Dynamic analysis of six-bar mechanical press for deep drawing

NASA Astrophysics Data System (ADS)

Mitsi, S.; Tsiafis, I.; Bouzakis, K. D.

2017-02-01

This paper analyzes the dynamical behavior of a six-bar linkage used in mechanical presses for metal forming such as deep drawing. In the under study mechanism, a four-bar linkage is connected to a slider through an articulated binary link. The motion of the six-bar linkage is studied by kinematic analysis developing an analytical method. Furthermore, using an iterative method and d’ Alembert’s principle, the joint forces and drive moment are evaluated considering joint frictions. The simulation results obtained with a MATLAB program are validated by comparing the theoretical values of the input moment with the ones obtained from the conservation of energy law.

Potential linkage for schizophrenia on chromosome 22q12-q13: A replication study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwab, S.G.; Bondy, B.; Wildenauer, D.B.

1995-10-09

In an attempt to replicate a potential linkage on chromosome 22q12-q13.1 reported by Pulver et al., we have analyzed 4 microsatellite markers which span this chromosomal region, including the IL2RB locus, for linkage with schizophrenia in 30 families from Israel and Germany. Linkage analysis by pairwise lod score analysis as well as by multipoint analysis did not provide evidence for a single major gene locus. However, a lod score of Z{sub max} = 0.612 was obtained for a dominant model of inheritance with the marker D22S304 at recombination fraction 0.2 by pairwise analysis. In addition, using a nonparametric method, sibmore » pair analysis, a P value of 0.068 corresponding to a lod score of 0.48 was obtained for this marker. This finding, together with those of Pulver et al., is suggestive of a genetic factor in this region, predisposing for schizophrenia in a subset of families. Further studies using nonparametric methods should be conducted in order to clarify this point. 32 refs., 1 fig., 4 tabs.« less

Construction of high-quality recombination maps with low-coverage genomic sequencing for joint linkage analysis in maize

USDA-ARS?s Scientific Manuscript database

A genome-wide association study (GWAS) is the foremost strategy used for finding genes that control human diseases and agriculturally important traits, but it often reports false positives. In contrast, its complementary method, linkage analysis, provides direct genetic confirmation, but with limite...

Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses.

PubMed

Yan, Liying; Huang, Lei; Xu, Liya; Huang, Jin; Ma, Fei; Zhu, Xiaohui; Tang, Yaqiong; Liu, Mingshan; Lian, Ying; Liu, Ping; Li, Rong; Lu, Sijia; Tang, Fuchou; Qiao, Jie; Xie, X Sunney

2015-12-29

In vitro fertilization (IVF), preimplantation genetic diagnosis (PGD), and preimplantation genetic screening (PGS) help patients to select embryos free of monogenic diseases and aneuploidy (chromosome abnormality). Next-generation sequencing (NGS) methods, while experiencing a rapid cost reduction, have improved the precision of PGD/PGS. However, the precision of PGD has been limited by the false-positive and false-negative single-nucleotide variations (SNVs), which are not acceptable in IVF and can be circumvented by linkage analyses, such as short tandem repeats or karyomapping. It is noteworthy that existing methods of detecting SNV/copy number variation (CNV) and linkage analysis often require separate procedures for the same embryo. Here we report an NGS-based PGD/PGS procedure that can simultaneously detect a single-gene disorder and aneuploidy and is capable of linkage analysis in a cost-effective way. This method, called "mutated allele revealed by sequencing with aneuploidy and linkage analyses" (MARSALA), involves multiple annealing and looping-based amplification cycles (MALBAC) for single-cell whole-genome amplification. Aneuploidy is determined by CNVs, whereas SNVs associated with the monogenic diseases are detected by PCR amplification of the MALBAC product. The false-positive and -negative SNVs are avoided by an NGS-based linkage analysis. Two healthy babies, free of the monogenic diseases of their parents, were born after such embryo selection. The monogenic diseases originated from a single base mutation on the autosome and the X-chromosome of the disease-carrying father and mother, respectively.

The score statistic of the LD-lod analysis: detecting linkage adaptive to linkage disequilibrium.

PubMed

Huang, J; Jiang, Y

2001-01-01

We study the properties of a modified lod score method for testing linkage that incorporates linkage disequilibrium (LD-lod). By examination of its score statistic, we show that the LD-lod score method adaptively combines two sources of information: (a) the IBD sharing score which is informative for linkage regardless of the existence of LD and (b) the contrast between allele-specific IBD sharing scores which is informative for linkage only in the presence of LD. We also consider the connection between the LD-lod score method and the transmission-disequilibrium test (TDT) for triad data and the mean test for affected sib pair (ASP) data. We show that, for triad data, the recessive LD-lod test is asymptotically equivalent to the TDT; and for ASP data, it is an adaptive combination of the TDT and the ASP mean test. We demonstrate that the LD-lod score method has relatively good statistical efficiency in comparison with the ASP mean test and the TDT for a broad range of LD and the genetic models considered in this report. Therefore, the LD-lod score method is an interesting approach for detecting linkage when the extent of LD is unknown, such as in a genome-wide screen with a dense set of genetic markers. Copyright 2001 S. Karger AG, Basel

Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder.

PubMed

Le Hellard, Stephanie; Lee, Andrew J; Underwood, Sarah; Thomson, Pippa A; Morris, Stewart W; Torrance, Helen S; Anderson, Susan M; Adams, Richard R; Navarro, Pau; Christoforou, Andrea; Houlihan, Lorna M; Detera-Wadleigh, Sevilla; Owen, Michael J; Asherson, Philip; Muir, Walter J; Blackwood, Douglas H R; Wray, Naomi R; Porteous, David J; Evans, Kathryn L

2007-03-15

Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.

Robust LOD scores for variance component-based linkage analysis.

PubMed

Blangero, J; Williams, J T; Almasy, L

2000-01-01

The variance component method is now widely used for linkage analysis of quantitative traits. Although this approach offers many advantages, the importance of the underlying assumption of multivariate normality of the trait distribution within pedigrees has not been studied extensively. Simulation studies have shown that traits with leptokurtic distributions yield linkage test statistics that exhibit excessive Type I error when analyzed naively. We derive analytical formulae relating the deviation from the expected asymptotic distribution of the lod score to the kurtosis and total heritability of the quantitative trait. A simple correction constant yields a robust lod score for any deviation from normality and for any pedigree structure, and effectively eliminates the problem of inflated Type I error due to misspecification of the underlying probability model in variance component-based linkage analysis.

Search for a schizophrenia susceptibility locus of human chromosome 22

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coon, H.; Hoff, M.; Holik, J.

1994-06-15

We used 10 highly informative DNA polymorphic markers and genetic linkage analysis to examine whether a gene locus predisposing to schizophrenia is located on chromosome 22, in 105 families with schizophrenia and schizoaffective disorder. The LOD score method, including analysis for heterogeneity, provided no conclusive evidence of linkage under a dominant, recessive, or penetrance free model of inheritance. Affected sib-pair analysis was inconclusive. Affected Pedigree Member (APM) analysis gave only suggestive evidence for linkage. Multipoint APM analysis, using 4 adjacent loci including D22S281 and IL2RB, a region of interest from the APM analysis, gave non-significant results for the three differentmore » weighting functions. 18 refs., 1 fig., 7 tabs.« less

The lod score method.

PubMed

Rice, J P; Saccone, N L; Corbett, J

2001-01-01

The lod score method originated in a seminal article by Newton Morton in 1955. The method is broadly concerned with issues of power and the posterior probability of linkage, ensuring that a reported linkage has a high probability of being a true linkage. In addition, the method is sequential, so that pedigrees or lod curves may be combined from published reports to pool data for analysis. This approach has been remarkably successful for 50 years in identifying disease genes for Mendelian disorders. After discussing these issues, we consider the situation for complex disorders, where the maximum lod score (MLS) statistic shares some of the advantages of the traditional lod score approach but is limited by unknown power and the lack of sharing of the primary data needed to optimally combine analytic results. We may still learn from the lod score method as we explore new methods in molecular biology and genetic analysis to utilize the complete human DNA sequence and the cataloging of all human genes.

Identification of Sialic Acid Linkages on Intact Glycopeptides via Differential Chemical Modification Using IntactGIG-HILIC

NASA Astrophysics Data System (ADS)

Yang, Shuang; Wu, Wells W.; Shen, Rong-Fong; Bern, Marshall; Cipollo, John

2018-04-01

Mass spectrometric analysis of intact glycopeptides can reveal detailed information about glycosite, glycan structural features, and their heterogeneity. Sialyl glycopeptides can be positively, negatively, or neutrally charged depending on pH of their buffer solution and ionization conditions. To detect sialoglycopeptides, a negative-ion mode mass spectrometry may be applied with a minimal loss of sialic acids, although the positively charged or neutral glycopeptides may be excluded. Alternatively, the sialyl glycopeptides can be identified using positive-ion mode analysis by doping a high concentration of sodium salts to the analytes. Although manipulation of unmodified sialoglycopeptides can be useful for analysis of samples, less than optimal ionization, facile loss of sialyl and unfavorable ionization of accompanying non-sialyl peptides make such strategies suboptimal. Currently available chemical derivatization methods, while stabilizing for sialic acid, mask sialic acid linkage configuration. Here, we report the development of a novel approach to neutralize sialic acids via sequentially chemical modification that also reveals their linkage configuration, often an important determinant in biological function. This method utilizes several components to facilitate glycopeptide identification. These include the following: solid phase derivatization, enhanced ionization of sialoglycopeptides, differentiation of sialic acid linkage, and enrichment of the modified glycopeptides by hydrophilic interaction liquid chromatography. This technology can be used as a tool for quantitative analysis of protein sialylation in diseases with determination of sialic acid linkage configuration. [Figure not available: see fulltext.

Does probabilistic modelling of linkage disequilibrium evolution improve the accuracy of QTL location in animal pedigree?

PubMed

Cierco-Ayrolles, Christine; Dejean, Sébastien; Legarra, Andrés; Gilbert, Hélène; Druet, Tom; Ytournel, Florence; Estivals, Delphine; Oumouhou, Naïma; Mangin, Brigitte

2010-10-22

Since 2001, the use of more and more dense maps has made researchers aware that combining linkage and linkage disequilibrium enhances the feasibility of fine-mapping genes of interest. So, various method types have been derived to include concepts of population genetics in the analyses. One major drawback of many of these methods is their computational cost, which is very significant when many markers are considered. Recent advances in technology, such as SNP genotyping, have made it possible to deal with huge amount of data. Thus the challenge that remains is to find accurate and efficient methods that are not too time consuming. The study reported here specifically focuses on the half-sib family animal design. Our objective was to determine whether modelling of linkage disequilibrium evolution improved the mapping accuracy of a quantitative trait locus of agricultural interest in these populations. We compared two methods of fine-mapping. The first one was an association analysis. In this method, we did not model linkage disequilibrium evolution. Therefore, the modelling of the evolution of linkage disequilibrium was a deterministic process; it was complete at time 0 and remained complete during the following generations. In the second method, the modelling of the evolution of population allele frequencies was derived from a Wright-Fisher model. We simulated a wide range of scenarios adapted to animal populations and compared these two methods for each scenario. Our results indicated that the improvement produced by probabilistic modelling of linkage disequilibrium evolution was not significant. Both methods led to similar results concerning the location accuracy of quantitative trait loci which appeared to be mainly improved by using four flanking markers instead of two. Therefore, in animal half-sib designs, modelling linkage disequilibrium evolution using a Wright-Fisher model does not significantly improve the accuracy of the QTL location when compared to a simpler method assuming complete and constant linkage between the QTL and the marker alleles. Finally, given the high marker density available nowadays, the simpler method should be preferred as it gives accurate results in a reasonable computing time.

Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Escamilla, M.A.; Reus, V.I.; Smith, L.B.

1996-05-31

Linkage disequilibrium (LD) analysis provides a powerful means for screening the genome to map the location of disease genes, such as those for bipolar disorder (BP). As described in this paper, the population of the Central Valley of Costa Rica, which is descended from a small number of founders, should be suitable for LD mapping; this assertion is supported by reconstruction of extended haplotypes shared by distantly related individuals in this population suffering low-frequency hearing loss (LFHL1), which has previously been mapped by linkage analysis. A sampling strategy is described for applying LD methods to map genes for BP, andmore » clinical and demographic characteristics of an initially collected sample are discussed. This sample will provide a complement to a previously collected set of Costa Rican BP families which is under investigation using standard linkage analysis. 42 refs., 4 figs., 2 tabs.« less

Can statistical linkage of missing variables reduce bias in treatment effect estimates in comparative effectiveness research studies?

PubMed

Crown, William; Chang, Jessica; Olson, Melvin; Kahler, Kristijan; Swindle, Jason; Buzinec, Paul; Shah, Nilay; Borah, Bijan

2015-09-01

Missing data, particularly missing variables, can create serious analytic challenges in observational comparative effectiveness research studies. Statistical linkage of datasets is a potential method for incorporating missing variables. Prior studies have focused upon the bias introduced by imperfect linkage. This analysis uses a case study of hepatitis C patients to estimate the net effect of statistical linkage on bias, also accounting for the potential reduction in missing variable bias. The results show that statistical linkage can reduce bias while also enabling parameter estimates to be obtained for the formerly missing variables. The usefulness of statistical linkage will vary depending upon the strength of the correlations of the missing variables with the treatment variable, as well as the outcome variable of interest.

Major strengths and weaknesses of the lod score method.

PubMed

Ott, J

2001-01-01

Strengths and weaknesses of the lod score method for human genetic linkage analysis are discussed. The main weakness is its requirement for the specification of a detailed inheritance model for the trait. Various strengths are identified. For example, the lod score (likelihood) method has optimality properties when the trait to be studied is known to follow a Mendelian mode of inheritance. The ELOD is a useful measure for information content of the data. The lod score method can emulate various "nonparametric" methods, and this emulation is equivalent to the nonparametric methods. Finally, the possibility of building errors into the analysis will prove to be essential for the large amount of linkage and disequilibrium data expected in the near future.

Data Linkage: A powerful research tool with potential problems

PubMed Central

2010-01-01

Background Policy makers, clinicians and researchers are demonstrating increasing interest in using data linked from multiple sources to support measurement of clinical performance and patient health outcomes. However, the utility of data linkage may be compromised by sub-optimal or incomplete linkage, leading to systematic bias. In this study, we synthesize the evidence identifying participant or population characteristics that can influence the validity and completeness of data linkage and may be associated with systematic bias in reported outcomes. Methods A narrative review, using structured search methods was undertaken. Key words "data linkage" and Mesh term "medical record linkage" were applied to Medline, EMBASE and CINAHL databases between 1991 and 2007. Abstract inclusion criteria were; the article attempted an empirical evaluation of methodological issues relating to data linkage and reported on patient characteristics, the study design included analysis of matched versus unmatched records, and the report was in English. Included articles were grouped thematically according to patient characteristics that were compared between matched and unmatched records. Results The search identified 1810 articles of which 33 (1.8%) met inclusion criteria. There was marked heterogeneity in study methods and factors investigated. Characteristics that were unevenly distributed among matched and unmatched records were; age (72% of studies), sex (50% of studies), race (64% of studies), geographical/hospital site (93% of studies), socio-economic status (82% of studies) and health status (72% of studies). Conclusion A number of relevant patient or population factors may be associated with incomplete data linkage resulting in systematic bias in reported clinical outcomes. Readers should consider these factors in interpreting the reported results of data linkage studies. PMID:21176171

Joint QTL linkage mapping for multiple-cross mating design sharing one common parent

USDA-ARS?s Scientific Manuscript database

Nested association mapping (NAM) is a novel genetic mating design that combines the advantages of linkage analysis and association mapping. This design provides opportunities to study the inheritance of complex traits, but also requires more advanced statistical methods. In this paper, we present th...

How Is Wilson Disease Inherited?

MedlinePlus

... ATP7B gene have been identified thus far. Testing Methods Available Linkage analysis (Haplotype analysis) Molecular genetic testing ... genetic counselor who can carefully discuss the best method of testing to perform and the benefits, limitations, ...

MCMC multilocus lod scores: application of a new approach.

PubMed

George, Andrew W; Wijsman, Ellen M; Thompson, Elizabeth A

2005-01-01

On extended pedigrees with extensive missing data, the calculation of multilocus likelihoods for linkage analysis is often beyond the computational bounds of exact methods. Growing interest therefore surrounds the implementation of Monte Carlo estimation methods. In this paper, we demonstrate the speed and accuracy of a new Markov chain Monte Carlo method for the estimation of linkage likelihoods through an analysis of real data from a study of early-onset Alzheimer's disease. For those data sets where comparison with exact analysis is possible, we achieved up to a 100-fold increase in speed. Our approach is implemented in the program lm_bayes within the framework of the freely available MORGAN 2.6 package for Monte Carlo genetic analysis (http://www.stat.washington.edu/thompson/Genepi/MORGAN/Morgan.shtml).

Markov chain Monte Carlo linkage analysis: effect of bin width on the probability of linkage.

PubMed

Slager, S L; Juo, S H; Durner, M; Hodge, S E

2001-01-01

We analyzed part of the Genetic Analysis Workshop (GAW) 12 simulated data using Monte Carlo Markov chain (MCMC) methods that are implemented in the computer program Loki. The MCMC method reports the "probability of linkage" (PL) across the chromosomal regions of interest. The point of maximum PL can then be taken as a "location estimate" for the location of the quantitative trait locus (QTL). However, Loki does not provide a formal statistical test of linkage. In this paper, we explore how the bin width used in the calculations affects the max PL and the location estimate. We analyzed age at onset (AO) and quantitative trait number 5, Q5, from 26 replicates of the general simulated data in one region where we knew a major gene, MG5, is located. For each trait, we found the max PL and the corresponding location estimate, using four different bin widths. We found that bin width, as expected, does affect the max PL and the location estimate, and we recommend that users of Loki explore how their results vary with different bin widths.

Analysis of whole exome sequencing with cardiometabolic traits using family-based linkage and association in the IRAS Family Study

PubMed Central

Tabb, Keri L.; Hellwege, Jacklyn N.; Palmer, Nicholette D.; Dimitrov, Latchezar; Sajuthi, Satria; Taylor, Kent D.; NG, Maggie C.Y.; Hawkins, Gregory A.; Chen, Yii-Der Ida; Brown, W. Mark; McWilliams, David; Williams, Adrienne; Lorenzo, Carlos; Norris, Jill M.; Long, Jirong; Rotter, Jerome I.; Curran, Joanne E.; Blangero, John; Wagenknecht, Lynne E.; Langefeld, Carl D.; Bowden, Donald W.

2017-01-01

Summary Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1,205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 LOD scores with 1,148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (p<5×10-08), with the strongest association between rs651821:C>T in APOA5, and triglyceride levels (p=3.67×10-10). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to dbSNP build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits. PMID:28067407

Design and analysis of an underactuated anthropomorphic finger for upper limb prosthetics.

PubMed

Omarkulov, Nurdos; Telegenov, Kuat; Zeinullin, Maralbek; Begalinova, Ainur; Shintemirov, Almas

2015-01-01

This paper presents the design of a linkage based finger mechanism ensuring extended range of anthropomorphic gripping motions. The finger design is done using a path-point generation method based on geometrical dimensions and motion of a typical index human finger. Following the design description, and its kinematics analysis, the experimental evaluation of the finger gripping performance is presented using the finger 3D printed prototype. The finger underactuation is achieved by utilizing mechanical linkage system, consisting of two crossed four-bar linkage mechanisms. It is shown that the proposed finger design can be used to design a five-fingered anthropomorphic hand and has the potential for upper limb prostheses development.

A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers

PubMed Central

Ji, Fei; Lee, Dayoung; Mendell, Nancy Role

2005-01-01

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. PMID:16451570

A power study of bivariate LOD score analysis of a complex trait and fear/discomfort with strangers.

PubMed

Ji, Fei; Lee, Dayoung; Mendell, Nancy Role

2005-12-30

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.

Use of Multivariate Linkage Analysis for Dissection of a Complex Cognitive Trait

PubMed Central

Marlow, Angela J.; Fisher, Simon E.; Francks, Clyde; MacPhie, I. Laurence; Cherny, Stacey S.; Richardson, Alex J.; Talcott, Joel B.; Stein, John F.; Monaco, Anthony P.; Cardon, Lon R.

2003-01-01

Replication of linkage results for complex traits has been exceedingly difficult, owing in part to the inability to measure the precise underlying phenotype, small sample sizes, genetic heterogeneity, and statistical methods employed in analysis. Often, in any particular study, multiple correlated traits have been collected, yet these have been analyzed independently or, at most, in bivariate analyses. Theoretical arguments suggest that full multivariate analysis of all available traits should offer more power to detect linkage; however, this has not yet been evaluated on a genomewide scale. Here, we conduct multivariate genomewide analyses of quantitative-trait loci that influence reading- and language-related measures in families affected with developmental dyslexia. The results of these analyses are substantially clearer than those of previous univariate analyses of the same data set, helping to resolve a number of key issues. These outcomes highlight the relevance of multivariate analysis for complex disorders for dissection of linkage results in correlated traits. The approach employed here may aid positional cloning of susceptibility genes in a wide spectrum of complex traits. PMID:12587094

Improving record linkage performance in the presence of missing linkage data.

PubMed

Ong, Toan C; Mannino, Michael V; Schilling, Lisa M; Kahn, Michael G

2014-12-01

Existing record linkage methods do not handle missing linking field values in an efficient and effective manner. The objective of this study is to investigate three novel methods for improving the accuracy and efficiency of record linkage when record linkage fields have missing values. By extending the Fellegi-Sunter scoring implementations available in the open-source Fine-grained Record Linkage (FRIL) software system we developed three novel methods to solve the missing data problem in record linkage, which we refer to as: Weight Redistribution, Distance Imputation, and Linkage Expansion. Weight Redistribution removes fields with missing data from the set of quasi-identifiers and redistributes the weight from the missing attribute based on relative proportions across the remaining available linkage fields. Distance Imputation imputes the distance between the missing data fields rather than imputing the missing data value. Linkage Expansion adds previously considered non-linkage fields to the linkage field set to compensate for the missing information in a linkage field. We tested the linkage methods using simulated data sets with varying field value corruption rates. The methods developed had sensitivity ranging from .895 to .992 and positive predictive values (PPV) ranging from .865 to 1 in data sets with low corruption rates. Increased corruption rates lead to decreased sensitivity for all methods. These new record linkage algorithms show promise in terms of accuracy and efficiency and may be valuable for combining large data sets at the patient level to support biomedical and clinical research. Copyright © 2014 Elsevier Inc. All rights reserved.

Linkage Analysis of Quantitative Refraction and Refractive Errors in the Beaver Dam Eye Study

PubMed Central

Duggal, Priya; Lee, Kristine E.; Cheng, Ching-Yu; Klein, Ronald; Bailey-Wilson, Joan E.; Klein, Barbara E. K.

2011-01-01

Purpose. Refraction, as measured by spherical equivalent, is the need for an external lens to focus images on the retina. While genetic factors play an important role in the development of refractive errors, few susceptibility genes have been identified. However, several regions of linkage have been reported for myopia (2q, 4q, 7q, 12q, 17q, 18p, 22q, and Xq) and for quantitative refraction (1p, 3q, 4q, 7p, 8p, and 11p). To replicate previously identified linkage peaks and to identify novel loci that influence quantitative refraction and refractive errors, linkage analysis of spherical equivalent, myopia, and hyperopia in the Beaver Dam Eye Study was performed. Methods. Nonparametric, sibling-pair, genome-wide linkage analyses of refraction (spherical equivalent adjusted for age, education, and nuclear sclerosis), myopia and hyperopia in 834 sibling pairs within 486 extended pedigrees were performed. Results. Suggestive evidence of linkage was found for hyperopia on chromosome 3, region q26 (empiric P = 5.34 × 10−4), a region that had shown significant genome-wide evidence of linkage to refraction and some evidence of linkage to hyperopia. In addition, the analysis replicated previously reported genome-wide significant linkages to 22q11 of adjusted refraction and myopia (empiric P = 4.43 × 10−3 and 1.48 × 10−3, respectively) and to 7p15 of refraction (empiric P = 9.43 × 10−4). Evidence was also found of linkage to refraction on 7q36 (empiric P = 2.32 × 10−3), a region previously linked to high myopia. Conclusions. The findings provide further evidence that genes controlling refractive errors are located on 3q26, 7p15, 7p36, and 22q11. PMID:21571680

Linkage of Recognition and Replication Functions by Assembling Combinatorial Antibody Fab Libraries Along Phage Surfaces

NASA Astrophysics Data System (ADS)

Kang, Angray S.; Barbas, Carlos F.; Janda, Kim D.; Benkovic, Stephen J.; Lerner, Richard A.

1991-05-01

We describe a method based on a phagemid vector with helper phage rescue for the construction and rapid analysis of combinatorial antibody Fab libraries. This approach should allow the generation and selection of many monoclonal antibodies. Antibody genes are expressed in concert with phage morphogenesis, thereby allowing incorporation of functional Fab molecules along the surface of filamentous phage. The power of the method depends upon the linkage of recognition and replication functions and is not limited to antibody molecules.

Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions

PubMed Central

Amin, Najaf; Hottenga, Jouke-Jan; Hansell, Narelle K; Janssens, A Cecile JW; de Moor, Marleen HM; Madden, Pamela AF; Zorkoltseva, Irina V; Penninx, Brenda W; Terracciano, Antonio; Uda, Manuela; Tanaka, Toshiko; Esko, Tonu; Realo, Anu; Ferrucci, Luigi; Luciano, Michelle; Davies, Gail; Metspalu, Andres; Abecasis, Goncalo R; Deary, Ian J; Raikkonen, Katri; Bierut, Laura J; Costa, Paul T; Saviouk, Viatcheslav; Zhu, Gu; Kirichenko, Anatoly V; Isaacs, Aaron; Aulchenko, Yurii S; Willemsen, Gonneke; Heath, Andrew C; Pergadia, Michele L; Medland, Sarah E; Axenovich, Tatiana I; de Geus, Eco; Montgomery, Grant W; Wright, Margaret J; Oostra, Ben A; Martin, Nicholas G; Boomsma, Dorret I; van Duijn, Cornelia M

2013-01-01

Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10−06, KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. PMID:23211697

Methods of analysis and resources available for genetic trait mapping.

PubMed

Ott, J

1999-01-01

Methods of genetic linkage analysis are reviewed and put in context with other mapping techniques. Sources of information are outlined (books, web sites, computer programs). Special consideration is given to statistical problems in canine genetic mapping (heterozygosity, inbreeding, marker maps).

A high density integrated genetic linkage map of soybean and the development of a 1,536 Universal Soy Linkage Panel for QTL mapping

USDA-ARS?s Scientific Manuscript database

Single nucleotide polymorphisms (SNPs) are the marker of choice for many researchers due to their abundance and the high-throughput methods available for their multiplex analysis. Only recently have SNP markers been available to researchers in soybean [Glycine max (L.) Merr.] with the release of th...

PrePhyloPro: phylogenetic profile-based prediction of whole proteome linkages

PubMed Central

Niu, Yulong; Liu, Chengcheng; Moghimyfiroozabad, Shayan; Yang, Yi

2017-01-01

Direct and indirect functional links between proteins as well as their interactions as part of larger protein complexes or common signaling pathways may be predicted by analyzing the correlation of their evolutionary patterns. Based on phylogenetic profiling, here we present a highly scalable and time-efficient computational framework for predicting linkages within the whole human proteome. We have validated this method through analysis of 3,697 human pathways and molecular complexes and a comparison of our results with the prediction outcomes of previously published co-occurrency model-based and normalization methods. Here we also introduce PrePhyloPro, a web-based software that uses our method for accurately predicting proteome-wide linkages. We present data on interactions of human mitochondrial proteins, verifying the performance of this software. PrePhyloPro is freely available at http://prephylopro.org/phyloprofile/. PMID:28875072

Systematic search for major genes in schizophrenia: Methodological issues and results from chromosome 12

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dawson, E.; Powell, J.F.; Sham, P.

1995-10-09

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity.more » None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis. 53 refs., 2 figs., 4 tabs.« less

An empirical Bayes method for updating inferences in analysis of quantitative trait loci using information from related genome scans.

PubMed

Zhang, Kui; Wiener, Howard; Beasley, Mark; George, Varghese; Amos, Christopher I; Allison, David B

2006-08-01

Individual genome scans for quantitative trait loci (QTL) mapping often suffer from low statistical power and imprecise estimates of QTL location and effect. This lack of precision yields large confidence intervals for QTL location, which are problematic for subsequent fine mapping and positional cloning. In prioritizing areas for follow-up after an initial genome scan and in evaluating the credibility of apparent linkage signals, investigators typically examine the results of other genome scans of the same phenotype and informally update their beliefs about which linkage signals in their scan most merit confidence and follow-up via a subjective-intuitive integration approach. A method that acknowledges the wisdom of this general paradigm but formally borrows information from other scans to increase confidence in objectivity would be a benefit. We developed an empirical Bayes analytic method to integrate information from multiple genome scans. The linkage statistic obtained from a single genome scan study is updated by incorporating statistics from other genome scans as prior information. This technique does not require that all studies have an identical marker map or a common estimated QTL effect. The updated linkage statistic can then be used for the estimation of QTL location and effect. We evaluate the performance of our method by using extensive simulations based on actual marker spacing and allele frequencies from available data. Results indicate that the empirical Bayes method can account for between-study heterogeneity, estimate the QTL location and effect more precisely, and provide narrower confidence intervals than results from any single individual study. We also compared the empirical Bayes method with a method originally developed for meta-analysis (a closely related but distinct purpose). In the face of marked heterogeneity among studies, the empirical Bayes method outperforms the comparator.

Analysis of sulfidic linkages formed in natural rubber latex medical gloves by using X-ray absorption near edge structure

NASA Astrophysics Data System (ADS)

Chankrachang, M.; Limphirat, W.; Yongyingsakthavorn, P.; Nontakaew, U.; Tohsan, A.

2017-09-01

A study of sulfidic linkages formed in natural rubber (NR) latex medical gloves by using X-ray Absorption Near Edge Structure (XANES) is presented in this paper. The NR latex compound was prepared by using prevulcanization method, that is, it was prevulcanized at room temperature for 24 hrs before utilization. After the 24 hrs of prevulcanization, the latex film samples were obtained by dipping process. The dipped films were subjected to vulcanize at 110°C for 5 to 25 min. It was observed that after the compound was prevulcanized for 24 hrs, polysulfidic linkages were mainly formed in the sample. It was however found that after curing at 110°C for 5-25 min, the polysulfidic linkages are tended to change into disulfide linkages. Especially, in the case of 25 minutes cured sample, disulfide linkages are found to be the main linkages. In term of tensile strength, it was observed that when cure time increased from 5 - 10 min, tensile strengths were also increased. But when the cure time of the film is 25 minutes, tensile strength was slightly dropped. The dropped of tensile strength when cure time is longer than 10 minutes can be ascribed to a degradation of polysulfidic and disulfidic linkages during curing. Therefore, by using XANES analysis, it was found to be very useful to understand the cure characteristic, thus it can be very helpful to optimize cure time and tensile properties of the product.

Computational Methods for Structural Mechanics and Dynamics

NASA Technical Reports Server (NTRS)

Stroud, W. Jefferson (Editor); Housner, Jerrold M. (Editor); Tanner, John A. (Editor); Hayduk, Robert J. (Editor)

1989-01-01

Topics addressed include: transient dynamics; transient finite element method; transient analysis in impact and crash dynamic studies; multibody computer codes; dynamic analysis of space structures; multibody mechanics and manipulators; spatial and coplanar linkage systems; flexible body simulation; multibody dynamics; dynamical systems; and nonlinear characteristics of joints.

Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p.

