bluuebunny/crossref_metadata_2025 huggingface dataset:
Demographic processes and ethnic residential segregation
Authors: Omer Itzhak
Published: January 2006

This paper examines the involvement of demographic processes in the residential segregation of ethnic groups in an urban area. For this purpose, a two‐part methodology has been employed. The first part comprises a conceptual framework which uses the concept of time–space resources as an analytical tool to clarify the structural constraints embedded in the changes in ethnic residential distribution. The second part comprises a simulation model of ethnic residential segregation. The model, which fits into the category of agent‐based simulation models, serves as a tool for heuristic study. The methodology has been applied to examine the implications of fluctuations in ethnic group diffusion and the residential mobility
rate on the majority–minority residential segregation, and on the internal ethnic segregation within the minority group.
Population growth and the environment: Can we eat the cake and have it?
Authors: Amir Shmuel
Published: January 2006

Continuous population growth and the concomitant maintenance of a growth sustaining environment are not in conflict only if the rates of both economic and biological processes are slowed down steadily. For this to happen, individual and social impatience‐lowering adaptations should be adopted, and the capital of the system, both economic and natural, has to be redistributed among the system interacting components to result in an ever more complex organizational web. In addition, these factors have to corroborate with a third element, the incorporation of an arsenal of varied technological innovations that improves the use of existing stocks.
Environmental refugees: Consequences and policies from a western perspective
Authors: Nash Alan E.
Published: January 2006

Using Canada as an example, this paper argues that the phenomenon of the environmental refugee poses a series of important public policy issues for countries of resettlement. Arguing that Canada has an obligation to aid environmental refugees, for reasons of both self‐interest
and self‐sacrifice, the paper then explores those reasons that have, so far, prevented Canada acting on these obligations. These lie, the paper argues, in a conjunction of both present public opinion and government practice. It is therefore in these realms that action to remove impediments to policy change must now occur.
Transition from the chaotic turbulence to the turbulent structures
Authors: Kingsep A.
Published: January 2006

Weak turbulence, similar to incoherent light, may be represented as an ensemble of quasi‐free quanta or Fourier harmonics. Unlike it, strongly turbulent state should be based on nonlinear structures. In particular, strong plasma turbulence may be constructed of discrete
formations, viz., Langmuir solitons. Instead for ‘infrared catastrophe’ typical of the weakly turbulent regime, one deals with the ‘relay race’ model providing the proper direction of the energetic flux over scales from the source towards the leakage.
Rotating shallow water modeling of planetary,astrophysical and plasma vortical structures (plasma transport across a magnetic field,model of the jupiter′s GRS, prediction of existence of giant vortices in spiral galaxies)
Authors: Nezlin M. V. , Rylov A. Yu , Snezhkin E. N. , Titishov K. B. , Chernikov G. P.
Published: January 2006

Three kinds of results have been described in this paper. Firstly, an experimental study of the Rossby vortex meridional drift on the rotating shallow water has been carried out. Owing to the stringent physical analogy between the Rossby vortices and drift vortices in the magnetized plasma, the results obtained have allowed one to make a conclusion that the
transport rate of the plasma, trapped by the drift vortices, across the magnetic field is equivalent to the “gyro‐Bohm” diffusion coefficient. Secondly, a model of big vortices of the type of the Great Red Spot of Jupiter, dominating in the atmospheres of the outer planets, has been produced. Thirdly, the rotating shallow water modeling has been carried out of the hydrodynamical generation mechanism of spiral structures in galaxies. Trailing spiral waves of various azimuthal modes, generated by a shear flow between fast rotating “nucleus” and slow rotating periphery, were produced. The spirals are similar to those existing in the real galaxies. The hydrodynamical concept of the spiral structure formation in galaxies has been substantiated. Strong anticyclonic vortices between the spiral arms of the structures under study have been discovered for the first time. The existence of analogous vortices in real galaxies has been predicted. (This prediction has been reliably confirmed recently in special
astronomical observations, carried out on the basis of the mentioned laboratory modeling and the prediction made – see the paper by A. Fridman et al. (Astrophysics and Space Science, 1997, 252, 115.)
Numerical simulations in astrophysics:Supernovae explosions, magnetorotational model and neutrino emission
Authors: Bisnovatyi-Kogan G. S.
Published: January 2006

Theories of stellar evolution and stellar explosion are based on results of numerical simulations and even qualitative results are not available to get analytically. Supernovae are the last stage in the evolution of massive stars, following the onset of instability, collapse and formation of a neutron star. Formation of a neutron star is accompanied by a huge amount of energy, approximately 20% of the rest mass energy of the star, but almost all this energy is released in the form of weakly interacting and hardly registrated neutrino. About 0.1% of the released neutrino energy would be enough for producing a supernovae explosion, but even transformation of such a small part of the neutrino energy into the kinetic energy of matter meets serious problems. Two variants are investigated for obtaining explosion. The first one is based on development of convective instability, and more effective heating of the outer layers by a neutrino flux.

