bluuebunny/crossref_metadata_2025 huggingface dataset:
Liraglutide mitigates TNF‐α induced pro‐atherogenic changes and microvesicle release in HUVEC from diabetic women
Authors: Di Tomo Pamela , Lanuti Paola , Di Pietro Natalia , Baldassarre Maria Pompea Antonia , Marchisio Marco , Pandolfi Assunta , Consoli Agostino , Formoso Gloria
Published: July 2017

Background

To evaluate whether exposure to GLP‐1 receptor agonist Liraglutide could modulate pro‐atherogenic alterations previously observed in endothelial cells obtained by women affected by gestational diabetes (GD), thus exposed in vivo to hyperglycemia, oxidative stress, and inflammation and to evaluate endothelial microvesicle (EMV) release, a new reliable biomarker of vascular stress/damage.

Methods

We studied Liraglutide effects and its plausible molecular mechanisms on monocyte cell adhesion and adhesion molecule expression and membrane exposure in control (C‐) human umbilical vein endothelial cells (HUVEC) as well as in HUVEC of women affected by GD exposed in vitro to TNF‐α. In the same model, we also investigated Liraglutide effects on EMV release.

Results

In response to TNF‐α, endothelial monocyte adhesion and VCAM‐1 and ICAM‐1 expression and exposure on plasma membrane was greater in GD‐HUVEC than C‐HUVEC. This was the case also for EMV release. In GD‐HUVEC, Liraglutide exposure significantly reduced TNF‐α induced endothelial monocyte adhesion as well as VCAM‐1 and ICAM‐1 expression and exposure on plasma membrane. In the same cells, Liraglutide exposure also reduced MAPK/NF‐kB activation, peroxynitrite levels, and EMV release.

Conclusions

TNF‐α induced pro‐atherogenic alterations are amplified in endothelial cells chronically exposed to hyperglycemia in vivo. Liraglutide mitigates TNF‐α effects and reduces cell stress/damage indicators, such as endothelial microvesicle (EMV) release. These results foster the notion that Liraglutide could exert a protective effect against hyperglycemia and inflammation triggered endothelial dysfunction.
Islands, mainland, and terrestrial fragments: How isolation shapes plant diversity
Authors: Martín‐Queller Emi , Albert Cécile H. , Dumas Pierre‐Jean , Saatkamp Arne
Published: July 2017

The fragmentation of natural habitats is a major threat for biodiversity. However, the impact and spatial scale of natural isolation mechanisms leading to species loss, compared to anthropogenic fragmentation, are not clear, mainly due to differences between fragments and islands, such as matrix permeability. We studied a 500 km2 Mediterranean region in France, including urban habitat fragments, continuous habitat, and continental‐shelf islands. On the basis of 295 floristic relevés, we built species–area relationships to compare isolation in fragments after urbanization, with continuous habitat and continental‐shelf islands. We assumed either no dispersal, infinite dispersal, or estimated intermediate levels of habitat reachability through graph theory. Isolation mechanisms occurred in fragments but with a lower strength than in near‐shore islands, and most importantly affected perennial plants. Annual plants were less affected, probably due to their smaller size and shorter life cycle. Isolation occurred at landscape level in fragments and at patch level in islands. The amount of reachable habitat (accounting for spatial configuration) explained local species richness in both systems, but the amount of habitat (no consideration of spatial configuration) was already a good predictor. These results suggest an important role of habitat amount around fragments in mitigating the isolation effects observed in near‐shore islands, and the importance of carefully considering different functional groups.
Sorting things out: Assessing effects of unequal specimen biomass on DNA metabarcoding
Authors: Elbrecht Vasco , Peinert Bianca , Leese Florian
Published: July 2017

Environmental bulk samples often contain many different taxa that vary several orders of magnitude in biomass. This can be problematic in DNA metabarcoding and metagenomic high‐throughput sequencing approaches, as large specimens contribute disproportionately high amounts of DNA template. Thus, a few specimens of high biomass will dominate the dataset, potentially leading to smaller specimens remaining undetected. Sorting of samples by specimen size (as a proxy for biomass) and balancing the amounts of tissue used per size fraction should improve detection rates, but this approach has not been systematically tested. Here, we explored the effects of size sorting on taxa detection using two freshwater macroinvertebrate bulk samples, collected from a low‐mountain stream in Germany. Specimens were morphologically identified and sorted into three size classes (body size < 2.5 × 5, 5 × 10, and up to 10 × 20 mm). Tissue powder from each size category was extracted individually and pooled based on tissue weight to simulate samples that were not sorted by biomass (“Unsorted”). Additionally, size fractions were pooled so that each specimen contributed approximately equal amounts of biomass (“Sorted”). Mock samples were amplified using four different DNA metabarcoding primer sets targeting the Cytochrome c oxidase I (COI) gene. Sorting taxa by size and pooling them proportionately according to their abundance lead to a more equal amplification of taxa compared to the processing of complete samples without sorting. The sorted samples recovered 30% more taxa than the unsorted samples at the same sequencing depth. Our results imply that sequencing depth can be decreased approximately fivefold when sorting the samples into three size classes and pooling by specimen abundance. Even coarse size sorting can substantially improve taxa detection using DNA metabarcoding. While high‐throughput sequencing will become more accessible and cheaper within the next years, sorting bulk samples by specimen biomass or size is a simple yet efficient method to reduce current sequencing costs.
Accounting for photodegradation dramatically improves prediction of carbon losses in dryland systems
Authors: Adair E. Carol , Parton William J. , King Jennifer Y. , Brandt Leslie A. , Lin Yang
Published: July 2017