PubMed

Visscher, P M; Haley, C S; Ewald, H; Mors, O; Egeland, J; Thiel, B; Ginns, E; Muir, W; Blackwood, D H

2005-02-05

To test the hypothesis that the same genetic loci confer susceptibility to, or protection from, disease in different populations, and that a combined analysis would improve the map resolution of a common susceptibility locus, we analyzed data from three studies that had reported linkage to bipolar disorder in a small region on chromosome 4p. Data sets comprised phenotypic information and genetic marker data on Scottish, Danish, and USA extended pedigrees. Across the three data sets, 913 individuals appeared in the pedigrees, 462 were classified, either as unaffected (323) or affected (139) with unipolar or bipolar disorder. A consensus linkage map was created from 14 microsatellite markers in a 33 cM region. Phenotypic and genetic data were analyzed using a variance component (VC) and allele sharing method. All previously reported elevated test statistics in the region were confirmed with one or both analysis methods, indicating the presence of one or more susceptibility genes to bipolar disorder in the three populations in the studied chromosome segment. When the results from both the VC and allele sharing method were considered, there was strong evidence for a susceptibility locus in the data from Scotland, some evidence in the data from Denmark and relatively less evidence in the data from the USA. The test statistics from the Scottish data set dominated the test statistics from the other studies, and no improved map resolution for a putative genetic locus underlying susceptibility in all three studies was obtained. Studies reporting linkage to the same region require careful scrutiny and preferably joint or meta analysis on the same basis in order to ensure that the results are truly comparable. (c) 2004 Wiley-Liss, Inc.

Genome-wide linkage and association analysis of cardiometabolic phenotypes in Hispanic Americans.

PubMed

Hellwege, Jacklyn N; Palmer, Nicholette D; Dimitrov, Latchezar; Keaton, Jacob M; Tabb, Keri L; Sajuthi, Satria; Taylor, Kent D; Ng, Maggie C Y; Speliotes, Elizabeth K; Hawkins, Gregory A; Long, Jirong; Ida Chen, Yii-Der; Lorenzo, Carlos; Norris, Jill M; Rotter, Jerome I; Langefeld, Carl D; Wagenknecht, Lynne E; Bowden, Donald W

2017-02-01

Linkage studies of complex genetic diseases have been largely replaced by genome-wide association studies, due in part to limited success in complex trait discovery. However, recent interest in rare and low-frequency variants motivates re-examination of family-based methods. In this study, we investigated the performance of two-point linkage analysis for over 1.6 million single-nucleotide polymorphisms (SNPs) combined with single variant association analysis to identify high impact variants, which are both strongly linked and associated with cardiometabolic traits in up to 1414 Hispanics from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of all 50 phenotypes yielded 83 557 000 LOD (logarithm of the odds) scores, with 9214 LOD scores ⩾3.0, 845 ⩾4.0 and 89 ⩾5.0, with a maximal LOD score of 6.49 (rs12956744 in the LAMA1 gene for tumor necrosis factor-α (TNFα) receptor 2). Twenty-seven variants were associated with P<0.005 as well as having an LOD score >4, including variants in the NFIB gene under a linkage peak with TNFα receptor 2 levels on chromosome 9. Linkage regions of interest included a broad peak (31 Mb) on chromosome 1q with acute insulin response (max LOD=5.37). This region was previously documented with type 2 diabetes in family-based studies, providing support for the validity of these results. Overall, we have demonstrated the utility of two-point linkage and association in comprehensive genome-wide array-based SNP genotypes.

Hereditary spastic paraplegia: LOD-score considerations for confirmation of linkage in a heterogeneous trait.

PubMed

Dubé, M P; Mlodzienski, M A; Kibar, Z; Farlow, M R; Ebers, G; Harper, P; Kolodny, E H; Rouleau, G A; Figlewicz, D A

1997-03-01

Hereditary spastic paraplegia (HSP) is a degenerative disorder of the motor system, defined by progressive weakness and spasticity of the lower limbs. HSP may be inherited as an autosomal dominant (AD), autosomal recessive, or an X-linked trait. AD HSP is genetically heterogeneous, and three loci have been identified so far: SPG3 maps to chromosome 14q, SPG4 to 2p, and SPG4a to 15q. We have undertaken linkage analysis with 21 uncomplicated AD families to the three AD HSP loci. We report significant linkage for three of our families to the SPG4 locus and exclude several families by multipoint linkage. We used linkage information from several different research teams to evaluate the statistical probability of linkage to the SPG4 locus for uncomplicated AD HSP families and established the critical LOD-score value necessary for confirmation of linkage to the SPG4 locus from Bayesian statistics. In addition, we calculated the empirical P-values for the LOD scores obtained with all families with computer simulation methods. Power to detect significant linkage, as well as type I error probabilities, were evaluated. This combined analytical approach permitted conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity.

Direct power comparisons between simple LOD scores and NPL scores for linkage analysis in complex diseases.

PubMed

Abreu, P C; Greenberg, D A; Hodge, S E

1999-09-01

Several methods have been proposed for linkage analysis of complex traits with unknown mode of inheritance. These methods include the LOD score maximized over disease models (MMLS) and the "nonparametric" linkage (NPL) statistic. In previous work, we evaluated the increase of type I error when maximizing over two or more genetic models, and we compared the power of MMLS to detect linkage, in a number of complex modes of inheritance, with analysis assuming the true model. In the present study, we compare MMLS and NPL directly. We simulated 100 data sets with 20 families each, using 26 generating models: (1) 4 intermediate models (penetrance of heterozygote between that of the two homozygotes); (2) 6 two-locus additive models; and (3) 16 two-locus heterogeneity models (admixture alpha = 1.0,.7,.5, and.3; alpha = 1.0 replicates simple Mendelian models). For LOD scores, we assumed dominant and recessive inheritance with 50% penetrance. We took the higher of the two maximum LOD scores and subtracted 0.3 to correct for multiple tests (MMLS-C). We compared expected maximum LOD scores and power, using MMLS-C and NPL as well as the true model. Since NPL uses only the affected family members, we also performed an affecteds-only analysis using MMLS-C. The MMLS-C was both uniformly more powerful than NPL for most cases we examined, except when linkage information was low, and close to the results for the true model under locus heterogeneity. We still found better power for the MMLS-C compared with NPL in affecteds-only analysis. The results show that use of two simple modes of inheritance at a fixed penetrance can have more power than NPL when the trait mode of inheritance is complex and when there is heterogeneity in the data set.

Pseudoautosomal region in schizophrenia: linkage analysis of seven loci by sib-pair and lod-score methods.

PubMed

d'Amato, T; Waksman, G; Martinez, M; Laurent, C; Gorwood, P; Campion, D; Jay, M; Petit, C; Savoye, C; Bastard, C

1994-05-01

In a previous study, we reported a nonrandom segregation between schizophrenia and the pseudoautosomal locus DXYS14 in a sample of 33 sibships. That study has been extended by the addition of 16 new sibships from 16 different families. Data from six other loci of the pseudoautosomal region and of the immediately adjacent part of the X specific region have also been analyzed. Two methods of linkage analysis were used: the affected sibling pair (ASP) method and the lod-score method. Lod-score analyses were performed on the basis of three different models--A, B, and C--all shown to be consistent with the epidemiological data on schizophrenia. No clear evidence for linkage was obtained with any of these models. However, whatever the genetic model and the disease classification, maximum lod scores were positive with most of the markers, with the highest scores generally being obtained for the DXYS14 locus. When the ASP method was used, the earlier finding of nonrandom segregation between schizophrenia and the DXYS14 locus was still supported in this larger data set, at an increased level of statistical significance. Findings of ASP analyses were not significant for the other loci. Thus, findings obtained from analyses using the ASP method, but not the lod-score method, were consistent with the pseudoautosomal hypothesis for schizophrenia.

Effect of Linkage Disequilibrium on the Identification of Functional Variants

PubMed Central

Thomas, Alun; Abel, Haley J; Di, Yanming; Faye, Laura L; Jin, Jing; Liu, Jin; Wu, Zheyan; Paterson, Andrew D

2011-01-01

We summarize the contributions of Group 9 of Genetic Analysis Workshop 17. This group addressed the problems of linkage disequilibrium and other longer range forms of allelic association when evaluating the effects of genotypes on phenotypes. Issues raised by long-range associations, whether a result of selection, stratification, possible technical errors, or chance, were less expected but proved to be important. Most contributors focused on regression methods of various types to illustrate problematic issues or to develop adaptations for dealing with high-density genotype assays. Study design was also considered, as was graphical modeling. Although no method emerged as uniformly successful, most succeeded in reducing false-positive results either by considering clusters of loci within genes or by applying smoothing metrics that required results from adjacent loci to be similar. Two unexpected results that questioned our assumptions of what is required to model linkage disequilibrium were observed. The first was that correlations between loci separated by large genetic distances can greatly inflate single-locus test statistics, and, whether the result of selection, stratification, possible technical errors, or chance, these correlations seem overabundant. The second unexpected result was that applying principal components analysis to genome-wide genotype data can apparently control not only for population structure but also for linkage disequilibrium. PMID:22128051

HIV-1 transmission linkage in an HIV-1 prevention clinical trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leitner, Thomas; Campbell, Mary S; Mullins, James I

2009-01-01

HIV-1 sequencing has been used extensively in epidemiologic and forensic studies to investigate patterns of HIV-1 transmission. However, the criteria for establishing genetic linkage between HIV-1 strains in HIV-1 prevention trials have not been formalized. The Partners in Prevention HSV/HIV Transmission Study (ClinicaITrials.gov NCT00194519) enrolled 3408 HIV-1 serodiscordant heterosexual African couples to determine the efficacy of genital herpes suppression with acyclovir in reducing HIV-1 transmission. The trial analysis required laboratory confirmation of HIV-1 linkage between enrolled partners in couples in which seroconversion occurred. Here we describe the process and results from HIV-1 sequencing studies used to perform transmission linkage determinationmore » in this clinical trial. Consensus Sanger sequencing of env (C2-V3-C3) and gag (p17-p24) genes was performed on plasma HIV-1 RNA from both partners within 3 months of seroconversion; env single molecule or pyrosequencing was also performed in some cases. For linkage, we required monophyletic clustering between HIV-1 sequences in the transmitting and seroconverting partners, and developed a Bayesian algorithm using genetic distances to evaluate the posterior probability of linkage of participants sequences. Adjudicators classified transmissions as linked, unlinked, or indeterminate. Among 151 seroconversion events, we found 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) to have indeterminate transmissions. Nine (8.3%) were linked by consensus gag sequencing only and 8 (7.4%) required deep sequencing of env. In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process.« less

Viral Linkage in HIV-1 Seroconverters and Their Partners in an HIV-1 Prevention Clinical Trial

PubMed Central

Campbell, Mary S.; Mullins, James I.; Hughes, James P.; Celum, Connie; Wong, Kim G.; Raugi, Dana N.; Sorensen, Stefanie; Stoddard, Julia N.; Zhao, Hong; Deng, Wenjie; Kahle, Erin; Panteleeff, Dana; Baeten, Jared M.; McCutchan, Francine E.; Albert, Jan; Leitner, Thomas; Wald, Anna; Corey, Lawrence; Lingappa, Jairam R.

2011-01-01

Background Characterization of viruses in HIV-1 transmission pairs will help identify biological determinants of infectiousness and evaluate candidate interventions to reduce transmission. Although HIV-1 sequencing is frequently used to substantiate linkage between newly HIV-1 infected individuals and their sexual partners in epidemiologic and forensic studies, viral sequencing is seldom applied in HIV-1 prevention trials. The Partners in Prevention HSV/HIV Transmission Study (ClinicalTrials.gov #NCT00194519) was a prospective randomized placebo-controlled trial that enrolled serodiscordant heterosexual couples to determine the efficacy of genital herpes suppression in reducing HIV-1 transmission; as part of the study analysis, HIV-1 sequences were examined for genetic linkage between seroconverters and their enrolled partners. Methodology/Principal Findings We obtained partial consensus HIV-1 env and gag sequences from blood plasma for 151 transmission pairs and performed deep sequencing of env in some cases. We analyzed sequences with phylogenetic techniques and developed a Bayesian algorithm to evaluate the probability of linkage. For linkage, we required monophyletic clustering between enrolled partners' sequences and a Bayesian posterior probability of ≥50%. Adjudicators classified each seroconversion, finding 108 (71.5%) linked, 40 (26.5%) unlinked, and 3 (2.0%) indeterminate transmissions, with linkage determined by consensus env sequencing in 91 (84%). Male seroconverters had a higher frequency of unlinked transmissions than female seroconverters. The likelihood of transmission from the enrolled partner was related to time on study, with increasing numbers of unlinked transmissions occurring after longer observation periods. Finally, baseline viral load was found to be significantly higher among linked transmitters. Conclusions/Significance In this first use of HIV-1 sequencing to establish endpoints in a large clinical trial, more than one-fourth of transmissions were unlinked to the enrolled partner, illustrating the relevance of these methods in the design of future HIV-1 prevention trials in serodiscordant couples. A hierarchy of sequencing techniques, analysis methods, and expert adjudication contributed to the linkage determination process. PMID:21399681

Privacy-preserving record linkage on large real world datasets.

PubMed

Randall, Sean M; Ferrante, Anna M; Boyd, James H; Bauer, Jacqueline K; Semmens, James B

2014-08-01

Record linkage typically involves the use of dedicated linkage units who are supplied with personally identifying information to determine individuals from within and across datasets. The personally identifying information supplied to linkage units is separated from clinical information prior to release by data custodians. While this substantially reduces the risk of disclosure of sensitive information, some residual risks still exist and remain a concern for some custodians. In this paper we trial a method of record linkage which reduces privacy risk still further on large real world administrative data. The method uses encrypted personal identifying information (bloom filters) in a probability-based linkage framework. The privacy preserving linkage method was tested on ten years of New South Wales (NSW) and Western Australian (WA) hospital admissions data, comprising in total over 26 million records. No difference in linkage quality was found when the results were compared to traditional probabilistic methods using full unencrypted personal identifiers. This presents as a possible means of reducing privacy risks related to record linkage in population level research studies. It is hoped that through adaptations of this method or similar privacy preserving methods, risks related to information disclosure can be reduced so that the benefits of linked research taking place can be fully realised. Copyright © 2013 Elsevier Inc. All rights reserved.

Case-Deletion Diagnostics for Maximum Likelihood Multipoint Quantitative Trait Locus Linkage Analysis

PubMed Central

Mendoza, Maria C.B.; Burns, Trudy L.; Jones, Michael P.

2009-01-01

Objectives Case-deletion diagnostic methods are tools that allow identification of influential observations that may affect parameter estimates and model fitting conclusions. The goal of this paper was to develop two case-deletion diagnostics, the exact case deletion (ECD) and the empirical influence function (EIF), for detecting outliers that can affect results of sib-pair maximum likelihood quantitative trait locus (QTL) linkage analysis. Methods Subroutines to compute the ECD and EIF were incorporated into the maximum likelihood QTL variance estimation components of the linkage analysis program MAPMAKER/SIBS. Performance of the diagnostics was compared in simulation studies that evaluated the proportion of outliers correctly identified (sensitivity), and the proportion of non-outliers correctly identified (specificity). Results Simulations involving nuclear family data sets with one outlier showed EIF sensitivities approximated ECD sensitivities well for outlier-affected parameters. Sensitivities were high, indicating the outlier was identified a high proportion of the time. Simulations also showed the enormous computational time advantage of the EIF. Diagnostics applied to body mass index in nuclear families detected observations influential on the lod score and model parameter estimates. Conclusions The EIF is a practical diagnostic tool that has the advantages of high sensitivity and quick computation. PMID:19172086

Large-scale SNP discovery and construction of a high-density genetic map of Colossoma macropomum through genotyping-by-sequencing

PubMed Central

Nunes, José de Ribamar da Silva; Liu, Shikai; Pértille, Fábio; Perazza, Caio Augusto; Villela, Priscilla Marqui Schmidt; de Almeida-Val, Vera Maria Fonseca; Hilsdorf, Alexandre Wagner Silva; Liu, Zhanjiang; Coutinho, Luiz Lehmann

2017-01-01

Colossoma macropomum, or tambaqui, is the largest native Characiform species found in the Amazon and Orinoco river basins, yet few resources for genetic studies and the genetic improvement of tambaqui exist. In this study, we identified a large number of single-nucleotide polymorphisms (SNPs) for tambaqui and constructed a high-resolution genetic linkage map from a full-sib family of 124 individuals and their parents using the genotyping by sequencing method. In all, 68,584 SNPs were initially identified using minimum minor allele frequency (MAF) of 5%. Filtering parameters were used to select high-quality markers for linkage analysis. We selected 7,734 SNPs for linkage mapping, resulting in 27 linkage groups with a minimum logarithm of odds (LOD) of 8 and maximum recombination fraction of 0.35. The final genetic map contains 7,192 successfully mapped markers that span a total of 2,811 cM, with an average marker interval of 0.39 cM. Comparative genomic analysis between tambaqui and zebrafish revealed variable levels of genomic conservation across the 27 linkage groups which allowed for functional SNP annotations. The large-scale SNP discovery obtained here, allowed us to build a high-density linkage map in tambaqui, which will be useful to enhance genetic studies that can be applied in breeding programs. PMID:28387238

A Simple Sampling Method for Estimating the Accuracy of Large Scale Record Linkage Projects.

PubMed

Boyd, James H; Guiver, Tenniel; Randall, Sean M; Ferrante, Anna M; Semmens, James B; Anderson, Phil; Dickinson, Teresa

2016-05-17

Record linkage techniques allow different data collections to be brought together to provide a wider picture of the health status of individuals. Ensuring high linkage quality is important to guarantee the quality and integrity of research. Current methods for measuring linkage quality typically focus on precision (the proportion of incorrect links), given the difficulty of measuring the proportion of false negatives. The aim of this work is to introduce and evaluate a sampling based method to estimate both precision and recall following record linkage. In the sampling based method, record-pairs from each threshold (including those below the identified cut-off for acceptance) are sampled and clerically reviewed. These results are then applied to the entire set of record-pairs, providing estimates of false positives and false negatives. This method was evaluated on a synthetically generated dataset, where the true match status (which records belonged to the same person) was known. The sampled estimates of linkage quality were relatively close to actual linkage quality metrics calculated for the whole synthetic dataset. The precision and recall measures for seven reviewers were very consistent with little variation in the clerical assessment results (overall agreement using the Fleiss Kappa statistics was 0.601). This method presents as a possible means of accurately estimating matching quality and refining linkages in population level linkage studies. The sampling approach is especially important for large project linkages where the number of record pairs produced may be very large often running into millions.

Linkage of Type 2 Diabetes on Chromosome 9p24 in Mexican Americans: Additional Evidence from the Veterans Administration Genetic Epidemiology Study (VAGES)

PubMed Central

Farook, Vidya S.; Coletta, Dawn K.; Puppala, Sobha; Schneider, Jennifer; Chittoor, Geetha; Hu, Shirley L.; Winnier, Deidre A.; Norton, Luke; Dyer, Thomas D.; Arya, Rector; Cole, Shelley A.; Carless, Melanie; Göring, Harald H.; Almasy, Laura; Mahaney, Michael C.; Comuzzie, Anthony G.; Curran, Joanne E.; Blangero, John; Duggirala, Ravindranath; Lehman, Donna M.; Jenkinson, Christopher P.; DeFronzo, Ralph A.

2014-01-01

Objective Type 2 diabetes (T2DM) is a complex metabolic disease and is more prevalent in certain ethnic groups such as the Mexican Americans. The goal of our study was to perform a genome-wide linkage analysis to localize T2DM susceptibility loci in Mexican Americans. Methods We used the phenotypic and genotypic data from 1,122 Mexican American individuals (307 families) who participated in the Veterans Administration Genetic Epidemiology Study (VAGES). Genome-wide linkage analysis was performed, using the variance components approach. Data from two additional Mexican American family studies, the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), were combined with the VAGES data to test for improved linkage evidence. Results After adjusting for covariate effects, T2DM was found to be under significant genetic influences (h2 = 0.62, P = 2.7 × 10−6). The strongest evidence for linkage of T2DM occurred between markers D9S1871 and D9S2169 on chromosome 9p24.2-p24.1 (LOD = 1.8). Given that we previously reported suggestive evidence for linkage of T2DM at this region in SAFDGS also, we found the significant and increased linkage evidence (LOD = 4.3, empirical P = 1.0 × 10−5, genome-wide P = 1.6 × 10−3) for T2DM at the same chromosomal region when we performed genome-wide linkage analysis of the VAGES data combined with SAFHS and SAFDGS data. Conclusion Significant T2DM linkage evidence was found on chromosome 9p24 in Mexican Americans. Importantly, the chromosomal region of interest in this study overlaps with several recent genome-wide association studies (GWASs) involving T2DM related traits. Given its overlap with such findings and our own initial T2DM association findings in the 9p24 chromosomal region, high throughput sequencing of the linked chromosomal region could identify the potential causal T2DM genes. PMID:24060607

An extension of the Maximum Lod Score method to X-linked loci.

PubMed

Cordell, H J; Kawaguchi, Y; Todd, J A; Farrall, M

1995-10-01

The Maximum Lod Score method for affected relative-pair analysis, introduced by Risch, is a powerful method for detecting linkage between an autosomal marker locus and disease. In order to use the method to detect linkage to markers on the X-chromosome, some modification is necessary. Here we extend the method to be applicable to X-chromosomal data, and derive genetic restrictions on the haplotype-sharing probabilities analogous to the 'possible triangle' restrictions described by Holmans for the autosomal case. Size criteria are derived using asymptotic theory and simulation, and the power is calculated for a number of possible underlying models. The method is applied to data from 284 type 1 diabetic families and evidence is found for the presence of one or more diabetogenic loci on the X-chromosome.

Barriers Influencing Linkage to Hypertension Care in Kenya: Qualitative Analysis from the LARK Hypertension Study.

PubMed

Naanyu, Violet; Vedanthan, Rajesh; Kamano, Jemima H; Rotich, Jackson K; Lagat, Kennedy K; Kiptoo, Peninah; Kofler, Claire; Mutai, Kennedy K; Bloomfield, Gerald S; Menya, Diana; Kimaiyo, Sylvester; Fuster, Valentin; Horowitz, Carol R; Inui, Thomas S

2016-03-01

Hypertension, the leading global risk factor for mortality, is characterized by low treatment and control rates in low- and middle-income countries. Poor linkage to hypertension care contributes to poor outcomes for patients. However, specific factors influencing linkage to hypertension care are not well known. To evaluate factors influencing linkage to hypertension care in rural western Kenya. Qualitative research study using a modified Health Belief Model that incorporates the impact of emotional and environmental factors on behavior. Mabaraza (traditional community assembly) participants (n = 242) responded to an open invitation to residents in their respective communities. Focus groups, formed by purposive sampling, consisted of hypertensive individuals, at-large community members, and community health workers (n = 169). We performed content analysis of the transcripts with NVivo 10 software, using both deductive and inductive codes. We used a two-round Delphi method to rank the barriers identified in the content analysis. We selected factors using triangulation of frequency of codes and themes from the transcripts, in addition to the results of the Delphi exercise. Sociodemographic characteristics of participants were summarized using descriptive statistics. We identified 27 barriers to linkage to hypertension care, grouped into individual (cognitive and emotional) and environmental factors. Cognitive factors included the asymptomatic nature of hypertension and limited information. Emotional factors included fear of being a burden to the family and fear of being screened for stigmatized diseases such as HIV. Environmental factors were divided into physical (e.g. distance), socioeconomic (e.g. poverty), and health system factors (e.g. popularity of alternative therapies). The Delphi results were generally consistent with the findings from the content analysis. Individual and environmental factors are barriers to linkage to hypertension care in rural western Kenya. Our analysis provides new insights and methodological approaches that may be relevant to other low-resource settings worldwide.

Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3–14

PubMed Central

Warner, J; Nyholt, D R; Busfield, F; Epstein, M; Burgess, J; Stranks, S; Hill, P; Perry‐Keene, D; Learoyd, D; Robinson, B; Teh, B T; Prins, J B; Cardinal, J W

2006-01-01

Bachground Familial isolated hyperparathyroidism (FIHP) is an autosomal dominantly inherited form of primary hyperparathyroidism. Although comprising only about 1% of cases of primary hyperparathyroidism, identification and functional analysis of a causative gene for FIHP is likely to advance our understanding of parathyroid physiology and pathophysiology. Methods A genome‐wide screen of DNA from seven pedigrees with FIHP was undertaken in order to identify a region of genetic linkage with the disorder. Results Multipoint linkage analysis identified a region of suggestive linkage (LOD score 2.68) on chromosome 2. Fine mapping with the addition of three other families revealed significant linkage adjacent to D2S2368 (maximum multipoint LOD score 3.43). Recombination events defined a 1.7 Mb region of linkage between D2S2368 and D2S358 in nine pedigrees. Sequencing of the two most likely candidate genes in this region, however, did not identify a gene for FIHP. Conclusions We conclude that a causative gene for FIHP lies within this interval on chromosome 2. This is a major step towards eventual precise identification of a gene for FIHP, likely to be a key component in the genetic regulation of calcium homeostasis. PMID:16525030

Development of a Thiolysis HPLC Method for the Analysis of Procyanidins in Cranberry Products.

PubMed

Gao, Chi; Cunningham, David G; Liu, Haiyan; Khoo, Christina; Gu, Liwei

2018-03-07

The objective of this study was to develop a thiolysis HPLC method to quantify total procyanidins, the ratio of A-type linkages, and A-type procyanidin equivalents in cranberry products. Cysteamine was utilized as a low-odor substitute of toluene-α-thiol for thiolysis depolymerization. A reaction temperature of 70 °C and reaction time of 20 min, in 0.3 M of HCl, were determined to be optimum depolymerization conditions. Thiolytic products of cranberry procyanidins were separated by RP-HPLC and identified using high-resolution mass spectrometry. Standards curves of good linearity were obtained on thiolyzed procyanidin dimer A2 and B2 external standards. The detection and quantification limits, recovery, and precision of this method were validated. The new method was applied to quantitate total procyanidins, average degree of polymerization, ratio of A-type linkages, and A-type procyanidin equivalents in cranberry products. Results showed that the method was suitable for quantitative and qualitative analysis of procyanidins in cranberry products.

Phase-Division-Based Dynamic Optimization of Linkages for Drawing Servo Presses

NASA Astrophysics Data System (ADS)

Zhang, Zhi-Gang; Wang, Li-Ping; Cao, Yan-Ke

2017-11-01

Existing linkage-optimization methods are designed for mechanical presses; few can be directly used for servo presses, so development of the servo press is limited. Based on the complementarity of linkage optimization and motion planning, a phase-division-based linkage-optimization model for a drawing servo press is established. Considering the motion-planning principles of a drawing servo press, and taking account of work rating and efficiency, the constraints of the optimization model are constructed. Linkage is optimized in two modes: use of either constant eccentric speed or constant slide speed in the work segments. The performances of optimized linkages are compared with those of a mature linkage SL4-2000A, which is optimized by a traditional method. The results show that the work rating of a drawing servo press equipped with linkages optimized by this new method improved and the root-mean-square torque of the servo motors is reduced by more than 10%. This research provides a promising method for designing energy-saving drawing servo presses with high work ratings.

Linkage and association analysis of obesity traits reveals novel loci and interactions with dietary n-3 fatty acids in an Alaska Native (Yup’ik) population

PubMed Central

Vaughan, Laura Kelly; Wiener, Howard W.; Aslibekyan, Stella; Allison, David B.; Havel, Peter J.; Stanhope, Kimber L.; O’Brien, Diane M.; Hopkins, Scarlett E.; Lemas, Dominick J.; Boyer, Bert B.; Tiwari, Hemant K.

2015-01-01

Objective To identify novel genetic markers of obesity-related traits and to identify gene-diet interactions with n-3 polyunsaturated fatty acid (n-3 PUFA) intake in Yup’ik people. Material and Methods We measured body composition, plasma adipokines and ghrelin in 982 participants enrolled in the Center for Alaska Native Health Research (CANHR) Study. We conducted a genome-wide SNP linkage scan and targeted association analysis, fitting additional models to investigate putative gene-diet interactions. Finally, we performed bioinformatic analysis to uncover likely candidate genes within the identified linkage peaks. Results We observed evidence of linkage for all obesity-related traits, replicating previous results and identifying novel regions of interest for adiponectin (10q26.13-2) and thigh circumference (8q21.11-13). Bioinformatic analysis revealed DOCK1, PTPRE (10q26.13-2) and FABP4 (8q21.11-13) as putative candidate genes in the newly identified regions. Targeted SNP analysis under the linkage peaks identified associations between three SNPs and obesity-related traits: rs1007750 on chromosome 8 and thigh circumference (P=0.0005), rs878953 on chromosome 5 and thigh skinfold (P=0.0004), and rs1596854 on chromosome 11 for waist circumference (P=0.0003). Finally, we showed that n-3 PUFA modified the association between obesity related traits and two additional variants (rs2048417 on chromosome 3 for adiponectin, P for interaction=0.0006 and rs730414 on chromosome 11 for percentage body fat, P for interaction=0.0004). Conclusions This study presents evidence of novel genomic regions and gene-diet interactions that may contribute to the pathophysiology of obesity-related traits among Yup’ik people. PMID:25772781

Molecular analysis and test of linkage between the FMR-I gene and infantile autism in multiplex families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hallmayer, J.; Pintado, E.; Lotspeich, L.

Approximately 2%-5% of autistic children show cytogenetic evidence of the fragile X syndrome. This report tests whether infantile autism in multiplex autism families arises from an unusual manifestion of the fragile X syndrome. This could arise either by expansion of the (CGG)n trinucleotide repeat in FMR-1 or from a mutation elsewhere in the gene. We studied 35 families that met stringent criteria for multiplex autism. Amplification of the trinucleotide repeat and analysis of methylation status were performed in 79 autistic children and in 31 of their unaffected siblings by Southern blot analysis. No examples of amplified repeats were seen inmore » the autistic or control children or in their parents or grandparents. We next examined the hypothesis that there was a mutation elsewhere in the FMR-1 gene, by linkage analysis in 32 of these families. We tested four different dominant models and a recessive model. Linkage to FMR-1 could be excluded (lod score between -24 and -62) in all models by using probes DXS548, FRAXAC1, and FRAXAC2 and the CGG repeat itself. Tests for heterogeneity in this sample were negative, and the occurrence of positive lod scores in this data set could be attributed to chance. Analysis of the data by the affected-sib method also did not show evidence for linkage of any marker to autism. These results enable us to reject the hypothesis that multiplex autism arises from expansion of the (CGG)n trinucleotide repeat in FMR-1. Further, because the overall lod scores for all probes in all models tested were highly negative, linkage to FMR-1 can also be ruled out in multiplex autistic families. 35 refs., 2 figs., 5 tabs.« less

The power to detect linkage in complex disease by means of simple LOD-score analyses.

PubMed Central

Greenberg, D A; Abreu, P; Hodge, S E

1998-01-01

Maximum-likelihood analysis (via LOD score) provides the most powerful method for finding linkage when the mode of inheritance (MOI) is known. However, because one must assume an MOI, the application of LOD-score analysis to complex disease has been questioned. Although it is known that one can legitimately maximize the maximum LOD score with respect to genetic parameters, this approach raises three concerns: (1) multiple testing, (2) effect on power to detect linkage, and (3) adequacy of the approximate MOI for the true MOI. We evaluated the power of LOD scores to detect linkage when the true MOI was complex but a LOD score analysis assumed simple models. We simulated data from 14 different genetic models, including dominant and recessive at high (80%) and low (20%) penetrances, intermediate models, and several additive two-locus models. We calculated LOD scores by assuming two simple models, dominant and recessive, each with 50% penetrance, then took the higher of the two LOD scores as the raw test statistic and corrected for multiple tests. We call this test statistic "MMLS-C." We found that the ELODs for MMLS-C are >=80% of the ELOD under the true model when the ELOD for the true model is >=3. Similarly, the power to reach a given LOD score was usually >=80% that of the true model, when the power under the true model was >=60%. These results underscore that a critical factor in LOD-score analysis is the MOI at the linked locus, not that of the disease or trait per se. Thus, a limited set of simple genetic models in LOD-score analysis can work well in testing for linkage. PMID:9718328

The power to detect linkage in complex disease by means of simple LOD-score analyses.

PubMed

Greenberg, D A; Abreu, P; Hodge, S E

1998-09-01

Maximum-likelihood analysis (via LOD score) provides the most powerful method for finding linkage when the mode of inheritance (MOI) is known. However, because one must assume an MOI, the application of LOD-score analysis to complex disease has been questioned. Although it is known that one can legitimately maximize the maximum LOD score with respect to genetic parameters, this approach raises three concerns: (1) multiple testing, (2) effect on power to detect linkage, and (3) adequacy of the approximate MOI for the true MOI. We evaluated the power of LOD scores to detect linkage when the true MOI was complex but a LOD score analysis assumed simple models. We simulated data from 14 different genetic models, including dominant and recessive at high (80%) and low (20%) penetrances, intermediate models, and several additive two-locus models. We calculated LOD scores by assuming two simple models, dominant and recessive, each with 50% penetrance, then took the higher of the two LOD scores as the raw test statistic and corrected for multiple tests. We call this test statistic "MMLS-C." We found that the ELODs for MMLS-C are >=80% of the ELOD under the true model when the ELOD for the true model is >=3. Similarly, the power to reach a given LOD score was usually >=80% that of the true model, when the power under the true model was >=60%. These results underscore that a critical factor in LOD-score analysis is the MOI at the linked locus, not that of the disease or trait per se. Thus, a limited set of simple genetic models in LOD-score analysis can work well in testing for linkage.

Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech

PubMed Central

Wijsman, Ellen M.; Nato, Alejandro Q.; Matsushita, Mark M.; Chapman, Kathy L.; Stanaway, Ian B.; Wolff, John; Oda, Kaori; Gabo, Virginia B.; Raskind, Wendy H.

2016-01-01

Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS. PMID:27120335

Probabilistic record linkage

PubMed Central

Sayers, Adrian; Ben-Shlomo, Yoav; Blom, Ashley W; Steele, Fiona

2016-01-01

Abstract Studies involving the use of probabilistic record linkage are becoming increasingly common. However, the methods underpinning probabilistic record linkage are not widely taught or understood, and therefore these studies can appear to be a ‘black box’ research tool. In this article, we aim to describe the process of probabilistic record linkage through a simple exemplar. We first introduce the concept of deterministic linkage and contrast this with probabilistic linkage. We illustrate each step of the process using a simple exemplar and describe the data structure required to perform a probabilistic linkage. We describe the process of calculating and interpreting matched weights and how to convert matched weights into posterior probabilities of a match using Bayes theorem. We conclude this article with a brief discussion of some of the computational demands of record linkage, how you might assess the quality of your linkage algorithm, and how epidemiologists can maximize the value of their record-linked research using robust record linkage methods. PMID:26686842

Dissecting the genetic heterogeneity of myopia susceptibility in an Ashkenazi Jewish population using ordered subset analysis

PubMed Central

Simpson, Claire L.; Wojciechowski, Robert; Ibay, Grace; Stambolian, Dwight

2011-01-01

Purpose Despite many years of research, most of the genetic factors contributing to myopia development remain unknown. Genetic studies have pointed to a strong inherited component, but although many candidate regions have been implicated, few genes have been positively identified. Methods We have previously reported 2 genomewide linkage scans in a population of 63 highly aggregated Ashkenazi Jewish families that identified a locus on chromosome 22. Here we used ordered subset analysis (OSA), conditioned on non-parametric linkage to chromosome 22 to detect other chromosomal regions which had evidence of linkage to myopia in subsets of the families, but not the overall sample. Results Strong evidence of linkage to a 19-cM linkage interval with a peak OSA nonparametric allele-sharing logarithm-of-odds (LOD) score of 3.14 on 20p12-q11.1 (ΔLOD=2.39, empirical p=0.029) was identified in a subset of 20 families that also exhibited strong evidence of linkage to chromosome 22. One other locus also presented with suggestive LOD scores >2.0 on chromosome 11p14-q14 and one locus on chromosome 6q22-q24 had an OSA LOD score=1.76 (ΔLOD=1.65, empirical p=0.02). Conclusions The chromosome 6 and 20 loci are entirely novel and appear linked in a subset of families whose myopia is known to be linked to chromosome 22. The chromosome 11 locus overlaps with the known Myopia-7 (MYP7, OMIM 609256) locus. Using ordered subset analysis allows us to find additional loci linked to myopia in subsets of families, and underlines the complex genetic heterogeneity of myopia even in highly aggregated families and genetically isolated populations such as the Ashkenazi Jews. PMID:21738393

Wide-cross whole-genome radiation hybrid mapping of cotton (Gossypium hirsutum L.).

PubMed Central

Gao, Wenxiang; Chen, Z Jeffrey; Yu, John Z; Raska, Dwaine; Kohel, Russell J; Womack, James E; Stelly, David M

2004-01-01

We report the development and characterization of a "wide-cross whole-genome radiation hybrid" (WWRH) panel from cotton (Gossypium hirsutum L.). Chromosomes were segmented by gamma-irradiation of G. hirsutum (n = 26) pollen, and segmented chromosomes were rescued after in vivo fertilization of G. barbadense egg cells (n = 26). A 5-krad gamma-ray WWRH mapping panel (N = 93) was constructed and genotyped at 102 SSR loci. SSR marker retention frequencies were higher than those for animal systems and marker retention patterns were informative. Using the program RHMAP, 52 of 102 SSR markers were mapped into 16 syntenic groups. Linkage group 9 (LG 9) SSR markers BNL0625 and BNL2805 had been colocalized by linkage analysis, but their order was resolved by differential retention among WWRH plants. Two linkage groups, LG 13 and LG 9, were combined into one syntenic group, and the chromosome 1 linkage group marker BNL4053 was reassigned to chromosome 9. Analyses of cytogenetic stocks supported synteny of LG 9 and LG 13 and localized them to the short arm of chromosome 17. They also supported reassignment of marker BNL4053 to the long arm of chromosome 9. A WWRH map of the syntenic group composed of linkage groups 9 and 13 was constructed by maximum-likelihood analysis under the general retention model. The results demonstrate not only the feasibility of WWRH panel construction and mapping, but also complementarity to traditional linkage mapping and cytogenetic methods. PMID:15280245

Linkage disequilibrium fine mapping of quantitative trait loci: A simulation study

PubMed Central

Abdallah, Jihad M; Goffinet, Bruno; Cierco-Ayrolles, Christine; Pérez-Enciso, Miguel

2003-01-01

Recently, the use of linkage disequilibrium (LD) to locate genes which affect quantitative traits (QTL) has received an increasing interest, but the plausibility of fine mapping using linkage disequilibrium techniques for QTL has not been well studied. The main objectives of this work were to (1) measure the extent and pattern of LD between a putative QTL and nearby markers in finite populations and (2) investigate the usefulness of LD in fine mapping QTL in simulated populations using a dense map of multiallelic or biallelic marker loci. The test of association between a marker and QTL and the power of the test were calculated based on single-marker regression analysis. The results show the presence of substantial linkage disequilibrium with closely linked marker loci after 100 to 200 generations of random mating. Although the power to test the association with a frequent QTL of large effect was satisfactory, the power was low for the QTL with a small effect and/or low frequency. More powerful, multi-locus methods may be required to map low frequent QTL with small genetic effects, as well as combining both linkage and linkage disequilibrium information. The results also showed that multiallelic markers are more useful than biallelic markers to detect linkage disequilibrium and association at an equal distance. PMID:12939203

Nance-Horan syndrome: linkage analysis in a family from The Netherlands.

PubMed

Bergen, A A; ten Brink, J; Schuurman, E J; Bleeker-Wagemakers, E M

1994-05-01

Linkage analysis was carried out in a Dutch family with Nance-Horan (NH) syndrome. Close linkage without recombination between NH and the Xp loci DXS207, DXS43, and DXS365 (zmax = 3.23) was observed. Multipoint linkage analysis and the analysis of recombinations in multiple informative meioses suggest the genetic order Xcen-DMD (exon 49)-DXS451-(NH, DXS207, DXS365, DXS43)-(STS, DXF30)-Xpter. These data refine the localization of the NH locus on the distal Xp.

Distribution of lod scores in oligogenic linkage analysis.

PubMed

Williams, J T; North, K E; Martin, L J; Comuzzie, A G; Göring, H H; Blangero, J

2001-01-01

In variance component oligogenic linkage analysis it can happen that the residual additive genetic variance bounds to zero when estimating the effect of the ith quantitative trait locus. Using quantitative trait Q1 from the Genetic Analysis Workshop 12 simulated general population data, we compare the observed lod scores from oligogenic linkage analysis with the empirical lod score distribution under a null model of no linkage. We find that zero residual additive genetic variance in the null model alters the usual distribution of the likelihood-ratio statistic.

Ascertainment correction for Markov chain Monte Carlo segregation and linkage analysis of a quantitative trait.

PubMed

Ma, Jianzhong; Amos, Christopher I; Warwick Daw, E

2007-09-01

Although extended pedigrees are often sampled through probands with extreme levels of a quantitative trait, Markov chain Monte Carlo (MCMC) methods for segregation and linkage analysis have not been able to perform ascertainment corrections. Further, the extent to which ascertainment of pedigrees leads to biases in the estimation of segregation and linkage parameters has not been previously studied for MCMC procedures. In this paper, we studied these issues with a Bayesian MCMC approach for joint segregation and linkage analysis, as implemented in the package Loki. We first simulated pedigrees ascertained through individuals with extreme values of a quantitative trait in spirit of the sequential sampling theory of Cannings and Thompson [Cannings and Thompson [1977] Clin. Genet. 12:208-212]. Using our simulated data, we detected no bias in estimates of the trait locus location. However, in addition to allele frequencies, when the ascertainment threshold was higher than or close to the true value of the highest genotypic mean, bias was also found in the estimation of this parameter. When there were multiple trait loci, this bias destroyed the additivity of the effects of the trait loci, and caused biases in the estimation all genotypic means when a purely additive model was used for analyzing the data. To account for pedigree ascertainment with sequential sampling, we developed a Bayesian ascertainment approach and implemented Metropolis-Hastings updates in the MCMC samplers used in Loki. Ascertainment correction greatly reduced biases in parameter estimates. Our method is designed for multiple, but a fixed number of trait loci. Copyright (c) 2007 Wiley-Liss, Inc.

Principal Component and Linkage Analysis of Cardiovascular Risk Traits in the Norfolk Isolate

PubMed Central

Cox, Hannah C.; Bellis, Claire; Lea, Rod A.; Quinlan, Sharon; Hughes, Roger; Dyer, Thomas; Charlesworth, Jac; Blangero, John; Griffiths, Lyn R.

2009-01-01

Objective(s) An individual's risk of developing cardiovascular disease (CVD) is influenced by genetic factors. This study focussed on mapping genetic loci for CVD-risk traits in a unique population isolate derived from Norfolk Island. Methods This investigation focussed on 377 individuals descended from the population founders. Principal component analysis was used to extract orthogonal components from 11 cardiovascular risk traits. Multipoint variance component methods were used to assess genome-wide linkage using SOLAR to the derived factors. A total of 285 of the 377 related individuals were informative for linkage analysis. Results A total of 4 principal components accounting for 83% of the total variance were derived. Principal component 1 was loaded with body size indicators; principal component 2 with body size, cholesterol and triglyceride levels; principal component 3 with the blood pressures; and principal component 4 with LDL-cholesterol and total cholesterol levels. Suggestive evidence of linkage for principal component 2 (h2 = 0.35) was observed on chromosome 5q35 (LOD = 1.85; p = 0.0008). While peak regions on chromosome 10p11.2 (LOD = 1.27; p = 0.005) and 12q13 (LOD = 1.63; p = 0.003) were observed to segregate with principal components 1 (h2 = 0.33) and 4 (h2 = 0.42), respectively. Conclusion(s): This study investigated a number of CVD risk traits in a unique isolated population. Findings support the clustering of CVD risk traits and provide interesting evidence of a region on chromosome 5q35 segregating with weight, waist circumference, HDL-c and total triglyceride levels. PMID:19339786

Sequencing of oligosaccharides using enzyme array digestion with electrochemical and fluorescent detections

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, M.; Lee, C.S.

1997-12-31

The objective of this study is to develop a rapid and sensitive method for oligosaccharide sequencing. The oligosaccharides are subjected to the enzyme array digestion with exoglycosidases of known and well-defined specificities. The enzyme array method involves the division of oligosaccharide sample into aliquots, and the incubation of each aliquot with a precisely defined mixture of exoglycosidases. In the enzyme array method, the presence of a specific linkage anywhere in the oligosaccharide is determined by the inability of an enzyme mixture lacking a given enzyme to cleave that linkage ( a stop point) and the ability of the other enzymesmore » to cleave the linkage up to that point. The direct quantification of released monosaccharides from the enzyme array can be achieved by using pulsed amperometric detection (PAD) or by fluorescent derivatization with a fluorophoric agent. The measured monosaccharide concentrations in combination with the enzyme array analysis provide detail characterization of oligosaccharides with their sugar composition, configuration, and linkage information, The released monosaccharides are further quantified by anion exchange chromatography and capillary electrophoresis for the comparison with the results obtained from PAD and fluorescence measurements. Our enzyme array-electrochemical (or fluorescent) detection method does not require any separation procedure and any prior labeling of oligosaccharide and have several practical advantages over the current carbohydrate sequencing techniques including simplicity, speed, and the ability to use small amounts of starting material.« less

Genome-Wide Linkage and Regional Association Study of Blood Pressure Response to the Cold Pressor Test in Han Chinese: The GenSalt Study

PubMed Central

Yang, Xueli; Gu, Dongfeng; He, Jiang; Hixson, James E.; Rao, Dabeeru C.; Lu, Fanghong; Mu, Jianjun; Jaquish, Cashell E.; Chen, Jing; Huang, Jianfeng; Shimmin, Lawrence C.; Rice, Treva K.; Chen, Jichun; Wu, Xigui; Liu, Depei; Kelly, Tanika N.

2014-01-01

Background Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT. Methods and Results A total of 1,961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds, LOD ≥ 2). A suggestive linkage signal was identified for systolic BP (SBP) response to CPT at 20p13-20p12.3, with a maximum multipoint LOD score of 2.37. Based on regional association analysis with 1,351 SNPs in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure (MAP) responses to CPT (P = 8.8×10−6) after FDR adjustment for multiple comparisons. A similar trend was also observed for SBP response (P = 0.03) and DBP response (P = 4.6×10−5). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with SBP response to CPT (P = 4.0×10−5 and 2.7×10−4, respectively), and variants in genes MCM8 and STK35 were associated with MAP response to CPT (P = 1.5×10−5 and 5.0×10−5, respectively). Conclusions Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2 and STK35 in this region. Further work is warranted to confirm these findings. Clinical Trial Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT00721721. PMID:25028485

Chromosome 14 and late-onset familial alzheimer disease (FAD)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schellenberg, G.D.; Anderson, L.; Nemens, E.

1993-09-01

Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analysis were used, in 49 families with a mean age at onset [>=]60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependentmore » penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score [>=]2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P<.02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset [>=]60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. 37 refs., 1 fig., 6 tabs.« less

The use of analytical sedimentation velocity to extract thermodynamic linkage.

PubMed

Cole, James L; Correia, John J; Stafford, Walter F

2011-11-01

For 25 years, the Gibbs Conference on Biothermodynamics has focused on the use of thermodynamics to extract information about the mechanism and regulation of biological processes. This includes the determination of equilibrium constants for macromolecular interactions by high precision physical measurements. These approaches further reveal thermodynamic linkages to ligand binding events. Analytical ultracentrifugation has been a fundamental technique in the determination of macromolecular reaction stoichiometry and energetics for 85 years. This approach is highly amenable to the extraction of thermodynamic couplings to small molecule binding in the overall reaction pathway. In the 1980s this approach was extended to the use of sedimentation velocity techniques, primarily by the analysis of tubulin-drug interactions by Na and Timasheff. This transport method necessarily incorporates the complexity of both hydrodynamic and thermodynamic nonideality. The advent of modern computational methods in the last 20 years has subsequently made the analysis of sedimentation velocity data for interacting systems more robust and rigorous. Here we review three examples where sedimentation velocity has been useful at extracting thermodynamic information about reaction stoichiometry and energetics. Approaches to extract linkage to small molecule binding and the influence of hydrodynamic nonideality are emphasized. These methods are shown to also apply to the collection of fluorescence data with the new Aviv FDS. Copyright © 2011 Elsevier B.V. All rights reserved.

The use of analytical sedimentation velocity to extract thermodynamic linkage

PubMed Central

Cole, James L.; Correia, John J.; Stafford, Walter F.

2011-01-01

For 25 years, the Gibbs Conference on Biothermodynamics has focused on the use of thermodynamics to extract information about the mechanism and regulation of biological processes. This includes the determination of equilibrium constants for macromolecular interactions by high precision physical measurements. These approaches further reveal thermodynamic linkages to ligand binding events. Analytical ultracentrifugation has been a fundamental technique in the determination of macromolecular reaction stoichiometry and energetics for 85 years. This approach is highly amenable to the extraction of thermodynamic couplings to small molecule binding in the overall reaction pathway. In the 1980’s this approach was extended to the use of sedimentation velocity techniques, primarily by the analysis of tubulin-drug interactions by Na and Timasheff. This transport method necessarily incorporates the complexity of both hydrodynamic and thermodynamic nonideality. The advent of modern computational methods in the last 20 years has subsequently made the analysis of sedimentation velocity data for interacting systems more robust and rigorous. Here we review three examples where sedimentation velocity has been useful at extracting thermodynamic information about reaction stoichiometry and energetics. Approaches to extract linkage to small molecule binding and the influence of hydrodynamic nonideality are emphasized. These methods are shown to also apply to the collection of fluorescence data with the new Aviv FDS. PMID:21703752

DNA Commission of the International Society for Forensic Genetics (ISFG): Guidelines on the use of X-STRs in kinship analysis.

PubMed

Tillmar, Andreas O; Kling, Daniel; Butler, John M; Parson, Walther; Prinz, Mechthild; Schneider, Peter M; Egeland, Thore; Gusmão, Leonor

2017-07-01

Forensic genetic laboratories perform an increasing amount of genetic analyses of the X chromosome, in particular to solve complex cases of kinship analysis. For some biological relationships X-chromosomal markers can be more informative than autosomal markers, and there are a large number of markers, methods and databases that have been described for forensic use. Due to their particular mode of inheritance, and their physical location on a single chromosome, some specific considerations are required when estimating the weight of evidence for X-chromosomal marker DNA data. The DNA Commission of the International Society for Forensic Genetics (ISFG) hereby presents guidelines and recommendations for the use of X-chromosomal markers in kinship analysis with a special focus on the biostatistical evaluation. Linkage and linkage disequilibrium (association of alleles) are of special importance for such evaluations and these concepts and the implications for likelihood calculations are described in more detail. Furthermore it is important to use appropriate computer software that accounts for linkage and linkage disequilibrium among loci, as well as for mutations. Even though some software exist, there is still a need for further improvement of dedicated software. Copyright © 2017 Elsevier B.V. All rights reserved.

Irish study of high-density Schizophrenia families: Field methods and power to detect linkage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendler, K.S.; Straub, R.E.; MacLean, C.J.

Large samples of multiplex pedigrees will probably be needed to detect susceptibility loci for schizophrenia by linkage analysis. Standardized ascertainment of such pedigrees from culturally and ethnically homogeneous populations may improve the probability of detection and replication of linkage. The Irish Study of High-Density Schizophrenia Families (ISHDSF) was formed from standardized ascertainment of multiplex schizophrenia families in 39 psychiatric facilities covering over 90% of the population in Ireland and Northern Ireland. We here describe a phenotypic sample and a subset thereof, the linkage sample. Individuals were included in the phenotypic sample if adequate diagnostic information, based on personal interview and/ormore » hospital record, was available. Only individuals with available DNA were included in the linkage sample. Inclusion of a pedigree into the phenotypic sample required at least two first, second, or third degree relatives with non-affective psychosis (NAP), one of whom had schizophrenia (S) or poor-outcome schizoaffective disorder (PO-SAD). Entry into the linkage sample required DNA samples on at least two individuals with NAP, of whom at least one had S or PO-SAD. Affection was defined by narrow, intermediate, and broad criteria. 75 refs., 6 tabs.« less

Nonlinear Analysis of Time Series in Genome-Wide Linkage Disequilibrium Data

NASA Astrophysics Data System (ADS)

Hernández-Lemus, Enrique; Estrada-Gil, Jesús K.; Silva-Zolezzi, Irma; Fernández-López, J. Carlos; Hidalgo-Miranda, Alfredo; Jiménez-Sánchez, Gerardo

2008-02-01

The statistical study of large scale genomic data has turned out to be a very important tool in population genetics. Quantitative methods are essential to understand and implement association studies in the biomedical and health sciences. Nevertheless, the characterization of recently admixed populations has been an elusive problem due to the presence of a number of complex phenomena. For example, linkage disequilibrium structures are thought to be more complex than their non-recently admixed population counterparts, presenting the so-called ancestry blocks, admixed regions that are not yet smoothed by the effect of genetic recombination. In order to distinguish characteristic features for various populations we have implemented several methods, some of them borrowed or adapted from the analysis of nonlinear time series in statistical physics and quantitative physiology. We calculate the main fractal dimensions (Kolmogorov's capacity, information dimension and correlation dimension, usually named, D0, D1 and D2). We also have made detrended fluctuation analysis and information based similarity index calculations for the probability distribution of correlations of linkage disequilibrium coefficient of six recently admixed (mestizo) populations within the Mexican Genome Diversity Project [1] and for the non-recently admixed populations in the International HapMap Project [2]. Nonlinear correlations showed up as a consequence of internal structure within the haplotype distributions. The analysis of these correlations as well as the scope and limitations of these procedures within the biomedical sciences are discussed.

Use of linkage mapping and centrality analysis across habitat gradients to conserve connectivity of gray wolf populations in western North America.

PubMed

Carroll, Carlos; McRae, Brad H; Brookes, Allen

2012-02-01

Centrality metrics evaluate paths between all possible pairwise combinations of sites on a landscape to rank the contribution of each site to facilitating ecological flows across the network of sites. Computational advances now allow application of centrality metrics to landscapes represented as continuous gradients of habitat quality. This avoids the binary classification of landscapes into patch and matrix required by patch-based graph analyses of connectivity. It also avoids the focus on delineating paths between individual pairs of core areas characteristic of most corridor- or linkage-mapping methods of connectivity analysis. Conservation of regional habitat connectivity has the potential to facilitate recovery of the gray wolf (Canis lupus), a species currently recolonizing portions of its historic range in the western United States. We applied 3 contrasting linkage-mapping methods (shortest path, current flow, and minimum-cost-maximum-flow) to spatial data representing wolf habitat to analyze connectivity between wolf populations in central Idaho and Yellowstone National Park (Wyoming). We then applied 3 analogous betweenness centrality metrics to analyze connectivity of wolf habitat throughout the northwestern United States and southwestern Canada to determine where it might be possible to facilitate range expansion and interpopulation dispersal. We developed software to facilitate application of centrality metrics. Shortest-path betweenness centrality identified a minimal network of linkages analogous to those identified by least-cost-path corridor mapping. Current flow and minimum-cost-maximum-flow betweenness centrality identified diffuse networks that included alternative linkages, which will allow greater flexibility in planning. Minimum-cost-maximum-flow betweenness centrality, by integrating both land cost and habitat capacity, allows connectivity to be considered within planning processes that seek to maximize species protection at minimum cost. Centrality analysis is relevant to conservation and landscape genetics at a range of spatial extents, but it may be most broadly applicable within single- and multispecies planning efforts to conserve regional habitat connectivity. ©2011 Society for Conservation Biology.

Nickel-Catalyzed Proton-Deuterium Exchange (HDX) Procedures for Glycosidic Linkage Analysis of Complex Carbohydrates.

PubMed

Price, Neil P J; Hartman, Trina M; Vermillion, Karl E

2015-07-21

The structural analysis of complex carbohydrates typically requires the assignment of three parameters: monosaccharide composition, the position of glycosidic linkages between monosaccharides, and the position and nature of noncarbohydrate substituents. The glycosidic linkage positions are often determined by permethylation analysis, but this can be complicated by high viscosity or poor solubility, resulting in under-methylation. This is a drawback because an under-methylated position may be misinterpreted as the erroneous site of a linkage or substituent. Here, we describe an alternative approach to linkage analysis that makes use of a nonreversible deuterium exchange of C-H protons on the carbohydrate backbone. The exchange reaction is conducted in deuterated water catalyzed by Raney nickel, and results in the selective exchange of C-H protons adjacent to free hydroxyl groups. Hence, the position of the residual C-H protons is indicative of the position of glycosidic linkages or other substituents and can be readily assigned by heteronuclear single quantum coherence-nuclear magnetic resonance (HSQC-NMR) or, following suitable derivatization, by gas chromatography-mass spectroscopy (GC/MS) analysis. Moreover, because the only changes to the parent sugar are proton/deuterium exchanges, the composition and linkage analysis can be determined in a single step.

Linkage of Viral Sequences among HIV-Infected Village Residents in Botswana: Estimation of Linkage Rates in the Presence of Missing Data

PubMed Central

Carnegie, Nicole Bohme; Wang, Rui; Novitsky, Vladimir; De Gruttola, Victor

2014-01-01

Linkage analysis is useful in investigating disease transmission dynamics and the effect of interventions on them, but estimates of probabilities of linkage between infected people from observed data can be biased downward when missingness is informative. We investigate variation in the rates at which subjects' viral genotypes link across groups defined by viral load (low/high) and antiretroviral treatment (ART) status using blood samples from household surveys in the Northeast sector of Mochudi, Botswana. The probability of obtaining a sequence from a sample varies with viral load; samples with low viral load are harder to amplify. Pairwise genetic distances were estimated from aligned nucleotide sequences of HIV-1C env gp120. It is first shown that the probability that randomly selected sequences are linked can be estimated consistently from observed data. This is then used to develop estimates of the probability that a sequence from one group links to at least one sequence from another group under the assumption of independence across pairs. Furthermore, a resampling approach is developed that accounts for the presence of correlation across pairs, with diagnostics for assessing the reliability of the method. Sequences were obtained for 65% of subjects with high viral load (HVL, n = 117), 54% of subjects with low viral load but not on ART (LVL, n = 180), and 45% of subjects on ART (ART, n = 126). The probability of linkage between two individuals is highest if both have HVL, and lowest if one has LVL and the other has LVL or is on ART. Linkage across groups is high for HVL and lower for LVL and ART. Adjustment for missing data increases the group-wise linkage rates by 40–100%, and changes the relative rates between groups. Bias in inferences regarding HIV viral linkage that arise from differential ability to genotype samples can be reduced by appropriate methods for accommodating missing data. PMID:24415932

Linkage of viral sequences among HIV-infected village residents in Botswana: estimation of linkage rates in the presence of missing data.

PubMed

Carnegie, Nicole Bohme; Wang, Rui; Novitsky, Vladimir; De Gruttola, Victor

2014-01-01

Linkage analysis is useful in investigating disease transmission dynamics and the effect of interventions on them, but estimates of probabilities of linkage between infected people from observed data can be biased downward when missingness is informative. We investigate variation in the rates at which subjects' viral genotypes link across groups defined by viral load (low/high) and antiretroviral treatment (ART) status using blood samples from household surveys in the Northeast sector of Mochudi, Botswana. The probability of obtaining a sequence from a sample varies with viral load; samples with low viral load are harder to amplify. Pairwise genetic distances were estimated from aligned nucleotide sequences of HIV-1C env gp120. It is first shown that the probability that randomly selected sequences are linked can be estimated consistently from observed data. This is then used to develop estimates of the probability that a sequence from one group links to at least one sequence from another group under the assumption of independence across pairs. Furthermore, a resampling approach is developed that accounts for the presence of correlation across pairs, with diagnostics for assessing the reliability of the method. Sequences were obtained for 65% of subjects with high viral load (HVL, n = 117), 54% of subjects with low viral load but not on ART (LVL, n = 180), and 45% of subjects on ART (ART, n = 126). The probability of linkage between two individuals is highest if both have HVL, and lowest if one has LVL and the other has LVL or is on ART. Linkage across groups is high for HVL and lower for LVL and ART. Adjustment for missing data increases the group-wise linkage rates by 40-100%, and changes the relative rates between groups. Bias in inferences regarding HIV viral linkage that arise from differential ability to genotype samples can be reduced by appropriate methods for accommodating missing data.

Genome-Wide Linkage Analysis to Identify Genetic Modifiers of ALK Mutation Penetrance in Familial Neuroblastoma

PubMed Central

Devoto, Marcella; Specchia, Claudia; Laudenslager, Marci; Longo, Luca; Hakonarson, Hakon; Maris, John; Mossé, Yael

2011-01-01

Background Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB. Methods To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations. Results The region with the highest LOD score was located at chromosome 2p23–p24 and included the ALK locus under models of dominant and recessive inheritance. Conclusions This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases. PMID:21734404

Genome-wide Linkage Analysis for Identifying Quantitative Trait Loci Involved in the Regulation of Lipoprotein a (Lpa) Levels

PubMed Central

López, Sonia; Buil, Alfonso; Ordoñez, Jordi; Souto, Juan Carlos; Almasy, Laura; Lathrop, Mark; Blangero, John; Blanco-Vaca, Francisco; Fontcuberta, Jordi; Soria, José Manuel

2009-01-01

Lipoprotein Lp(a) levels are highly heritable and are associated with cardiovascular risk. We performed a genome-wide linkage analysis to delineate the genomic regions that influence the concentration of Lp(a) in families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. Lp(a) levels were measured in 387 individuals belonging to 21 extended Spanish families. A total of 485 DNA microsatellite markers were genotyped to provide a 7.1 cM genetic map. A variance component linkage method was used to evaluate linkage and to detect quantitative trait loci (QTLs). The main QTL that showed strong evidence of linkage with Lp(a) levels was located at the structural gene for apo(a) on Chromosome 6 (LOD score=13.8). Interestingly, another QTL influencing Lp(a) concentration was located on Chromosome 2 with a LOD score of 2.01. This region contains several candidate genes. One of them is the tissue factor pathway inhibitor (TFPI), which has antithrombotic action and also has the ability to bind lipoproteins. However, quantitative trait association analyses performed with 12 SNPs in TFPI gene revealed no association with Lp(a) levels. Our study confirms previous results on the genetic basis of Lp(a) levels. In addition, we report a new QTL on Chromosome 2 involved in the quantitative variation of Lp(a). These data should serve as the basis for further detection of candidate genes and to elucidate the relationship between the concentration of Lp(a) and cardiovascular risk. PMID:18560444

Limited privacy protection and poor sensitivity: Is it time to move on from the statistical linkage key-581?

PubMed

Randall, Sean M; Ferrante, Anna M; Boyd, James H; Brown, Adrian P; Semmens, James B

2016-08-01

The statistical linkage key (SLK-581) is a common tool for record linkage in Australia, due to its ability to provide some privacy protection. However, newer privacy-preserving approaches may provide greater privacy protection, while allowing high-quality linkage. To evaluate the standard SLK-581, encrypted SLK-581 and a newer privacy-preserving approach using Bloom filters, in terms of both privacy and linkage quality. Linkage quality was compared by conducting linkages on Australian health datasets using these three techniques and examining results. Privacy was compared qualitatively in relation to a series of scenarios where privacy breaches may occur. The Bloom filter technique offered greater privacy protection and linkage quality compared to the SLK-based method commonly used in Australia. The adoption of new privacy-preserving methods would allow both greater confidence in research results, while significantly improving privacy protection. © The Author(s) 2016.

Exploiting Genome Structure in Association Analysis

PubMed Central

Kim, Seyoung

2014-01-01

Abstract A genome-wide association study involves examining a large number of single-nucleotide polymorphisms (SNPs) to identify SNPs that are significantly associated with the given phenotype, while trying to reduce the false positive rate. Although haplotype-based association methods have been proposed to accommodate correlation information across nearby SNPs that are in linkage disequilibrium, none of these methods directly incorporated the structural information such as recombination events along chromosome. In this paper, we propose a new approach called stochastic block lasso for association mapping that exploits prior knowledge on linkage disequilibrium structure in the genome such as recombination rates and distances between adjacent SNPs in order to increase the power of detecting true associations while reducing false positives. Following a typical linear regression framework with the genotypes as inputs and the phenotype as output, our proposed method employs a sparsity-enforcing Laplacian prior for the regression coefficients, augmented by a first-order Markov process along the sequence of SNPs that incorporates the prior information on the linkage disequilibrium structure. The Markov-chain prior models the structural dependencies between a pair of adjacent SNPs, and allows us to look for association SNPs in a coupled manner, combining strength from multiple nearby SNPs. Our results on HapMap-simulated datasets and mouse datasets show that there is a significant advantage in incorporating the prior knowledge on linkage disequilibrium structure for marker identification under whole-genome association. PMID:21548809

Computer Simulation Is an Undervalued Tool for Genetic Analysis: A Historical View and Presentation of SHIMSHON – A Web-Based Genetic Simulation Package

PubMed Central

Greenberg, David A.

