indicated compatibility of the data with mendelian codominant inheritance of a rare major autosomal gene that produces earlier age of onset of the cancer. Segregation at this putative locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60, respectively. The gene was involved in only 22% of all lung cancers in persons up to age 70, a reflection of an increasing proportion of noncarriers succumbing to the effects of long-term exposure to tobacco.
- [Show abstract] [Hide abstract] ABSTRACT: A stepwise oligogenic method is developed that can be used to adjust the phenotype of a quantitative trait for the effects of a previously identified single-locus component. This method assumes that a single-locus component can be adequately identified through the use of segregation and/or linkage analysis under a 1-locus model and that the variation due to that locus can be removed from the phenotype leaving a residual that can be parameterized in terms of an additional single-locus component. Segregation and/or linkage analysis can then be used in an attempt to identify an additional single-locus component in the residual phenotype. This stepwise process can be repeated until no further single-locus effects are identified. The method is illustrated using family data on the specific activity of dopamine-beta-hydroxylase (DBH), which a number of studies have suggested may be due either to the combined effects of single-locus and multifactorial components or to the combined effects of 2 loci.
- [Show abstract] [Hide abstract] ABSTRACT: As part of a study of the possible subgroups of unipolar affective disease, 27 families were ascertained as depression spectrum disease (DSD) families. The purpose of this study was an investigation of the linkage relationships between DSD and 30 genetic markers using the robust sib-pair and lod-score methods. Using the sib-pair methods, evidence for linkage was found with orosomucoid (ORM) on chromosome 9q (p = 0.006), regardless of whether only individuals with unipolar depression, alcoholism, or antisocial personality were considered to be affected, or whether individuals with any psychiatric disorder were considered to be affected. Weak evidence of linkage with ORM was corroborated using lod-score methods when a narrow definition of depression spectrum disease was used, although stronger evidence of linkage was found with ORM when any psychiatric disorder was considered to be affected. The maximum lod-score for ORM was 1.68 at a male recombination fraction of 0.23 and a female recombination fraction of 0.01.
- [Show abstract] [Hide abstract] ABSTRACT: In a study of the subgroups of unipolar affective disease, 13 families were ascertained as pure depressive disease (PDD) families. Here we investigate linkage relationships between PDD and 30 genetic markers in these families. Using the robust sib-pair method of linkage analysis, evidence for possible linkage or association was found with five loci: the ABO and MNS blood groups, immunoglobulin kappa (IGK), proline rich parotid salivary protein (PR) and glyoxylase-1 (GLO1). Weak evidence of linkage with ABO was supported using the lod score method of analysis. The maximum lod score between PDD and ABO was 1.42 at a male recombination fraction of 0.09 and a female recombination fraction of 0.03. When these results from the sib-pair analysis were combined with the results from two previous sib-pair studies on PDD, the ABO, MNS and IGK loci were found to be significant (P = 0.05, P = 0.005, P = 0.05, respectively, not allowing for multiple tests).
- [Show abstract] [Hide abstract] ABSTRACT: A more powerful robust test for linkage is developed from the methodology of Haseman and Elston [Behav Genet 2(1):3–19, 1972]. This new robust test uses weighted least-squares (WLS) methods to detect linkage between a quantitative trait and a polymorphic marker. For comparison, the characteristics of a test for linkage that uses known trait genotypes for the parents are also studied. Sample sizes needed to detect linkage, calculated using asymptotic results, are compared for 1) the usual Haseman-Elston method, 2) the WLS method, and 3) the method that uses parental trait genotype data. The WLS method needs at most twice the number of sib pairs as does the method that used information on the trait genotypes of the parents. The small sample properties of the Haseman-Elston (H-E) and WLS tests are investigated by simulation. The power calculations for the H-E method are found to be accurate. The power of the WLS method is overestimated when fewer than 300 sib pairs are studied, but the WLS method is nonetheless more powerful than the usual H-E method. In samples of fewer than 300 sib pairs, the WLS test tends to be anticonservative. Treating all sib pairs from sibships of size 3 or 5 as independent does not increase the significance of the tests.
- [Show abstract] [Hide abstract] ABSTRACT: Association and linkage relationships between alcoholism and 30 polymorphic marker loci were studied in a total of 42 families: 27 families originally collected as part of a study on depression spectrum disease, 14 previously reported families with depression spectrum disease, and 1 family with familial alcoholism. Since heterogeneity within a sample can confound genetic linkage analysis, obscuring linkage relationships, alcoholism was studied in these families as a disorder unrelated to depression or antisocial personality. No allelic associations were found to be significant after allowing for the multiple tests. In a sib-pair linkage analysis, significant differences between the mean proportion of genes identical by descent in concordant and discordant sib pairs were found for the esterase-D (ESD) marker locus (p less than or equal to .01). This suggested that a linkage may exist between a gene for alcoholism and the ESD locus on chromosome 13q. Lod score linkage analysis yielded odds in favor of linkage to ESD of 44 to 1, most of the information relevant to linkage residing in a single family in which three offspring were classified as alcoholic and five were not.