Traditional models of decomposition fail to capture litter mass loss patterns in dryland systems. This shortcoming has stimulated research into alternative drivers of decomposition, including photodegradation. Here, we use aboveground litter decomposition data for dryland (arid) sites from the Long‐term Intersite Decomposition Experiment Team data set to test hypotheses (models) about the mechanisms and impacts of photodegradation. Incorporating photodegradation into a traditional biotic decomposition model substantially improved model predictions for mass loss at these dryland sites, especially after four years. The best model accounted for the effects of solar radiation via photodegradation loss from the intermediate cellulosic and lignin pools and direct inhibition of microbial decomposition. Despite the concurrent impacts of photodegradation and inhibition on mass loss, the best photodegradation model increased mass loss by an average of 12% per year compared to the biotic‐only decomposition model. The best model also allowed soil infiltration into litterbags to reduce photodegradation and inhibition of microbial decomposition by shading litter from solar radiation. Our modeling results did not entirely support the popular hypothesis that initial lignin content increases the effects of photodegradation on litter mass loss; surprisingly, higher initial lignin content decreased the rate of cellulosic photodegradation. Importantly, our results suggest that mass loss rates due to photodegradation may be comparable to biotic decomposition rates: Mass loss due to photodegradation alone resulted in litter mass losses of 6–15% per year, while mass loss due to biotic decomposition ranged from 20% per year during early‐stage decomposition to 3% per year during late‐stage decomposition. Overall, failing to account for the impacts of solar radiation on litter mass loss under‐predicted long‐term litter mass loss by approximately 26%. Thus, not including photodegradation in dryland decomposition models likely results in large underestimations of carbon loss from dryland systems.
Product Isomer Distribution in the Sequential Functionalization of Cyclic PIII2N2 Frameworks
Authors: Bawari Deependra , Prashanth Billa , Jaiswal Kuldeep , Choudhury Angshuman Roy , Singh Sanjay
Published: July 2017

We have demonstrated stepwise functionalization of chlorophosph(III)azane, [ClP(µ‐NtBu)]2 with organic azides and chalcogens (S and Se). The in situ 31P{1H} NMR spectroscopic investigations reveal that conversion of the basic PIII2N2 framework, leading to PV2N2 proceeds via (PIII/PV)N2 intermediates. Under controlled conditions, the (PIII/PV)N2 intermediate species can be isolated, providing details of the reaction pathway and distribution of the cis and trans isomers of the PV2N2 products. It has also been demonstrated that neat reactions at elevated temperatures expedite the formation of PV2N2 products, without significantly affecting the yields and relative distribution of the cis and trans isomers. All new compounds reported here are potential building blocks for the assembly of inorganic macrocycles and polymers.
A Facile One‐Pot Synthesis of 1,2,3‐Tri‐ and 1,1,2,3‐Tetrasubstituted Bis(guanidine)s from Bis(thiourea)s
Authors: Vass Valentin , Dehmel Maximilian , Lehni Florian , Kretschmer Robert
Published: July 2017

A facile and efficient one‐pot strategy for the preparation of 1,2,3‐tri‐ and 1,1,2,3‐tetrasubstituted bis(guanidine)s by starting from from readily available bis(thiourea)s has been successfully developed. The reaction provides products that contain a range of terminal and bridging groups. After a simple workup procedure, the products were obtained in analytically pure and in good to excellent yields.
From Chitin to α‐Glycosides of N‐Acetylglucosamine Using Catalytic Copper Triflate in a Heated Sealed‐Vessel Reactor
Authors: Frem Dany , Urban Dominique , Norsikian Stéphanie , Beau Jean‐Marie
Published: July 2017

The selective preparation of α‐glycosides of GlcNAc has been accomplished using a direct copper(II) triflate catalyzed glycosylation between α‐d‐glucosamine pentaacetate, readily available from chitin, and a range of alcohol acceptors. The α‐selectivity results from a post‐glycosylation anomerization.
Interface Engineering of electron Transport Layer‐Free Planar Perovskite Solar Cells with Efficiency Exceeding 15 %
Authors: Huang Feiyue , Wei Yuelin , Gu Lin , Guo Qiyao , Xu Hui , Luo Dan , Jin Shao , Yang Xiaomin , Huang Yunfang , Wu Jihuai
Published: July 2017

A high‐performance electron transport layer (ETL)‐free planar fluorine‐doped tin oxide (FTO)/perovskite/hole‐transport material/Au solar cell was prepared. We revealed that a plasma‐cleaning pretreatment for FTO substrates could significantly improve the quality of perovskite films, leading to the promotion of charge separation, an increase in the electron‐transport rate, and a decrease in the recombination reaction at the FTO/perovskite interface. Finally, the efficiency of the cells was greatly improved. A power conversion efficiency of over 15 % and a fill factor of 0.68 were achieved under AM 1.5G 100 mW cm−2 irradiation without the use of a compact n‐type metal‐oxide blocking layer.
Topography of generalized periodic epileptiform discharges in postanoxic nonconvulsive status epilepticus
Authors: Sakellariou Dimitris Fotis , Kostopoulos George Kostantinos , Richardson Mark Philip , Koutroumanidis Michalis
Published: July 2017