2011-01-01

Computer simulation methods are under-used tools in genetic analysis because simulation approaches have been portrayed as inferior to analytic methods. Even when simulation is used, its advantages are not fully exploited. Here, I present SHIMSHON, our package of genetic simulation programs that have been developed, tested, used for research, and used to generated data for Genetic Analysis Workshops (GAW). These simulation programs, now web-accessible, can be used by anyone to answer questions about designing and analyzing genetic disease studies for locus identification. This work has three foci: (1) the historical context of SHIMSHON's development, suggesting why simulation has not been more widely used so far. (2) Advantages of simulation: computer simulation helps us to understand how genetic analysis methods work. It has advantages for understanding disease inheritance and methods for gene searches. Furthermore, simulation methods can be used to answer fundamental questions that either cannot be answered by analytical approaches or cannot even be defined until the problems are identified and studied, using simulation. (3) I argue that, because simulation was not accepted, there was a failure to grasp the meaning of some simulation-based studies of linkage. This may have contributed to perceived weaknesses in linkage analysis; weaknesses that did not, in fact, exist. PMID:22189467

Genetic diversity, linkage disequilibrium, population structure and construction of a core collection of Prunus avium L. landraces and bred cultivars.

PubMed

Campoy, José Antonio; Lerigoleur-Balsemin, Emilie; Christmann, Hélène; Beauvieux, Rémi; Girollet, Nabil; Quero-García, José; Dirlewanger, Elisabeth; Barreneche, Teresa

2016-02-24

Depiction of the genetic diversity, linkage disequilibrium (LD) and population structure is essential for the efficient organization and exploitation of genetic resources. The objectives of this study were to (i) to evaluate the genetic diversity and to detect the patterns of LD, (ii) to estimate the levels of population structure and (iii) to identify a 'core collection' suitable for association genetic studies in sweet cherry. A total of 210 genotypes including modern cultivars and landraces from 16 countries were genotyped using the RosBREED cherry 6 K SNP array v1. Two groups, mainly bred cultivars and landraces, respectively, were first detected using STRUCTURE software and confirmed by Principal Coordinate Analysis (PCoA). Further analyses identified nine subgroups using STRUCTURE and Discriminant Analysis of Principal Components (DAPC). Several sub-groups correspond to different eco-geographic regions of landraces distribution. Linkage disequilibrium was evaluated showing lower values than in peach, the reference Prunus species. A 'core collection' containing 156 accessions was selected using the maximum length sub tree method. The present study constitutes the first population genetics analysis in cultivated sweet cherry using a medium-density SNP (single nucleotide polymorphism) marker array. We provided estimations of linkage disequilibrium, genetic structure and the definition of a first INRA's Sweet Cherry core collection useful for breeding programs, germplasm management and association genetics studies.

On normality, ethnicity, and missing values in quantitative trait locus mapping

PubMed Central

Labbe, Aurélie; Wormald, Hanna

2005-01-01

Background This paper deals with the detection of significant linkage for quantitative traits using a variance components approach. Microsatellite markers were obtained for the Genetic Analysis Workshop 14 Collaborative Study on the Genetics of Alcoholism data. Ethnic heterogeneity, highly skewed quantitative measures, and a high rate of missing values are all present in this dataset and well known to impact upon linkage analysis. This makes it a good candidate for investigation. Results As expected, we observed a number of changes in LOD scores, especially for chromosomes 1, 7, and 18, along with the three factors studied. A dramatic example of such changes can be found in chromosome 7. Highly significant linkage to one of the quantitative traits became insignificant when a proper normalizing transformation of the trait was used and when analysis was carried out on an ethnically homogeneous subset of the original pedigrees. Conclusion In agreement with existing literature, transforming a trait to ensure normality using a Box-Cox transformation is highly recommended in order to avoid false-positive linkages. Furthermore, pedigrees should be sorted by ethnic groups and analyses should be carried out separately. Finally, one should be aware that the inclusion of covariates with a high rate of missing values reduces considerably the number of subjects included in the model. In such a case, the loss in power may be large. Imputation methods are then recommended. PMID:16451664

[Linkage analysis of susceptibility loci in 2 target chromosomes in pedigrees with paranoid schizophrenia and undifferentiated schizophrenia].

PubMed

Zeng, Li-ping; Hu, Zheng-mao; Mu, Li-li; Mei, Gui-sen; Lu, Xiu-ling; Zheng, Yong-jun; Li, Pei-jian; Zhang, Ying-xue; Pan, Qian; Long, Zhi-gao; Dai, He-ping; Zhang, Zhuo-hua; Xia, Jia-hui; Zhao, Jing-ping; Xia, Kun

2011-06-01

To investigate the relationship of susceptibility loci in chromosomes 1q21-25 and 6p21-25 and schizophrenia subtypes in Chinese population. A genomic scan and parametric and non-parametric analyses were performed on 242 individuals from 36 schizophrenia pedigrees, including 19 paranoid schizophrenia and 17 undifferentiated schizophrenia pedigrees, from Henan province of China using 5 microsatellite markers in the chromosome region 1q21-25 and 8 microsatellite markers in the chromosome region 6p21-25, which were the candidates of previous studies. All affected subjects were diagnosed and typed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR; American Psychiatric Association, 2000). All subjects signed informed consent. In chromosome 1, parametric analysis under the dominant inheritance mode of all 36 pedigrees showed that the maximum multi-point heterogeneity Log of odds score method (HLOD) score was 1.33 (α = 0.38). The non-parametric analysis and the single point and multi-point nonparametric linkage (NPL) scores suggested linkage at D1S484, D1S2878, and D1S196. In the 19 paranoid schizophrenias pedigrees, linkage was not observed for any of the 5 markers. In the 17 undifferentiated schizophrenia pedigrees, the multi-point NPL score was 1.60 (P= 0.0367) at D1S484. The single point NPL score was 1.95(P= 0.0145) and the multi-point NPL score was 2.39 (P= 0.0041) at D1S2878. Additionally, the multi-point NPL score was 1.74 (P= 0.0255) at D1S196. These same three loci showed suggestive linkage during the integrative analysis of all 36 pedigrees. In chromosome 6, parametric linkage analysis under the dominant and recessive inheritance and the non-parametric linkage analysis of all 36 pedigrees and the 17 undifferentiated schizophrenia pedigrees, linkage was not observed for any of the 8 markers. In the 19 paranoid schizophrenias pedigrees, parametric analysis showed that under recessive inheritance mode the maximum single-point HLOD score was 1.26 (α = 0.40) and the multi-point HLOD was 1.12 (α = 0.38) at D6S289 in the chromosome 6p23. In nonparametric analysis, the single-point NPL score was 1.52 (P= 0.0402) and the multi-point NPL score was 1.92 (P= 0.0206) at D6S289. Susceptibility genes correlated with undifferentiated schizophrenia pedigrees from D1S484, D1S2878, D1S196 loci, and those correlated with paranoid schizophrenia pedigrees from D6S289 locus are likely present in chromosome regions 1q23.3 and 1q24.2, and chromosome region 6p23, respectively.

Nickel-catalyzed proton-deuterium exchange (HDX) procedures for glycosidic linkage analysis of complex carbohydrates

USDA-ARS?s Scientific Manuscript database

The structural analysis of complex carbohydrates typically requires the assignment of three parameters: monosaccharide composition, the position of glycosidic linkages between monosaccharides, and the position and nature of non-carbohydrate substituents. The glycosidic linkage positions are often de...

Estimating parameters for probabilistic linkage of privacy-preserved datasets.

PubMed

Brown, Adrian P; Randall, Sean M; Ferrante, Anna M; Semmens, James B; Boyd, James H

2017-07-10

Probabilistic record linkage is a process used to bring together person-based records from within the same dataset (de-duplication) or from disparate datasets using pairwise comparisons and matching probabilities. The linkage strategy and associated match probabilities are often estimated through investigations into data quality and manual inspection. However, as privacy-preserved datasets comprise encrypted data, such methods are not possible. In this paper, we present a method for estimating the probabilities and threshold values for probabilistic privacy-preserved record linkage using Bloom filters. Our method was tested through a simulation study using synthetic data, followed by an application using real-world administrative data. Synthetic datasets were generated with error rates from zero to 20% error. Our method was used to estimate parameters (probabilities and thresholds) for de-duplication linkages. Linkage quality was determined by F-measure. Each dataset was privacy-preserved using separate Bloom filters for each field. Match probabilities were estimated using the expectation-maximisation (EM) algorithm on the privacy-preserved data. Threshold cut-off values were determined by an extension to the EM algorithm allowing linkage quality to be estimated for each possible threshold. De-duplication linkages of each privacy-preserved dataset were performed using both estimated and calculated probabilities. Linkage quality using the F-measure at the estimated threshold values was also compared to the highest F-measure. Three large administrative datasets were used to demonstrate the applicability of the probability and threshold estimation technique on real-world data. Linkage of the synthetic datasets using the estimated probabilities produced an F-measure that was comparable to the F-measure using calculated probabilities, even with up to 20% error. Linkage of the administrative datasets using estimated probabilities produced an F-measure that was higher than the F-measure using calculated probabilities. Further, the threshold estimation yielded results for F-measure that were only slightly below the highest possible for those probabilities. The method appears highly accurate across a spectrum of datasets with varying degrees of error. As there are few alternatives for parameter estimation, the approach is a major step towards providing a complete operational approach for probabilistic linkage of privacy-preserved datasets.

Pedigree data analysis with crossover interference.

PubMed Central

Browning, Sharon

2003-01-01

We propose a new method for calculating probabilities for pedigree genetic data that incorporates crossover interference using the chi-square models. Applications include relationship inference, genetic map construction, and linkage analysis. The method is based on importance sampling of unobserved inheritance patterns conditional on the observed genotype data and takes advantage of fast algorithms for no-interference models while using reweighting to allow for interference. We show that the method is effective for arbitrarily many markers with small pedigrees. PMID:12930760

Nickel-catalyzed proton-deuterium exchange (HDX) for linkage analysis of complex carbohydrates

USDA-ARS?s Scientific Manuscript database

The structural assignment of complex carbohydrates typically requires the analysis of at least three parameters: 1. composition; 2. linkage; and 3. substituents. These are often assigned on a small scale by gas chromatography/mass spectrometry (GC/MS). Linkage positions are determined by permethylat...

Data cleaning and management protocols for linked perinatal research data: a good practice example from the Smoking MUMS (Maternal Use of Medications and Safety) Study.

PubMed

Tran, Duong Thuy; Havard, Alys; Jorm, Louisa R

2017-07-11

Data cleaning is an important quality assurance in data linkage research studies. This paper presents the data cleaning and preparation process for a large-scale cross-jurisdictional Australian study (the Smoking MUMS Study) to evaluate the utilisation and safety of smoking cessation pharmacotherapies during pregnancy. Perinatal records for all deliveries (2003-2012) in the States of New South Wales (NSW) and Western Australia were linked to State-based data collections including hospital separation, emergency department and death data (mothers and babies) and congenital defect notifications (babies in NSW) by State-based data linkage units. A national data linkage unit linked pharmaceutical dispensing data for the mothers. All linkages were probabilistic. Twenty two steps assessed the uniqueness of records and consistency of items within and across data sources, resolved discrepancies in the linkages between units, and identified women having records in both States. State-based linkages yielded a cohort of 783,471 mothers and 1,232,440 babies. Likely false positive links relating to 3703 mothers were identified. Corrections of baby's date of birth and age, and parity were made for 43,578 records while 1996 records were flagged as duplicates. Checks for the uniqueness of the matches between State and national linkages detected 3404 ID clusters, suggestive of missed links in the State linkages, and identified 1986 women who had records in both States. Analysis of content data can identify inaccurate links that cannot be detected by data linkage units that have access to personal identifiers only. Perinatal researchers are encouraged to adopt the methods presented to ensure quality and consistency among studies using linked administrative data.

Localization of genes involved in the metabolic syndrome using multivariate linkage analysis.

PubMed

Olswold, Curtis; de Andrade, Mariza

2003-12-31

There are no well accepted criteria for the diagnosis of the metabolic syndrome. However, the metabolic syndrome is identified clinically by the presence of three or more of these five variables: larger waist circumference, higher triglyceride levels, lower HDL-cholesterol concentrations, hypertension, and impaired fasting glucose. We use sets of two or three variables, which are available in the Framingham Heart Study data set, to localize genes responsible for this syndrome using multivariate quantitative linkage analysis. This analysis demonstrates the applicability of using multivariate linkage analysis and how its use increases the power to detect linkage when genes are involved in the same disease mechanism.

An Assessment of the Condition of Coral Reefs off the Former Navy Bombing Ranges at Isla De Culebra and Isla De Vieques, Puerto Rico

DTIC Science & Technology

2005-04-01

Bray-Curtis distance measure with an Unweighted Pair Group Method with Arithmetic Averages ( UPGMA ) linkage method to perform a cluster analysis of the...59 35 Comparison of reef condition indicators clustering by UPGMA analysis...Polyvinyl Chloride RBD Red-band Disease SACEX Supporting Arms Coordination Exercise SAV Submerged Aquatic Vegetation SD Standard Deviation UPGMA

Estimation and test for linkage between markers: a comparison of lod score and χ (2) test in a linkage study of maritime pine (Pinus pinaster Ait.).

PubMed

Gerber, S; Rodolphe, F

1994-06-01

The first step in the construction of a linkage map involves the estimation and test for linkage between all possible pairs of markers. The lod score method is used in many linkage studies for the latter purpose. In contrast with classical statistical tests, this method does not rely on the choice of a first-type error level. We thus provide a comparison between the lod score and a χ (2) test on linkage data from a gymnosperm, the maritime pine. The lod score appears to be a very conservative test with the usual thresholds. Its severity depends on the type of data used.

A guide to evaluating linkage quality for the analysis of linked data.

PubMed

Harron, Katie L; Doidge, James C; Knight, Hannah E; Gilbert, Ruth E; Goldstein, Harvey; Cromwell, David A; van der Meulen, Jan H

2017-10-01

Linked datasets are an important resource for epidemiological and clinical studies, but linkage error can lead to biased results. For data security reasons, linkage of personal identifiers is often performed by a third party, making it difficult for researchers to assess the quality of the linked dataset in the context of specific research questions. This is compounded by a lack of guidance on how to determine the potential impact of linkage error. We describe how linkage quality can be evaluated and provide widely applicable guidance for both data providers and researchers. Using an illustrative example of a linked dataset of maternal and baby hospital records, we demonstrate three approaches for evaluating linkage quality: applying the linkage algorithm to a subset of gold standard data to quantify linkage error; comparing characteristics of linked and unlinked data to identify potential sources of bias; and evaluating the sensitivity of results to changes in the linkage procedure. These approaches can inform our understanding of the potential impact of linkage error and provide an opportunity to select the most appropriate linkage procedure for a specific analysis. Evaluating linkage quality in this way will improve the quality and transparency of epidemiological and clinical research using linked data. © The Author 2017. Published by Oxford University Press on behalf of the International Epidemiological Association.

Meta-analysis of genome-wide scans for blood pressure in African American and Nigerian samples. The National Heart, Lung, and Blood Institute GeneLink Project.

PubMed

Rice, Treva; Cooper, Richard S; Wu, Xiaodong; Bouchard, Claude; Rankinen, Tuomo; Rao, D C; Jaquish, Cashell E; Fabsitz, Richard R; Province, Michael A

2006-03-01

In many genetic studies of complex traits, sample sizes are often too small to detect linkages of low-to-moderate effects. However, the combined linkage evidence across several studies can be synthesized using meta-analysis with the aim of providing more definitive support of linkage. In the current study using the National Heart, Lung, and Blood Institute (NHLBI) GeneLink Project, a meta-analysis based on a modification of Fisher's method of pooling P values was used to investigate linkage for systolic blood pressure (SBP) and diastolic blood pressure (DBP) values across three studies involving African American and Nigerian families (HyperGEN, Health, Risk Factors, Exercise Training and Genetics [HERITAGE], and Genetics of Hypertension in Blacks). The meta results suggest two regions (2p and 7p) provide enhanced linkage evidence compared with the individual study results. The maximal meta Lod score of 2.9 on 2p14-p13.1 (64-78 cM) represented approximately 1-Lod unit increase over the respective individual study scores. This general region has been implicated previously involving primarily families of white ethnicity and provides confirmatory evidence that this QTL is common across ethnic groups. The second finding at 7p21.3-p15.3 (8-25 cM) provided a meta Lod of 3.5. Although region was implicated primarily in the Nigerian subjects the low-level but consistent support involving the African American families (individual Lod score of 1.0) suggests a novel QTL with respect to BP variation in individuals of black ethnicity. Follow-up studies involving positional cloning efforts of the combined families showing linkage evidence in these regions (particularly 2p) may be warranted to verify these findings and identify the genes and causative variants.

Motor sequencing deficit as an endophenotype of speech sound disorder: A genome-wide linkage analysis in a multigenerational family

PubMed Central

Peter, Beate; Matsushita, Mark; Raskind, Wendy H.

2012-01-01

Objectives The purpose of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD. Methods In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were conducted using a genome-wide panel of 404 microsatellites. Results In seven of the ten family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect component traits of language impairment. Conclusions Results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification. PMID:22517379

The importance of including local correlation times in the calculation of inter-proton distances from NMR measurements: ignoring local correlation times leads to significant errors in the conformational analysis of the Glc alpha1-2Glc alpha linkage by NMR spectroscopy.

PubMed

Mackeen, Mukram; Almond, Andrew; Cumpstey, Ian; Enis, Seth C; Kupce, Eriks; Butters, Terry D; Fairbanks, Antony J; Dwek, Raymond A; Wormald, Mark R

2006-06-07

The experimental determination of oligosaccharide conformations has traditionally used cross-linkage 1H-1H NOE/ROEs. As relatively few NOEs are observed, to provide sufficient conformational constraints this method relies on: accurate quantification of NOE intensities (positive constraints); analysis of absent NOEs (negative constraints); and hence calculation of inter-proton distances using the two-spin approximation. We have compared the results obtained by using 1H 2D NOESY, ROESY and T-ROESY experiments at 500 and 700 MHz to determine the conformation of the terminal Glc alpha1-2Glc alpha linkage in a dodecasaccharide and a related tetrasaccharide. For the tetrasaccharide, the NOESY and ROESY spectra produced the same qualitative pattern of linkage cross-peaks but the quantitative pattern, the relative peak intensities, was different. For the dodecasaccharide, the NOESY and ROESY spectra at 500 MHz produced a different qualitative pattern of linkage cross-peaks, with fewer peaks in the NOESY spectrum. At 700 MHz, the NOESY and ROESY spectra of the dodecasaccharide produced the same qualitative pattern of peaks, but again the relative peak intensities were different. These differences are due to very significant differences in the local correlation times for different proton pairs across this glycosidic linkage. The local correlation time for each proton pair was measured using the ratio of the NOESY and T-ROESY cross-relaxation rates, leaving the NOESY and ROESY as independent data sets for calculating the inter-proton distances. The inter-proton distances calculated including the effects of differences in local correlation times give much more consistent results.

Recombination patterns reveal information about centromere location on linkage maps.

PubMed

Limborg, Morten T; McKinney, Garrett J; Seeb, Lisa W; Seeb, James E

2016-05-01

Linkage mapping is often used to identify genes associated with phenotypic traits and for aiding genome assemblies. Still, many emerging maps do not locate centromeres - an essential component of the genomic landscape. Here, we demonstrate that for genomes with strong chiasma interference, approximate centromere placement is possible by phasing the same data used to generate linkage maps. Assuming one obligate crossover per chromosome arm, information about centromere location can be revealed by tracking the accumulated recombination frequency along linkage groups, similar to half-tetrad analyses. We validate the method on a linkage map for sockeye salmon (Oncorhynchus nerka) with known centromeric regions. Further tests suggest that the method will work well in other salmonids and other eukaryotes. However, the method performed weakly when applied to a male linkage map (rainbow trout; O. mykiss) characterized by low and unevenly distributed recombination - a general feature of male meiosis in many species. Further, a high frequency of double crossovers along chromosome arms in barley reduced resolution for locating centromeric regions on most linkage groups. Despite these limitations, our method should work well for high-density maps in species with strong recombination interference and will enrich many existing and future mapping resources. © 2015 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.

A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gill, M.; Vallada, H.; Collier, D.

1996-02-16

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showedmore » 252 alleles shared compared with 188 alleles not shared (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that there may be a susceptibility locus for schizophrenia at 22q12. 27 refs., 3 tabs.« less

Accommodating Chromosome Inversions in Linkage Analysis

PubMed Central

Chen, Gary K.; Slaten, Erin; Ophoff, Roel A.; Lange, Kenneth

2006-01-01

This work develops a population-genetics model for polymorphic chromosome inversions. The model precisely describes how an inversion changes the nature of and approach to linkage equilibrium. The work also describes algorithms and software for allele-frequency estimation and linkage analysis in the presence of an inversion. The linkage algorithms implemented in the software package Mendel estimate recombination parameters and calculate the posterior probability that each pedigree member carries the inversion. Application of Mendel to eight Centre d'Étude du Polymorphisme Humain pedigrees in a region containing a common inversion on 8p23 illustrates its potential for providing more-precise estimates of the location of an unmapped marker or trait gene. Our expanded cytogenetic analysis of these families further identifies inversion carriers and increases the evidence of linkage. PMID:16826515

Methylation analysis of polysaccharides: Technical advice.

PubMed

Sims, Ian M; Carnachan, Susan M; Bell, Tracey J; Hinkley, Simon F R

2018-05-15

Glycosyl linkage (methylation) analysis is used widely for the structural determination of oligo- and poly-saccharides. The procedure involves derivatisation of the individual component sugars of a polysaccharide to partially methylated alditol acetates which are analysed and quantified by gas chromatography-mass spectrometry. The linkage positions for each component sugar can be determined by correctly identifying the partially methylated alditol acetates. Although the methods are well established, there are many technical aspects to this procedure and both careful attention to detail and considerable experience are required to achieve a successful methylation analysis and to correctly interpret the data generated. The aim of this article is to provide the technical details and critical procedural steps necessary for a successful methylation analysis and to assist researchers (a) with interpreting data correctly and (b) in providing the comprehensive data required for reviewers to fully assess the work. Copyright © 2018 Elsevier Ltd. All rights reserved.

Smoothing of the bivariate LOD score for non-normal quantitative traits.

PubMed

Buil, Alfonso; Dyer, Thomas D; Almasy, Laura; Blangero, John

2005-12-30

Variance component analysis provides an efficient method for performing linkage analysis for quantitative traits. However, type I error of variance components-based likelihood ratio testing may be affected when phenotypic data are non-normally distributed (especially with high values of kurtosis). This results in inflated LOD scores when the normality assumption does not hold. Even though different solutions have been proposed to deal with this problem with univariate phenotypes, little work has been done in the multivariate case. We present an empirical approach to adjust the inflated LOD scores obtained from a bivariate phenotype that violates the assumption of normality. Using the Collaborative Study on the Genetics of Alcoholism data available for the Genetic Analysis Workshop 14, we show how bivariate linkage analysis with leptokurtotic traits gives an inflated type I error. We perform a novel correction that achieves acceptable levels of type I error.

[Analysis of HLA haplotype frequency and linkage disequilibrium in patients with acute lymphoblastic leukemia from Northern Chinese Han].

PubMed

Gao, Su-qing; Cheng, Liang-hong; Lu, Liang; Jing, Shi-zheng; Cheng, Xi; Zhang, Yin-ze; Zou, Hong-yan; Deng, Zhi-hui

2009-02-01

To analyze the difference between the frequencies of HLA-A-B, B-DRB1 and A-B-DRB1 haplotype, as well as their linkage disequilibrium pattern in patients with acute lymphoblastic leukemia(ALL) and healthy controls from Northern Chinese Han. The frequencies of HLA-A-B, B-DRB1, A-B-DR haplotypes and linkage disequilibrium were estimated by Expectation Maximization method based on the genotypes of 643 patients with ALL and 2 0359 unrelated healthy donors, and the statistical significance between the two groups were estimated by chi-square test. Linkage disequilibrium was analyzed with population genetic methods. The most common HLA-A-B, B-DRB1, and A-B-DR haplotypes were A30-B13, A2-B46, A33-B58, B13-DR7, B46-DR9, B52-DR15, B58-DR17, A30-B13-DR7, A33-B58-DR17 and A1-B37-DR10 in both groups. The frequencies of A30-B13, A2-B46, A33-B44, B13-DR7, A30-B13-DR7 and A2-B46-DR9 haplotypes and linkage disequilibrium value were significantly decreased (P<0.05) in the patient group than that in the control group. On the other hand, the frequencies of A2-B52, A31-B61, A24- B8, B60-DR9, B27-DR4, B52-DR14, B44-DR17, B27-DR12 and A11-B27-DR12 haplotypes and linkage disequilibrium value were significantly increased (P<0.05) in the patient group than that in the control group. There are some common and positive linkage disequilibrium haplotypes in both the ALL patients and the healthy donors in Northern Chinese Han. Interestingly, some haplotypes and their linkage disequilibrium patterns had significantly different distributions between the two groups. The study provided basic data for the relationship of ALL and HLA haplotype and for finding the HLA-A, B, DR matching donors.

A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease

PubMed Central

2010-01-01

Background The inability of aspirin (ASA) to adequately suppress platelet aggregation is associated with future risk of coronary artery disease (CAD). Heritability studies of agonist-induced platelet function phenotypes suggest that genetic variation may be responsible for ASA responsiveness. In this study, we leverage independent information from genome-wide linkage and association data to determine loci controlling platelet phenotypes before and after treatment with ASA. Methods Clinical data on 37 agonist-induced platelet function phenotypes were evaluated before and after a 2-week trial of ASA (81 mg/day) in 1231 European American and 846 African American healthy subjects with a family history of premature CAD. Principal component analysis was performed to minimize the number of independent factors underlying the covariance of these various phenotypes. Multi-point sib-pair based linkage analysis was performed using a microsatellite marker set, and single-SNP association tests were performed using markers from the Illumina 1 M genotyping chip from deCODE Genetics, Inc. All analyses were performed separately within each ethnic group. Results Several genomic regions appear to be linked to ASA response factors: a 10 cM region in African Americans on chromosome 5q11.2 had several STRs with suggestive (p-value < 7 × 10-4) and significant (p-value < 2 × 10-5) linkage to post aspirin platelet response to ADP, and ten additional factors had suggestive evidence for linkage (p-value < 7 × 10-4) to thirteen genomic regions. All but one of these factors were aspirin response variables. While the strength of genome-wide SNP association signals for factors showing evidence for linkage is limited, especially at the strict thresholds of genome-wide criteria (N = 9 SNPs for 11 factors), more signals were considered significant when the association signal was weighted by evidence for linkage (N = 30 SNPs). Conclusions Our study supports the hypothesis that platelet phenotypes in response to ASA likely have genetic control and the combined approach of linkage and association offers an alternative approach to prioritizing regions of interest for subsequent follow-up. PMID:20529293

Genome-wide QTL analysis for anxiety trait in bipolar disorder type I.

PubMed

Contreras, J; Hare, E; Chavarría-Soley, G; Raventós, H

2018-07-01

Genetic studies have been consistent that bipolar disorder type I (BPI) runs in families and that this familial aggregation is strongly influenced by genes. In a preliminary study, we proved that anxiety trait meets endophenotype criteria for BPI. We assessed 619 individuals from the Central Valley of Costa Rica (CVCR) who have received evaluation for anxiety following the same methodological procedure used for the initial pilot study. Our goal was to conduct a multipoint quantitative trait linkage analysis to identify quantitative trait loci (QTLs) related to anxiety trait in subjects with BPI. We conducted the statistical analyses using Quantitative Trait Loci method (Variance-components models), implemented in Sequential Oligogenic Linkage Analysis Routines (SOLAR), using 5606 single nucleotide polymorphism (SNPs). We identified a suggestive linkage signal with a LOD score of 2.01 at chromosome 2 (2q13-q14). Since confounding factors such as substance abuse, medical illness and medication history were not assessed in our study, these conclusions should be taken as preliminary. We conclude that region 2q13-q14 may harbor a candidate gene(s) with an important role in the pathophysiology of BPI and anxiety. Published by Elsevier B.V.

Clinical Application of an Innovative Multiplex-Fluorescent-Labeled STRs Assay for Prader-Willi Syndrome and Angelman Syndrome.

PubMed

Zhang, Kaihui; Liu, Shu; Feng, Bing; Yang, Yali; Zhang, Haiyan; Dong, Rui; Liu, Yi; Gai, Zhongtao

2016-01-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two clinically distinct neurodevelopmental disorders caused by absence of paternally or maternally expressed imprinted genes on chr15q11.2-q13.3. Three mechanisms are known to be involved in the pathogenesis: microdeletions, uniparental disomy (UPD) and imprinting defects. Both disorders are difficult to be definitely diagnosed at early age if no available molecular cytogenetic tests. In this study, we identified 5 AS patients with the maternal deletion and 26 PWS patients with paternal deletion on chr15q11-q13 by using an innovative multiplex-fluorescent-labeled short tandem repeats (STRs) assay based on linkage analysis, and validated by the methylation-specific PCR and array comparative genomic hybridization techniques. More interesting, one of these PWS patients was confirmed as maternal uniparental isodisomy by the STR linkage analysis. The phenotypic and genotypic characteristics of these individuals were also presented. Our results indicate that the new linkage analysis is much faster and easier for large-scale screening deletion and uniparental disomy, thus providing a valuable method for early diagnosis of PWS/AS patients, which is critical for genetic diagnosis, management and improvement of prognosis.

Clinical Application of an Innovative Multiplex-Fluorescent-Labeled STRs Assay for Prader-Willi Syndrome and Angelman Syndrome

PubMed Central

Feng, Bing; Yang, Yali; Zhang, Haiyan; Dong, Rui; Liu, Yi; Gai, Zhongtao

2016-01-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two clinically distinct neurodevelopmental disorders caused by absence of paternally or maternally expressed imprinted genes on chr15q11.2-q13.3. Three mechanisms are known to be involved in the pathogenesis: microdeletions, uniparental disomy (UPD) and imprinting defects. Both disorders are difficult to be definitely diagnosed at early age if no available molecular cytogenetic tests. In this study, we identified 5 AS patients with the maternal deletion and 26 PWS patients with paternal deletion on chr15q11-q13 by using an innovative multiplex-fluorescent-labeled short tandem repeats (STRs) assay based on linkage analysis, and validated by the methylation-specific PCR and array comparative genomic hybridization techniques. More interesting, one of these PWS patients was confirmed as maternal uniparental isodisomy by the STR linkage analysis. The phenotypic and genotypic characteristics of these individuals were also presented. Our results indicate that the new linkage analysis is much faster and easier for large-scale screening deletion and uniparental disomy, thus providing a valuable method for early diagnosis of PWS/AS patients, which is critical for genetic diagnosis, management and improvement of prognosis. PMID:26841067

Quantifying sources of bias in longitudinal data linkage studies of child abuse and neglect: measuring impact of outcome specification, linkage error, and partial cohort follow-up.

PubMed

Parrish, Jared W; Shanahan, Meghan E; Schnitzer, Patricia G; Lanier, Paul; Daniels, Julie L; Marshall, Stephen W

2017-12-01

Health informatics projects combining statewide birth populations with child welfare records have emerged as a valuable approach to conducting longitudinal research of child maltreatment. The potential bias resulting from linkage misspecification, partial cohort follow-up, and outcome misclassification in these studies has been largely unexplored. This study integrated epidemiological survey and novel administrative data sources to establish the Alaska Longitudinal Child Abuse and Neglect Linkage (ALCANLink) project. Using these data we evaluated and quantified the impact of non-linkage misspecification and single source maltreatment ascertainment use on reported maltreatment risk and effect estimates. The ALCANLink project integrates the 2009-2011 Alaska Pregnancy Risk Assessment Monitoring System (PRAMS) sample with multiple administrative databases through 2014, including one novel administrative source to track out-of-state emigration. For this project we limited our analysis to the 2009 PRAMS sample. We report on the impact of linkage quality, cohort follow-up, and multisource outcome ascertainment on the incidence proportion of reported maltreatment before age 6 and hazard ratios of selected characteristics that are often available in birth cohort linkage studies of maltreatment. Failure to account for out-of-state emigration biased the incidence proportion by 12% (from 28.3% w to 25.2% w ), and the hazard ratio (HR) by as much as 33% for some risk factors. Overly restrictive linkage parameters biased the incidence proportion downwards by 43% and the HR by as much as 27% for some factors. Multi-source linkages, on the other hand, were of little benefit for improving reported maltreatment ascertainment. Using the ALCANLink data which included a novel administrative data source, we were able to observe and quantify bias to both the incidence proportion and HR in a birth cohort linkage study of reported child maltreatment. Failure to account for out-of-state emigration and low-quality linkage methods may induce bias in longitudinal data linkage studies of child maltreatment which other researchers should be aware of. In this study multi-agency linkage did not lead to substantial increased detection of reported maltreatment. The ALCANLink methodology may be a practical approach for other states interested in developing longitudinal birth cohort linkage studies of maltreatment that requires limited resources to implement, provides comprehensive data elements, and can facilitate comparability between studies.