The second model is based on transformation of a rotational energy of a rapidly rotating neutron star with its envelope into the energy of explosion due to action of a magnetic field as a
transformation mechanism. Calculations in this model in 1‐ and 2‐dimensions give a stable value of transformation of the rotational energy into the energy of explosion on the level of few percents. This occurrance to be enough for explanation of the energy release in supernova explosion. The last model gives a direct demonstration of nonlinear interaction between hydrodynamical and hydromagnetic systems. At first a field is amplified by differential rotation, then
this enhanced field leads to transformation of the rotational energy into the energy of explosion.
Inefficient equilibria in transition economy
Authors: Guriev Sergei , Pospelov Igor
Published: January 2006

The paper studies a general equilibrium in an economy where all market participants face a bid‐ask spread. The spread may be caused by indirect business taxes, middlemen rent‐seeking, delays in payments or liquidity constraints or price uncertainty. Wherever it comes from the spread causes inefficiency of the market equilibrium. We discuss some institutions
that can decrease the inefficiency. One is second currency (barter exchange) in the inter‐firm transactions. It is shown that the general equilibrium in an economy with second currency is effective though is still different from Arrow–Debreu equilibrium. Another solution can be introduction of mutual trade credit. In the economy with trade credit there are multiple
equilibria that are more efficient than original bid‐ask spread but still not as efficient as Arrow–Debreu one, too. The implications for firms′ integration and applicability to Russian economy are discussed.

The paper generalizes some results obtained of research work that has been done in the Department of Mathematical Modeling of Economic Systems of Computing Center, Russian Academy of Science under Academician Petrov over last few years (Petrov et al., 1996, essays on Mathematical Modelling of Economy: Energoatomizdat.) We have
successfully used some models of inefficient equilibrium in several applied projects.
On the fractality of the biological tree‐like structures
Authors: Kalda Jaan
Published: January 2006

The fractal tree‐like structures can be divided into three classes, according to the value of the similarity dimension Ds : Ds < D, Ds = D and Ds > D, where D is the topological dimension of the embedding space. It is argued that most of the physiological tree‐like structures have Ds ≥ D. The notion of the self‐overlapping exponent is introduced to characterise the trees with Ds > D. A model of the human blood‐vessel system is proposed. The model is consistent with the processes governing the growth of the blood‐vessels and yields Ds = 3.4. The model is used to analyse the transport of passive component by blood.
Dental Microwear Variability on Buccal Tooth Enamel Surfaces of Extant Catarrhini and the Miocene Fossil Dryopithecus laietanus (Hominoidea)
Authors: Galbany J. , Moyà-Solà S. , Pérez-Pérez A.
Published: January 2006

Analyses of buccal tooth microwear have been used to trace dietary habits of modern hunter-gatherer populations. In these populations, the average den-sity and length of striations on the buccal surfaces of teeth are significantly cor-related with the abrasive potential of food items consumed. In non-human pri-mates, tooth microwear patterns on both occlusal and buccal wear facets have been thoroughly studied and the results applied to the characterization of dietary habits of fossil species. In this paper, we present inter- and intra-specific buccal microwear variability analyses in extant Cercopithecoidea (Cercopithecus mitis, C. neglectus, Chlorocebus aethiops, Colobus spp., Papio anubis) and Hominoidea (Gorilla gorilla, Pan troglodytes, Pongo pygmaeus). The results are tentatively compared to buccal microwear patterns of the Miocene fossils Dryopithecus and Oreopithecus. Significant differences in striation density and length are found among the fossil taxa studied and the extant primates, sug-gesting that buccal microwear can be used to identify dietary differences among taxa. The Dryopithecus buccal microwear pattern most closely resembles that of abrasive, tough plant foods consumers, such as the gorilla, in contrast to stud-ies of dental morphology that suggest a softer, frugivorous diet. Results for Ore-opithecus were equivocal, but suggest a more abrasive diet than that previously thought.
CARD15 Single Nucleotide Polymorphisms 8, 12 and 13 Are Not Increased in Ethnic Danes with Sarcoidosis
Authors: Milman Nils , Nielsen Ole Haagen , Hviid Thomas Vauvert F. , Fenger Kirsten
Published: January 2006