We studied slow (≤2.5 Hz) nonevolving generalized periodic epileptiform discharges (GPEDs) in the electroencephalogram (EEG) of comatose patients after cardiac arrest (CA) in search of evidence that could assist early diagnosis of possible hypoxic nonconvulsive status epilepticus (NCSE) and its differentiation from terminal brain anoxia (BA), which can present with a similar EEG pattern. We investigated the topography of the GPEDs in the first post‐CA EEGs of 13 patients, using voltage‐mapping, and compared findings between two patients with NCSE and GPEDs > 2.5 Hz (group 1), and 11 with GPEDs ≤ 2 Hz, of whom six had possible NCSE (group 2) and five had terminal BA (group 3). Voltage mapping showed frontal maximum for the negative phase of the GPEDs in all patients of groups 1 and 2, but not in any of the patients of group 3, who invariably showed maximization of the negative phase posteriorly. Morphology, amplitude, and duration of the GPEDs varied across the groups, without distinctive features for possible NCSE. These findings provide evidence that, in hypoxic coma after CA with slow GPEDs, anterior topography of the maximum GPED negativity on voltage mapping may be a distinctive biomarker for possible NCSE contributing to the coma.
Oxford Genome Screen for Asthma‐Associated Traits
Authors: Cookson William O.C.M. , Abeçasis Goncalo R.
Published: July 2017

A genome screen for linkage of quantitative traits underlying asthma has been carried out previously by our group on 80 families sub‐selected for discordant phenotypes from a general population sample. The families contained a total of 203 offspring forming 172 sib‐pairs. Genotypic data for at a total of 296 markers were available. This paper describes the ascertainment, phenotypic data, and genotypic data made available for Genetic Analysis Workshop 12. © 2001 Wiley‐Liss, Inc.
Nonparametric Linkage Regression II: Identification of Influential Pedigrees in Tests for Linkage
Authors: Davis Cralen C. , Brown W. Mark , Lange Ethan M. , Rich Stephen S. , Langefeld Carl D.
Published: July 2017

We applied case‐deletion‐based diagnostics to the combined Caucasian genome scan data for asthma and IgE from the Collaborative Study on the Genetics of Asthma (CSGA) and German family studies in order to identify influential pedigrees in tests for linkage. These methods identified 12 pedigrees whose data appear not to fit the asthma linkage model and for whom alternative genetic and nongenetic explanations can be explored. The methods also identified four pedigrees for chromosome 1 and two pedigrees for chromosome 2 that provide strong evidence for linkage at their respective loci. Similarly, these methods helped identify four pedigrees that strongly influenced the linkage tests for IgE. From these data, we can construct an enriched subset of pedigrees to be used in further analysis for mapping region‐specific putative trait predisposing loci. © 2001 Wiley‐Liss, Inc.
Sex‐ and Age‐of‐Onset‐Based Locus Heterogeneity in Asthma
Authors: Srivastava Anil , Cotton Cecilia , Paterson Andrew D.
Published: July 2017

Asthma is a complex disease with a genetic component. The results of genome‐wide linkage studies imply that locus heterogeneity is likely to be an important feature of the genetics of asthma. To attempt to reduce locus heterogeneity, we hypothesized that the following may form the bases for locus heterogeneity at some asthma susceptibility loci: sex of affected individuals, parental origin of alleles shared by affected sib pairs, and age of onset of wheeze. Analysis of such strata may assist in the identification of novel susceptibility loci, or reveal the basis for locus heterogeneity at previously identified loci. Genotype and phenotype data from genome‐wide linkage searches for asthma susceptibility loci from three populations were analyzed. Some regions demonstrated evidence for linkage to affected individuals of a particular sex. There was evidence for excess maternal allele sharing at regions on chromosomes 9 and 11. Regions on chromosomes 2 and 6 were linked to late and early age at onset of wheeze in asthma, respectively. These analyses suggest that the bases that we selected for stratification may be appropriate at certain susceptibility loci for asthma, and may therefore assist in the fine mapping of such loci. Differences in such variables between studies may explain apparent nonreplication of linkage results. © 2001 Wiley‐Liss, Inc.
Genetic Analysis of Quantitative Traits in Highly Ascertained Samples: Total Serum IgE in Families with Asthma
Authors: Bethony Jeffrey , Williams Jeff T. , Almasy Laura , Corrêa-Oliveira Rodrigo , Blangero John C. , Williams-Blangero Sarah
Published: July 2017

The objective of this study was to compare the effect of an approximate ascertainment correction using proband phenotypes with heuristic corrections based on sample trait means and on published “standard” population values. Data were from the Collaborative Study on the Genetics of Asthma, which comprises 225 families ascertained through sib pairs affected with asthma. In variance component linkage analysis of IgE no lod scores greater than 3.0 were observed, either with or without several attempted corrections for ascertainment. The ascertained nature of the sample may have compromised the power to detect linkage to a quantitative trait (IgE) associated with the focal phenotype (asthma). © 2001 Wiley‐Liss, Inc.
Detection of Parent‐of‐Origin Effects for Atopy by Model‐Free and Model‐Based Linkage Analyses
Authors: Demenais Florence , Chaudru Valérie , Martinez Maria
Published: July 2017

Parent‐of‐origin effects for atopy were investigated by a model‐free affected sib‐pair (ASP) method and two model‐based approaches in the Busselton nuclear families. Among the regions showing potential linkages to atopy by the ASP method, a significant excess of paternal allele sharing as compared with maternal allele sharing was observed for a cluster of three markers on chromosome 13. The two model‐based methods, which specify either sex‐specific recombination rates or different penetrances for heterozygotes according to the parental origin of disease allele (imprinting), led to the same results, both suggesting a paternal effect. Thus, these two ways of modelling parent‐of‐origin effects appear equivalent in nuclear family data. Further simulations arc needed to investigate whether the mechanisms underlying parent‐of‐origin effects can be distinguished in larger pedigree structures. © 2001 Wiley‐Liss, Inc.
Comparison of Sib Pair‐Based Approaches for Identifying Quantitative Trait Loci Underlying Asthma in the Busselton Families
Authors: Shugart Yin Y. , Specchia Claudia , Li Hui-Hua , Doan Betty Q. , Mathias Rasika A. , Devoto Marcella
Published: July 2017