Plasminogen activator inhibitor type 1 gene is located at region q21. 3-q22 of chromosome 7 and genetically linked with cystic fibrosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Klinger, K.W.; Winqvist, R.; Riccio, A.

1987-12-01

The regional chromosomal location of the human gene for plasminogen activator inhibitor type 1 (PAI1) was determined by three independent methods of gene mapping. PAI1 was localized first to 7cen-q32 and then to 7q21.3-q22 by Southern blot hybridization analysis of a panel of human and mouse somatic cell hybrids with a PAI1 cDNA probe and in situ hybridization, respectively. The authors frequent HindIII restriction fragment length polymorphism (RFLP) of the PAI1 gene with an information content of 0.369. In family studies using this polymorphism, genetic linkage was found between PAI1 and the loci for erythropoietin (EPO), paraoxonase (PON), the metmore » protooncogene (MET), and cystic fibrosis (CF), all previously assigned to the middle part of the long arm of chromosome 7. The linkage with EPO was closest with an estimated genetic distance of 3 centimorgans, whereas that to CF was 20 centimorgans. A three-point genetic linkage analysis and data from previous studies showed that the most likely order of these loci is EPO, PAI1, PON, (MET, CF), with PAI1 being located centromeric to CF. The PAI1 RFLP may prove to be valuable in ordering genetic markers in the CF-linkage group and may also be valuable in genetic analysis of plasminogen activation-related diseases, such as certain thromboembolic disorders and cancer.« less

Strategy and model building in the fourth dimension: a null model for genotype x age interaction as a Gaussian stationary stochastic process.

PubMed

Diego, Vincent P; Almasy, Laura; Dyer, Thomas D; Soler, Júlia M P; Blangero, John

2003-12-31

Using univariate and multivariate variance components linkage analysis methods, we studied possible genotype x age interaction in cardiovascular phenotypes related to the aging process from the Framingham Heart Study. We found evidence for genotype x age interaction for fasting glucose and systolic blood pressure. There is polygenic genotype x age interaction for fasting glucose and systolic blood pressure and quantitative trait locus x age interaction for a linkage signal for systolic blood pressure phenotypes located on chromosome 17 at 67 cM.

LDRD final report : leveraging multi-way linkages on heterogeneous data.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dunlavy, Daniel M.; Kolda, Tamara Gibson

2010-09-01

This report is a summary of the accomplishments of the 'Leveraging Multi-way Linkages on Heterogeneous Data' which ran from FY08 through FY10. The goal was to investigate scalable and robust methods for multi-way data analysis. We developed a new optimization-based method called CPOPT for fitting a particular type of tensor factorization to data; CPOPT was compared against existing methods and found to be more accurate than any faster method and faster than any equally accurate method. We extended this method to computing tensor factorizations for problems with incomplete data; our results show that you can recover scientifically meaningfully factorizations withmore » large amounts of missing data (50% or more). The project has involved 5 members of the technical staff, 2 postdocs, and 1 summer intern. It has resulted in a total of 13 publications, 2 software releases, and over 30 presentations. Several follow-on projects have already begun, with more potential projects in development.« less

Multicolor in situ hybridization and linkage analysis order Charcot-Marie-Tooth type I (CMTIA) gene-region markers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lebo, R.V.; Lynch, E.D.; Golbus, M.S.

1992-01-01

This study demonstrates a clear and current role for multicolor in situ hybridization in expediting positional cloning studies of unknown disease genes. Nine polymorphic DNA cosmids have been mapped to eight ordered locations spanning the Charcot-Marie-Tooth type 1 (CMT1A) disease gene region in distal band 17p11.2, by multicolor in situ hybridization. When used with linkage analysis, these methods have generated a fine physical map and have firmly assigned the CMT1A gene to distal band 17p11.2. Linkage analysis with four CMT1A pedigrees mapped the CMT1A gene with respect to two flanking markers. Additional loci were physically mapped and ordered by inmore » situ hybridization and analysis of phase-known recombinants in CMT1A pedigrees. These data demonstrate the ability of in situ hybridization to resolve loci within 0.5 Mb on early-metaphase chromosomes. Multicolor in situ hybridization also excluded the possibility of pericentric inversions in two unrelated patients with CMT1 and neurofibromatosis type 1. When used with pulsed-field gel electrophoresis, multicolor in situ hybridization can establish physical location, order, and distance in closely spaced chromosome loci.« less

Single-tube tetradecaplex panel of highly polymorphic microsatellite markers < 1 Mb from F8 for simplified preimplantation genetic diagnosis of hemophilia A.

PubMed

Zhao, M; Chen, M; Tan, A S C; Cheah, F S H; Mathew, J; Wong, P C; Chong, S S

2017-07-01

Essentials Preimplantation genetic diagnosis (PGD) of severe hemophilia A relies on linkage analysis. Simultaneous multi-marker screening can simplify selection of informative markers in a couple. We developed a single-tube tetradecaplex panel of polymorphic markers for hemophilia A PGD use. Informative markers can be used for linkage analysis alone or combined with mutation detection. Background It is currently not possible to perform single-cell preimplantation genetic diagnosis (PGD) to directly detect the common inversion mutations of the factor VIII (F8) gene responsible for severe hemophilia A (HEMA). As such, PGD for such inversion carriers relies on indirect analysis of linked polymorphic markers. Objectives To simplify linkage-based PGD of HEMA, we aimed to develop a panel of highly polymorphic microsatellite markers located near the F8 gene that could be simultaneously genotyped in a multiplex-PCR reaction. Methods We assessed the polymorphism of various microsatellite markers located ≤ 1 Mb from F8 in 177 female subjects. Highly polymorphic markers were selected for co-amplification with the AMELX/Y indel dimorphism in a single-tube reaction. Results Thirteen microsatellite markers located within 0.6 Mb of F8 were successfully co-amplified with AMELX/Y in a single-tube reaction. Observed heterozygosities of component markers ranged from 0.43 to 0.84, and ∼70-80% of individuals were heterozygous for ≥ 5 markers. The tetradecaplex panel successfully identified fully informative markers in a couple interested in PGD for HEMA because of an intragenic F8 point mutation, with haplotype phasing established through a carrier daughter. In-vitro fertilization (IVF)-PGD involved single-tube co-amplification of fully informative markers with AMELX/Y and the mutation-containing F8 amplicon, followed by microsatellite analysis and amplicon mutation-site minisequencing analysis. Conclusions The single-tube multiplex-PCR format of this highly polymorphic microsatellite marker panel simplifies identification and selection of informative markers for linkage-based PGD of HEMA. Informative markers can also be easily co-amplified with mutation-containing F8 amplicons for combined mutation detection and linkage analysis. © 2017 International Society on Thrombosis and Haemostasis.

Ocular findings associated with a Cys39Arg mutation in the Norrie disease gene.

PubMed

Joos, K M; Kimura, A E; Vandenburgh, K; Bartley, J A; Stone, E M

1994-12-01

To diagnose the carriers and noncarriers in a family affected with Norrie disease based on molecular analysis. Family members from three generations, including one affected patient, two obligate carriers, one carrier identified with linkage analysis, one noncarrier identified with linkage analysis, and one female family member with indeterminate carrier status, were examined clinically and electrophysiologically. Linkage analysis had previously failed to determine the carrier status of one female family member in the third generation. Blood samples were screened for mutations in the Norrie disease gene with single-strand conformation polymorphism analysis. The mutation was characterized by dideoxy-termination sequencing. Ophthalmoscopy and electroretinographic examination failed to detect the carrier state. The affected individuals and carriers in this family were found to have a transition from thymidine to cytosine in the first nucleotide of codon 39 of the Norrie disease gene, causing a cysteine-to-arginine mutation. Single-strand conformation polymorphism analysis identified a patient of indeterminate status (by linkage) to be a noncarrier of Norrie disease. Ophthalmoscopy and electroretinography could not identify carriers of this Norrie disease mutation. Single-strand conformation polymorphism analysis was more sensitive and specific than linkage analysis in identifying carriers in this family.

Identification of carbohydrate anomers using ion mobility-mass spectrometry.

PubMed

Hofmann, J; Hahm, H S; Seeberger, P H; Pagel, K

2015-10-08

Carbohydrates are ubiquitous biological polymers that are important in a broad range of biological processes. However, owing to their branched structures and the presence of stereogenic centres at each glycosidic linkage between monomers, carbohydrates are harder to characterize than are peptides and oligonucleotides. Methods such as nuclear magnetic resonance spectroscopy can be used to characterize glycosidic linkages, but this technique requires milligram amounts of material and cannot detect small amounts of coexisting isomers. Mass spectrometry, on the other hand, can provide information on carbohydrate composition and connectivity for even small amounts of sample, but it cannot be used to distinguish between stereoisomers. Here, we demonstrate that ion mobility-mass spectrometry--a method that separates molecules according to their mass, charge, size, and shape--can unambiguously identify carbohydrate linkage-isomers and stereoisomers. We analysed six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration. Our data show that coexisting carbohydrate isomers can be identified, and relative concentrations of the minor isomer as low as 0.1 per cent can be detected. In addition, the analysis is rapid, and requires no derivatization and only small amounts of sample. These results indicate that ion mobility-mass spectrometry is an effective tool for the analysis of complex carbohydrates. This method could have an impact on the field of carbohydrate synthesis similar to that of the advent of high-performance liquid chromatography on the field of peptide assembly in the late 1970s.

Identification of carbohydrate anomers using ion mobility-mass spectrometry

NASA Astrophysics Data System (ADS)

Hofmann, J.; Hahm, H. S.; Seeberger, P. H.; Pagel, K.

2015-10-01

Carbohydrates are ubiquitous biological polymers that are important in a broad range of biological processes. However, owing to their branched structures and the presence of stereogenic centres at each glycosidic linkage between monomers, carbohydrates are harder to characterize than are peptides and oligonucleotides. Methods such as nuclear magnetic resonance spectroscopy can be used to characterize glycosidic linkages, but this technique requires milligram amounts of material and cannot detect small amounts of coexisting isomers. Mass spectrometry, on the other hand, can provide information on carbohydrate composition and connectivity for even small amounts of sample, but it cannot be used to distinguish between stereoisomers. Here, we demonstrate that ion mobility-mass spectrometry--a method that separates molecules according to their mass, charge, size, and shape--can unambiguously identify carbohydrate linkage-isomers and stereoisomers. We analysed six synthetic carbohydrate isomers that differ in composition, connectivity, or configuration. Our data show that coexisting carbohydrate isomers can be identified, and relative concentrations of the minor isomer as low as 0.1 per cent can be detected. In addition, the analysis is rapid, and requires no derivatization and only small amounts of sample. These results indicate that ion mobility-mass spectrometry is an effective tool for the analysis of complex carbohydrates. This method could have an impact on the field of carbohydrate synthesis similar to that of the advent of high-performance liquid chromatography on the field of peptide assembly in the late 1970s.

Environmental Gradient Analysis, Ordination, and Classification in Environmental Impact Assessments.

DTIC Science & Technology

1987-09-01

agglomerative clustering algorithms for mainframe computers: (1) the unweighted pair-group method that V uses arithmetic averages ( UPGMA ), (2) the...hierarchical agglomerative unweighted pair-group method using arithmetic averages ( UPGMA ), which is also called average linkage clustering. This method was...dendrograms produced by weighted clustering (93). Sneath and Sokal (94), Romesburg (84), and Seber• (90) also strongly recommend the UPGMA . A dendrogram

Ensuring Privacy When Integrating Patient-Based Datasets: New Methods and Developments in Record Linkage.

PubMed

Brown, Adrian P; Ferrante, Anna M; Randall, Sean M; Boyd, James H; Semmens, James B

2017-01-01

In an era where the volume of structured and unstructured digital data has exploded, there has been an enormous growth in the creation of data about individuals that can be used for understanding and treating disease. Joining these records together at an individual level provides a complete picture of a patient's interaction with health services and allows better assessment of patient outcomes and effectiveness of treatment and services. Record linkage techniques provide an efficient and cost-effective method to bring individual records together as patient profiles. These linkage procedures bring their own challenges, especially relating to the protection of privacy. The development and implementation of record linkage systems that do not require the release of personal information can reduce the risks associated with record linkage and overcome legal barriers to data sharing. Current conceptual and experimental privacy-preserving record linkage (PPRL) models show promise in addressing data integration challenges. Enhancing and operationalizing PPRL protocols can help address the dilemma faced by some custodians between using data to improve quality of life and dealing with the ethical, legal, and administrative issues associated with protecting an individual's privacy. These methods can reduce the risk to privacy, as they do not require personally identifying information to be shared. PPRL methods can improve the delivery of record linkage services to the health and broader research community.

Ensuring Privacy When Integrating Patient-Based Datasets: New Methods and Developments in Record Linkage

PubMed Central

Brown, Adrian P.; Ferrante, Anna M.; Randall, Sean M.; Boyd, James H.; Semmens, James B.

2017-01-01

In an era where the volume of structured and unstructured digital data has exploded, there has been an enormous growth in the creation of data about individuals that can be used for understanding and treating disease. Joining these records together at an individual level provides a complete picture of a patient’s interaction with health services and allows better assessment of patient outcomes and effectiveness of treatment and services. Record linkage techniques provide an efficient and cost-effective method to bring individual records together as patient profiles. These linkage procedures bring their own challenges, especially relating to the protection of privacy. The development and implementation of record linkage systems that do not require the release of personal information can reduce the risks associated with record linkage and overcome legal barriers to data sharing. Current conceptual and experimental privacy-preserving record linkage (PPRL) models show promise in addressing data integration challenges. Enhancing and operationalizing PPRL protocols can help address the dilemma faced by some custodians between using data to improve quality of life and dealing with the ethical, legal, and administrative issues associated with protecting an individual’s privacy. These methods can reduce the risk to privacy, as they do not require personally identifying information to be shared. PPRL methods can improve the delivery of record linkage services to the health and broader research community. PMID:28303240

Distribution and magnitude of type I error of model-based multipoint lod scores: implications for multipoint mod scores.

PubMed

Xing, Chao; Elston, Robert C

2006-07-01

The multipoint lod score and mod score methods have been advocated for their superior power in detecting linkage. However, little has been done to determine the distribution of multipoint lod scores or to examine the properties of mod scores. In this paper we study the distribution of multipoint lod scores both analytically and by simulation. We also study by simulation the distribution of maximum multipoint lod scores when maximized over different penetrance models. The multipoint lod score is approximately normally distributed with mean and variance that depend on marker informativity, marker density, specified genetic model, number of pedigrees, pedigree structure, and pattern of affection status. When the multipoint lod scores are maximized over a set of assumed penetrances models, an excess of false positive indications of linkage appear under dominant analysis models with low penetrances and under recessive analysis models with high penetrances. Therefore, caution should be taken in interpreting results when employing multipoint lod score and mod score approaches, in particular when inferring the level of linkage significance and the mode of inheritance of a trait.

A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples

PubMed Central

Sebastiani, Paola; Zhao, Zhenming; Abad-Grau, Maria M; Riva, Alberto; Hartley, Stephen W; Sedgewick, Amanda E; Doria, Alessandro; Montano, Monty; Melista, Efthymia; Terry, Dellara; Perls, Thomas T; Steinberg, Martin H; Baldwin, Clinton T

2008-01-01

Background One of the challenges of the analysis of pooling-based genome wide association studies is to identify authentic associations among potentially thousands of false positive associations. Results We present a hierarchical and modular approach to the analysis of genome wide genotype data that incorporates quality control, linkage disequilibrium, physical distance and gene ontology to identify authentic associations among those found by statistical association tests. The method is developed for the allelic association analysis of pooled DNA samples, but it can be easily generalized to the analysis of individually genotyped samples. We evaluate the approach using data sets from diverse genome wide association studies including fetal hemoglobin levels in sickle cell anemia and a sample of centenarians and show that the approach is highly reproducible and allows for discovery at different levels of synthesis. Conclusion Results from the integration of Bayesian tests and other machine learning techniques with linkage disequilibrium data suggest that we do not need to use too stringent thresholds to reduce the number of false positive associations. This method yields increased power even with relatively small samples. In fact, our evaluation shows that the method can reach almost 70% sensitivity with samples of only 100 subjects. PMID:18194558

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

PubMed Central

Ng, MYM; Levinson, DF; Faraone, SV; Suarez, BK; DeLisi, LE; Arinami, T; Riley, B; Paunio, T; Pulver, AE; Irmansyah; Holmans, PA; Escamilla, M; Wildenauer, DB; Williams, NM; Laurent, C; Mowry, BJ; Brzustowicz, LM; Maziade, M; Sklar, P; Garver, DL; Abecasis, GR; Lerer, B; Fallin, MD; Gurling, HMD; Gejman, PV; Lindholm, E; Moises, HW; Byerley, W; Wijsman, EM; Forabosco, P; Tsuang, MT; Hwu, H-G; Okazaki, Y; Kendler, KS; Wormley, B; Fanous, A; Walsh, D; O’Neill, FA; Peltonen, L; Nestadt, G; Lasseter, VK; Liang, KY; Papadimitriou, GM; Dikeos, DG; Schwab, SG; Owen, MJ; O’Donovan, MC; Norton, N; Hare, E; Raventos, H; Nicolini, H; Albus, M; Maier, W; Nimgaonkar, VL; Terenius, L; Mallet, J; Jay, M; Godard, S; Nertney, D; Alexander, M; Crowe, RR; Silverman, JM; Bassett, AS; Roy, M-A; Mérette, C; Pato, CN; Pato, MT; Roos, J Louw; Kohn, Y; Amann-Zalcenstein, D; Kalsi, G; McQuillin, A; Curtis, D; Brynjolfson, J; Sigmundsson, T; Petursson, H; Sanders, AR; Duan, J; Jazin, E; Myles-Worsley, M; Karayiorgou, M; Lewis, CM

2009-01-01

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (PSR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for ‘aggregate’ genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. PMID:19349958

Linkage analysis of autopsy-confirmed familial Alzheimer disease supports an Alzheimer disease locus in 8q24.

PubMed

Sillén, Anna; Brohede, Jesper; Forsell, Charlotte; Lilius, Lena; Andrade, Jorge; Odeberg, Jacob; Kimura, Toru; Winblad, Bengt; Graff, Caroline

2011-01-01

We have previously reported the results of an extended genome-wide scan of Swedish Alzheimer disease (AD)-affected families; in this paper, we analyzed a subset of these families with autopsy-confirmed AD. We report the fine-mapping, using both microsatellite markers and single-nucleotide polymorphisms (SNPs), in the observed maximum logarithm of the odds (LOD)-2 unit (LOD(max)-2) region under the identified linkage peak, linkage analysis of the fine-mapping data with additionally analyzed pedigrees, and association analysis of SNPs selected from candidate genes in the linked interval. The subset was made on the criterion of at least one autopsy-confirmed AD case per family, resulting in 24 families. Linkage analysis of a family subset having at least one autopsy-confirmed AD case showed a significant nonparametric single-point LOD score of 4.4 in 8q24. Fine-mapping under the linkage peak with 10 microsatellite markers yielded an increase in the multipoint (mpt) LOD score from 2.1 to 3.0. SNP genotyping was performed on 21 selected candidate transcripts of the LOD(max)-2 region. Both family-based association and linkage analysis were performed on extended material from 30 families, resulting in a suggestive linkage at peak marker rs6577853 (mpt LOD score = 2.4). The 8q24 region has been implicated to be involved in AD etiology. Copyright © 2011 S. Karger AG, Basel.

Linkage of the National Health Interview Survey to air quality data.

PubMed

Parker, Jennifer D; Kravets, Nataliya; Woodruff, Tracey J

2008-02-01

This report describes the linkage between the National Health Interview Survey (NHIS) and air monitoring data from the U.S. Environmental Protection Agency (EPA). There have been few linkages of these data sources, partly because of restrictions on releasing geographic detail from NHIS on public-use files in order to protect participant confidentiality. Pollution exposures for NHIS respondents were calculated by averaging the annual average exposure estimates from EPA air monitors both within 5, 10, 15, and 20 miles of the respondent's block-group location (which is available on restricted NHIS data files) and by county of residence. The 1987-2005 linked data files--referred to as NHIS-EPAAnnualAir--were used to describe the percentage of NHIS respondents linked and the median exposures by linkage method, survey year, and pollutant. Using the 2005 NHIS-EPAAnnualAir data file, the percentage linked and median exposure were described by respondent characteristics, linkage method, and pollutant. Many decisions were made to define pollution exposures for NHIS respondents, including monitor selection, location assignment for NHIS respondents, and geographic linkage criteria. Geographic linkage criteria for assigning area-level exposure estimates affected the percentage and composition of respondents included in the resulting linked sample. Median exposure estimates, however, were similar among geographic linkage methods. NHIS-EPAAnnualAir data files for 1985 through 2005 are currently available to users in the NCHS Research Data Center.

Reactivity of phosphorus mononitride and interstellar formation of molecules containing phospazo linkage: A computational study on the reaction between HSi (X2Γ) and PN (X1Σ+)

NASA Astrophysics Data System (ADS)

Bhasi, Priya; Nhlabatsi, Zanele P.; Sitha, Sanyasi

2017-12-01

Phosphorus mononitride (PN) shows some interesting chemistry due to its low dissociation energy (compared to N2) and small dipole moment (zero dipole moment for N2). In this work, a reaction between HSi (X2Γ) and PN (X1Σ+) has been studied using various computational methods. Analysis of the doublet surface of the HSi+PN reaction indicates that the reaction is exothermic in nature leading to the formation of various products. In view of the barrierless association of the reactants and exothermic nature for the product formation, it is suggested that species like HPNSi, cyclic-SiN(H)P (these two most stable isomers have phosphazo linkage) and HSiNP (third most stable isomer has phosphdiazo linkage) can possibly be detected in the interstellar medium. In view of the potential applications of phosphazo compounds in amide synthesis and pervasive nature of amide linkages in the nature, possible interstellar prebiotic applications can be advocated for these compounds.

Large-scale linkage analysis of 1302 affected relative pairs with rheumatoid arthritis

PubMed Central

Hamshere, Marian L; Segurado, Ricardo; Moskvina, Valentina; Nikolov, Ivan; Glaser, Beate; Holmans, Peter A

2007-01-01

Rheumatoid arthritis is the most common systematic autoimmune disease and its etiology is believed to have both strong genetic and environmental components. We demonstrate the utility of including genetic and clinical phenotypes as covariates within a linkage analysis framework to search for rheumatoid arthritis susceptibility loci. The raw genotypes of 1302 affected relative pairs were combined from four large family-based samples (North American Rheumatoid Arthritis Consortium, United Kingdom, European Consortium on Rheumatoid Arthritis Families, and Canada). The familiality of the clinical phenotypes was assessed. The affected relative pairs were subjected to autosomal multipoint affected relative-pair linkage analysis. Covariates were included in the linkage analysis to take account of heterogeneity within the sample. Evidence of familiality was observed with age at onset (p << 0.001) and rheumatoid factor (RF) IgM (p << 0.001), but not definite erosions (p = 0.21). Genome-wide significant evidence for linkage was observed on chromosome 6. Genome-wide suggestive evidence for linkage was observed on chromosomes 13 and 20 when conditioning on age at onset, chromosome 15 conditional on gender, and chromosome 19 conditional on RF IgM after allowing for multiple testing of covariates. PMID:18466440

Linkage analysis in a Dutch family with X-linked recessive congenital stationary night blindness (XL-CSNB).

PubMed

Berger, W; van Duijnhoven, G; Pinckers, A; Smits, A; Ropers, H H; Cremers, F

1995-01-01

Linkage analysis has been performed in a large Dutch pedigree with X-linked recessive congenital stationary night blindness (CSNB) by utilizing 16 DNA markers from the proximal short arm of the human X chromosome (Xp21.1-11.2). Thirteen polymorphic markers are at least partially informative and have enabled pairwise and multipoint linkage analysis. For three loci, i.e. DXS228, the monoamine oxidase B gene and the Norrie disease gene (NDG), multipoint linkage studies have yielded maximum lod scores of > 3.0 at a recombination fraction of zero. Analysis of recombination events has enabled us to rule out the possibility that the underlying defect in this family is allelic to RP3; the gene defect could also be excluded from the proximal part of the region known to carry RP2. Linkage data are consistent with a possible involvement of the NDG but mutations in the open reading frame of this gene have not been found.

Use of graph theory measures to identify errors in record linkage.

PubMed

Randall, Sean M; Boyd, James H; Ferrante, Anna M; Bauer, Jacqueline K; Semmens, James B

2014-07-01

Ensuring high linkage quality is important in many record linkage applications. Current methods for ensuring quality are manual and resource intensive. This paper seeks to determine the effectiveness of graph theory techniques in identifying record linkage errors. A range of graph theory techniques was applied to two linked datasets, with known truth sets. The ability of graph theory techniques to identify groups containing errors was compared to a widely used threshold setting technique. This methodology shows promise; however, further investigations into graph theory techniques are required. The development of more efficient and effective methods of improving linkage quality will result in higher quality datasets that can be delivered to researchers in shorter timeframes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Genetic Studies of Stuttering in a Founder Population

PubMed Central

Wittke-Thompson, Jacqueline K.; Ambrose, Nicoline; Yairi, Ehud; Roe, Cheryl; Cook, Edwin H.; Ober, Carole; Cox, Nancy J.

2007-01-01

Genome-wide linkage and association analyses were conducted to identify genetic determinants of stuttering in a founder population in which 48 individuals affected with stuttering are connected in a single 232-person genealogy. A novel approach was devised to account for all necessary relationships to enable multipoint linkage analysis. Regions with nominal evidence for linkage were found on chromosomes 3 (P=0.013, 208.8 centiMorgans (cM)), 13 (P=0.012, 52.6 cM), and 15 (P=0.02, 100 cM). Regions with nominal evidence for association with stuttering that overlapped with a linkage signal are located on chromosomes 3 (P=0.0047, 195 cM), 9 (P=0.0067, 46.5 cM), and 13 (P=0.0055, 52.6 cM). We also conducted the first meta-analysis for stuttering using results from linkage studies in the Hutterites and The Illinois International Genetics of Stuttering Project and identified regions with nominal evidence for linkage on chromosomes 2 (P=0.013, 180–195 cM) and 5 (P=0.0051, 105–120 cM; P=0.015, 120–135 cM). None of the linkage signals detected in the Hutterite sample alone, or in the meta-analysis, meet genome-wide criteria for significance, although some of the stronger signals overlap linkage mapping signals previously reported for other speech and language disorders. PMID:17276504

Feasibility of motion laws for planar one degree of freedom linkage mechanisms at dead point configurations

NASA Astrophysics Data System (ADS)

Lores García, E.; Veciana Fontanet, J. M.; Jordi Nebot, L.

2018-01-01

This paper proposes an analytical solution of the Inverse Kinematics (IK) problem at dead point configurations for any planar one degree of freedom linkage mechanism, with regard to the continuity Cn of the motion law. The systems analyzed are those whose elements are linked with lower pairs and do not present redundancies. The study aims to provide the user with some rules to facilitate the design of feasible motion profiles to be reproduced by conventional electrical actuators at these configurations. During the last decades, several methods and techniques have been developed to study this specific configuration. However, these techniques are mainly focused on solving numerically the IK indeterminacy, rather than analyzing the motion laws that the mechanisms are able to perform at these particular configurations. The analysis presented in this paper has been carried out differentiating and applying l'Hôpital's rule to the system of constraint equations ϕ (q) of the mechanism. The study also considers the feasibility of the time-domain profiles to be reproduced with conventional electrical actuators (i.e. AC/DC motors, linear actuators, etc.). To show the usefulness and effectiveness of the method, the development includes the analytical application and numerical simulations for two common one degree of freedom systems: a slider-crank and a four linkage mechanisms. Finally, experimental results are presented on a four linkage mechanism test bed.

Effectiveness of service linkages in primary mental health care: a narrative review part 1

PubMed Central

2011-01-01

Background With the move to community care and increased involvement of generalist health care providers in mental health, the need for health service partnerships has been emphasised in mental health policy. Within existing health system structures the active strategies that facilitate effective partnership linkages are not clear. The objective of this study was to examine the evidence from peer reviewed literature regarding the effectiveness of service linkages in primary mental health care. Methods A narrative and thematic review of English language papers published between 1998 and 2009. Studies of analytic, descriptive and qualitative designs from Australia, New Zealand, UK, Europe, USA and Canada were included. Data were extracted to examine what service linkages have been used in studies of collaboration in primary mental health care. Findings from the randomised trials were tabulated to show the proportion that demonstrated clinical, service delivery and economic benefits. Results A review of 119 studies found ten linkage types. Most studies used a combination of linkage types and so the 42 RCTs were grouped into four broad linkage categories for meaningful descriptive analysis of outcomes. Studies that used multiple linkage strategies from the suite of "direct collaborative activities" plus "agreed guidelines" plus "communication systems" showed positive clinical (81%), service (78%) and economic (75%) outcomes. Most evidence of effectiveness came from studies of depression. Long term benefits were attributed to medication concordance and the use of case managers with a professional background who received expert supervision. There were fewer randomised trials related to collaborative care of people with psychosis and there were almost none related to collaboration with the wider human service sectors. Because of the variability of study types we did not exclude on quality or attempt to weight findings according to power or effect size. Conclusion There is strong evidence to support collaborative primary mental health care for people with depression when linkages involve "direct collaborative activity", plus "agreed guidelines" and "communication systems". PMID:21481236

INTEGRATING A LANDSCAPE HYDROLOGIC ANALYSIS FOR WATERSHED ASSESSMENT

EPA Science Inventory

Methods to provide linkages between a hydrologic modeling tool (AGW A) and landscape assessment tool (A TtILA) for determining the vulnerability of semi-arid landscapes to natural and human-induced landscape pattern changes have been developed. The objective of this study is to ...

Linkage analysis of quantitative refraction and refractive errors in the Beaver Dam Eye Study.

PubMed

Klein, Alison P; Duggal, Priya; Lee, Kristine E; Cheng, Ching-Yu; Klein, Ronald; Bailey-Wilson, Joan E; Klein, Barbara E K

2011-07-13

Refraction, as measured by spherical equivalent, is the need for an external lens to focus images on the retina. While genetic factors play an important role in the development of refractive errors, few susceptibility genes have been identified. However, several regions of linkage have been reported for myopia (2q, 4q, 7q, 12q, 17q, 18p, 22q, and Xq) and for quantitative refraction (1p, 3q, 4q, 7p, 8p, and 11p). To replicate previously identified linkage peaks and to identify novel loci that influence quantitative refraction and refractive errors, linkage analysis of spherical equivalent, myopia, and hyperopia in the Beaver Dam Eye Study was performed. Nonparametric, sibling-pair, genome-wide linkage analyses of refraction (spherical equivalent adjusted for age, education, and nuclear sclerosis), myopia and hyperopia in 834 sibling pairs within 486 extended pedigrees were performed. Suggestive evidence of linkage was found for hyperopia on chromosome 3, region q26 (empiric P = 5.34 × 10(-4)), a region that had shown significant genome-wide evidence of linkage to refraction and some evidence of linkage to hyperopia. In addition, the analysis replicated previously reported genome-wide significant linkages to 22q11 of adjusted refraction and myopia (empiric P = 4.43 × 10(-3) and 1.48 × 10(-3), respectively) and to 7p15 of refraction (empiric P = 9.43 × 10(-4)). Evidence was also found of linkage to refraction on 7q36 (empiric P = 2.32 × 10(-3)), a region previously linked to high myopia. The findings provide further evidence that genes controlling refractive errors are located on 3q26, 7p15, 7p36, and 22q11.

Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica.

PubMed

Celedón, Juan C; Soto-Quiros, Manuel E; Avila, Lydiana; Lake, Stephen L; Liang, Catherine; Fournier, Eduardo; Spesny, Mitzi; Hersh, Craig P; Sylvia, Jody S; Hudson, Thomas J; Verner, Andrei; Klanderman, Barbara J; Freimer, Nelson B; Silverman, Edwin K; Weiss, Scott T

2007-01-01

Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33 at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support interval for the observed linkage peak (142-147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci) that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans.

