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PubMed1997

Logistic transmission modeling for the simulated data of GAW10 problem 2.

A recently developed nonparametric method is a generalization of the transmission disequilibrium test across all alleles of a locus. This approach has been applied to Problem 2 of GAW10 and has been extended to explore the combined contribution of neighboring loci for chromosomes 1, 5, and 8. When applied to the chromosome 5 data of the first replicate of the nuclear pedigrees from Problem 2 of GAW10, the data show that four of the 25 loci obtain a probability less than 0.05. However, when combined models composed of each potentially significant marker (p < 0.05) and its nearest neighbors are considered, the combined contributions of G14 and G15 are the most significant (p = 0.007). Consequently, the region near G14 and G15 is identified as the best candidate region in chromosome 5 for linkage to the common disease.

Case-Control Studies↗
PubMed1997

Probabilities of identity-by-descent patterns in sibships when the parents are not genotyped.

An assumption-free algorithm has been applied to compute the probabilities of all possible identity-by-descent (IBD) configurations when the parents have not been genotyped. These probabilities can be used to determine the amount of information that a particular sibship will bring to a nonparametric linkage analysis. It is shown that the number of possible configurations can be extremely large even when the markers are closely spaced and are rather polymorphic. Further, it is not always possible to reduce this number to a manageable one simply by consideration of the relative probabilities of the configurations.

Algorithms↗
PubMed1999

Regional inference with averaged P values increases the power to detect linkage.

Controversy exists with respect to the choice of an appropriate critical value when testing for linkage in a genomic screen. A number of critical values have been proposed for single-locus and multi-locus linkage analyses. In this study, criteria based on multiple single-locus analyses (i.e., regional test criteria) are evaluated using simulation methods for three different map densities. Tests based on single loci, multiple consecutive single loci, and moving averages of consecutive single loci are considered. Appropriate critical values are determined based on results from simulations under the null hypothesis of no linkage. The power of each "regional test " was compared to the power of a single-locus test. Results suggest that the best power was found when averaging P values over an interval size of 9-15 cM, and that testing the average of P values from two consecutive loci is superior to testing each single locus separately. The increase in power ranged from 7- 29% over the simulations considered.

Bias↗
PubMed1995

Expression of an endogenous galactose-binding lectin correlates with neoplastic progression in the colon.

BACKGROUND: Galectin-3 is an endogenous galactose-binding protein that is expressed in a wide range of normal and neoplastic tissues and is thought to be involved in cellular adhesion and growth regulation. Conflicting data have been reported regarding the expression of galectin-3 during carcinogenesis in the colon. METHODS: The authors studied the expression of galectin-3 in 153 tissue specimens, including 29 adenomas containing early cancer, 66 colon carcinomas of known Dukes' stage with available long term patient survival data, and 23 additional primary carcinomas with 35 associated metastases. An immunohistochemical scoring system was used that considers tumor heterogeneity and yields an integrated numeric score subject to statistical analysis. Genetically related colon cancer cells with different metastatic capabilities also were compared by Western blot analysis. RESULTS: Galectin-3 expression was significantly higher in high grade dysplasia and early invasive cancers compared with the adenomatous tissue from which they evolved (mean staining score, 2.33 vs. 1.15; P = 0.001). Galectin-3 expression in invasive cancers varied according to Dukes' stage, indicating a linear relationship with advancing stage (P = 0.008). Enhanced expression correlated with decreased long term patient survival (P = 0.021). Metastases expressed a higher level of galectin-3 compared with the primary cancers from which they evolved (P < 0.005) as did cultured cells of high metastatic capability compared with their counterparts with low metastatic potential. CONCLUSION: Galectin-3 expression in colonic mucosa is related to neoplastic transformation and metastatic progression.