Background: Mutations of the caspase-activating recruitment domain 15 (CARD15) gene on chromosome 16 are associated with chronic inflammatory granulomatous bowel disease (Crohn’s disease). Sarcoidosis is a systemic granulomatous disease with unknown etiology, which shares histological features with Crohn’s disease. Objectives: To evaluate whether ethnic Danes with sarcoidosis have an increased frequency of CARD15 mutations compared to healthy control subjects. Methods: Genotyping for CARD15 mutations R702W, G908R, and L1007fsinsC, also designated single nucleotide polymorphism (SNP) SNP8, SNP12 and SNP13, respectively, were performed by capillary electrophoresis single-strand confirmation polymorphism in 53 patients with histologically verified sarcoidosis and in 103 healthy controls. Results: The frequencies of CARD15 mutations in sarcoidosis patients were: SNP8, 4/106 chromosomes (3.8%); SNP12, 2/106 chromosomes (1.9%); SNP13, 2/106 chromosomes (1.9%); SNP8+SNP12+SNP13, 8/106 chromosomes (7.6%). All 8 patients were heterozygous. The frequencies in controls were: SNP8, 9/206 chromosomes (4.4%); SNP12, 2/206 chromosomes (1.0%); SNP13, 4/206 chromosomes (1.9%); SNP8+SNP12+SNP13, 15/206 chromosomes (7.3%). All controls were heterozygous. The differences were not statistically significant (p > 0.05). Furthermore, the course of disease was not significantly different in the 8 patients with CARD15 mutations and the 45 patients without mutations. Conclusion: The frequency of CARD15 mutations is not increased in ethnic Danish patients with sarcoidosis, and heterozygosity for such mutations apparently has no influence on the course of disease.
Longitudinal Changes in Muscle Strength and Mass after Acute Stroke
Authors: Carin-Levy Gail , Greig Carolyn , Young Archie , Lewis Susan , Hannan Jim , Mead Gillian
Published: January 2006

Background: Reduced mobility after stroke may cause a loss of muscle mass which may, in theory, contribute to disability. We investigated longitudinal changes in muscle strength, lean cross-sectional area and muscle mass in all limbs after acute stroke. Methods: We recruited 17 patients within 72 h of hospital admission and measured (a) hand grip strength, (b) knee extensor strength and (c) arm and leg lean cross-sectional area on 6 occasions over 6 months. Appendicular and total muscle mass (dual-energy X-ray absorptiometry) were measured at 3 weeks and 6 months. Results: There was no significant change over time in the strength, lean cross-sectional area and muscle mass of the arms or legs. We noted that muscle strength was substantially lower in all limbs compared with population norms. Conclusion: We found no evidence of a decline in muscle strength or mass in any limb after the stroke, which could have been attributed to reduced mobility. The observed muscle weakness in the ipsilateral side may have pre-dated the stroke.
The Conflict over Cicero's House: An Analysis of the Ritual Element in De domo sua
Authors: Lisdorf Anders
Published: December 2005

According to the Romans themselves ritual was at the heart of their culture. Strangely, this centrality of ritual has not been matched by a corresponding sensitivity to how ritual was to be interpreted. Ritual has most often been viewed as an empty formalism devoid of any true belief. It is argued in this article that this view of ritual is an ethnocentric construct stemming from a Christian conception of belief, which does not adequately account for the peculiarities of ritual based religions. Taking the seemingly obscure and little studied case of the conflict over Cicero's house as a case, it is argued that E. Thomas Lawson's and Robert N. McCauley's ritual theory might help to overcome this misconception of ritual. This enables us to see how Cicero explicates implicit beliefs entailed by the ritual actions. Ultimately the evidence seems to support the reverse interpretation: that ritual was taken very seriously.
The New Fair Labor Standards Act Regulations and the Sales Force: Who Is Entitled to Overtime Pay?
Authors: Honorée André L. , Wyld David C.
Published: January 2006

The enactment of the Fairpay Overtime Initiative (FOI) in August 2004 fundamentally changed the manner in which employers determine the overtime eligibility of their workforce. For the first time, this controversial addition to the Fair Labor Standards Act specifically designated the outside sales position as exempt from overtime benefits. This article points out the diverse set of preconditions, salary considerations, and strict provisions of this new exempt category as well as possible means to classify as exempt other members of an organization's sales force. An illustrative model is presented as a practical tool to assist in the proper determination of any position within an organization's sales force. It provides a number of specific recommendations, criticisms, and implications that are relevant to any organization employing individuals engaged in sales.
Effects of population structure on genetic association studies
Authors: Xu Hongyan , Shete Sanjay
Published: December 2005

Population-based case-control association is a promising approach for unravelling the genetic basis of complex diseases. One potential problem of this approach is the presence of population structure in the samples. Using the Collaborative Study on the Genetics of Alcoholism (COGA) single-nucleotide polymorphism (SNP) datasets, we addressed three questions: How can the degree of population structure be quantified, and how does the population structure affect association studies? How accurate and efficient is the genomic control method in correcting for population structure? The amount of population structure in the COGA SNP data was found to inflate the p-value in association tests. Genomic control was found to be effective only when the appropriate number of markers was used in the control group in order to correctly calibrate the test. The approach presented in this paper could be used to select the appropriate number of markers for use in the genomic control method of correcting population structure.
A new family-based association test via a least-squares method
Authors: Yang Song , Joo Jungnam , Feng Ziding , Lin Jing-Ping
Published: December 2005

To test the association between a dichotomous phenotype and genetic marker based on family data, we propose a least-squares method using the vector of phenotypes and their cross products within each family. This new approach allows covariate adjustment and is numerically much simpler to implement compared to likelihood- based methods. The new approach is asymptotically equivalent to the generalized estimating equation approach with a diagonal working covariance matrix, thus avoiding some difficulties with the working covariance matrix reported previously in the literature. When applied to the data from Collaborative Study on the Genetics of Alcoholism, this new method shows a significant association between the marker rs1037475 and alcoholism.
A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers
Authors: Ji Fei , Lee Dayoung , Mendell Nancy Role
Published: December 2005