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

PubMed

Greenberg, David A; Zhang, Junying; Shmulewitz, Dvora; Strug, Lisa J; Zimmerman, Regina; Singh, Veena; Marathe, Sudhir

2005-12-30

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also simulated some marker x marker linkage disequilibrium around some of the genes and also in areas without disease genes. We tried two different methods to simulate the linkage disequilibrium.

A Parallel Genetic Algorithm to Discover Patterns in Genetic Markers that Indicate Predisposition to Multifactorial Disease

PubMed Central

Rausch, Tobias; Thomas, Alun; Camp, Nicola J.; Cannon-Albright, Lisa A.; Facelli, Julio C.

2008-01-01

This paper describes a novel algorithm to analyze genetic linkage data using pattern recognition techniques and genetic algorithms (GA). The method allows a search for regions of the chromosome that may contain genetic variations that jointly predispose individuals for a particular disease. The method uses correlation analysis, filtering theory and genetic algorithms (GA) to achieve this goal. Because current genome scans use from hundreds to hundreds of thousands of markers, two versions of the method have been implemented. The first is an exhaustive analysis version that can be used to visualize, explore, and analyze small genetic data sets for two marker correlations; the second is a GA version, which uses a parallel implementation allowing searches of higher-order correlations in large data sets. Results on simulated data sets indicate that the method can be informative in the identification of major disease loci and gene-gene interactions in genome-wide linkage data and that further exploration of these techniques is justified. The results presented for both variants of the method show that it can help genetic epidemiologists to identify promising combinations of genetic factors that might predispose to complex disorders. In particular, the correlation analysis of IBD expression patterns might hint to possible gene-gene interactions and the filtering might be a fruitful approach to distinguish true correlation signals from noise. PMID:18547558

Bringing the Best of Two Worlds Together for Social Capital Research in Education: Social Network Analysis and Symbolic Interactionism

ERIC Educational Resources Information Center

Lee, Moosung

2014-01-01

This article proposes an analytical consideration for social capital research in education by exploring a pragmatic combination of social network analysis (SNA) and symbolic interactionism (SI) as a research method. The article first delineates the theoretical linkages of social capital theory with SNA and SI. The article then discusses how SNA…

Parent-Of-Origin Effects in Autism Identified through Genome-Wide Linkage Analysis of 16,000 SNPs

PubMed Central

Fradin, Delphine; Cheslack-Postava, Keely; Ladd-Acosta, Christine; Newschaffer, Craig; Chakravarti, Aravinda; Arking, Dan E.; Feinberg, Andrew; Fallin, M. Daniele

2010-01-01

Background Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association. Methods and Findings We have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE) and the National Institute of Mental Health (NIMH) autism repository. We report parametric (GH, Genehunter) and allele-sharing linkage (Aspex) results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LODGH = 3.79, empirical p<0.005 and LODAspex = 2.96, p = 0.008), 15 (LODGH = 3.09, empirical p<0.005 and LODAspex = 3.62, empirical p = 0.003) and 20 (LODGH = 3.36, empirical p<0.005 and LODAspex = 3.38, empirical p = 0.006). Conclusions These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism. PMID:20824079

Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

PubMed Central

Igo, Robert P.; Iyengar, Sudha K.; Nicholas, Susanne B.; Goddard, Katrina A.B.; Langefeld, Carl D.; Hanson, Robert L.; Duggirala, Ravindranath; Divers, Jasmin; Abboud, Hanna; Adler, Sharon G.; Arar, Nedal H.; Horvath, Amanda; Elston, Robert C.; Bowden, Donald W.; Guo, Xiuqing; Ipp, Eli; Kao, W.H. Linda; Kimmel, Paul L.; Knowler, William C.; Meoni, Lucy A.; Molineros, Julio; Nelson, Robert G.; Pahl, Madeline V.; Parekh, Rulan S.; Rasooly, Rebekah S.; Schelling, Jeffrey R.; Shah, Vallabh O.; Smith, Michael W.; Winkler, Cheryl A.; Zager, Philip G.; Sedor, John R.; Freedman, Barry I.

2011-01-01

Background Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. Methods A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. Results Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. Conclusion These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN. PMID:21454968

Hierarchic Agglomerative Clustering Methods for Automatic Document Classification.

ERIC Educational Resources Information Center

Griffiths, Alan; And Others

1984-01-01

Considers classifications produced by application of single linkage, complete linkage, group average, and word clustering methods to Keen and Cranfield document test collections, and studies structure of hierarchies produced, extent to which methods distort input similarity matrices during classification generation, and retrieval effectiveness…

Genetic linkage map and comparative genome analysis for the estuarine Atlantic killifish (Fundulus heteroclitus)

EPA Pesticide Factsheets

Genetic linkage maps are valuable tools in evolutionary biology; however, their availability for wild populations is extremely limited. Fundulus heteroclitus (Atlantic killifish) is a non-migratory estuarine fish that exhibits high allelic and phenotypic diversity partitioned among subpopulations that reside in disparate environmental conditions. An ideal candidate model organism for studying gene-environment interactions, the molecular toolbox for F. heteroclitus is limited. We identified hundreds of novel microsatellites which, when combined with existing microsatellites and single nucleotide polymorphisms (SNPs), were used to construct the first genetic linkage map for this species. By integrating independent linkage maps from three genetic crosses, we developed a consensus map containing 24 linkage groups, consistent with the number of chromosomes reported for this species. These linkage groups span 2300 centimorgans (cM) of recombinant genomic space, intermediate in size relative to the current linkage maps for the teleosts, medaka and zebrafish. Comparisons between fish genomes support a high degree of synteny between the consensus F. heteroclitus linkage map and the medaka and (to a lesser extent) zebrafish physical genome assemblies.This dataset is associated with the following publication:Waits , E., J. Martinson , B. Rinner, S. Morris, D. Proestou, D. Champlin , and D. Nacci. Genetic linkage map and comparative genome analysis for the estuarine Atlanti

The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity.

PubMed

Christensen, G B; Knight, S; Camp, N J

2009-11-01

We present the "sumLINK" statistic--the sum of multipoint LOD scores for the subset of pedigrees with nominally significant linkage evidence at a given locus--as an alternative to common methods to identify susceptibility loci in the presence of heterogeneity. We also suggest the "sumLOD" statistic (the sum of positive multipoint LOD scores) as a companion to the sumLINK. sumLINK analysis identifies genetic regions of extreme consistency across pedigrees without regard to negative evidence from unlinked or uninformative pedigrees. Significance is determined by an innovative permutation procedure based on genome shuffling that randomizes linkage information across pedigrees. This procedure for generating the empirical null distribution may be useful for other linkage-based statistics as well. Using 500 genome-wide analyses of simulated null data, we show that the genome shuffling procedure results in the correct type 1 error rates for both the sumLINK and sumLOD. The power of the statistics was tested using 100 sets of simulated genome-wide data from the alternative hypothesis from GAW13. Finally, we illustrate the statistics in an analysis of 190 aggressive prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics, where we identified a new susceptibility locus. We propose that the sumLINK and sumLOD are ideal for collaborative projects and meta-analyses, as they do not require any sharing of identifiable data between contributing institutions. Further, loci identified with the sumLINK have good potential for gene localization via statistical recombinant mapping, as, by definition, several linked pedigrees contribute to each peak.

Familial aggregation and linkage analysis with covariates for metabolic syndrome risk factors.

PubMed

Naseri, Parisa; Khodakarim, Soheila; Guity, Kamran; Daneshpour, Maryam S

2018-06-15

Mechanisms of metabolic syndrome (MetS) causation are complex, genetic and environmental factors are important factors for the pathogenesis of MetS In this study, we aimed to evaluate familial and genetic influences on metabolic syndrome risk factor and also assess association between FTO (rs1558902 and rs7202116) and CETP(rs1864163) genes' single nucleotide polymorphisms (SNP) with low HDL_C in the Tehran Lipid and Glucose Study (TLGS). The design was a cross-sectional study of 1776 members of 227 randomly-ascertained families. Selected families contained at least one affected metabolic syndrome and at least two members of the family had suffered a loss of HDL_C according to ATP III criteria. In this study, after confirming the familial aggregation with intra-trait correlation coefficients (ICC) of Metabolic syndrome (MetS) and the quantitative lipid traits, the genetic linkage analysis of HDL_C was performed using conditional logistic method with adjusted sex and age. The results of the aggregation analysis revealed a higher correlation between siblings than between parent-offspring pairs representing the role of genetic factors in MetS. In addition, the conditional logistic model with covariates showed that the linkage results between HDL_C and three marker, rs1558902, rs7202116 and rs1864163 were significant. In summary, a high risk of MetS was found in siblings confirming the genetic influences of metabolic syndrome risk factor. Moreover, the power to detect linkage increases in the one parameter conditional logistic model regarding the use of age and sex as covariates. Copyright © 2018. Published by Elsevier B.V.

Composite Bloom Filters for Secure Record Linkage.

PubMed

Durham, Elizabeth Ashley; Kantarcioglu, Murat; Xue, Yuan; Toth, Csaba; Kuzu, Mehmet; Malin, Bradley

2014-12-01

The process of record linkage seeks to integrate instances that correspond to the same entity. Record linkage has traditionally been performed through the comparison of identifying field values ( e.g., Surname ), however, when databases are maintained by disparate organizations, the disclosure of such information can breach the privacy of the corresponding individuals. Various private record linkage (PRL) methods have been developed to obscure such identifiers, but they vary widely in their ability to balance competing goals of accuracy, efficiency and security. The tokenization and hashing of field values into Bloom filters (BF) enables greater linkage accuracy and efficiency than other PRL methods, but the encodings may be compromised through frequency-based cryptanalysis. Our objective is to adapt a BF encoding technique to mitigate such attacks with minimal sacrifices in accuracy and efficiency. To accomplish these goals, we introduce a statistically-informed method to generate BF encodings that integrate bits from multiple fields, the frequencies of which are provably associated with a minimum number of fields. Our method enables a user-specified tradeoff between security and accuracy. We compare our encoding method with other techniques using a public dataset of voter registration records and demonstrate that the increases in security come with only minor losses to accuracy.

Composite Bloom Filters for Secure Record Linkage

PubMed Central

Durham, Elizabeth Ashley; Kantarcioglu, Murat; Xue, Yuan; Toth, Csaba; Kuzu, Mehmet; Malin, Bradley

2014-01-01

The process of record linkage seeks to integrate instances that correspond to the same entity. Record linkage has traditionally been performed through the comparison of identifying field values (e.g., Surname), however, when databases are maintained by disparate organizations, the disclosure of such information can breach the privacy of the corresponding individuals. Various private record linkage (PRL) methods have been developed to obscure such identifiers, but they vary widely in their ability to balance competing goals of accuracy, efficiency and security. The tokenization and hashing of field values into Bloom filters (BF) enables greater linkage accuracy and efficiency than other PRL methods, but the encodings may be compromised through frequency-based cryptanalysis. Our objective is to adapt a BF encoding technique to mitigate such attacks with minimal sacrifices in accuracy and efficiency. To accomplish these goals, we introduce a statistically-informed method to generate BF encodings that integrate bits from multiple fields, the frequencies of which are provably associated with a minimum number of fields. Our method enables a user-specified tradeoff between security and accuracy. We compare our encoding method with other techniques using a public dataset of voter registration records and demonstrate that the increases in security come with only minor losses to accuracy. PMID:25530689

MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers

PubMed Central

Gaunt, Tom R; Rodriguez, Santiago; Zapata, Carlos; Day, Ian NM

2006-01-01

Background Various software tools are available for the display of pairwise linkage disequilibrium across multiple single nucleotide polymorphisms. The HapMap project also presents these graphics within their website. However, these approaches are limited in their use of data from multiallelic markers and provide limited information in a graphical form. Results We have developed a software package (MIDAS – Multiallelic Interallelic Disequilibrium Analysis Software) for the estimation and graphical display of interallelic linkage disequilibrium. Linkage disequilibrium is analysed for each allelic combination (of one allele from each of two loci), between all pairwise combinations of any type of multiallelic loci in a contig (or any set) of many loci (including single nucleotide polymorphisms, microsatellites, minisatellites and haplotypes). Data are presented graphically in a novel and informative way, and can also be exported in tabular form for other analyses. This approach facilitates visualisation of patterns of linkage disequilibrium across genomic regions, analysis of the relationships between different alleles of multiallelic markers and inferences about patterns of evolution and selection. Conclusion MIDAS is a linkage disequilibrium analysis program with a comprehensive graphical user interface providing novel views of patterns of linkage disequilibrium between all types of multiallelic and biallelic markers. Availability Available from and PMID:16643648

Autosomal Dominant Nonsyndromic Cleft Lip and Palate: Significant Evidence of Linkage at 18q21.1

PubMed Central

Beiraghi, Soraya ; Nath, Swapan K. ; Gaines, Matthew ; Mandhyan, Desh D. ; Hutchings, David ; Ratnamala, Uppala ; McElreavey, Ken ; Bartoloni, Lucia ; Antonarakis, Gregory S. ; Antonarakis, Stylianos E. ; Radhakrishna, Uppala 

2007-01-01

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital facial defects, with an incidence of 1 in 700–1,000 live births among individuals of European descent. Several linkage and association studies of NSCL/P have suggested numerous candidate genes and genomic regions. A genomewide linkage analysis of a large multigenerational family (UR410) with NSCL/P was performed using a single-nucleotide–polymorphism array. Nonparametric linkage (NPL) analysis provided significant evidence of linkage for marker rs728683 on chromosome 18q21.1 (NPL=43.33 and P=.000061; nonparametric LOD=3.97 and P=.00001). Parametric linkage analysis with a dominant mode of inheritance and reduced penetrance resulted in a maximum LOD score of 3.61 at position 47.4 Mb on chromosome 18q21.1. Haplotype analysis with informative crossovers defined a 5.7-Mb genomic region spanned by proximal marker rs1824683 (42,403,918 bp) and distal marker rs768206 (48,132,862 bp). Thus, a novel genomic region on 18q21.1 was identified that most likely harbors a high-risk variant for NSCL/P in this family; we propose to name this locus “OFC11” (orofacial cleft 11). PMID:17564975

Some methods for blindfolded record linkage

PubMed Central

Churches, Tim; Christen, Peter

2004-01-01

Background The linkage of records which refer to the same entity in separate data collections is a common requirement in public health and biomedical research. Traditionally, record linkage techniques have required that all the identifying data in which links are sought be revealed to at least one party, often a third party. This necessarily invades personal privacy and requires complete trust in the intentions of that party and their ability to maintain security and confidentiality. Dusserre, Quantin, Bouzelat and colleagues have demonstrated that it is possible to use secure one-way hash transformations to carry out follow-up epidemiological studies without any party having to reveal identifying information about any of the subjects – a technique which we refer to as "blindfolded record linkage". A limitation of their method is that only exact comparisons of values are possible, although phonetic encoding of names and other strings can be used to allow for some types of typographical variation and data errors. Methods A method is described which permits the calculation of a general similarity measure, the n-gram score, without having to reveal the data being compared, albeit at some cost in computation and data communication. This method can be combined with public key cryptography and automatic estimation of linkage model parameters to create an overall system for blindfolded record linkage. Results The system described offers good protection against misdeeds or security failures by any one party, but remains vulnerable to collusion between or simultaneous compromise of two or more parties involved in the linkage operation. In order to reduce the likelihood of this, the use of last-minute allocation of tasks to substitutable servers is proposed. Proof-of-concept computer programmes written in the Python programming language are provided to illustrate the similarity comparison protocol. Conclusion Although the protocols described in this paper are not unconditionally secure, they do suggest the feasibility, with the aid of modern cryptographic techniques and high speed communication networks, of a general purpose probabilistic record linkage system which permits record linkage studies to be carried out with negligible risk of invasion of personal privacy. PMID:15222890

Genetic studies of stuttering in a founder population.

PubMed

Wittke-Thompson, Jacqueline K; Ambrose, Nicoline; Yairi, Ehud; Roe, Cheryl; Cook, Edwin H; Ober, Carole; Cox, Nancy J

2007-01-01

Genome-wide linkage and association analyses were conducted to identify genetic determinants of stuttering in a founder population in which 48 individuals affected with stuttering are connected in a single 232-person genealogy. A novel approach was devised to account for all necessary relationships to enable multipoint linkage analysis. Regions with nominal evidence for linkage were found on chromosomes 3 (P=0.013, 208.8 centiMorgans (cM)), 13 (P=0.012, 52.6 cM), and 15 (P=0.02, 100 cM). Regions with nominal evidence for association with stuttering that overlapped with a linkage signal are located on chromosomes 3 (P=0.0047, 195 cM), 9 (P=0.0067, 46.5 cM), and 13 (P=0.0055, 52.6 cM). We also conducted the first meta-analysis for stuttering using results from linkage studies in the Hutterites and The Illinois International Genetics of Stuttering Project and identified regions with nominal evidence for linkage on chromosomes 2 (P=0.013, 180-195 cM) and 5 (P=0.0051, 105-120 cM; P=0.015, 120-135 cM). None of the linkage signals detected in the Hutterite sample alone, or in the meta-analysis, meet genome-wide criteria for significance, although some of the stronger signals overlap linkage mapping signals previously reported for other speech and language disorders. After reading this article, the reader will be able to: (1) summarize information about the background of common disorders and methodology of genetic studies; (2) evaluate the role of genetics in stuttering; (3) discuss the value of using founder populations in genetic studies; (4) articulate the importance of combining several studies in a meta-analysis; (5) discuss the overlap of genetic signals identified in stuttering with other speech and language disorders.

Genetic Structure, Linkage Disequilibrium and Association Mapping of Verticillium Wilt Resistance in Elite Cotton (Gossypium hirsutum L.) Germplasm Population

PubMed Central

Zhao, Yunlei; Wang, Hongmei; Chen, Wei; Li, Yunhai

2014-01-01

Understanding the population structure and linkage disequilibrium in an association panel can effectively avoid spurious associations and improve the accuracy in association mapping. In this study, one hundred and fifty eight elite cotton (Gossypium hirsutum L.) germplasm from all over the world, which were genotyped with 212 whole genome-wide marker loci and phenotyped with an disease nursery and greenhouse screening method, were assayed for population structure, linkage disequilibrium, and association mapping of Verticillium wilt resistance. A total of 480 alleles ranging from 2 to 4 per locus were identified from all collections. Model-based analysis identified two groups (G1 and G2) and seven subgroups (G1a–c, G2a–d), and differentiation analysis showed that subgroup having a single origin or pedigree was apt to differentiate with those having a mixed origin. Only 8.12% linked marker pairs showed significant LD (P<0.001) in this association panel. The LD level for linked markers is significantly higher than that for unlinked markers, suggesting that physical linkage strongly influences LD in this panel, and LD level was elevated when the panel was classified into groups and subgroups. The LD decay analysis for several chromosomes showed that different chromosomes showed a notable change in LD decay distances for the same gene pool. Based on the disease nursery and greenhouse environment, 42 marker loci associated with Verticillium wilt resistance were identified through association mapping, which widely were distributed among 15 chromosomes. Among which 10 marker loci were found to be consistent with previously identified QTLs and 32 were new unreported marker loci, and QTL clusters for Verticillium wilt resistanc on Chr.16 were also proved in our study, which was consistent with the strong linkage in this chromosome. Our results would contribute to association mapping and supply the marker candidates for marker-assisted selection of Verticillium wilt resistance in cotton. PMID:24466016

Mapping heritability and molecular genetic associations with cortical features using probabilistic brain atlases: methods and applications to schizophrenia.

PubMed

Cannon, Tyrone D; Thompson, Paul M; van Erp, Theo G M; Huttunen, Matti; Lonnqvist, Jouko; Kaprio, Jaakko; Toga, Arthur W

2006-01-01

There is an urgent need to decipher the complex nature of genotype-phenotype relationships within the multiple dimensions of brain structure and function that are compromised in neuropsychiatric syndromes such as schizophrenia. Doing so requires sophisticated methodologies to represent population variability in neural traits and to probe their heritable and molecular genetic bases. We have recently developed and applied computational algorithms to map the heritability of, as well as genetic linkage and association to, neural features encoded using brain imaging in the context of three-dimensional (3D), populationbased, statistical brain atlases. One set of algorithms builds on our prior work using classical twin study methods to estimate heritability by fitting biometrical models for additive genetic, unique, and common environmental influences. Another set of algorithms performs regression-based (Haseman-Elston) identical-bydescent linkage analysis and genetic association analysis of DNA polymorphisms in relation to neural traits of interest in the same 3D population-based brain atlas format. We demonstrate these approaches using samples of healthy monozygotic (MZ) and dizygotic (DZ) twin pairs, as well as MZ and DZ twin pairs discordant for schizophrenia, but the methods can be generalized to other classes of relatives and to other diseases. The results confirm prior evidence of genetic influences on gray matter density in frontal brain regions. They also provide converging evidence that the chromosome 1q42 region is relevant to schizophrenia by demonstrating linkage and association of markers of the Transelin-Associated-Factor-X and Disrupted-In- Schizophrenia-1 genes with prefrontal cortical gray matter deficits in twins discordant for schizophrenia.

A randomised controlled trial to compare opt-in and opt-out parental consent for childhood vaccine safety surveillance using data linkage: study protocol.

PubMed

Berry, Jesia G; Ryan, Philip; Braunack-Mayer, Annette J; Duszynski, Katherine M; Xafis, Vicki; Gold, Michael S

2011-01-04

The Vaccine Assessment using Linked Data (VALiD) trial compared opt-in and opt-out parental consent for a population-based childhood vaccine safety surveillance program using data linkage. A subsequent telephone interview of all households enrolled in the trial elicited parental intent regarding the return or non-return of reply forms for opt-in and opt-out consent. This paper describes the rationale for the trial and provides an overview of the design and methods. Single-centre, single-blind, randomised controlled trial (RCT) stratified by firstborn status. Mothers who gave birth at one tertiary South Australian hospital were randomised at six weeks post-partum to receive an opt-in or opt-out reply form, along with information explaining data linkage. The primary outcome at 10 weeks post-partum was parental participation in each arm, as indicated by the respective return or non-return of a reply form (or via telephone or email response). A subsequent telephone interview at 10 weeks post-partum elicited parental intent regarding the return or non-return of the reply form, and attitudes and knowledge about data linkage, vaccine safety, consent preferences and vaccination practices. Enrolment began in July 2009 and 1,129 households were recruited in a three-month period. Analysis has not yet been undertaken. The participation rate and selection bias for each method of consent will be compared when the data are analysed. The VALiD RCT represents the first trial of opt-in versus opt-out consent for a data linkage study that assesses consent preferences and intent compared with actual opting in or opting out behaviour, and socioeconomic factors. The limitations to generalisability are discussed. Australian New Zealand Clinical Trials Registry ACTRN12610000332022.

Nance-Horan syndrome: localization within the region Xp21.1-Xp22.3 by linkage analysis.

PubMed

Stambolian, D; Lewis, R A; Buetow, K; Bond, A; Nussbaum, R

1990-07-01

Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome (MIM 302350) is a disease of unknown pathogenesis characterized by congenital cataracts and dental anomalies. We performed linkage analysis in three kindreds with NHS by using six RFLP markers between Xp11.3 and Xp22.3. Close linkage was found between NHS and polymorphic loci DXS43 (theta = 0 with lod score 2.89), DXS41 (theta = 0 with lod score 3.44), and DXS67 (theta = 0 with lod score 2.74), defined by probes pD2, p99-6, and pB24, respectively. Recombinations were found with the marker loci DXS84 (theta = .04 with lod score 4.13), DXS143 (theta = .06 with lod score 3.11) and DXS7 (theta = .09 with lod score 1.68). Multipoint linkage analysis determined the NHS locus to be linked completely to DXS41 (lod score = 7.07). Our linkage results, combined with analysis of Xp interstitial deletions, suggest that the NHS locus is located within or close to the Xp22.1-Xp22.2 region.

Nance-Horan syndrome: localization within the region Xp21.1-Xp22.3 by linkage analysis.

PubMed Central

Stambolian, D; Lewis, R A; Buetow, K; Bond, A; Nussbaum, R

1990-01-01

Nance-Horan Syndrome (NHS) or X-linked cataract-dental syndrome (MIM 302350) is a disease of unknown pathogenesis characterized by congenital cataracts and dental anomalies. We performed linkage analysis in three kindreds with NHS by using six RFLP markers between Xp11.3 and Xp22.3. Close linkage was found between NHS and polymorphic loci DXS43 (theta = 0 with lod score 2.89), DXS41 (theta = 0 with lod score 3.44), and DXS67 (theta = 0 with lod score 2.74), defined by probes pD2, p99-6, and pB24, respectively. Recombinations were found with the marker loci DXS84 (theta = .04 with lod score 4.13), DXS143 (theta = .06 with lod score 3.11) and DXS7 (theta = .09 with lod score 1.68). Multipoint linkage analysis determined the NHS locus to be linked completely to DXS41 (lod score = 7.07). Our linkage results, combined with analysis of Xp interstitial deletions, suggest that the NHS locus is located within or close to the Xp22.1-Xp22.2 region. PMID:1971992

Linkage localization of X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Trofatter, J.; Haines, J.L.

1993-02-01

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived frommore » work with four VSSR markers - AR, PGKP1, DXS453, and DXYS1X - in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 ([theta] = 0). 32 refs., 3 figs., 2 tabs.« less

Introductory Guide to the Statistics of Molecular Genetics

ERIC Educational Resources Information Center

Eley, Thalia C.; Rijsdijk, Fruhling

2005-01-01

Background: This introductory guide presents the main two analytical approaches used by molecular geneticists: linkage and association. Methods: Traditional linkage and association methods are described, along with more recent advances in methodologies such as those using a variance components approach. Results: New methods are being developed all…

Pregnancy associated death in record linkage studies relative to delivery, termination of pregnancy, and natural losses: A systematic review with a narrative synthesis and meta-analysis

PubMed Central

Reardon, David C; Thorp, John M

2017-01-01

Objectives: Measures of pregnancy associated deaths provide important guidance for public health initiatives. Record linkage studies have significantly improved identification of deaths associated with childbirth but relatively few have also examined deaths associated with pregnancy loss even though higher rates of maternal death have been associated with the latter. Following PRISMA guidelines we undertook a systematic review of record linkage studies examining the relative mortality risks associated with pregnancy loss to develop a narrative synthesis, a meta-analysis, and to identify research opportunities. Methods: MEDLINE and SCOPUS were searched in July 2015 using combinations of: mortality, maternal death, record linkage, linked records, pregnancy associated mortality, and pregnancy associated death to identify papers using linkage of death certificates to independent records identifying pregnancy outcomes. Additional studies were identified by examining all citations for relevant studies. Results: Of 989 studies, 11 studies from three countries reported mortality rates associated with termination of pregnancy, miscarriage or failed pregnancy. Within a year of their pregnancy outcomes, women experiencing a pregnancy loss are over twice as likely to die compared to women giving birth. The heightened risk is apparent within 180 days and remains elevated for many years. There is a dose effect, with exposure to each pregnancy loss associated with increasing risk of death. Higher rates of death from suicide, accidents, homicide and some natural causes, such as circulatory diseases, may be from elevated stress and risk taking behaviors. Conclusions: Both miscarriage and termination of pregnancy are markers for reduced life expectancy. This association should inform research and new public health initiatives including screening and interventions for patients exhibiting known risk factors. PMID:29163945

Appliation of rad-sequencing to linkage mapping in citrus

USDA-ARS?s Scientific Manuscript database

High density linkage maps can be developed for modest cost using high-throughput DNA sequencing to genotype a defined fraction (representation) of the genome. We developed linkage maps in two citrus populations using the RAD (Restriction site Associated DNA) genotyping method which involves restrict...

Mass spectrometric method to determine the chain length of oligosaccharides attached to phenolic polymers by nonglycosidic linkages

Treesearch

James L. Minor; Roger C. Pettersen

1987-01-01

In many plants, a portion of the polysaccharides appears to have a very low degree of cross-linking with aromatic polymers such as lignin or flavolans. The proportion of cross-linked units may be enriched for study by enzymatically hydrolyzing the nonbonded carbohydrates. A convenient method is described for the simultaneous analysis of sugar content and apparent chain...

Infrared Spectroscopic Analysis of Linkage Isomerism in Metal-Thiocyanate Complexes

ERIC Educational Resources Information Center

Baer, Carl; Pike, Jay

2010-01-01

We developed an experiment suitable for an advanced inorganic chemistry laboratory that utilizes a cooperative learning environment, which allows students to develop an empirical method of determining the bonding mode of a series of unknown metal-thiocyanate complexes. Students synthesize the metal-thiocyanate complexes and obtain the FT-IR…

Combined genome-wide linkage and targeted association analysis of head circumference in autism spectrum disorder families.

PubMed

Woodbury-Smith, M; Bilder, D A; Morgan, J; Jerominski, L; Darlington, T; Dyer, T; Paterson, A D; Coon, H

2017-01-01

It has long been recognized that there is an association between enlarged head circumference (HC) and autism spectrum disorder (ASD), but the genetics of HC in ASD is not well understood. In order to investigate the genetic underpinning of HC in ASD, we undertook a genome-wide linkage study of HC followed by linkage signal targeted association among a sample of 67 extended pedigrees with ASD. HC measurements on members of 67 multiplex ASD extended pedigrees were used as a quantitative trait in a genome-wide linkage analysis. The Illumina 6K SNP linkage panel was used, and analyses were carried out using the SOLAR implemented variance components model. Loci identified in this way formed the target for subsequent association analysis using the Illumina OmniExpress chip and imputed genotypes. A modification of the qTDT was used as implemented in SOLAR. We identified a linkage signal spanning 6p21.31 to 6p22.2 (maximum LOD = 3.4). Although targeted association did not find evidence of association with any SNP overall, in one family with the strongest evidence of linkage, there was evidence for association (rs17586672, p  = 1.72E-07). Although this region does not overlap with ASD linkage signals in these same samples, it has been associated with other psychiatric risk, including ADHD, developmental dyslexia, schizophrenia, specific language impairment, and juvenile bipolar disorder. The genome-wide significant linkage signal represents the first reported observation of a potential quantitative trait locus for HC in ASD and may be relevant in the context of complex multivariate risk likely leading to ASD.

A New Method for Assessing How Sensitivity and Specificity of Linkage Studies Affects Estimation

PubMed Central

Moore, Cecilia L.; Amin, Janaki; Gidding, Heather F.; Law, Matthew G.

2014-01-01

Background While the importance of record linkage is widely recognised, few studies have attempted to quantify how linkage errors may have impacted on their own findings and outcomes. Even where authors of linkage studies have attempted to estimate sensitivity and specificity based on subjects with known status, the effects of false negatives and positives on event rates and estimates of effect are not often described. Methods We present quantification of the effect of sensitivity and specificity of the linkage process on event rates and incidence, as well as the resultant effect on relative risks. Formulae to estimate the true number of events and estimated relative risk adjusted for given linkage sensitivity and specificity are then derived and applied to data from a prisoner mortality study. The implications of false positive and false negative matches are also discussed. Discussion Comparisons of the effect of sensitivity and specificity on incidence and relative risks indicate that it is more important for linkages to be highly specific than sensitive, particularly if true incidence rates are low. We would recommend that, where possible, some quantitative estimates of the sensitivity and specificity of the linkage process be performed, allowing the effect of these quantities on observed results to be assessed. PMID:25068293

Teaching Principles of Linkage and Gene Mapping with the Tomato.