The goal of this study is to determine the linkage relationship between IgE levels and the 269 microsatellite markers using the Genetic Analysis Workshop 12 Busselton data set. Analyses were carried out using both traditional and new Haseman‐Elston methods, the maximum likelihood quantitative trait locus estimation (MLE QTL) method and the nonparametric (NP QTL) method. Our analyses confirmed some of the signals reported by Daniels et al. [Nature 383:247–50, 1996]. We also observed that several significant signals reported in the original report became insignificant (D6S76 and D11S96) and several new signals showed up after the data were reanalyzed using the new Haseman‐Elston method, the MLE QTL method, and the NP QTL method. Based on the original and the current analyses, we recommend that follow‐up studies of three regions including D7S2250, FCER1B, D11S901, and six markers on chromosome 16 be given higher priority. © 2001 Wiley‐Liss, Inc.
A Bivariate Haseman‐Elston Method and Application to the Analysis of Asthma‐Related Phenotypes on Chromosome 5q
Authors: Ziegler Andreas , Böddeker Inke R. , Geller Frank
Published: July 2017

We propose a bivariate combination of different Haseman‐Elston (HE) methods for model free linkage analysis of quantitative traits. Adjustments for correlations of phenotypes and sibship sizes > 2 are performed using generalized estimating equations (GEE). All calculations are carried out with freely available software packages. We illustrate the application of standard HE methods, the unified HE method, and our novel approach to asthma‐associated quantitative traits from the COAG‐Perth data set [Palmer et al., 1998, Am J Respir Crit Care Med 158:1825–30]. Our multipoint analyses provide evidence for linkage between log IgE levels adjusted for age, gender and antigen‐specific IgE titers. Our results are consistent with previous findings that suggest the existence of loci regulating asthma‐associated quantitative traits in the 5q31–33 chromosomal region. Simulation studies are required to compare the power of our novel bivariate HE with other HE approaches and the variance component method. © 2001 Wiley‐Liss, Inc.
A Kinship Analysis of Asthma Among the Hutterites
Authors: Lin Jennifer , Hinrichs Anthony , Suarez Brian K.
Published: July 2017

A formal kinship analysis of asthma in a large Hutterite kindred indicates that cases are significantly more related to one another than are age matched controls. The higher kinship coefficient is shown to be due to an increased probability of the condensed identity state ∆8 which, in turn, is shown to be due to an increased probability of detailed identity state δ10. © 2001 Wiley‐Liss, Inc.
Genome‐Wide Approaches for Identifying Interacting Susceptibility Regions for Asthma
Authors: Colilla Susan , Tsalenko Anya , Pluznikov Anna , Cox Nancy J.
Published: July 2017

A genome‐wide correlation analysis and cluster analysis were utilized to determine chromosomal regions that had similar nonparametric linkage scores across families in order to locate interacting susceptibility loci for asthma. Conditional analysis was performed to detect any increase in lod score over baseline. Eight of the strongest 5% of the correlations in the German and CSGA asthma data sets occurred in both data sets. The strongest positive correlations found in both data sets were between the 200 cM region on chromosome 2 with chromosome 12 at 90–120 cM (r = 0.26) and also with chromosome 6 at 40–70 cM (r = 0.24). While the cluster analysis did not find any regions that clustered across data sets, this method did detect clustering in regions that have been previously linked to asthma. © 2001 Wiley‐Liss, Inc.
Two‐Trait‐Locus Linkage Analyses of Asthma Susceptibility
Authors: Nath Swapan K. , Chen Chien-Hsiun , Schork Nicholas J.
Published: July 2017

A genome‐wide search was conducted to identify chromosomal regions likely to harbor genes for asthma susceptibility. One hundred and twelve Caucasian families ascertained through a proband with a diagnosis of asthma by the Collaborative Study on the Genetics of Asthma (CSGA) were used for this search. Genotype data on 323 polymorphic markers were analyzed via parametric and nonparametric linkage analysis in an initial genome scan to identify potential asthma susceptibility region(s). The regions where hlod or nonparametric linkage scores were greater than 2.0 were selected for further investigation using two‐trait‐locus linkage analysis models. © 2001 Wiley‐Liss, Inc.
Oligogenic Approaches to the Predisposition of Asthma in Ethnically Diverse Populations
Authors: Stassen Hans H. , Scharfetter Christian
Published: July 2017