Complex diseases are often reported along with disease-related traits (DRT). Sometimes investigators consider both disease and DRT phenotypes separately and sometimes they consider individuals as affected if they have either the disease or the DRT, or both. We propose instead to consider the joint distribution of the disease and the DRT and do a linkage analysis assuming a pleiotropic model. We evaluated our results through analysis of the simulated datasets provided by Genetic Analysis Workshop 14. We first conducted univariate linkage analysis of the simulated disease, Kofendrerd Personality Disorder and one of its simulated associated traits, phenotype b (fear/discomfort with strangers). Subsequently, we considered the bivariate phenotype, which combined the information on Kofendrerd Personality Disorder and fear/discomfort with strangers. We developed a program to perform bivariate linkage analysis using an extension to the Elston-Stewart peeling method of likelihood calculation. Using this program we considered the microsatellites within 30 cM of the gene pleiotropic for this simulated disease and DRT. Based on 100 simulations of 300 families we observed excellent power to detect linkage within 10 cM of the disease locus using the DRT and the bivariate trait.
Genes, age, and alcoholism: analysis of GAW14 data
Authors: Apprey Victor , Afful Joseph , Harrell Jules P , Taylor Robert E , Bonney George E
Published: December 2005

A genetic analysis of age of onset of alcoholism was performed on the Collaborative Study on the Genetics of Alcoholism data released for Genetic Analysis Workshop 14. Our study illustrates an application of the log-normal age of onset model in our software Genetic Epidemiology Models (GEMs). The phenotype ALDX1 of alcoholism was studied. The analysis strategy was to first find the markers of the Affymetrix SNP dataset with significant association with age of onset, and then to perform linkage analysis on them. ALDX1 revealed strong evidence of linkage for marker tsc0041591 on chromosome 2 and suggestive linkage for marker tsc0894042 on chromosome 3. The largest separation in mean ages of onset of ALDX1 was 19.76 and 24.41 between male smokers who are carriers of the risk allele of tsc0041591 and the non-carriers, respectively. Hence, male smokers who are carriers of marker tsc0041591 on chromosome 2 have an average onset of ALDX1 almost 5 years earlier than non-carriers.
A genome-wide linkage and association study using COGA data
Authors: Zhu Xiaofeng , Cooper Richard , Kan Donghui , Cao Guichan , Wu Xiaodong
Published: December 2005

Background

Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses.

Methods

Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleotide polymorphisms (SNPs). Family based genome-wide association test was also conducted using the SNPs.

Results

Nonparametric linkage analysis revealed weak linkage evidence on chromosome 7, and association analysis identified SNP tsc0515272 on chromosome 3 as significantly associated with alcoholism.

Conclusion

Linkage analysis may require large sample sizes and high quality genotyping and marker maps to adequately improve power, while association analysis could hold more promise in efforts to identify variants responsible for complex traits.
Whole-genome association studies on alcoholism comparing different phenotypes using single-nucleotide polymorphisms and microsatellites
Authors: Chen Liang , Liu Nianjun , Wang Shuang , Oh Cheongeun , Carriero Nicholas J , Zhao Hongyu
Published: December 2005

Alcoholism is a complex disease. As with other common diseases, genetic variants underlying alcoholism have been illusive, possibly due to the small effect from each individual susceptible variant, gene × environment and gene × gene interactions and complications in phenotype definition. We conducted association tests, the family-based association tests (FBAT) and the backward haplotype transmission association (BHTA), on the Collaborative Study of the Genetics of Alcoholism (COGA) data provided by Genetic Analysis Workshop (GAW) 14. Efron's local false discovery rate method was applied to control the proportion of false discoveries. For FBAT, we compared the results based on different types of genetic markers (single-nucleotide polymorphisms (SNPs) versus microsatellites) and different phenotype definitions (clinical diagnoses versus electrophysiological phenotypes). Significant association results were found only between SNPs and clinical diagnoses. In contrast, significant results were found only between microsatellites and electrophysiological phenotypes. In addition, we obtained the association results for SNPs and microsatellites using COGA diagnosis as phenotype based on BHTA. In this case, the results for SNPs and microsatellites are more consistent. Compared to FBAT, more significant markers are detected with BHTA.
Diagnosis of alcoholism based on neural network analysis of phenotypic risk factors
Authors: Falk Catherine T
Published: December 2005

Background

Alcoholism is a serious public health problem. It has both genetic and environmental causes. In an effort to gain understanding of the underlying genetic susceptibility to alcoholism, a long-term study has been undertaken. The Collaborative Study on the Genetics of Alcoholism (COGA) provides a rich source of genetic and phenotypic data. One ongoing problem is the difficulty of reliably diagnosing alcoholism, despite many known risk factors and measurements. We have applied a well known pattern-matching method, neural network analysis, to phenotypic data provided to participants in Genetic Analysis Workshop 14 by COGA. The aim is to train the network to recognize complex phenotypic patterns that are characteristic of those with alcoholism as well as those who are free of symptoms. Our results indicate that this approach may be helpful in the diagnosis of alcoholism.