Adenoma↗
PubMed2000

Basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is characterized by marked interpatient variation in tumor accrual. The authors previously reported that presentation with a cluster of BCC is associated with an inherited predisposition to develop many additional lesions suggesting clustering is a critical event. A cluster is defined as the presence of two or more new, primary BCCs, at initial or later presentation. METHODS: The authors recruited 927 cases and determined whether 1) clustering was an early or late event and 2) tumor accrual was altered after clustering. RESULTS: In the cases, 669 patients developed only 1 lesion, 112 patients presented more than once but with single lesions (single presentation phenotype[SPP]-more), 94 cases had a cluster at first presentation (multiple presentation phenotype [MPP]-cluster initial), and 52 cases first presented with 1 lesion but later had a cluster (MPP-cluster later). The authors found that 1) clustering occurred relatively late. The mean ages at first presentation with 1 BCC of the SPP-more (61.5 years) and MPP-cluster later patients (60.4 years) were similar although presentations with clusters in the MPP-cluster initial (67.6 years, P = 0.0002) and -cluster later cases (68.1 years, P = 0.002) occurred significantly later. 2) Clustering was associated with increased accrual. Thus, 26 patients (MPP-cluster later/a) in the MPP-cluster later group had a additional BCC postcluster. Mean accrual post-cluster (1.99 BCC/year) in these cases was significantly increased (P = 0.0001) compared with precluster accrual (0.39 BCC/year). CONCLUSIONS: The authors found that the formation of BCC clusters represents a critical event such that after a cluster presentation, tumor accrual is significantly increased. Cluster presentation is a relatively late event suggesting reduced effectiveness in immune surveillance.

Age Factors↗
PubMed2000

Clustering methods applied to allele sharing data.

Here we focus on using clustering methods to disentangle the interacting factors that lead to the presentation of complex diseases. Relative pairs are placed in discrete subgroups, or classes, based upon their pattern of allele sharing at a sequence of markers and on concomitant risk factors. The relationship between the locus information and the affectation status of the relative pairs within each subgroup then can be assessed. Cluster analysis (CLA) and latent class analysis (LCA) were applied to sibling allele sharing data from GAW11 simulated data, and to an existing Alzheimer's disease (AD) dataset. Both methods were able to identify markers linked to all 3 disease loci in the GAW11 data. LCA and CLA also replicated regions of chromosomes identified in an analysis of the AD data using affected-sib-pair methods. These analyses indicate that classification tools may be useful for detecting susceptibility genes for complex traits.

Aged↗
PubMed2002

Dopamine transporter polymorphism associated with externalizing behavior problems in children.

Early childhood externalizing behavior is a stable and heritable pattern of aggressive and delinquent behavior that often leads to the development of serious psychiatric disorders such as conduct disorder and attention deficit hyperactivity disorder. We examined the relationship between parent reported externalizing behavior (assessed at ages 4, 7, and 9 years) and the VNTR polymorphism of the 3' untranslated region of SLC6A3 (DAT1) in a community sample of 790 children ascertained as part of our longitudinal twin and adoption studies. We applied the sibling-based methodology developed by Fulker et al. [1999: Am J Hum Genet 64:259-267] for estimating allelic association with quantitative traits, while controlling for population stratification. An extension of these methods allowed for the inclusion of monozygotic twins, dizygotic twins, siblings, and singletons. We have demonstrated that the 9-repeat variant of the DAT1 is a significant risk allele for externalizing behavior at ages 4 (P=0.001) and 7 years (P=0.02). Although the effect size was negligible at age 9 (P=0.92), a formal test of the developmental decrease in effect across the three ages was non-significant (P=0.70).

Adolescent↗
PubMed1995

Analysis of variability of clinical manifestations in Waardenburg syndrome.