- [Show abstract] [Hide abstract] ABSTRACT: The use of a recently developed in vitro model for retroviral integration provides a means of statistically testing hypotheses concerning the distribution of integration sites and hypotheses about the sequence of proviral orientations. In this study, three null hypotheses are formulated and applied to previously published data. Statistical analyses of these data suggest that the distribution of integration sites may not be uniform, and the sequence of proviral orientations is not random. On the basis of these results and the observed clustering of orientations, it was postulated that if a DNA sequence was involved in nonrandom proviral integration, that sequence would be found in the regions where the orientations change direction with respect to the target DNA ("I" regions). Computer analyses for homologous and complementary DNA sequences were performed on all possible pairs of identifiable "I" regions. A common sequence (at least 8 bp in size) was found in three out of four regions and that sequence was absent elsewhere in the target DNA. A model, with features of recombination reminiscent of chi sequences in bacteria, is proposed that may account for these results.
- [Show abstract] [Hide abstract] ABSTRACT: Our evidence thus suggests that the recessive gene for Usher syndrome may be loosely linked to GC on the long arm of chromosome 4, a region whose map is already well known (Murray et al., 1986; Pakstis et al., 1986). This preliminary finding is presently being corroborated and extended to identify a restriction fragment length polymorphism that will permit more precise localization of the gene for this form of hereditary deaf-blindness.
- [Show abstract] [Hide abstract] ABSTRACT: Previous studies have presented evidence suggesting that levels of dopamine-beta-hydroxylase (DBH) activity are controlled by a gene linked to the ABO blood group locus. In this study, linkage analyses in four large families of whites and one family of blacks were performed on the untransformed and on the square root--and natural log--transformed DBH activity. In the families of white individuals, the results of both the sib-pair and lod-score linkage analyses strongly indicate that a gene regulating DBH activity is linked to the ABO blood group locus on chromosome 9q (i.e., lod score 5.88 at a recombination fraction of .0). However, the transformation used has a large effect on the maximum lod score and estimated recombination fraction. This putative gene does not appear to be polymorphic in the family of blacks.
- [Show abstract] [Hide abstract] ABSTRACT: We tested for linkage between panic disorder and a battery of 29 genetic markers in 26 families. Linkage between panic disorder and 18 of the marker loci could be excluded at a recombination fraction of 0.00, nine at a recombination fraction of 0.05, and four at a recombination fraction of 0.10. The 18 loci are distributed over ten chromosomes. One locus was suggestive of linkage. The maximum lod score for alpha-haptoglobin was 2.27 at a recombination fraction of 0.0, representing odds in favor of linkage of 186.1. alpha-Haptoglobin has been mapped to chromosome 16q22. The results demonstrate that linkage studies of psychiatric disorders can yield informative results by identifying tentative linkages that merit further investigation and by excluding regions of the genome from future linkage searches.
- [Show abstract] [Hide abstract] ABSTRACT: A segregation analysis was performed on the bronchial response to a standardized methacholine inhalation challenge obtained from members of 83 families that were part of a Natural History of Asthma study population. Each bronchial response was expressed as the area under the best fitting parabolic dose-response curve. Standard methods of statistical analysis demonstrated that age, sex, and recent respiratory infection had a significant effect on the bronchial response to methacholine inhalation. Segregation analysis indicated that, although a familial component exists in the transmission of bronchial response to methacholine, the bimodal distribution of the bronchial response is not due to segregation at a single autosomal locus.
- [Show abstract] [Hide abstract] ABSTRACT: The genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels was evaluated using segregation analysis techniques in a large multigenerational kindred with a high prevalence of coronary heart disease and myocardial infarction. Univariate segregation analysis of HDL-C levels with the effects of age and sex removed by regression provided evidence of a Mendelian mode of inheritance for a portion of the variability in HDL-C levels. Subsequent analyses included low-density-lipoprotein cholesterol (LDL-C) levels and several behavioral and anthropometric variables that affect HDL-C levels. Pedigree discriminant analysis was used to find the linear functions of the variables that maximized the likelihood given the pedigree structure and assuming monogenic segregation. The best linear function was found to be approximately equivalent to the log of the HDL-C to LDL-C ratio, with concomitant and environmental effects removed by regression. Genetic hypotheses were tested by cross-validation; linear functions derived from data on each side of the kindred were used to test hypotheses on the other side of the kindred. On one side of the kindred, all hypotheses were accepted. On the other side of the kindred, only Mendelian inheritance of the linear function was indicated. Segregation of the age- and sex-adjusted HDL-C values, and of the linear function, was evaluated using a regressive model that allows for intrafamilial correlations in addition to a monogenic effect. All analyses provide evidence for levels of HDL-C being controlled by a major locus with neither dominant nor recessive expression.
Louisiana State University Health Sciences Center New Orleans
New Orleans, Louisiana, United States
- Department of Medicine
LSU Medical CenterNew Orleans, Louisiana, United States