Results

Training and testing of input/output pairs of risk factors by means of a "feed-forward back-propagation" neural network resulted in reliability of about 94% in predicting the presence or absence of alcoholism based on 36 input phenotypic risk factors. Pruning the neural network to remove relatively uninformative factors resulted in a reduced network of 14 input factors that was still 95% reliable. Some of the factors selected by the pruning steps have been identified as traits that show either linkage or association to potential candidate regions.

Conclusion

The complex, multivariate picture formed by known risk factors for alcoholism can be incorporated into a neural network analysis that reliably predicts the presence or absence of alcoholism about 94–95% of the time. Several characteristics that were identified by a pruned neural network have previously been shown to be important in this disease based on more traditional linkage and association studies. Neural networks therefore provide one less traditional approach to both identifying alcoholic individuals and determining the most informative risk factors.
Data mining of the GAW14 simulated data using rough set theory and tree-based methods
Authors: Wei Liang-Ying , Huang Cheng-Lung , Chen Chien-Hsiun
Published: December 2005

Rough set theory and decision trees are data mining methods used for dealing with vagueness and uncertainty. They have been utilized to unearth hidden patterns in complicated datasets collected for industrial processes. The Genetic Analysis Workshop 14 simulated data were generated using a system that implemented multiple correlations among four consequential layers of genetic data (disease-related loci, endophenotypes, phenotypes, and one disease trait). When information of one layer was blocked and uncertainty was created in the correlations among these layers, the correlation between the first and last layers (susceptibility genes and the disease trait in this case), was not easily directly detected. In this study, we proposed a two-stage process that applied rough set theory and decision trees to identify genes susceptible to the disease trait. During the first stage, based on phenotypes of subjects and their parents, decision trees were built to predict trait values. Phenotypes retained in the decision trees were then advanced to the second stage, where rough set theory was applied to discover the minimal subsets of genes associated with the disease trait. For comparison, decision trees were also constructed to map susceptible genes during the second stage. Our results showed that the decision trees of the first stage had accuracy rates of about 99% in predicting the disease trait. The decision trees and rough set theory failed to identify the true disease-related loci.
Analysis of alcoholism data using support vector machines
Authors: Yu Robert , Shete Sanjay
Published: December 2005

A supervised learning method, support vector machine, was used to analyze the microsatellite marker dataset of the Collaborative Study on the Genetics of Alcoholism Problem 1 for the Genetic Analysis Workshop 14. Twelve binary-valued phenotype variables were chosen for analyses using the markers from all autosomal chromosomes. Using various polynomial kernel functions of the support vector machine and randomly divided genome regions, we were able to observe the association of some marker sets with the chosen phenotypes and thus reduce the size of the dataset. The successful classifications established with the chosen support vector machine kernel function had high levels of correctness for each prediction, e.g., 96% in the fourfold cross-validations. However, owing to the limited sample data, we were not able to test the predictions of the classifiers in the new sample data.
Use of susceptibility scoring in conjunction with the genotypic transmission disequilibrium test
Authors: Benke Kelly S , Chase Gary A , Fallin Daniele M
Published: December 2005

We explored the utility of selecting a genetically predisposed subgroup to increase the finding of a genetic signal in the Genetic Analysis Workshop 14 Collaborative Study on the Genetics of Alcoholism dataset. A subgroup of affected probands with low environmental risk exposures was defined using a susceptibility score calculated from an environmental risk model. Thirty-nine probands with highly positive scores were selected, along with their parents, for use in a genotypic transmission disequilibrium test (TDT) test. We compared the results of the genotypic TDT in this subgroup to the TDT results using all probands and their parents. For some markers, the susceptibility scoring approach resulted in smaller p-values, while for other markers, evidence for a genetic signal weakened. Further explorations into genetic and environmental population characteristics that benefit from this approach are warranted.
A new Bayesian approach incorporating covariate information for heterogeneity and its comparison with HLOD
Authors: Biswas Swati , Lin Shili , Berry Donald A
Published: December 2005

We consider a new Bayesian approach for heterogeneity that can take into account categorical covariates, if available. We use the Genetic Analysis Workshop 14 simulated data to first compare the Bayesian approach with the heterogeneity LOD, when no covariate information is used. We find that the former is more powerful, while the two approaches have comparable false-positive rates. We then include informative covariates in the Bayesian approach and find that it tends to give more precise interval estimates of the disease gene location than when covariates are not included. We had knowledge of the simulation models at the time we performed the analyses.
Performance comparison of two-point linkage methods using microsatellite markers flanking known disease locations
Authors: Logue Mark W , George Andrew W , Spence M Anne , Vieland Veronica J
Published: December 2005