Expression of clinical findings of Waardenburg syndrome type 1 (WS1) and type 2 (WS2) is extremely variable. Using our collection of 26 WS1 and 8 WS2 families, we analyzed the occurrence, severity, and symmetry of clinical manifestations associated with WS. We found significant differences between WS1 and WS2 in deafness, and in pigmentary and craniofacial anomalies. Factor analysis was used to identify manifestations which covaried, resulting in 2 orthogonal factors. Since mean factor scores were found to differ when compared between WS1 and WS2, we suggest that these factors could be useful in distinguishing WS types. We found that the WS gene was transmitted from mothers more often than from fathers. We also extensively examined the W-Index, a continuous measure of dystopia canthorum. Our data suggest that use of the W-Index to discriminate between affected WS1 and WS2 individuals may be problematic since 1) ranges of W-Index scores of affected and unaffected individuals overlapped considerably within both WS1 and WS2, and 2) a considerable number of both affected and unaffected WS2 individuals exhibited W-index scores consistent with dystopia canthorum. Misclassification of families may have implications for risk assessment of deafness, since WS2 families have been reported to have greater incidence of deafness, as confirmed in our study.

Age Factors↗
PubMed1994

Altitude, language, and class I HLA allele frequencies in Papua New Guinea.

Class I HLA gene frequencies show considerable variation over short geographical distances in Papua New Guinea. Hypothesis to account for this invoke natural selection, population structure, the pattern of population movement, or past demographic changes. To determine the role of the various factors in shaping this distribution, we have studied correlations between HLA-based genetic distances, geographical distances, altitude, and linguistic differences in Papua New Guinea. Linguistic differences at the family or stock level within the Trans-New Guinea Phylum generally correspond to genetic differences. However, on the basis of their HLA gene frequencies, speakers of Austronesian (AN) languages do not form a distinct group of populations. Linguistic variation and spatial autocorrelation do not fully account for the altitudinal cline differences noted in gene frequencies, particularly at the HLA-A locus. We propose that the distribution of HLA gene frequencies in Papua New Guinea is partially under the control of selection operating differentially along the altitude gradient.

Alleles↗
PubMed2005

Joint effect of selection, linkage and partial inbreeding on additive genetic variance in an infinite population.

Under the inifinitesimal model of gene effects, selection reduces the additive genetic variance by inducing negative linkage disequilibrium among selected genes. If the selected genes are linked, the decay of linkage disequilibrium is delayed, and the reduction of additive genetic variance is enhanced. Inbreeding in an infinite population also alters the additive genetic variance through the generation of positive association among genes within a locus. In the present study, the joint effect of selection, linkage and partial inbreeding (partial selfing or partial full-sib mating) on the additive genetic variance was modeled. The recurrence relations of the additive genetic variance between successive generations and the prediction equation of the asymptotic additive genetic variance were derived. Numerical computation showed that although partially inbred populations initially maintain larger genetic variances, the accumulated effect of selection overrides the effect of inbreeding. Stochastic simulation was carried out to check the precision of prediction, showing that the obtained equations give a satisfactory prediction during initial generations. However, the predicted values always overestimate the simulated values, especially in later generations. Based on these results, possible extensions and perspectives of the assumed model were discussed.

Animals↗
PubMed2006

A score test for determining sample size in matched case-control studies with categorical exposure.

The paper considers the problem of determining the number of matched sets in 1 : M matched case-control studies with a categorical exposure having k + 1 categories, k > or = 1. The basic interest lies in constructing a test statistic to test whether the exposure is associated with the disease. Estimates of the k odds ratios for 1 : M matched case-control studies with dichotomous exposure and for 1 : 1 matched case-control studies with exposure at several levels are presented in Breslow and Day (1980), but results holding in full generality were not available so far. We propose a score test for testing the hypothesis of no association between disease and the polychotomous exposure. We exploit the power function of this test statistic to calculate the required number of matched sets to detect specific departures from the null hypothesis of no association. We also consider the situation when there is a natural ordering among the levels of the exposure variable. For ordinal exposure variables, we propose a test for detecting trend in disease risk with increasing levels of the exposure variable. Our methods are illustrated with two datasets, one is a real dataset on colorectal cancer in rats and the other a simulated dataset for studying disease-gene association.