Using the genome‐wide screening data of the Collaborative Study on the Genetics of Asthma (CSGA) (226 families, 1,461 genotyped subjects, 323 marker loci) and Hutterite studies (129 families, 690 genotyped subjects, 365 marker loci), we applied a genetic similarity function in order to quantify the inter‐individual genetic distances d(xi,xj) between feature vectors xi, xj
made up by the allelic patterns of subjects i,,j with respect to loci l1, l2, ..., ln. Based on this similarity function, we structurally decomposed the genetic diversity of the CSGA population in order to address the question of ethnicity‐related asthma vulnerability for genetically homogenous CSGA subgroups. The question of ethnicity‐independent asthma vulnerability was investigated with all CSGA families as training and the Hutterite families as replication samples. We evaluated the between‐sib similarities, which were expected to deviate from “0.5” in affected sib pairs if the region of interest contained markers close to disease‐causing genes. The reference value 0.5 was derived by determining the parent‐offspring similarities, which are always 0.5, irrespective of the affection status of parents and offspring. We found 18 vulnerability loci on chromosomes 1, 3, 4, 5, 6, 8, 12, 13, and 14, which were remarkably reproducible in the CSGA and the Hutterite data and constituted an ethnicity‐independent oligogcnic model. © 2001 Wiley‐Liss, Inc.
Segregation Analysis of Asthma and Respiratory Allergy in Population‐Based Samples of Families
Authors: Schnell Audrey H. , Palmer Lyle J. , Elston Robert C.
Published: July 2017

Class A regressive multiple logistic segregation models with a sibling covariate were used to investigate the underlying determinants of asthma and respiratory allergy (defined from specific IgE levels to inhaled allergens) in the randomly recruited Caucasian families from the Genetic Analysis Workshop 12 asthma data sets — Perth, Busselton, and Southampton. For asthma, both a purely multifactorial model and a major gene (dominant or recessive) model with multifactorial effects fitted the data. For respiratory allergy, a dominant, dominant with multifactorial effects and a purely multifactorial model all fitted the data. However, homogeneity of the three studies was rejected for both traits indicating that the three populations are significantly different and should be analyzed separately. This finding has implications for the meta‐analysis of asthma linkage studies. © 2001 Wiley‐Liss, Inc.
Genome Scan for Linkage to Asthma Using a Linkage Disequilibrium‐lod Score Test
Authors: Jiang Yanming , Sleger Susan L. , Huang Jian
Published: July 2017

We report a genome‐wide linkage study of asthma on the German and Collaborative Study on the Genetics of Asthma (CSGA) data. Using a combined linkage and linkage disequilibrium test and the nonparametric linkage score, we identified 13 markers from the German data, 1 marker from the African American (CSGA) data, and 7 markers from the Caucasian (CSGA) data in which the p‐values ranged between 0.0001 and 0.0100. From our analysis and taking into account previous published linkage studies of asthma, we suggest that three regions in chromosome 5 (around D5S418, D5S644, and D5S422), one region in chromosome 6 (around three neighboring markers D6S1281, D6S291, and D6S1019), one region in chromosome 11 (around D11S2362), and two regions in chromosome 12 (around D12S351 and D12S324) especially merit further investigation. © 2001 Wiley‐Liss, Inc.
Haplotype Sharing Tests of Linkage Disequilibrium in a Hutterite Asthma Data Set
Authors: Levinson Douglas F. , Nolte Ilja , te Meerman Gerard J.
Published: July 2017

The Genetic Analysis Workshop 12 genome scan data set for “strict” asthma in a Hutterite population was analyzed using haplotype sharing analysis (HSA), which tests for differences in mean length of haplotype sharing around each marker for pairs of chromosomes in cases versus controls. The regions of chromosome 1 and 8 where evidence for linkage was observed in published analyses were negative by HSA. HSA yielded positive results on chromosomes 7, 12, 16, 18, and 21 (p = 0.003 on 21q). Although there are reports of support for linkage to asthma in some of these regions, it is not known whether any represent true positives. Further study is needed of the possible role of length‐based measures of linkage disequilibrium in recent population isolates. © 2001 Wiley‐Liss, Inc.
Comparison of the QTDT Analysis for IgE in the CSGA Data Set
Authors: Page Grier P. , Wilcox Marsha A. , Occhiuto Jane , Adak Sudeshna , Neuberg Donna , Bajorunaite Ruta , George Varghese
Published: July 2017

Over the past few years at least 13 transmission/disequilibrium test (TDT)‐based tests have been developed for quantitative (Q) traits for the assessment of association or linkage in the presence of the other. A total of six of these QTDT methods were used to analyze log10IgE in the Collaborative Study on the Genetics of Asthma data set. Only moderate agreement was found between the tests. The results of the QTDT analyses were only slightly affected by the use of gender and age as covariates. Results from analysis of IgE and log10IgE were inconsistent. Our conclusion is that there is only modest agreement among the QTDT methods examined, covariates should be used even if they have a small effect, and that data should be normalized before analysis. © 2001 Wiley‐Liss, Inc.
Evolution of the Simulated Data Problem
Authors: Thomas Duncan C. , Borecki Ingrid B. , Thomson Glenys , Weiss Ken , Almasy Laura , Blangero John , Nielsen Dahlia , Terwilliger Joseph , Zaykin Dmitri , MacCluer Jean
Published: July 2017

The simulated data problem was designed via an interactive process by the Simulation Problem Organizing Committee and the selected data simulators. Based on discussions at the previous Genetic Analysis Workshop, many of the features of previous simulation problems, such as a complex disease, genome scan, and replication, were retained and in addition, a population genetics model was used to generate the simulated genes. We describe the process that was used to structure the problem and summarize the discussions about many of the scientific issues that were considered. © 2001 Wiley‐Liss, Inc.
GAW12: Simulated Genome Scan, Sequence, and Family Data for a Common Disease
Authors: Almasy Laura , Terwilliger Joseph D. , Nielsen Dahlia , Dyer Thomas D. , Zaykin Dmitri , Blangero John
Published: July 2017