The Genetic Analysis Workshop 14 simulated data presents an interesting, challenging, and plausible example of a complex disease interaction in a dataset. This paper summarizes the ease of detection for each of the simulated Kofendrerd Personality Disorder (KPD) genes across all of the replicates for five standard linkage statistics. Using the KPD affection status, we have analyzed the microsatellite markers flanking each of the disease genes, plus an additional 2 markers that were not linked to any of the disease loci. All markers were analyzed using the following two-point linkage methods: 1) a MMLS, which is a standard admixture LOD score maximized over θ, α, and mode of inheritance, 2) a MLS calculated by GENEHUNTER, 3) the Kong and Cox LOD score as computed by MERLIN, 4) a MOD score (standard heterogeneity LOD maximized over θ, α, and a grid of genetic model parameters), and 5) the PPL, a Bayesian statistic that directly measures the strength of evidence for linkage to a marker. All of the major loci (D1–D4) were detectable with varying probabilities in the different populations. However, the modifier genes (D5 and D6) were difficult to detect, with similar distributions under the null and alternative across populations and statistics. The pooling of the four datasets in each replicate (n = 350 pedigrees) greatly improved the chance of detecting the major genes using all five methods, but failed to increase the chance to detect D5 and D6.
Standard linkage and association methods identify the mechanism of four susceptibility genes for a simulated complex disease
Authors: Pankratz Nathan , Edenberg Ellen , Foroud Tatiana
Published: December 2005

The simulated dataset of the Genetic Analysis Workshop 14 provided affection status and the presence or absence of 12 traits. It was determined that all affected individuals must have traits E, F and H (EFH phenotype) and they must also have either trait B (B subtype) or traits C, D, and G (CDG subtype). A genome screen was performed, and linkage peaks were identified on chromosomes 1, 3, 5, and 9 using microsatellite markers. Dense panels of single-nucleotide polymorphism (SNP) markers were ordered for each of the four linkage peaks. In each case, association analyses identified a single SNP that accounted for the linkage evidence. The SNP on chromosome 1 appeared to primarily influence the B subtype, while the SNPs on chromosomes 5 and 9 primarily influenced the CDG subtype. The chromosome 3 SNP had the strongest effect and influenced both subtypes, as well as the requisite EFH phenotype. Recognizing the two subtypes prior to linkage analysis was key to identifying these loci using only a single replicate. This highlights the need in real life situations for careful examination of the phenotypic data prior to genetic analysis.
Extension of multifactor dimensionality reduction for identifying multilocus effects in the GAW14 simulated data
Authors: Mei Hao , Ma Deqiong , Ashley-Koch Allison , Martin Eden R
Published: December 2005

The multifactor dimensionality reduction (MDR) is a model-free approach that can identify gene × gene or gene × environment effects in a case-control study. Here we explore several modifications of the MDR method. We extended MDR to provide model selection without crossvalidation, and use a chi-square statistic as an alternative to prediction error (PE). We also modified the permutation test to provide different levels of stringency. The extended MDR (EMDR) includes three permutation tests (fixed, non-fixed, and omnibus) to obtain p-values of multilocus models. The goal of this study was to compare the different approaches implemented in the EMDR method and evaluate the ability to identify genetic effects in the Genetic Analysis Workshop 14 simulated data. We used three replicates from the simulated family data, generating matched pairs from family triads. The results showed: 1) chi-square and PE statistics give nearly consistent results; 2) results of EMDR without cross-validation matched that of EMDR with 10-fold cross-validation; 3) the fixed permutation test reports false-positive results in data from loci unrelated to the disease, but the non-fixed and omnibus permutation tests perform well in preventing false positives, with the omnibus test being the most conservative. We conclude that the non-cross-validation test can provide accurate results with the advantage of high efficiency compared to 10-cross-validation, and the non-fixed permutation test provides a good compromise between power and false-positive rate.
Analysis of genes for alcoholism using two-disease-locus models
Authors: Wu Chih-Chieh , Shete Sanjay
Published: December 2005

Using model-based two-locus methods for mapping genes, we analyzed the family data from the Collaborative Study on the Genetics of Alcoholism. Microsatellite data from 143 families ascertained through having three or more individuals affected with alcohol dependence were used for this investigation. Four regions showing evidence for linkage were identified using single-locus models from previous investigations. We investigated the genetic linkage, pattern of disease inheritance, and pair-wise genetic epistasis of these loci using the TLINKAGE program for two-disease-locus analysis.
Whole-genome variance components linkage analysis using single-nucleotide polymorphisms versus microsatellites on quantitative traits of derived phenotypes from factor analysis of electroencephalogram waves
Authors: Yu Yi , Meng Yan , Ma Qianli , Farrell John , Farrer Lindsay A , Wilcox Marsha A
Published: December 2005