Algorithms↗
PubMed1987

Nonrandom sampling in human genetics: skewness and kurtosis.

When a multivariate normal sample is chosen from a truncated space of one of its components one can no longer make use of the normality assumption for the sample observations or for the estimates derived from them. In this paper, skewness and kurtosis for each component are derived analytically under a broad class of nonrandom sampling. It is shown that the distortions in skewness and kurtosis produced by nonrandomness are negligible, except those for the component with respect to which the selection of sampling regions is based. The usual tests of normality from sample values of skewness and kurtosis measures remain valid under nonrandom sampling, except for the selection variable. The implications of these analytical results in the context of commingling analysis in genetic epidemiology are discussed. It is recommended that when samples of families are obtained through nonrandomly ascertained probands, a commingling analysis should treat each relative class separately, since such analyses based on the pooled sample of individuals may involve unspecified bias in the levels of the test procedure.

Genetics, Medical↗
PubMed1988

Twin study of genetic and environmental effects on lipid levels.

A study of 106 pairs of monozygotic (MZ) and 94 pairs of dizygotic (DZ) twins tested the hypothesis that part of the previously described genetic influence on blood lipid levels can be ascribed to closer similarities among MZ than among DZ twin pairs in environmental factors that affect lipid levels. Participants were adult twin volunteers (age 17-66; 64 male and 136 female pairs) who were selected from the NH & MRC Twin Registry or were respondents to advertisements. They completed a 4-day weighed food diary from which mean nutrient intake was derived. Information on lifestyle and demographic variables was obtained by questionnaire and a nonfasting blood sample was taken for measures of total, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol and the HDL2 and HDL3 subfractions. Height and weight were measured, and body mass index (BMI) was calculated (kg/m2). Estimates of the heritability of sex-adjusted lipid levels were 0.72 for total cholesterol, 0.79 for HDL cholesterol, 0.69 for HDL2, 0.20 for HDL3, 1.06 for LDL cholesterol, and 0.44 for sex-adjusted BMI. In all cases except for HDL3, genetic variance was statistically significant. After adjusting for the effects of environmental variables in three different ways, the estimates of heritability were somewhat lower for total cholesterol, HDL2, and BMI, and those for HDL cholesterol (borderline) and LDL cholesterol (definitely) remained statistically significant but were decreased. A genetic influence on HDL3 was not found. Adjusted heritability estimates obtained from one method of analysis were 0.35 for total cholesterol, 0.49 for HDL, 0.04 for HDL2, -0.34 for HDL3, 0.66 for LDL, and 0.32 for BMI. These results suggest that the assumptions made in the classical twin study approach are not appropriate when examining genetic effects on lipid levels or BMI, or indeed on any biological variable that may be affected by environmental factors that tend to be more similar in MZ twins than in DZ twins. In these circumstances, more complex models may be needed to differentiate between genetic and environmental influences.

Adolescent↗
PubMed1995

Weighted pairwise correlation and transmission disequilibrium in a common oligogenic disease.

Weighted pairwise correlation (WPC) linkage analysis and the transmission disequilibrium test (TDT) for allelic association were applied to simulated family data for a common oligogenic disorder in order to localize genes that increase levels of Q1. Preliminary linear models indicated that Q1 increases with age, Q2, Q3, and the occurrence of D5G28 allele 3 (D5G28(3). WPC provided evidence for linkage of Q1 to Major Gene 1, D5G28 (p < 0.0001), and to other loci when ranks based on age and affection status (Q1 < or > 87.5) were used to define the phenotype. D5G28 was the only locus linked to Q1 (p = 0.01) when the phenotype was defined as Q1 adjusted for age, Q2, Q3, and D5G28(3). The TDT indicated linkage disequilibrium between a gene for elevated Q1 (> 87.5) and alleles at loci adjacent to D5G28: D5G29(2) was apparently protective (p = 0.008) while allele 8 was associated with risk (p = 0.007); D5G30(7) was also apparently protective (p = 0.02). However, significant disequilibrium was not found for D5G28(3), possibly due to lack of adjustment of Q1 and small sample size. These results imply that the combined use of WPC and the TDT may be an effective strategy for genomic screens in complex disorders defined by quantitative traits, especially when the trait can be adjusted for age and other relevant factors.