The Genetic Analysis Workshop (GAW) 12 simulated data involves a common disease defined by imposing a threshold on a quantitative liability distribution. Associated with the disease are five quantitative risk factors, a quantitative environmental exposure, and a dichotomous environmental variable. Age at disease onset and household membership were also simulated. Genotype data, including 2,855 microsatellites on 22 autosomes, were simulated for 1,497 individuals in 23 families. Phenotype data and sequence data for seven candidate genes were provided for 1,000 of these indiviudals who were “living” and available for study. Data were simulated for 50 replicate samples in each of two populations, a general population and a population isolate formed from a small group of founders. © 2001 Wiley‐Liss, Inc.
Detection of Misspecified Relationships in Inbred and Outbred Pedigrees
Authors: Sun Lei , Abney Mark , McPeek Mary Sara
Published: July 2017

Genome screen data collected for linkage analysis can be used to detect pedigree errors. We have developed methods applicable to a broad range of relationships. We discuss applications of our methods to data on asthma, in which we detect a number of likely misspecified relative pairs. We propose a graphical method for error detection in complex inbred pedigrees, with application to the Hutterites. © 2001 Wiley‐Liss, Inc.
Comparison of Novel and Existing Methods for Detection of Linkage Disequilibrium Using Parent‐Child Trios in the GAW12 Genetic Isolate Simulated Data
Authors: Bailey-Wilson J.E. , Sorant A.J.M. , Malley J.D. , Presciuttini S. , Redner R.A. , Severini T.A. , Badner J.A. , Pajevic S. , Jufer R. , Baffoe-Bonnie A. , Kao L. , Doan B.Q. , Goldstein J.L. , Holmes T.N. , Behneman D. , Mandal D.M. , Turley T.N. , Weissbecker K.A. , O'Neill J. , Pugh E.W.
Published: July 2017

A novel method for joint detection of association caused by linkage disequilibrium (LD) and estimation of both recombination fraction and linkage disequilibrium parameters was compared to several existing implementations of the transmission/disequilibrium test (TDT) and modifications of the TDT in the simulated genetic isolate data from Genetic Analysis Workshop 12. The first completely genotyped trio of affected child and parents was selected from each family in each replicate so that the TDT tests are valid tests of linkage and association, rather than being only valid as tests for linkage. In general, power to detect LD using the genome‐wide scan markers was inadequate in the individual replicate samples, but the power was better when analyzing several SNP markers in candidate gene 1. © 2001 Wiley‐Liss, Inc.
Preliminary Implementation of New Data Mining Techniques for the Analysis of Simulation Data from Genetic Analysis Workshop 12: Problem 2
Authors: Flodman Pamela , Macula Anthony J. , Spence M. Anne , Torney David C.
Published: July 2017

We introduce a new data mining method applicable to complex disease genetics. Our approach is suited to a broad spectrum of diseases, identifying the noteworthy sharing of combinations of alleles in unrelated affected individuals. Furthermore, this approach may be extended to comprise the common types of genotype data, including single‐nucleotide polymorphisms, candidate‐gene sequences, etc. Using a method derived from data‐mining computer algorithms, we analyze a data set of unrelated affected individuals chosen from the simulated pedigrees of problem 2 of the Genetics Analysis Workshop 12. We observe that most marker subsets containing a flanking marker for each of six or seven of the disease‐gene loci yield significant numbers of individuals manifesting substantially similar genotypes. However, initial attempts (blind to the generating model) to identify the predisposing loci have not been successful. Refining our methods so that such loci may routinely be found and validated is underway. © 2001 Wiley‐Liss, Inc.
Description of Three Data Sets: Collaborative Study on the Genetics of Asthma (CSGA), the German Affected‐Sib‐Pair Study, and the Hutterites of South Dakota
Authors: Meyers Deborah A. , Wjst Mathias , Ober Carole
Published: July 2017

Three different data sets with clinical data and markers from genome‐wide screens were submitted for analysis at Genetic Analysis Workshop 12. In each study, participants were carefully characterized for asthma and related phenotypes. Testing for bronchial hyper‐responsiveness using methacholine and standardized protocols was performed. Total serum IgE levels were measured using standardized techniques. In addition, similar questionnaire data on symptoms and relevant environmental exposures were obtained. Relevant clinical data and genotypes for the polymorphic markers used for each genome‐wide screen were submitted. The data set from the United States Collaborative Study on the Genetics of Asthma represents a heterogeneous population consisting of both Caucasian and African American families ascertained through two siblings with clinical asthma from multiple centers. Likewise, the families from the German Asthma Genetics Group were also ascertained through two siblings with asthma at multiple centers. In a contrast to these data sets, Dr. Carole Ober and her collaborators submitted data from the inbred Hutterite population in South Dakota. © 2001 Wiley‐Liss, Inc.
Identifying Susceptibility Genes Using Linkage and Linkage Disequilibrium Analysis in Large Pedigrees
Authors: Meng Zhaoling , Zaykin Dmitri V. , Karnoub Maha C. , Sreekumar G.P. , St. Jean Pamela L. , Ehm Margaret G.
Published: July 2017

Linkage and linkage disequilibrium tests are powerful tools for mapping complex disease genes. We investigated two approaches to identifying markers associated with disease. One method applied linkage analysis and then linkage disequilibrium tests to markers within linked regions. The other method looked for linkage disequilibrium with disease using all markers. Additionally, we investigated using Simes’ test to combine p‐values from linkage disequilibrium tests for nearby markers. We applied both approaches to all replicates of the Genetic Analysis Workshop 12 problem 2 isolated population data set. We reported results from the 25th replicate as if it were a real problem and assessed the power of our methods using all replicates. Using all replicates, we found that testing all markers for linkage disequilibrium with disease was more powerful than identifying markers that were in linkage with disease and then testing markers within those regions for linkage disequilibrium with the implementations that we chose. Using Simes’ test to combine p‐values for linkage disequilibrium tests on correlated markers seemed to be of marginal value. © 2001 Wiley‐Liss, Inc.
The Use of Sequential Designs in Genome Scans for Asthma Susceptibility Loci With Affected Sib Pairs
Authors: Böddeker Inke R. , Müller Hans-Helge , Kreβ Ralf , Geller Frank , Ziegler Andreas , Schäfer Helmut
Published: July 2017