Alcohol dependence is a serious public health problem. We studied data from families participating in the Collaborative Study on the Genetics of Alcoholism (COGA) and made available to participants in the Genetic Analysis Workshop 14 (GAW14) in order to search for genes predisposing to alcohol dependence. Using factor analysis, we identified four factors (F1, F2, F3, F4) related to the electroencephalogram traits. We conducted variance components linkage analysis with each of the factors. Our results using the Affymetrix single-nucleotide polymorphism dataset showed significant evidence for a novel linkage of F3 (factor comprised of the three midline channel EEG measures from the target case of the Visual Oddball experiment ttdt2, 3, 4) to chromosome 18 (LOD = 3.45). This finding was confirmed by analyses of the microsatellite data (LOD = 2.73) and Illumina SNP data (LOD = 3.30). We also demonstrated that, in a sample like the COGA data, a dense single-nucleotide polymorphism map provides better linkage signals than low-resolution microsatellite map with quantitative traits.
The effect of missing data on linkage disequilibrium mapping and haplotype association analysis in the GAW14 simulated datasets
Authors: McCaskie Pamela A , Carter Kim W , McCaskie Simon R , Palmer Lyle J
Published: December 2005

We used our newly developed linkage disequilibrium (LD) plotting software, JLIN, to plot linkage disequilibrium between pairs of single-nucleotide polymorphisms (SNPs) for three chromosomes of the Genetic Analysis Workshop 14 Aipotu simulated population to assess the effect of missing data on LD calculations. Our haplotype analysis program, SIMHAP, was used to assess the effect of missing data on haplotype-phenotype association. Genotype data was removed at random, at levels of 1%, 5%, and 10%, and the LD calculations and haplotype association results for these levels of missingness were compared to those for the complete dataset. It was concluded that ignoring individuals with missing data substantially affects the number of regions of LD detected which, in turn, could affect tagging SNPs chosen to generate haplotypes.
An analysis of identical single-nucleotide polymorphisms genotyped by two different platforms
Authors: Suarez Brian K , Taylor Chelsea , Bertelsen Sarah , Bierut Laura J , Dunn Gerald , Jin Carol H , Kauwe John SK , Paterson Andrew D , Hinrichs Anthony L
Published: December 2005

The overlap of 94 single-nucleotide polymorphisms (SNP) among the 4,720 and 11,120 SNPs contained in the linkage panels of Illumina and Affymetrix, respectively, allows an assessment of the discrepancy rate produced by these two platforms. Although the no-call rate for the Affymetrix platform is approximately 8.6 times greater than for the Illumina platform, when both platforms make a genotypic call, the agreement is an impressive 99.85%. To determine if disputed genotypes can be resolved without sequencing, we studied recombination in the region of the discrepancy for the most discrepant SNP rs958883 (typed by Illumina) and tsc02060848 (typed by Affymetrix). We find that the number of inferred recombinants is substantially higher for the Affymetrix genotypes compared to the Illumina genotypes. We illustrate this with pedigree 10043, in which 3 of 7 versus 0 of 7 offspring must be double recombinants using the genotypes from the Affymetrix and the Illumina platforms, respectively. Of the 36 SNPs with one or more discrepancies, we identified a subset that appears to cluster in families. Some of this clustering may be due to the presence of a second segregating SNP that obliterates a Xba I site (the restriction enzyme used in the Affymetrix platform), resulting in a fragment too long (>1,000 bp) to be amplified.
Examining the effect of linkage disequilibrium on multipoint linkage analysis
Authors: Huang Qiqing , Shete Sanjay , Swartz Michael , Amos Christopher I
Published: December 2005

Most linkage programs assume linkage equilibrium among multiple linked markers. This assumption may lead to bias for tightly linked markers where strong linkage disequilibrium (LD) exists. We used simulated data from Genetic Analysis Workshop 14 to examine the possible effect of LD on multipoint linkage analysis. Single-nucleotide polymorphism packets from a non-disease-related region that was generated with LD were used for both model-free and parametric linkage analyses. Results showed that high LD among markers can induce false-positive evidence of linkage for affected sib-pair analysis when parental data are missing. Bias can be eliminated with parental data and can be reduced when additional markers not in LD are included in the analyses.
Shedding of PECAM-1 during HIV infection: a potential role for soluble PECAM-1 in the pathogenesis of NeuroAIDS
Authors: Eugenin E A , Gamss R , Buckner C , Buono D , Klein R S , Schoenbaum E E , Calderon T M , Berman J W
Published: December 2005