ERIC Educational Resources Information Center

Hawk, James A.; And Others

1980-01-01

A three-point linkage system in tomatoes is used to explain concepts of gene mapping, linking and statistical analysis. The system is designed for teaching the effective use of statistics, and the power of genetic analysis from statistical analysis of phenotypic ratios. (Author/SA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pham, Grace H.; Rana, Ambar S. J. B.; Korkmaz, E. Nihal

Ubiquitin (Ub) chains regulate a wide range of biological processes, and Ub chain connectivity is a critical determinant of the many regulatory roles that this post-translational modification plays in cells. To understand how distinct Ub chains orchestrate different biochemical events, we and other investigators have developed enzymatic and non-enzymatic methods to synthesize Ub chains of well-defined length and connectivity. A number of chemical approaches have been used to generate Ub oligomers connected by non-native linkages; however, few studies have examined the extent to which non-native linkages recapitulate the structural and functional properties associated with native isopeptide bonds. Here, we comparemore » the structure and function of Ub dimers bearing native and non-native linkages. Using small-angle X-ray scattering (SAXS) analysis, we show that scattering profiles for the two types of dimers are similar. Moreover, using an experimental structural library and atomistic simulations to fit the experimental SAXS profiles, we find that the two types of Ub dimers can be matched to analogous structures. An important application of non-native Ub oligomers is to probe the activity and selectivity of deubiquitinases. Through steady-state kinetic analyses, we demonstrate that different families of deubiquitinases hydrolyze native and non-native isopeptide linkages with comparable efficiency and selectivity. Considering the significant challenges associated with building topologically diverse native Ub chains, our results illustrate that chains harboring non-native linkages can serve as surrogate substrates for explorations of Ub function.« less

Monte Carlo simulations on marker grouping and ordering.

PubMed

Wu, J; Jenkins, J; Zhu, J; McCarty, J; Watson, C

2003-08-01

Four global algorithms, maximum likelihood (ML), sum of adjacent LOD score (SALOD), sum of adjacent recombinant fractions (SARF) and product of adjacent recombinant fraction (PARF), and one approximation algorithm, seriation (SER), were used to compare the marker ordering efficiencies for correctly given linkage groups based on doubled haploid (DH) populations. The Monte Carlo simulation results indicated the marker ordering powers for the five methods were almost identical. High correlation coefficients were greater than 0.99 between grouping power and ordering power, indicating that all these methods for marker ordering were reliable. Therefore, the main problem for linkage analysis was how to improve the grouping power. Since the SER approach provided the advantage of speed without losing ordering power, this approach was used for detailed simulations. For more generality, multiple linkage groups were employed, and population size, linkage cutoff criterion, marker spacing pattern (even or uneven), and marker spacing distance (close or loose) were considered for obtaining acceptable grouping powers. Simulation results indicated that the grouping power was related to population size, marker spacing distance, and cutoff criterion. Generally, a large population size provided higher grouping power than small population size, and closely linked markers provided higher grouping power than loosely linked markers. The cutoff criterion range for achieving acceptable grouping power and ordering power differed for varying cases; however, combining all situations in this study, a cutoff criterion ranging from 50 cM to 60 cM was recommended for achieving acceptable grouping power and ordering power for different cases.

Mapping carcass and meat quality QTL on Sus Scrofa chromosome 2 in commercial finishing pigs

PubMed Central

Heuven, Henri CM; van Wijk, Rik HJ; Dibbits, Bert; van Kampen, Tony A; Knol, Egbert F; Bovenhuis, Henk

2009-01-01

Quantitative trait loci (QTL) affecting carcass and meat quality located on SSC2 were identified using variance component methods. A large number of traits involved in meat and carcass quality was detected in a commercial crossbred population: 1855 pigs sired by 17 boars from a synthetic line, which where homozygous (A/A) for IGF2. Using combined linkage and linkage disequilibrium mapping (LDLA), several QTL significantly affecting loin muscle mass, ham weight and ham muscles (outer ham and knuckle ham) and meat quality traits, such as Minolta-L* and -b*, ultimate pH and Japanese colour score were detected. These results agreed well with previous QTL-studies involving SSC2. Since our study is carried out on crossbreds, different QTL may be segregating in the parental lines. To address this question, we compared models with a single QTL-variance component with models allowing for separate sire and dam QTL-variance components. The same QTL were identified using a single QTL variance component model compared to a model allowing for separate variances with minor differences with respect to QTL location. However, the variance component method made it possible to detect QTL segregating in the paternal line (e.g. HAMB), the maternal lines (e.g. Ham) or in both (e.g. pHu). Combining association and linkage information among haplotypes improved slightly the significance of the QTL compared to an analysis using linkage information only. PMID:19284675

Linkage Analysis of a Model Quantitative Trait in Humans: Finger Ridge Count Shows Significant Multivariate Linkage to 5q14.1

PubMed Central

Medland, Sarah E; Loesch, Danuta Z; Mdzewski, Bogdan; Zhu, Gu; Montgomery, Grant W; Martin, Nicholas G

2007-01-01

The finger ridge count (a measure of pattern size) is one of the most heritable complex traits studied in humans and has been considered a model human polygenic trait in quantitative genetic analysis. Here, we report the results of the first genome-wide linkage scan for finger ridge count in a sample of 2,114 offspring from 922 nuclear families. Both univariate linkage to the absolute ridge count (a sum of all the ridge counts on all ten fingers), and multivariate linkage analyses of the counts on individual fingers, were conducted. The multivariate analyses yielded significant linkage to 5q14.1 (Logarithm of odds [LOD] = 3.34, pointwise-empirical p-value = 0.00025) that was predominantly driven by linkage to the ring, index, and middle fingers. The strongest univariate linkage was to 1q42.2 (LOD = 2.04, point-wise p-value = 0.002, genome-wide p-value = 0.29). In summary, the combination of univariate and multivariate results was more informative than simple univariate analyses alone. Patterns of quantitative trait loci factor loadings consistent with developmental fields were observed, and the simple pleiotropic model underlying the absolute ridge count was not sufficient to characterize the interrelationships between the ridge counts of individual fingers. PMID:17907812

Sociocultural Meanings of Nanotechnology: Research Methodologies

NASA Astrophysics Data System (ADS)

Bainbridge, William Sims

2004-06-01

This article identifies six social-science research methodologies that will be useful for charting the sociocultural meaning of nanotechnology: web-based questionnaires, vignette experiments, analysis of web linkages, recommender systems, quantitative content analysis, and qualitative textual analysis. Data from a range of sources are used to illustrate how the methods can delineate the intellectual content and institutional structure of the emerging nanotechnology culture. Such methods will make it possible in future to test hypotheses such as that there are two competing definitions of nanotechnology - the technical-scientific and the science-fiction - that are influencing public perceptions by different routes and in different directions.

Genomewide scan identifies susceptibility locus for dyslexia on Xq27 in an extended Dutch family

PubMed Central

de Kovel, C G F; Hol, F; Heister, J; Willemen, J; Sandkuijl, L; Franke, B; Padberg, G

2004-01-01

Context: Dyslexia is a common disorder with a strong genetic component, but despite significant research effort, the aetiology is still largely unknown. Objective: To identify loci contributing to dyslexia risk. Methods: This was a genomewide linkage analysis in a single large family. Dutch families with at least two first degree relatives suffering from dyslexia participated in the study. Participants were recruited through an advertisement campaign in papers and magazines. The main outcome measure was linkage between genetic markers and dyslexia phenotype. Results: Using parametric linkage analysis, we found strong evidence for a locus influencing dyslexia on Xq27.3 (multipoint lod = 3.68). Recombinations in two family members flanked an 8 cM region, comprising 11 currently confirmed genes. All four males carrying the risk haplotype had very low scores on the reading tests. The presentation in females was more variable, but 8/9 females carrying the risk haplotype were diagnosed dyslexic by our composite score, so we considered the putative risk allele to be dominant with reduced penetrance. Linkage was not found in an additional collection of affected sibling pairs. Conclusions: A locus influencing dyslexia risk is probably located between markers DXS1227 and DXS8091 on the X chromosome, closely situated to a locus indicated by a published genome scan of English sibling pairs. Although the locus may not be a common cause for dyslexia, the relatively small and gene poor region offers hope to identify the responsible gene. PMID:15342694

Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele

PubMed Central

Radhakrishna, Uppala; Nath, Swapan K; McElreavey, Ken; Ratnamala, Uppala; Sun, Celi; Maiti, Amit K; Gagnebin, Maryline; Béna, Frédérique; Newkirk, Heather L; Sharp, Andrew J; Everman, David B; Murray, Jeffrey C; Schwartz, Charles E; Antonarakis, Stylianos E; Butler, Merlin G

2017-01-01

Background Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. Methods and findings A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5–64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. Conclusions The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors’ knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement. PMID:22499347

Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis

PubMed Central

Ullah, Rahim; Ansar, Muhammad; Durrani, Zaka Ullah; Lee, Kwanghyuk; Santos-Cortez, Regie Lyn P.; Muhammad, Dost; Ali, Mahboob; Zia, Muhammad; Ayub, Muhammad; Khan, Suliman; Smith, Josh D.; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael; Leal, Suzanne M.; Ahmad, Wasim

2016-01-01

Background Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. Methods The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. Results Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). Conclusion The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members. PMID:26578203

Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy.

PubMed

Norton, Nadine; Li, Duanxiang; Rampersaud, Evadnie; Morales, Ana; Martin, Eden R; Zuchner, Stephan; Guo, Shengru; Gonzalez, Michael; Hedges, Dale J; Robertson, Peggy D; Krumm, Niklas; Nickerson, Deborah A; Hershberger, Ray E

2013-04-01

BACKGROUND- Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. METHODS AND RESULTS- We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. CONCLUSIONS- These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

Genotyping-by-sequencing enables linkage mapping in three octoploid cultivated strawberry families

PubMed Central

Salinas, Natalia; Tennessen, Jacob A.; Zurn, Jason D.; Sargent, Daniel James; Hancock, James; Bassil, Nahla V.

2017-01-01

Genotyping-by-sequencing (GBS) was used to survey genome-wide single-nucleotide polymorphisms (SNPs) in three biparental strawberry (Fragaria × ananassa) populations with the goal of evaluating this technique in a species with a complex octoploid genome. GBS sequence data were aligned to the F. vesca ‘Fvb’ reference genome in order to call SNPs. Numbers of polymorphic SNPs per population ranged from 1,163 to 3,190. Linkage maps consisting of 30–65 linkage groups were produced from the SNP sets derived from each parent. The linkage groups covered 99% of the Fvb reference genome, with three to seven linkage groups from a given parent aligned to any particular chromosome. A phylogenetic analysis performed using the POLiMAPS pipeline revealed linkage groups that were most similar to ancestral species F. vesca for each chromosome. Linkage groups that were most similar to a second ancestral species, F. iinumae, were only resolved for Fvb 4. The quantity of missing data and heterogeneity in genome coverage inherent in GBS complicated the analysis, but POLiMAPS resolved F. × ananassa chromosomal regions derived from diploid ancestor F. vesca. PMID:28875078

Ignoring Intermarker Linkage Disequilibrium Induces False-Positive Evidence of Linkage for Consanguineous Pedigrees when Genotype Data Is Missing for Any Pedigree Member

PubMed Central

Li, Bingshan; Leal, Suzanne M.

2008-01-01

Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al. [1] that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for autosomal recessive consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. False-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage, and which family members aid in its reduction, is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. For the situation, when parental genotypes are unavailable, false-positive evidence for linkage can be reduced by including genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents in the analysis. PMID:18073490

Correlation between quantitative traits and correlation between corresponding LOD scores: detection of pleiotropic effects.

PubMed

Ulgen, Ayse; Han, Zhihua; Li, Wentian

2003-12-31

We address the question of whether statistical correlations among quantitative traits lead to correlation of linkage results of these traits. Five measured quantitative traits (total cholesterol, fasting glucose, HDL cholesterol, blood pressure, and triglycerides), and one derived quantitative trait (total cholesterol divided by the HDL cholesterol) are used for phenotype correlation studies. Four of them are used for linkage analysis. We show that although correlation among phenotypes partially reflects the correlation among linkage analysis results, the LOD-score correlations are on average low. The most significant peaks found by using different traits do not often overlap. Studying covariances at specific locations in LOD scores may provide clues for further bivariate linkage analyses.

Method to Eliminate Flux Linkage DC Component in Load Transformer for Static Transfer Switch

PubMed Central

2014-01-01

Many industrial and commercial sensitive loads are subject to the voltage sags and interruptions. The static transfer switch (STS) based on the thyristors is applied to improve the power quality and reliability. However, the transfer will result in severe inrush current in the load transformer, because of the DC component in the magnetic flux generated in the transfer process. The inrush current which is always 2~30 p.u. can cause the disoperation of relay protective devices and bring potential damage to the transformer. The way to eliminate the DC component is to transfer the related phases when the residual flux linkage of the load transformer and the prospective flux linkage of the alternate source are equal. This paper analyzes how the flux linkage of each winding in the load transformer changes in the transfer process. Based on the residual flux linkage when the preferred source is completely disconnected, the method to calculate the proper time point to close each phase of the alternate source is developed. Simulation and laboratory experiments results are presented to show the effectiveness of the transfer method. PMID:25133255

Method to eliminate flux linkage DC component in load transformer for static transfer switch.

PubMed

He, Yu; Mao, Chengxiong; Lu, Jiming; Wang, Dan; Tian, Bing

2014-01-01

Many industrial and commercial sensitive loads are subject to the voltage sags and interruptions. The static transfer switch (STS) based on the thyristors is applied to improve the power quality and reliability. However, the transfer will result in severe inrush current in the load transformer, because of the DC component in the magnetic flux generated in the transfer process. The inrush current which is always 2 ~ 30 p.u. can cause the disoperation of relay protective devices and bring potential damage to the transformer. The way to eliminate the DC component is to transfer the related phases when the residual flux linkage of the load transformer and the prospective flux linkage of the alternate source are equal. This paper analyzes how the flux linkage of each winding in the load transformer changes in the transfer process. Based on the residual flux linkage when the preferred source is completely disconnected, the method to calculate the proper time point to close each phase of the alternate source is developed. Simulation and laboratory experiments results are presented to show the effectiveness of the transfer method.

A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND)

PubMed Central

Thameem, Farook; Igo, Robert P.; Freedman, Barry I.; Langefeld, Carl; Hanson, Robert L.; Schelling, Jeffrey R.; Elston, Robert C.; Duggirala, Ravindranath; Nicholas, Susanne B.; Goddard, Katrina A. B.; Divers, Jasmin; Guo, Xiuqing; Ipp, Eli; Kimmel, Paul L.; Meoni, Lucy A.; Shah, Vallabh O.; Smith, Michael W.; Winkler, Cheryl A.; Zager, Philip G.; Knowler, William C.; Nelson, Robert G.; Pahl, Madeline V.; Parekh, Rulan S.; Kao, W. H. Linda; Rasooly, Rebekah S.; Adler, Sharon G.; Abboud, Hanna E.; Iyengar, Sudha K.; Sedor, John R.

2013-01-01

Objective Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR. Methods Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula. Results The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. Conclusion The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN. PMID:24358131

Some methods for blindfolded record linkage.

PubMed

Churches, Tim; Christen, Peter

2004-06-28

The linkage of records which refer to the same entity in separate data collections is a common requirement in public health and biomedical research. Traditionally, record linkage techniques have required that all the identifying data in which links are sought be revealed to at least one party, often a third party. This necessarily invades personal privacy and requires complete trust in the intentions of that party and their ability to maintain security and confidentiality. Dusserre, Quantin, Bouzelat and colleagues have demonstrated that it is possible to use secure one-way hash transformations to carry out follow-up epidemiological studies without any party having to reveal identifying information about any of the subjects - a technique which we refer to as "blindfolded record linkage". A limitation of their method is that only exact comparisons of values are possible, although phonetic encoding of names and other strings can be used to allow for some types of typographical variation and data errors. A method is described which permits the calculation of a general similarity measure, the n-gram score, without having to reveal the data being compared, albeit at some cost in computation and data communication. This method can be combined with public key cryptography and automatic estimation of linkage model parameters to create an overall system for blindfolded record linkage. The system described offers good protection against misdeeds or security failures by any one party, but remains vulnerable to collusion between or simultaneous compromise of two or more parties involved in the linkage operation. In order to reduce the likelihood of this, the use of last-minute allocation of tasks to substitutable servers is proposed. Proof-of-concept computer programmes written in the Python programming language are provided to illustrate the similarity comparison protocol. Although the protocols described in this paper are not unconditionally secure, they do suggest the feasibility, with the aid of modern cryptographic techniques and high speed communication networks, of a general purpose probabilistic record linkage system which permits record linkage studies to be carried out with negligible risk of invasion of personal privacy.

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

PubMed Central

2012-01-01

Background Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. Methods Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. Results Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2–3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. Conclusions Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2–3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region. PMID:22712434

Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography

DOE PAGES

Lei, Dongsheng; Marras, Alexander E.; Liu, Jianfang; ...

2018-02-09

Scaffolded DNA origami has proven to be a powerful and efficient technique to fabricate functional nanomachines by programming the folding of a single-stranded DNA template strand into three-dimensional (3D) nanostructures, designed to be precisely motion-controlled. Although two-dimensional (2D) imaging of DNA nanomachines using transmission electron microscopy and atomic force microscopy suggested these nanomachines are dynamic in 3D, geometric analysis based on 2D imaging was insufficient to uncover the exact motion in 3D. In this paper, we use the individual-particle electron tomography method and reconstruct 129 density maps from 129 individual DNA origami Bennett linkage mechanisms at ~6-14 nm resolution. The statisticalmore » analyses of these conformations lead to understanding the 3D structural dynamics of Bennett linkage mechanisms. Moreover, our effort provides experimental verification of a theoretical kinematics model of DNA origami, which can be used as feedback to improve the design and control of motion via optimized DNA sequences and routing.« less

Three-dimensional structural dynamics of DNA origami Bennett linkages using individual-particle electron tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lei, Dongsheng; Marras, Alexander E.; Liu, Jianfang

Scaffolded DNA origami has proven to be a powerful and efficient technique to fabricate functional nanomachines by programming the folding of a single-stranded DNA template strand into three-dimensional (3D) nanostructures, designed to be precisely motion-controlled. Although two-dimensional (2D) imaging of DNA nanomachines using transmission electron microscopy and atomic force microscopy suggested these nanomachines are dynamic in 3D, geometric analysis based on 2D imaging was insufficient to uncover the exact motion in 3D. In this paper, we use the individual-particle electron tomography method and reconstruct 129 density maps from 129 individual DNA origami Bennett linkage mechanisms at ~6-14 nm resolution. The statisticalmore » analyses of these conformations lead to understanding the 3D structural dynamics of Bennett linkage mechanisms. Moreover, our effort provides experimental verification of a theoretical kinematics model of DNA origami, which can be used as feedback to improve the design and control of motion via optimized DNA sequences and routing.« less

Selective digestion of Ba2+/Ca2+ alginate gel microdroplets for single-cell handling

NASA Astrophysics Data System (ADS)

Odaka, Masao; Hattori, Akihiro; Matsuura, Kenji; Yasuda, Kenji

2018-06-01

Cells encapsuled by polymer microdroplets are an effective platform for the identification and separation of individual cells for single-cell-based analysis. However, a key challenge is to maintain and release the captured cells in the microdroplets selectively, nondestructively, and noninvasively. We developed a simple method of encapsulating cells in alginate microdroplets having different digestion characteristics. Cells were diluted with an alginate polymer of sol state and encapsulated into microdroplets with Ba2+ and Ca2+ by a spray method. When a chelating buffer was applied, alginate gel microdroplets were digested according to the difference in chelating efficiency of linkage-divalent cations; hence, two types of alginate microdroplets were formed. Moreover, we examined the capability of the alginate gel to exchange linkage-divalent cations and found that both Ca2+ exchange in Ba-alginate microdroplets and Ba2+ exchange in Ca-alginate microdroplets occurred. These results indicate that the potential applications of a mixture of alginate microdroplets with different divalent cations control the selective digestion of microdroplets to improve the high-throughput, high-content microdroplet-based separation, analysis, or storage of single cells.

Global disulfide bond profiling for crude snake venom using dimethyl labeling coupled with mass spectrometry and RADAR algorithm.

PubMed

Huang, Sheng Yu; Chen, Sung Fang; Chen, Chun Hao; Huang, Hsuan Wei; Wu, Wen Guey; Sung, Wang Chou

2014-09-02

Snake venom consists of toxin proteins with multiple disulfide linkages to generate unique structures and biological functions. Determination of these cysteine connections usually requires the purification of each protein followed by structural analysis. In this study, dimethyl labeling coupled with LC-MS/MS and RADAR algorithm was developed to identify the disulfide bonds in crude snake venom. Without any protein separation, the disulfide linkages of several cytotoxins and PLA2 could be solved, including more than 20 disulfide bonds. The results show that this method is capable of analyzing protein mixture. In addition, the approach was also used to compare native cytotoxin 3 (CTX III) and its scrambled isomer, another category of protein mixture, for unknown disulfide bonds. Two disulfide-linked peptides were observed in the native CTX III, and 10 in its scrambled form, X-CTX III. This is the first study that reports a platform for the global cysteine connection analysis on a protein mixture. The proposed method is simple and automatic, offering an efficient tool for structural and functional studies of venom proteins.

Linkage studies in primary open angle glaucoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Avramopoulos, D.; Grigoriadu, M.; Kitsos, G.

1994-09-01

Glaucoma is a leading cause of blindness worldwide. The majority of glaucoma is associated with an open, normal appearing anterior chamber angle and is termed primary open angle glaucoma (POAG, MIM 137760). It is characterized by elevated intraocular pressure and onset in middle age or later. A subset of POAG with juvenile onset has recently been linked to chromosome 1q in two families with autosomal dominant inheritance. Eleven pedigrees with autosomal dominant POG (non-juvenile-onset) have been identified in Epirus, Greece. In the present study DNA samples have been collected from 50 individuals from one large pedigree, including 12 affected individuals.more » Preliminary results of linkage analysis with chromosome 1 microsatellites using the computer program package LINKAGE Version 5.1 showed no linkage with the markers previously linked to juvenile-onset POAG. Further linkage analysis is being pursued, and the results will be presented.« less

Linkages Between Clinical Practices and Community Organizations for Prevention: A Literature Review and Environmental Scan

PubMed Central

Hinnant, Laurie W.; Kane, Heather; Horne, Joseph; McAleer, Kelly; Roussel, Amy

2012-01-01

Objectives. We conducted a literature review and environmental scan to develop a framework for interventions that utilize linkages between clinical practices and community organizations for the delivery of preventive services, and to identify and characterize these efforts. Methods. We searched 4 major health services and social science electronic databases and conducted an Internet search to identify examples of linkage interventions in the areas of tobacco cessation, obesity, nutrition, and physical activity. Results. We identified 49 interventions, of which 18 examples described their evaluation methods or reported any intervention outcomes. Few conducted evaluations that were rigorous enough to capture changes in intermediate or long-term health outcomes. Outcomes in these evaluations were primarily patient-focused and did not include organizational or linkage characteristics. Conclusions. An attractive option to increase the delivery of preventive services is to link primary care practices to community organizations; evidence is not yet conclusive, however, that such linkage interventions are effective. Findings provide recommendations to researchers and organizations that fund research, and call for a framework and metrics to study linkage interventions. PMID:22690974

Development of Electromagnetically Actuated Vacuum Circuit Breaker for 72kV Rated Switchgear

NASA Astrophysics Data System (ADS)

Kim, Tae-Hyun; Tsukima, Mitsuru; Maruyama, Akihiko; Takahara, Osamu; Haruna, Kazushi; Yano, Tomotaka; Matsunaga, Toshihiro; Imamura, Kazuaki; Arioka, Masahiro; Takeuchi, Toshie

A new electromagnetically actuated vacuum circuit breaker (VCB) has been developed for a 72kV rated switchgear. Each phase of this VCB has a plurality of compact electromagnetic actuators linked mechanically providing the required driving energy. The mechanical linkage working as a lever magnifies an actuator stroke to the required stroke of a 72kV rated vacuum interrupter. An electromagnetic analysis coupled with motion, which considers the mechanical linkage of the plural actuators, has been developed for designing the driving behavior of this VCB. Using this analytical method and a quality engineering method known as the Taguchi method, we have clarified effective parameters to reduce the time difference of the driving behavior for tolerance specifications. Moreover, analyzing the oscillatory behavior closing the contacts, a structure of this VCB has been designed to reduce the bounce duration. The developed new VCB has been confirmed that a time difference is short enough and bounce duration is reduced. This VCB is highly reliable against variations in manufacturing and environment.

Mapping Quantitative Trait Loci in Crosses between Outbred Lines Using Least Squares

PubMed Central

Haley, C. S.; Knott, S. A.; Elsen, J. M.

1994-01-01

The use of genetic maps based upon molecular markers has allowed the dissection of some of the factors underlying quantitative variation in crosses between inbred lines. For many species crossing inbred lines is not a practical proposition, although crosses between genetically very different outbred lines are possible. Here we develop a least squares method for the analysis of crosses between outbred lines which simultaneously uses information from multiple linked markers. The method is suitable for crosses where the lines may be segregating at marker loci but can be assumed to be fixed for alternative alleles at the major quantitative trait loci (QTLs) affecting the traits under analysis (e.g., crosses between divergent selection lines or breeds with different selection histories). The simultaneous use of multiple markers from a linkage group increases the sensitivity of the test statistic, and thus the power for the detection of QTLs, compared to the use of single markers or markers flanking an interval. The gain is greater for more closely spaced markers and for markers of lower information content. Use of multiple markers can also remove the bias in the estimated position and effect of a QTL which may result when different markers in a linkage group vary in their heterozygosity in the F(1) (and thus in their information content) and are considered only singly or a pair at a time. The method is relatively simple to apply so that more complex models can be fitted than is currently possible by maximum likelihood. Thus fixed effects and effects of background genotype can be fitted simultaneously with the exploration of a single linkage group which will increase the power to detect QTLs by reducing the residual variance. More complex models with several QTLs in the same linkage group and two-locus interactions between QTLs can similarly be examined. Thus least squares provides a powerful tool to extend the range of crosses from which QTLs can be dissected whilst at the same time allowing flexible and realistic models to be explored. PMID:8005424

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.

PubMed

Leu, Costin; de Kovel, Carolien G F; Zara, Federico; Striano, Pasquale; Pezzella, Marianna; Robbiano, Angela; Bianchi, Amedeo; Bisulli, Francesca; Coppola, Antonietta; Giallonardo, Anna Teresa; Beccaria, Francesca; Trenité, Dorothée Kasteleijn-Nolst; Lindhout, Dick; Gaus, Verena; Schmitz, Bettina; Janz, Dieter; Weber, Yvonne G; Becker, Felicitas; Lerche, Holger; Kleefuss-Lie, Ailing A; Hallman, Kerstin; Kunz, Wolfram S; Elger, Christian E; Muhle, Hiltrud; Stephani, Ulrich; Møller, Rikke S; Hjalgrim, Helle; Mullen, Saul; Scheffer, Ingrid E; Berkovic, Samuel F; Everett, Kate V; Gardiner, Mark R; Marini, Carla; Guerrini, Renzo; Lehesjoki, Anna-Elina; Siren, Auli; Nabbout, Rima; Baulac, Stephanie; Leguern, Eric; Serratosa, Jose M; Rosenow, Felix; Feucht, Martha; Unterberger, Iris; Covanis, Athanasios; Suls, Arvid; Weckhuysen, Sarah; Kaneva, Radka; Caglayan, Hande; Turkdogan, Dilsad; Baykan, Betul; Bebek, Nerses; Ozbek, Ugur; Hempelmann, Anne; Schulz, Herbert; Rüschendorf, Franz; Trucks, Holger; Nürnberg, Peter; Avanzini, Giuliano; Koeleman, Bobby P C; Sander, Thomas

2012-02-01

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Using lod-score differences to determine mode of inheritance: a simple, robust method even in the presence of heterogeneity and reduced penetrance.

PubMed

Greenberg, D A; Berger, B

1994-10-01

Determining the mode of inheritance is often difficult under the best of circumstances, but when segregation analysis is used, the problems of ambiguous ascertainment procedures, reduced penetrance, heterogeneity, and misdiagnosis make mode-of-inheritance determinations even more unreliable. The mode of inheritance can also be determined using a linkage-based method (maximized maximum lod score or mod score) and association-based methods, which can overcome many of these problems. In this work, we determined how much information is necessary to reliably determine the mode of inheritance from linkage data when heterogeneity and reduced penetrance are present in the data set. We generated data sets under both dominant and recessive inheritance with reduced penetrance and with varying fractions of linked and unlinked families. We then analyzed those data sets, assuming reduced penetrance, both dominant and recessive inheritance, and no heterogeneity. We investigated the reliability of two methods for determining the mode of inheritance from the linkage data. The first method examined the difference (delta) between the maximum lod scores calculated under the two mode-of-inheritance assumptions. We found that if delta was > 1.5, then the higher of the two maximum lod scores reflected the correct mode of inheritance with high reliability and that a delta of 2.5 appeared to practically guarantee a correct mode-of-inheritance inference. Furthermore, this reliability appeared to be virtually independent of alpha, the fraction of linked families in the data set, although the reliability decreased slightly as alpha fell below .50.(ABSTRACT TRUNCATED AT 250 WORDS)

Empirical characteristics of family-based linkage to a complex trait: the ADIPOQ region and adiponectin levels.

PubMed

Hellwege, Jacklyn N; Palmer, Nicholette D; Mark Brown, W; Brown, Mark W; Ziegler, Julie T; Sandy An, S; An, Sandy S; Guo, Xiuqing; Ida Chen, Y-D; Chen, Ida Y-D; Taylor, Kent; Hawkins, Gregory A; Ng, Maggie C Y; Speliotes, Elizabeth K; Lorenzo, Carlos; Norris, Jill M; Rotter, Jerome I; Wagenknecht, Lynne E; Langefeld, Carl D; Bowden, Donald W

2015-02-01

We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 × 10(-50)). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 × 10(-4). When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 × 10(-5). Linked and/or associated variants ranged in frequency (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants.

Detection of linkage between a quantitative trait and a marker locus by the lod score method: sample size and sampling considerations.

PubMed

Demenais, F; Lathrop, G M; Lalouel, J M

1988-07-01

A simulation study is here conducted to measure the power of the lod score method to detect linkage between a quantitative trait and a marker locus in various situations. The number of families necessary to detect such linkage with 80% power is assessed for different sets of parameters at the trait locus and different values of the recombination fraction. The effects of varying the mode of sampling families and the sibship size are also evaluated.

Evaluation of hierarchical agglomerative cluster analysis methods for discrimination of primary biological aerosol

NASA Astrophysics Data System (ADS)

Crawford, I.; Ruske, S.; Topping, D. O.; Gallagher, M. W.

2015-07-01

In this paper we present improved methods for discriminating and quantifying Primary Biological Aerosol Particles (PBAP) by applying hierarchical agglomerative cluster analysis to multi-parameter ultra violet-light induced fluorescence (UV-LIF) spectrometer data. The methods employed in this study can be applied to data sets in excess of 1×106 points on a desktop computer, allowing for each fluorescent particle in a dataset to be explicitly clustered. This reduces the potential for misattribution found in subsampling and comparative attribution methods used in previous approaches, improving our capacity to discriminate and quantify PBAP meta-classes. We evaluate the performance of several hierarchical agglomerative cluster analysis linkages and data normalisation methods using laboratory samples of known particle types and an ambient dataset. Fluorescent and non-fluorescent polystyrene latex spheres were sampled with a Wideband Integrated Bioaerosol Spectrometer (WIBS-4) where the optical size, asymmetry factor and fluorescent measurements were used as inputs to the analysis package. It was found that the Ward linkage with z-score or range normalisation performed best, correctly attributing 98 and 98.1 % of the data points respectively. The best performing methods were applied to the BEACHON-RoMBAS ambient dataset where it was found that the z-score and range normalisation methods yield similar results with each method producing clusters representative of fungal spores and bacterial aerosol, consistent with previous results. The z-score result was compared to clusters generated with previous approaches (WIBS AnalysiS Program, WASP) where we observe that the subsampling and comparative attribution method employed by WASP results in the overestimation of the fungal spore concentration by a factor of 1.5 and the underestimation of bacterial aerosol concentration by a factor of 5. We suggest that this likely due to errors arising from misatrribution due to poor centroid definition and failure to assign particles to a cluster as a result of the subsampling and comparative attribution method employed by WASP. The methods used here allow for the entire fluorescent population of particles to be analysed yielding an explict cluster attribution for each particle, improving cluster centroid definition and our capacity to discriminate and quantify PBAP meta-classes compared to previous approaches.

Functional linear models for association analysis of quantitative traits.