We use optimized group sequential study designs to analyze data from two genome scans (German and CSGA) for asthma susceptibility loci with affected sib pairs from Genetic Analysis Workshop (GAW) 12. Results are compared with those from a fixed sample design and the sequential probability ratio test (SPRT). The SPRT does not reach significance at any position. Using the fixed sample design, evidence for linkage is found on chromosomes 6 and 9 in the German and on chromosome 1 in the CSGA scan. The group sequential designs identify the same regions on chromosomes 1 and 6 with a reduced sample size. © 2001 Wiley‐Liss, Inc.
Model‐Free Linkage Analysis: Performance Under Real‐World Conditions
Authors: Barmada M.M. , O'Connell J.R.
Published: July 2017

The simulated data of the Genetic Analysis Workshop 12 problem set affords an ideal environment for testing real‐world performance of model‐free linkage analysis methods. To this end, we applied three different methods of model‐free linkage analysis: mod scores [Hodge and Elston, Genet Epidemiol 11:329–42, 1994], maximized maximum lod score (MMLS) [Greenberg et al., Am J Hum Genet 63:870–9, 1998], and nonparametric linkage (NPL) scores [Whittemore and Halpern, Biometrics 50:118–27, 1994], as well as standard parametric linkage analysis to the detection of major gene 6 (MG6) using only the qualitative disease status data. Our results indicate that both mod scores and NPL scores perform well, even in the presence of an extremely complicated disease model. MMLS analysis did not perform well, except at the disease locus itself. © 2001 Wiley‐Liss, Inc.
Locating the Genes Underlying a Simulated Complex Disease by Discriminant Analysis
Authors: Li Xia , Rao Shaoqi , Elston Robert C. , Olson Jane M. , Moser Kathy L. , Zhang Tianwen , Guo Zheng
Published: July 2017

The purpose of this study was to propose and evaluate a novel multivariate approach for genetic mapping of complex binary human diseases. This approach uses the application of either of two methods of standard (stepwise) discriminant analysis to detect linkage based on the differential marker identity‐by‐descent distributions among the three affection groups of sib pairs (concordantly affected, discordant, and concordantly unaffected). One of the advantages of this approach is that it allows for simultaneously testing all markers, as well as other genetic and environmental factors, in a single multivariate setting. We have explored its properties and behaviors via an application to the simulated data in Genetic Analysis Workshop 12. © 2001 Wiley‐Liss, Inc.
To Type or Not To Type: The Use of Unaffected Siblings in Nonparametric Linkage Analysis
Authors: Majewski Jacek
Published: July 2017

Unaffected individuals are often disregarded in nonparametric linkage analysis. Because of the presumed high complexity of genetic interactions and the resulting low penetrance of any single genetic effect, the statistical contribution of unaffected sib pairs is thought to be considerably lower than that of the affecteds. However, in cases where a large number of unaffected family members are available for genotyping — as is the case in the simulated Genetic Analysis Workshop 12 data set — the relatively low value of the unaffected sibs may be offset by their number. In this paper, I demonstrate that unaffected siblings do contain a significant amount of statistical information, and show that the most powerful method of nonparametric analysis utilizes both affected and unaffected individuals. I also show that selecting the unaffected individuals based on their age is the most cost effective and usually the most powerful strategy. © 2001 Wiley‐Liss, Inc.
Parametric Linkage Analysis and Disequilibrium Methods to Identify Loci for Complex Disease
Authors: McClintick Jeanette , Koller Daniel L. , Pankratz Nathan , Kirkwood Sandra C. , Naughton Brian , Foroud Tatiana
Published: July 2017

A two‐step process was used to find loci contributing to the qualitative disease phenotype in the Genetic Analysis Workshop (GAW) 12 simulated data. The first step used parametric linkage analysis with a limited number of dominant and recessive models to detect linkage to chromosomal regions. Subsequently, a subset of the simulated biallelic sequence polymorphisms was used for transmission/disequilibrium tests and to build haplotypes to fine map the disease‐predisposing polymorphism(s). A haplotype, strongly associated with the disease phenotype whose proximal end was within 39 base pairs of the functional allele for simulated major gene 6, was identified in the isolated population. © 2001 Wiley‐Liss, Inc.
Linkage Disequilibrium Mapping of Complex Genetic Diseases Using Multiallelic Markers
Authors: Houwing-Duistermaat Jeanine J. , Elston Robert C.
Published: July 2017

Various measures of allelic association are proposed and applied to affection status and markers in the region of major gene 6. The performance of the measures arc compared in bias and efficiency to estimate the location of major gene 6. Since the aim is to find disease specific genes, corrections for covariates and environmental factors are made. Furthermore, all the measures allow for more than one allele to be associated with the trait. The location of the disease gene is estimated by fitting a quadratic curve with allelic association as dependent and the position of the marker as independent variable. Confidence intervals are obtained by applying Fieller's theorem. Two of the three proposed measures succeeded in finding the true position of gene 6. Since this is a fine mapping approach, we asked for the answers. © 2001 Wiley‐Liss, Inc.
Clustering of Pedigrees Using Marker Allele Frequencies: Impact on Linkage Analysis
Authors: Grigull Joerg , Alexandrova Roumiana , Paterson Andrew D.
Published: July 2017