Human immunodeficiency virus (HIV) infection is characterized by viral entry into the central nervous system (CNS), which is mediated, in part, by the transmigration of HIV-infected monocytes into the brain. The elaboration of chemokines and other factors by these infected cells contributes to CNS inflammation and cognitive impairment in a significant number of HIV-infected individuals. Recently, we demonstrated that HIV-infected monocyte transmigration into the CNS is enhanced greatly by the chemokine CC chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1. Platelet endothelial cell adhesion molecule-1 (PECAM-1) plays an important role in leukocyte transmigration across the endothelium of the systemic vasculature by mediating homophilic interactions between endothelial cells (EC)-EC and EC-leukocytes, thus preserving vessel integrity. The role of PECAM-1 in HIV-infected leukocyte transmigration across the blood brain barrier (BBB) and NeuroAIDS has not been characterized. We demonstrate that in brain tissue from individuals with HIV encephalitis, there is an accumulation of cleaved, soluble forms of the extracellular region of PECAM-1 (sPECAM-1). In addition, HIV-infected individuals have elevated levels of sPECAM-1 in their sera. Our in vitro data demonstrate that HIV-infected leukocytes, when treated with CCL2, shed sPECAM-1, suggesting a mechanism of extracellular PECAM-1 cleavage and release dependent on HIV infection and CCL2. We hypothesize that sPECAM-1 production by HIV-infected leukocytes, resulting in the accumulation of sPECAM-1 within the CNS vasculature and the generation of truncated, intracellular forms of PECAM-1 within leukocytes, alters PECAM-1 interactions between EC-EC and EC-leukocytes, thus contributing to enhanced transmigration of HIV-infected leukocytes into the CNS and changes in BBB permeability during the pathogenesis of NeuroAIDS.
Localization of human neutrophil interleukin-8 (CXCL-8) to organelle(s) distinct from the classical granules and secretory vesicles
Authors: Pellmé Sara , Mörgelin Matthias , Tapper Hans , Mellqvist Ulf-Henrik , Dahlgren Claes , Karlsson Anna
Published: December 2005

Mature human neutrophils contain small amounts of interleukin-8 [CXC chemokine ligand 8 (CXCL-8)], which upon proinflammatory activation, increases significantly. It has been suggested that the CXCL-8 content of resting human neutrophils is stored in the secretory vesicles. Here, we have used a fractionation technique, which allows isolation of these vesicles, and we find that CXCL-8 neither colocalizes with the secretory vesicles nor with markers of any of the classical neutrophil granules. To increase resolution in the system, we induced CXCL-8 production by lipopolysaccharide. After 8 h of stimulation, CXCL-8 was visualized within the cell using immunoelectron microscopy. The images revealed CXCL-8-containing stuctures resembling neutrophil granules, and these were distinct from all known neutrophil organelles, as shown by double immunostaining. Further, the CXCL-8 organelle was present in nonstimulated neutrophil cytoplasts, entities lacking all other known granules and secretory vesicles. Upon fractionation of the cytoplasts, CXCL-8 was found to partly cofractionate with calnexin, a marker for endoplasmic reticulum (ER). Thus, part of CXCL-8 may be localized to the ER or ER-like structures in the neutrophil.
No association of apolipoprotein E ε4 genotype with faster progression or less recovery of relapses in a Spanish cohort of multiple sclerosis
Authors: Sedano M J , Calmarza P , Perez L , Trejo J M
Published: December 2005

Background Recent data have suggested a faster deterioration of multiple sclerosis (MS) patients who harbour the o4 allele of the apolipoprotein E (APOE) gene. We investigate the relationship of APOE genotypes with disease severity and clinical recovery of relapses in a MS population of the north of Spain.

Methods One hundred and thirty-three patients with clinically defined MS were studied. Disease course (relapsing versus progressive), age of onset, duration of the disease and disability measured by the Expanded Disability Status Scale (EDSS) were recorded. Worsening was measured by the Progression Index (PI) and by EDSS 4 and 6 latencies. In 79 patients with relapsing-remitting (RR) MS the degree of clinical recovery of relapses (total versus partial) was assessed.

Results The frequency of the APOE o4 allele in our patients was similar to that found in other southern European populations. APOE o4 patients did not have a faster progression as assessed by PI and EDSS 4 and 6 latencies. Among 79 patients with RRMS there were no significant differences in the degree of recovery of relapses.

Conclusions In this MS population, APOE o4 polymorphism is not associated with a more severe clinical course and does not appear to influence recovery of exacerbations.
Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1
Authors: Gilli F , Marnetto F , Caldano M , Sala A , Malucchi S , Capobianco M , Bertolotto A
Published: December 2005

Biological activity of interferon-beta (IFNβ) can be assessed by measuring IFN-stimulated genes (ISGs). Among them, myxovirus resistance protein A (MxA) appears to have the highest specificity, but it has no role in the pathogenesis of multiple sclerosis (MS). To investigate the reliability of MxA as a biomarker, we compared its expression to that of two other ISGs: TNF-related apoptosis-inducing ligand (TRAIL) and X-linked inhibitor of apoptosis factor-1 (XAF-1). Both were shown to be involved in immunoregulatory mechanisms and might play a role in MS. Quantitative-PCR measurements were performed in peripheral blood mononuclear cells from 73 MS patients after short-term and long-term treatment with IFNβ. A time-dependent response for multiple ISGs was observed in all patients after short-term treatment. In contrast, long-term treatment induced concurrent inhibition of ISGs in 12.3% (9/73) of patients, in whom neutralizing antibodies (NAbs) were detectable. Besides, 22% (16/73) of chronically treated patients showed a non-NAbs-related abrogation of TRAIL expression. In summary, 1) MxA expression was significantly higher than both TRAIL and XAF-1, and 2) MxA was the most sensitive gene to detect decreased bioavailability due to NAbs. These findings identify MxA as an appropriate biomarker for IFNβ, although there is no evidence for a functional role of it in MS.