Alleles↗
PubMed1999

Nonparametric linkage and family-based association studies of a simulated complex disorder.

Affected sibling pairs are widely used to identify chromosomal regions harboring genetic loci underlying common disease. We explore the utility of nonparametric sibling pair and family-based association methods to search for disease susceptibility loci in simulated pedigree data for a qualitative disease trait. Logistic regression was used to model gene x gene and gene x environment interactions when significant linkage and association were detected. Using these methods, we were able to detect three of the four susceptibility loci underlying the disease trait with multipoint lod scores of 1.0 or greater.

Alleles↗
PubMed2006

Significance of hepatitis B virus genotypes A to E in a cohort of patients with chronic hepatitis B in the Seine Saint Denis District of Paris (France).

The aim of this study was to examine the genetic variability of the hepatitis B virus (HBV) and its significance. HBV genotypes, core promoter and precore mutants were characterized in 109 consecutive patients with biopsy-proven HBV chronic hepatitis. Genotypes A (26.6%), B (12.8%), C (18.3%), D (18.3%), and E (14.7%) indicate a wide genotypic distribution. Patients were from Asia (30.3%), Europe (28.4%), Sub Saharan Africa (23.9%), the Caribbean (10.1%), North Africa (5.5%), and Madagascar (1.8%). HBV genotypes A and D (HBV/A and /D) infected all subgroups except Asian patients. HBV/B or /C were found in 97% of Asian patients, whereas HBV/E only infected sub-Saharan African and Caribbean patients. Differences according to genotypes were: an increased prevalence of anti-HBe antibodies in patients infected with HBV/D (P = 0.003), higher serum transaminases in patients infected with HBV/A and/D (P = 0.043), more severe liver fibrosis in patients infected with HBV/A, /C and/D (P = 0.02). Precore and core promoter mutants were found in 87% of anti-HBe positive patients, and were associated with HBV/D (P = 0.04) and severe liver fibrosis (P = 0.002). It is concluded that HBV genotypes A, B, C, D, and E circulate in the Seine Saint Denis District, reflecting the geographical origin of patients. HBV/A, /C and/D seem to be associated with more severe hepatic disease.

Adult↗
PubMed2006

Hepatitis B genotypes, precore and core promoter mutants circulating in Tunisia.

Hepatitis B virus (HBV) is characterized by genetic heterogeneity, including genotypes and mutations. Eight genotypes (A-H) have been identified throughout the world with a characteristic geographical distribution. Previous studies also suggest that the viral genotypes may correlate with differences in clinical features of the infection. Two types of mutations were particularly described, precore and basal promoter mutations; they may play an important role in the clinical outcome of HBV infection. The aim of this study was to investigate the prevalence of HBV genotypes and HBV variants in Tunisia, and their eventual association with severity of liver disease. Using a molecular method, HBV genotypes, precore and basal core promoter mutations were determined in 56 asymptomatic carriers and in 82 patients with histologically verified chronic liver disease and hepatocellular carcinoma (HCC). Three genotypes (D, A, and E) were detected; the prevalence was 80%, 8%, and 9%, respectively. No significant difference was observed for genotype D with clinical status. HBV mutants were detected in 93% of cases, precore mutants were the most prevalent. Basal core promoter mutants were observed in 61% of cases, they were frequently characterized by a double mutation in 1762 and 1764. Co-infection by these two types of mutants was detected in 50% of cases. Genotype D was the most prevalent HBV genotype in Tunisia. High circulation of precore and basal core promoter mutants are common in chronic hepatitis B infection in Tunisia.

Adolescent↗