Ethnicity may form the basis for locus heterogeneity at certain susceptibility loci for complex diseases. Classification of pedigrees into ethnic groups is usually based upon self‐report, but this may not be sensitive or specific. We investigated whether it is possible to cluster families from an admixed population using pedigree‐specific marker allele frequencies. We used 323 autosomal microsatellite markers from 216 pedigrees who described themselves as either Caucasian or African American. First, we compared the stated ethnicity of pedigrees with clusters using pedigree‐specific marker allele frequencies as input for a self‐organizing map, a type of neural network. Using data from different chromosomes, nine pedigrees which were self‐reported as African American were clustered with the Caucasian pedigrees. Removal of these nine pedigrees from the African American group did not markedly affect linkage results. We then proceeded to determine whether there was further heterogeneity between pedigrees using 1 x 3 nodes. Forty‐four pedigrees were clustered in a group intermediate to the African American or Caucasian clusters. This group was composed of 36 and 8 pedigrees that described themselves as African American and Caucasian, respectively. Linkage analysis was performed in this group and results compared with the groups based upon self‐reported ethnicity. Linkage to a region on chromosome 3 was observed in this intermediate group, which was more significant than any of the results obtained when pedigrees were grouped using self‐reported ethnicity. Use of marker data may assist in clustering pedigrees with similar ethnic backgrounds and may increase the power for genetic linkage studies. © 2001 Wiley‐Liss, Inc.
The Power of Transmission Disequilibrium Tests for Quantitative Traits
Authors: Li Jinming , Wang Dai , Dong Jianping , Jiang Renfang , Zhang Kui , Zhang Shuanglin , Zhao Hongyu , Sun Fengzhu
Published: July 2017

We develop a score statistic to test for linkage in the presence of linkage disequilibrium for quantitative traits. We then extend this method to analyze multiple tightly linked markers. One potential limitation with the use of many genetic markers is the large number of degrees of freedom involved that may reduce the overall power to detect linkage. To overcome this limitation, we propose to group haplotypes on the basis of haplotype similarity before performing transmission disequilibrium tests. Finally, we apply these methods to the Genetic Analysis Workshop 12 simulated data and compare their power. © 2001 Wiley‐Liss, Inc.
SNPing Away at Candidate Genes
Authors: Suchard Marc A. , Bailey Julia N. , Elashoff David A. , Sinsheimer Janet S.
Published: July 2017

We develop regression methodology to identify subsets of single nucleotide polymorphisms (SNPs) within candidate genes related to quantitative traits and apply our methods to the simulated Genetic Analysis Workshop (GAW) 12 data set. In the data set we find 694 SNP loci with minimum allele frequencies of at least 0.01. We assume an additive casual model between these SNPs and all five quantitative traits. After initial screening using one‐way analysis of variance, we employ a computationally efficient, simulated annealing algorithm to select among all possible subsets of SNP loci, using a generalization of Mallows’ Cp as our optimality criterion. The simple transition kernel we develop evaluates new subsets in O(1), by requiring just three arithmetic operations to calculate the proposed RSS based on the Gauss‐Jordan pivot. We identify an SNP loci located at 6–5782 related to traits 2 and 3 and several sites on gene 2 related to trait 5 using a subsample of 1,000 individuals and the full data set (n = 8,250) for comparison. © 2001 Wiley‐Liss, Inc.
Common Disease Analysis Using Multivariate Adaptive Regression Splines (MARS): Genetic Analysis Workshop 12 Simulated Sequence Data
Authors: York Timothy P. , Eaves Lindon J.
Published: July 2017

A newly developed modern analytic approach, Multivariate Adaptive Regression Splines (MARS), was used to identify both genetic and non‐genetic factors involved in the etiology of a common disease. We tested this method on the simulated data provided by the Genetic Analysis Workshop (GAW) 12 in problem 2 for the isolated population. MARS simultaneously analyzes all inputs, in this case DNA sequence variants and non‐genetic data, and selectively prunes away variables contributing insignificantly to fit by internal cross‐validation to arrive at a generalizable predictive model of the response. The relevant factors identified, by means of an importance value computed by MARS, were assumed to be associated with risk to the disease. The application of a series of subsequent models identified the quantitative traits and a single major gene contributing directly to risk liability using five sets of 7,000 individuals. © 2001 Wiley‐Liss, Inc.
Population Based Linkage Disequilibrium Mapping of QTL: An Application to Simulated Data in an Isolated Population
Authors: Zhao Jinying , Li Wuju , Xiong Momiao
Published: July 2017

Despite successes in mapping and cloning genes involved in rare Mendelian diseases, genetic dissection of quantitative traits into single Mendelian factors still remains a challenging task. As the dense map of single nucleotide polymorphism (SNP) markers becomes available in the near future, linkage disequilibrium (LD) mapping will become one of major tools for mapping and identifying quantitative trait loci (QTL). In this report, we present a population‐based linkage disequilibrium mapping of QTL. This method unifies the analysis of mapping QTL in humans and in model organisms and can be used for randomly sampled individuals. The proposed method is applied to search for polymorphism sites within the candidate genes 2 and 6, which influence quantitative traits Q1 and Q2 or Q5, in a simulated data set in an isolated population. © 2001 Wiley‐Liss, Inc.