PubMed

Fan, Ruzong; Wang, Yifan; Mills, James L; Wilson, Alexander F; Bailey-Wilson, Joan E; Xiong, Momiao

2013-11-01

Functional linear models are developed in this paper for testing associations between quantitative traits and genetic variants, which can be rare variants or common variants or the combination of the two. By treating multiple genetic variants of an individual in a human population as a realization of a stochastic process, the genome of an individual in a chromosome region is a continuum of sequence data rather than discrete observations. The genome of an individual is viewed as a stochastic function that contains both linkage and linkage disequilibrium (LD) information of the genetic markers. By using techniques of functional data analysis, both fixed and mixed effect functional linear models are built to test the association between quantitative traits and genetic variants adjusting for covariates. After extensive simulation analysis, it is shown that the F-distributed tests of the proposed fixed effect functional linear models have higher power than that of sequence kernel association test (SKAT) and its optimal unified test (SKAT-O) for three scenarios in most cases: (1) the causal variants are all rare, (2) the causal variants are both rare and common, and (3) the causal variants are common. The superior performance of the fixed effect functional linear models is most likely due to its optimal utilization of both genetic linkage and LD information of multiple genetic variants in a genome and similarity among different individuals, while SKAT and SKAT-O only model the similarities and pairwise LD but do not model linkage and higher order LD information sufficiently. In addition, the proposed fixed effect models generate accurate type I error rates in simulation studies. We also show that the functional kernel score tests of the proposed mixed effect functional linear models are preferable in candidate gene analysis and small sample problems. The methods are applied to analyze three biochemical traits in data from the Trinity Students Study. © 2013 WILEY PERIODICALS, INC.

An improved recommendation algorithm via weakening indirect linkage effect

NASA Astrophysics Data System (ADS)

Chen, Guang; Qiu, Tian; Shen, Xiao-Quan

2015-07-01

We propose an indirect-link-weakened mass diffusion method (IMD), by considering the indirect linkage and the source object heterogeneity effect in the mass diffusion (MD) recommendation method. Experimental results on the MovieLens, Netflix, and RYM datasets show that, the IMD method greatly improves both the recommendation accuracy and diversity, compared with a heterogeneity-weakened MD method (HMD), which only considers the source object heterogeneity. Moreover, the recommendation accuracy of the cold objects is also better elevated in the IMD than the HMD method. It suggests that eliminating the redundancy induced by the indirect linkages could have a prominent effect on the recommendation efficiency in the MD method. Project supported by the National Natural Science Foundation of China (Grant No. 11175079) and the Young Scientist Training Project of Jiangxi Province, China (Grant No. 20133BCB23017).

Maximum likelihood estimation of linkage disequilibrium in half-sib families.

PubMed

Gomez-Raya, L

2012-05-01

Maximum likelihood methods for the estimation of linkage disequilibrium between biallelic DNA-markers in half-sib families (half-sib method) are developed for single and multifamily situations. Monte Carlo computer simulations were carried out for a variety of scenarios regarding sire genotypes, linkage disequilibrium, recombination fraction, family size, and number of families. A double heterozygote sire was simulated with recombination fraction of 0.00, linkage disequilibrium among dams of δ=0.10, and alleles at both markers segregating at intermediate frequencies for a family size of 500. The average estimates of δ were 0.17, 0.25, and 0.10 for Excoffier and Slatkin (1995), maternal informative haplotypes, and the half-sib method, respectively. A multifamily EM algorithm was tested at intermediate frequencies by computer simulation. The range of the absolute difference between estimated and simulated δ was between 0.000 and 0.008. A cattle half-sib family was genotyped with the Illumina 50K BeadChip. There were 314,730 SNP pairs for which the sire was a homo-heterozygote with average estimates of r2 of 0.115, 0.067, and 0.111 for half-sib, Excoffier and Slatkin (1995), and maternal informative haplotypes methods, respectively. There were 208,872 SNP pairs for which the sire was double heterozygote with average estimates of r2 across the genome of 0.100, 0.267, and 0.925 for half-sib, Excoffier and Slatkin (1995), and maternal informative haplotypes methods, respectively. Genome analyses for all possible sire genotypes with 829,042 tests showed that ignoring half-sib family structure leads to upward biased estimates of linkage disequilibrium. Published inferences on population structure and evolution of cattle should be revisited after accommodating existing half-sib family structure in the estimation of linkage disequilibrium.

Maximum Likelihood Estimation of Linkage Disequilibrium in Half-Sib Families

PubMed Central

Gomez-Raya, L.

2012-01-01

Maximum likelihood methods for the estimation of linkage disequilibrium between biallelic DNA-markers in half-sib families (half-sib method) are developed for single and multifamily situations. Monte Carlo computer simulations were carried out for a variety of scenarios regarding sire genotypes, linkage disequilibrium, recombination fraction, family size, and number of families. A double heterozygote sire was simulated with recombination fraction of 0.00, linkage disequilibrium among dams of δ = 0.10, and alleles at both markers segregating at intermediate frequencies for a family size of 500. The average estimates of δ were 0.17, 0.25, and 0.10 for Excoffier and Slatkin (1995), maternal informative haplotypes, and the half-sib method, respectively. A multifamily EM algorithm was tested at intermediate frequencies by computer simulation. The range of the absolute difference between estimated and simulated δ was between 0.000 and 0.008. A cattle half-sib family was genotyped with the Illumina 50K BeadChip. There were 314,730 SNP pairs for which the sire was a homo-heterozygote with average estimates of r2 of 0.115, 0.067, and 0.111 for half-sib, Excoffier and Slatkin (1995), and maternal informative haplotypes methods, respectively. There were 208,872 SNP pairs for which the sire was double heterozygote with average estimates of r2 across the genome of 0.100, 0.267, and 0.925 for half-sib, Excoffier and Slatkin (1995), and maternal informative haplotypes methods, respectively. Genome analyses for all possible sire genotypes with 829,042 tests showed that ignoring half-sib family structure leads to upward biased estimates of linkage disequilibrium. Published inferences on population structure and evolution of cattle should be revisited after accommodating existing half-sib family structure in the estimation of linkage disequilibrium. PMID:22377635

Measurement methods for human exposure analysis.

PubMed Central

Lioy, P J

1995-01-01

The general methods used to complete measurements of human exposures are identified and illustrations are provided for the cases of indirect and direct methods used for exposure analysis. The application of the techniques for external measurements of exposure, microenvironmental and personal monitors, are placed in the context of the need to test hypotheses concerning the biological effects of concern. The linkage of external measurements to measurements made in biological fluids is explored for a suite of contaminants. This information is placed in the context of the scientific framework used to conduct exposure assessment. Examples are taken from research on volatile organics and for a large scale problem: hazardous waste sites. PMID:7635110

Assigning Peptide Disulfide Linkage Pattern Among Regio-Isomers via Methoxy Addition to Disulfide and Tandem Mass Spectrometry

NASA Astrophysics Data System (ADS)

Durand, Kirt L.; Tan, Lei; Stinson, Craig A.; Love-Nkansah, Chasity B.; Ma, Xiaoxiao; Xia, Yu

2017-06-01

Pinpointing disulfide linkage pattern is critical in the characterization of proteins and peptides consisting of multiple disulfide bonds. Herein, we report a method based on coupling online disulfide modification and tandem mass spectrometry (MS/MS) to distinguish peptide disulfide regio-isomers. Such a method relies on a new disulfide bond cleavage reaction in solution, involving methanol as a reactant and 254 nm ultraviolet (UV) irradiation. This reaction leads to selective cleavage of a disulfide bond and formation of sulfenic methyl ester (-SOCH3) at one cysteine residue and a thiol (-SH) at the other. Under low energy collision-induced dissociation (CID), cysteine sulfenic methyl ester motif produces a signature methanol loss (-32 Da), allowing its identification from other possible isomeric structures such as S-hydroxylmethyl (-SCH2OH) and methyl sulfoxide (-S(O)-CH3). Since disulfide bond can be selectively cleaved and modified upon methoxy addition, subsequent MS2 CID of the methoxy addition product provides enhanced sequence coverage as demonstrated by the analysis of bovine insulin. More importantly, this reaction does not induce disulfide scrambling, likely due to the fact that radical intermediates are not involved in the process. An approach based on methoxy addition followed by MS3 CID has been developed for assigning disulfide linkage patterns in peptide disulfide regio-isomers. This methodology was successfully applied to characterizing peptide systems having two disulfide bonds and three disulfide linkage isomers: side-by-side, overlapped, and looped-within-a-loop configurations. [Figure not available: see fulltext.

Functional analysis of truncated and site-directed mutagenesis dextransucrases to produce different type dextrans.

PubMed

Wang, Chao; Zhang, Hong-Bin; Li, Meng-Qi; Hu, Xue-Qin; Li, Yao

2017-07-01

Dextrans with distinct molecular size and structure are increasingly being used in the food and pharmaceutical industries. Dextran is produced by dextransucrase (DSR, EC2.4.5.1), which is produced by Leuconostoc mesenteroides. DSR belongs to glycosyl hydrolase family (GH70) and synthesizes branched α-glucan (dextran) with both 5% α(1-3) and 95% α(1-6) glycosidic linkages. The DSR gene dex-YG (Genebank, Accession No. DQ345760) was cloned from the wild strain Leuconostoc mesenteroides 0326. This study generated a series of C-terminally truncated variants of dextransucrase and substituting the amino-acid residues in the active site of DSR. With shorter length of DSR, its polysaccharide-synthesizing capability was impaired heavily, whereas oligosaccharide (acting as prebiotics)-synthesizing capability increased significantly, efficiently producing special sizes of dextran. All truncated mutant enzymes were active. Results demonstrated that the catalytic domain dextransucrase was likely in 800 aa or less. Based on the three-dimensional structure model of dextransucrase built through homology modeling methods, the DSR and its mutants with the acceptor substrate of maltose and donor substrate of sucrose were studied by molecular-docking method. Substituting these amino-acid residues significantly affected enzyme activities. Compared with the wild-type dextran, mutant enzymes catalyzed the synthesis of a-glucan with 1-9% α(1-3) and 90-98% α(1-6) branching linkages. Some mutants introduced a small amount of α(1-4) linkages and α(1-2) linkages. This strategy can be effectively used for the rational protein design of dextransucrase. Copyright © 2017 Elsevier Inc. All rights reserved.

A genome-wide linkage study of mammographic density, a risk factor for breast cancer

PubMed Central

2011-01-01

Introduction Mammographic breast density is a highly heritable (h2 > 0.6) and strong risk factor for breast cancer. We conducted a genome-wide linkage study to identify loci influencing mammographic breast density (MD). Methods Epidemiological data were assembled on 1,415 families from the Australia, Northern California and Ontario sites of the Breast Cancer Family Registry, and additional families recruited in Australia and Ontario. Families consisted of sister pairs with age-matched mammograms and data on factors known to influence MD. Single nucleotide polymorphism (SNP) genotyping was performed on 3,952 individuals using the Illumina Infinium 6K linkage panel. Results Using a variance components method, genome-wide linkage analysis was performed using quantitative traits obtained by adjusting MD measurements for known covariates. Our primary trait was formed by fitting a linear model to the square root of the percentage of the breast area that was dense (PMD), adjusting for age at mammogram, number of live births, menopausal status, weight, height, weight squared, and menopausal hormone therapy. The maximum logarithm of odds (LOD) score from the genome-wide scan was on chromosome 7p14.1-p13 (LOD = 2.69; 63.5 cM) for covariate-adjusted PMD, with a 1-LOD interval spanning 8.6 cM. A similar signal was seen for the covariate adjusted area of the breast that was dense (DA) phenotype. Simulations showed that the complete sample had adequate power to detect LOD scores of 3 or 3.5 for a locus accounting for 20% of phenotypic variance. A modest peak initially seen on chromosome 7q32.3-q34 increased in strength when only the 513 families with at least two sisters below 50 years of age were included in the analysis (LOD 3.2; 140.7 cM, 1-LOD interval spanning 9.6 cM). In a subgroup analysis, we also found a LOD score of 3.3 for DA phenotype on chromosome 12.11.22-q13.11 (60.8 cM, 1-LOD interval spanning 9.3 cM), overlapping a region identified in a previous study. Conclusions The suggestive peaks and the larger linkage signal seen in the subset of pedigrees with younger participants highlight regions of interest for further study to identify genes that determine MD, with the goal of understanding mammographic density and its involvement in susceptibility to breast cancer. PMID:22188651

Privacy preserving interactive record linkage (PPIRL)

PubMed Central

Kum, Hye-Chung; Krishnamurthy, Ashok; Machanavajjhala, Ashwin; Reiter, Michael K; Ahalt, Stanley

2014-01-01

Objective Record linkage to integrate uncoordinated databases is critical in biomedical research using Big Data. Balancing privacy protection against the need for high quality record linkage requires a human–machine hybrid system to safely manage uncertainty in the ever changing streams of chaotic Big Data. Methods In the computer science literature, private record linkage is the most published area. It investigates how to apply a known linkage function safely when linking two tables. However, in practice, the linkage function is rarely known. Thus, there are many data linkage centers whose main role is to be the trusted third party to determine the linkage function manually and link data for research via a master population list for a designated region. Recently, a more flexible computerized third-party linkage platform, Secure Decoupled Linkage (SDLink), has been proposed based on: (1) decoupling data via encryption, (2) obfuscation via chaffing (adding fake data) and universe manipulation; and (3) minimum information disclosure via recoding. Results We synthesize this literature to formalize a new framework for privacy preserving interactive record linkage (PPIRL) with tractable privacy and utility properties and then analyze the literature using this framework. Conclusions Human-based third-party linkage centers for privacy preserving record linkage are the accepted norm internationally. We find that a computer-based third-party platform that can precisely control the information disclosed at the micro level and allow frequent human interaction during the linkage process, is an effective human–machine hybrid system that significantly improves on the linkage center model both in terms of privacy and utility. PMID:24201028

Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myocloni epilepsy: No evidence for an epilepsy locus in the HLA region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whitehouse, W.P.; Rees, M.; Curtis, D.

1993-09-01

Evidence for a locus (EJM1) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6889, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessivemore » inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype. 39 refs., 4 figs., 2 tabs.« less

Selective DNA Pooling for Determination of Linkage between a Molecular Marker and a Quantitative Trait Locus

PubMed Central

Darvasi, A.; Soller, M.

1994-01-01

Selective genotyping is a method to reduce costs in marker-quantitative trait locus (QTL) linkage determination by genotyping only those individuals with extreme, and hence most informative, quantitative trait values. The DNA pooling strategy (termed: ``selective DNA pooling'') takes this one step further by pooling DNA from the selected individuals at each of the two phenotypic extremes, and basing the test for linkage on marker allele frequencies as estimated from the pooled samples only. This can reduce genotyping costs of marker-QTL linkage determination by up to two orders of magnitude. Theoretical analysis of selective DNA pooling shows that for experiments involving backcross, F(2) and half-sib designs, the power of selective DNA pooling for detecting genes with large effect, can be the same as that obtained by individual selective genotyping. Power for detecting genes with small effect, however, was found to decrease strongly with increase in the technical error of estimating allele frequencies in the pooled samples. The effect of technical error, however, can be markedly reduced by replication of technical procedures. It is also shown that a proportion selected of 0.1 at each tail will be appropriate for a wide range of experimental conditions. PMID:7896115

DOE Office of Scientific and Technical Information (OSTI.GOV)

May, M.; Schwartz, C.; Huston, S.

The Opitz GBBB syndrome (OS) is characterized in part by widely spaced inner ocular canthi and hypospadias. Recently, linkage analysis showed that the gene for the X-linked form to be located in an 18 cM region spanning Xp22. We have now conducted linkage analysis in a family previously published as having the BBB syndrome and found tight linkage to DXS7104 (Z = 3.3, {theta} = 0.0). Our data narrows the candidate region to 4 cM and should facilitate the identification and characterization of one of the genes involved in midline development. 21 refs., 1 fig., 1 tab.

High-frequency stock linkage and multi-dimensional stationary processes

NASA Astrophysics Data System (ADS)

Wang, Xi; Bao, Si; Chen, Jingchao

2017-02-01

In recent years, China's stock market has experienced dramatic fluctuations; in particular, in the second half of 2014 and 2015, the market rose sharply and fell quickly. Many classical financial phenomena, such as stock plate linkage, appeared repeatedly during this period. In general, these phenomena have usually been studied using daily-level data or minute-level data. Our paper focuses on the linkage phenomenon in Chinese stock 5-second-level data during this extremely volatile period. The method used to select the linkage points and the arbitrage strategy are both based on multi-dimensional stationary processes. A new program method for testing the multi-dimensional stationary process is proposed in our paper, and the detailed program is presented in the paper's appendix. Because of the existence of the stationary process, the strategy's logarithmic cumulative average return will converge under the condition of the strong ergodic theorem, and this ensures the effectiveness of the stocks' linkage points and the more stable statistical arbitrage strategy.

Linkage mapping of beta 2 EEG waves via non-parametric regression.

PubMed

Ghosh, Saurabh; Begleiter, Henri; Porjesz, Bernice; Chorlian, David B; Edenberg, Howard J; Foroud, Tatiana; Goate, Alison; Reich, Theodore

2003-04-01

Parametric linkage methods for analyzing quantitative trait loci are sensitive to violations in trait distributional assumptions. Non-parametric methods are relatively more robust. In this article, we modify the non-parametric regression procedure proposed by Ghosh and Majumder [2000: Am J Hum Genet 66:1046-1061] to map Beta 2 EEG waves using genome-wide data generated in the COGA project. Significant linkage findings are obtained on chromosomes 1, 4, 5, and 15 with findings at multiple regions on chromosomes 4 and 15. We analyze the data both with and without incorporating alcoholism as a covariate. We also test for epistatic interactions between regions of the genome exhibiting significant linkage with the EEG phenotypes and find evidence of epistatic interactions between a region each on chromosome 1 and chromosome 4 with one region on chromosome 15. While regressing out the effect of alcoholism does not affect the linkage findings, the epistatic interactions become statistically insignificant. Copyright 2003 Wiley-Liss, Inc.

A Model for New Linkages for Prior Learning Assessment

ERIC Educational Resources Information Center

Kalz, Marco; van Bruggen, Jan; Giesbers, Bas; Waterink, Wim; Eshuis, Jannes; Koper, Rob

2008-01-01

Purpose: The purpose of this paper is twofold: first the paper aims to sketch the theoretical basis for the use of electronic portfolios for prior learning assessment; second it endeavours to introduce latent semantic analysis (LSA) as a powerful method for the computation of semantic similarity between texts and a basis for a new observation link…

Application of the ToxMiner Database: Network Analysis of Linkage between ToxCast Phase I Chemicals and Thyroid Related Disease Outcomes

EPA Science Inventory

The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effecti...

THREaD Mapper Studio: a novel, visual web server for the estimation of genetic linkage maps

PubMed Central

Cheema, Jitender; Ellis, T. H. Noel; Dicks, Jo

2010-01-01

The estimation of genetic linkage maps is a key component in plant and animal research, providing both an indication of the genetic structure of an organism and a mechanism for identifying candidate genes associated with traits of interest. Because of this importance, several computational solutions to genetic map estimation exist, mostly implemented as stand-alone software packages. However, the estimation process is often largely hidden from the user. Consequently, problems such as a program crashing may occur that leave a user baffled. THREaD Mapper Studio (http://cbr.jic.ac.uk/threadmapper) is a new web site that implements a novel, visual and interactive method for the estimation of genetic linkage maps from DNA markers. The rationale behind the web site is to make the estimation process as transparent and robust as possible, while also allowing users to use their expert knowledge during analysis. Indeed, the 3D visual nature of the tool allows users to spot features in a data set, such as outlying markers and potential structural rearrangements that could cause problems with the estimation procedure and to account for them in their analysis. Furthermore, THREaD Mapper Studio facilitates the visual comparison of genetic map solutions from third party software, aiding users in developing robust solutions for their data sets. PMID:20494977

Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index

PubMed Central

Minster, Ryan L.; Sanders, Jason L.; Singh, Jatinder; Kammerer, Candace M.; Barmada, M. Michael; Matteini, Amy M.; Zhang, Qunyuan; Wojczynski, Mary K.; Daw, E. Warwick; Brody, Jennifer A.; Arnold, Alice M.; Lunetta, Kathryn L.; Murabito, Joanne M.; Christensen, Kaare; Perls, Thomas T.; Province, Michael A.

2015-01-01

Background. The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. Methods. We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for mortality risk in 3,140 individuals selected for familial longevity from the Long Life Family Study. The genome-wide association study used the Long Life Family Study as the discovery cohort and individuals from the Cardiovascular Health Study and the Framingham Heart Study as replication cohorts. Results. There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10− 6) and nominally replicated in the Cardiovascular Health Study and Framingham Heart Study. Linkage results revealed significant evidence (log-odds score = 3.36) for a quantitative trait locus for mortality-optimized HAI in women on chromosome 9p24–p23. However, results of fine-mapping studies did not implicate any specific candidate genes within this region of interest. Conclusions. ZNF704 may be a potential candidate gene for studies of the genetic underpinnings of longevity. PMID:25758594

Evidence for a gene influencing reading disability on chromosome 6p in two populations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, S.D.; Brower, A.M.; Kimberling, W.J.

1994-09-01

A genetic contribution to specific reading disability has been demonstrated by twin studies, and segregation analysis has supported a dominant gene effect. In an effort to localize genes influencing reading disability, we have ascertained two independent populations of families: kindreds which were selected to have a three generation history of reading diability in an autosomal dominant pattern; and families with dizygotic twins, at least one of which has been diagnosed with reading disability. All available family members were given a battery of tests to measure reading and spelling ability and intelligence, and qualitative and quantitative phenotypes for reading disability weremore » derived. Blood samples were obtained for genotyping on all consenting family members, in concordance with IRB requirements. Linkage analysis was performed by the sib pair method utilizing the S.A.G.E. (1992) package and by a differential regression technique developed by DeFries and Fulker (1985). In both populations and by both linkage techniques, several markers in the HLA region of chromosome 6p showed results suggestive of linkage, with the effect most pronounced in the twin families. Significance levels were enhanced when only the more severely affected subjects were analyzed with the differential regression technique.« less

Mapping Quantitative Field Resistance Against Apple Scab in a 'Fiesta' x 'Discovery' Progeny.

PubMed

Liebhard, R; Koller, B; Patocchi, A; Kellerhals, M; Pfammatter, W; Jermini, M; Gessler, C

2003-04-01

ABSTRACT Breeding of resistant apple cultivars (Malus x domestica) as a disease management strategy relies on the knowledge and understanding of the underlying genetics. The availability of molecular markers and genetic linkage maps enables the detection and the analysis of major resistance genes as well as of quantitative trait loci (QTL) contributing to the resistance of a genotype. Such a genetic linkage map was constructed, based on a segregating population of the cross between apple cvs. Fiesta (syn. Red Pippin) and Discovery. The progeny was observed for 3 years at three different sites in Switzerland and field resistance against apple scab (Venturia inaequalis) was assessed. Only a weak correlation was detected between leaf scab and fruit scab. A QTL analysis was performed, based on the genetic linkage map consisting of 804 molecular markers and covering all 17 chromosomes of apple. With the maximum likelihood-based interval mapping method, eight genomic regions were identified, six conferring resistance against leaf scab and two conferring fruit scab resistance. Although cv. Discovery showed a much stronger resistance against scab in the field, most QTL identified were attributed to the more susceptible parent 'Fiesta'. This indicated a high degree of homozygosity at the scab resistance loci in 'Discovery', preventing their detection in the progeny due to the lack of segregation.

Mapping of a possible X-linked form of familial developmental dysphasia (FDD) in a single large pedigree

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dunne, P.W.; Doody, R.S.; Epstein, H.F.

Children diagnosed with developmental dysphasia develop speech very late without exhibiting sensory or motor dysfunction, and when they do begin to speak their grammar is abnormal. A large three-generation British pedigree was recently identified in which 16 out of 30 members were diagnosed as dysphasic. Assuming a dominant mode of inheritance with homogeneous phenotypic expression and complete penetrance among affected members, we showed by simulation analysis that this pedigree has the power to detect linkage to marker loci with an average maximum LOD score of 3.67 at {theta}=0.1. Given the absence of male-to-male transmission and a ratio of female tomore » male affecteds (10/6) in this pedigree within the expected range for an X-linked dominant mode of inheritance, we decided to begin a genome-wide linkage analysis with microsatellite markers on the human X chromosome. Fifteen individuals (10 affected) from three generations were genotyped with 35 polymorphic STS`s (Research Genetics) which were approximately uniformly distributed along the X chromosome. Two-point linkage was assessed using the MLINK and ILINK programs from the LINKAGE package. Markers DXS1223, DXS987, DXS996 and DXS1060 on Xp22 showed consistent linkage to the disease locus with a maximum LOD score of 0.86 at a distance of 22 cM for DXS1060. If further analysis with additional markers and additional family members confirms X-linkage, such a localization would provide support for Lehrke`s hypothesis for X-linkage of major intellectual traits including verbal functioning.« less

Linkage analysis of systolic blood pressure: a score statistic and computer implementation

PubMed Central

Wang, Kai; Peng, Yingwei

2003-01-01

A genome-wide linkage analysis was conducted on systolic blood pressure using a score statistic. The randomly selected Replicate 34 of the simulated data was used. The score statistic was applied to the sibships derived from the general pedigrees. An add-on R program to GENEHUNTER was developed for this analysis and is freely available. PMID:14975145

Neuropsychological Endophenotype Approach to Genome-wide Linkage Analysis Identifies Susceptibility Loci for ADHD on 2q21.1 and 13q12.11

PubMed Central

Rommelse, Nanda N.J.; Arias-Vásquez, Alejandro; Altink, Marieke E.; Buschgens, Cathelijne J.M.; Fliers, Ellen; Asherson, Philip; Faraone, Stephen V.; Buitelaar, Jan K.; Sergeant, Joseph A.; Oosterlaan, Jaap; Franke, Barbara

2008-01-01

ADHD linkage findings have not all been consistently replicated, suggesting that other approaches to linkage analysis in ADHD might be necessary, such as the use of (quantitative) endophenotypes (heritable traits associated with an increased risk for ADHD). Genome-wide linkage analyses were performed in the Dutch subsample of the International Multi-Center ADHD Genetics (IMAGE) study comprising 238 DSM-IV combined-type ADHD probands and their 112 affected and 195 nonaffected siblings. Eight candidate neuropsychological ADHD endophenotypes with heritabilities > 0.2 were used as quantitative traits. In addition, an overall component score of neuropsychological functioning was used. A total of 5407 autosomal single-nucleotide polymorphisms (SNPs) were used to run multipoint regression-based linkage analyses. Two significant genome-wide linkage signals were found, one for Motor Timing on chromosome 2q21.1 (LOD score: 3.944) and one for Digit Span on 13q12.11 (LOD score: 3.959). Ten suggestive linkage signals were found (LOD scores ≥ 2) on chromosomes 2p, 2q, 3p, 4q, 8q, 12p, 12q, 14q, and 17q. The suggestive linkage signal for the component score that was found at 2q14.3 (LOD score: 2.878) overlapped with the region significantly linked to Motor Timing. Endophenotype approaches may increase power to detect susceptibility loci in ADHD and possibly in other complex disorders. PMID:18599010

Evaluating the Use of Existing Data Sources, Probabilistic Linkage, and Multiple Imputation to Build Population-based Injury Databases Across Phases of Trauma Care

PubMed Central

Newgard, Craig; Malveau, Susan; Staudenmayer, Kristan; Wang, N. Ewen; Hsia, Renee Y.; Mann, N. Clay; Holmes, James F.; Kuppermann, Nathan; Haukoos, Jason S.; Bulger, Eileen M.; Dai, Mengtao; Cook, Lawrence J.

2012-01-01

Objectives The objective was to evaluate the process of using existing data sources, probabilistic linkage, and multiple imputation to create large population-based injury databases matched to outcomes. Methods This was a retrospective cohort study of injured children and adults transported by 94 emergency medical systems (EMS) agencies to 122 hospitals in seven regions of the western United States over a 36-month period (2006 to 2008). All injured patients evaluated by EMS personnel within specific geographic catchment areas were included, regardless of field disposition or outcome. The authors performed probabilistic linkage of EMS records to four hospital and postdischarge data sources (emergency department [ED] data, patient discharge data, trauma registries, and vital statistics files) and then handled missing values using multiple imputation. The authors compare and evaluate matched records, match rates (proportion of matches among eligible patients), and injury outcomes within and across sites. Results There were 381,719 injured patients evaluated by EMS personnel in the seven regions. Among transported patients, match rates ranged from 14.9% to 87.5% and were directly affected by the availability of hospital data sources and proportion of missing values for key linkage variables. For vital statistics records (1-year mortality), estimated match rates ranged from 88.0% to 98.7%. Use of multiple imputation (compared to complete case analysis) reduced bias for injury outcomes, although sample size, percentage missing, type of variable, and combined-site versus single-site imputation models all affected the resulting estimates and variance. Conclusions This project demonstrates the feasibility and describes the process of constructing population-based injury databases across multiple phases of care using existing data sources and commonly available analytic methods. Attention to key linkage variables and decisions for handling missing values can be used to increase match rates between data sources, minimize bias, and preserve sampling design. PMID:22506952

Linkages and Interactions Analysis of Major Effect Drought Grain Yield QTLs in Rice.

PubMed

Vikram, Prashant; Swamy, B P Mallikarjuna; Dixit, Shalabh; Trinidad, Jennylyn; Sta Cruz, Ma Teresa; Maturan, Paul C; Amante, Modesto; Kumar, Arvind

2016-01-01

Quantitative trait loci conferring high grain yield under drought in rice are important genomic resources for climate resilient breeding. Major and consistent drought grain yield QTLs usually co-locate with flowering and/or plant height QTLs, which could be due to either linkage or pleiotropy. Five mapping populations used for the identification of major and consistent drought grain yield QTLs underwent multiple-trait, multiple-interval mapping test (MT-MIM) to estimate the significance of pleiotropy effects. Results indicated towards possible linkages between the drought grain yield QTLs with co-locating flowering and/or plant height QTLs. Linkages of days to flowering and plant height were eliminated through a marker-assisted breeding approach. Drought grain yield QTLs also showed interaction effects with flowering QTLs. Drought responsiveness of the flowering locus on chromosome 3 (qDTY3.2) has been revealed through allelic analysis. Considering linkage and interaction effects associated with drought QTLs, a comprehensive marker-assisted breeding strategy was followed to develop rice genotypes with improved grain yield under drought stress.

Seed colour loci, homoeology and linkage groups of the C genome chromosomes revealed in Brassica rapa–B. oleracea monosomic alien addition lines

PubMed Central

Heneen, Waheeb K.; Geleta, Mulatu; Brismar, Kerstin; Xiong, Zhiyong; Pires, J. Chris; Hasterok, Robert; Stoute, Andrew I.; Scott, Roderick J.; King, Graham J.; Kurup, Smita

2012-01-01

Background and Aims Brassica rapa and B. oleracea are the progenitors of oilseed rape B. napus. The addition of each chromosome of B. oleracea to the chromosome complement of B. rapa results in a series of monosomic alien addition lines (MAALs). Analysis of MAALs determines which B. oleracea chromosomes carry genes controlling specific phenotypic traits, such as seed colour. Yellow-seeded oilseed rape is a desirable breeding goal both for food and livestock feed end-uses that relate to oil, protein and fibre contents. The aims of this study included developing a missing MAAL to complement an available series, for studies on seed colour control, chromosome homoeology and assignment of linkage groups to B. oleracea chromosomes. Methods A new batch of B. rapa–B. oleracea aneuploids was produced to generate the missing MAAL. Seed colour and other plant morphological features relevant to differentiation of MAALs were recorded. For chromosome characterization, Snow's carmine, fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) were used. Key Results The final MAAL was developed. Morphological traits that differentiated the MAALs comprised cotyledon number, leaf morphology, flower colour and seed colour. Seed colour was controlled by major genes on two B. oleracea chromosomes and minor genes on five other chromosomes of this species. Homoeologous pairing was largely between chromosomes with similar centromeric positions. FISH, GISH and a parallel microsatellite marker analysis defined the chromosomes in terms of their linkage groups. Conclusions A complete set of MAALs is now available for genetic, genomic, evolutionary and breeding perspectives. Defining chromosomes that carry specific genes, physical localization of DNA markers and access to established genetic linkage maps contribute to the integration of these approaches, manifested in the confirmed correspondence of linkage groups with specific chromosomes. Applications include marker-assisted selection and breeding for yellow seeds. PMID:22628364

A linkage analysis toolkit for studying allosteric networks in ion channels

PubMed Central

2013-01-01

A thermodynamic approach to studying allosterically regulated ion channels such as the large-conductance voltage- and Ca2+-dependent (BK) channel is presented, drawing from principles originally introduced to describe linkage phenomena in hemoglobin. In this paper, linkage between a principal channel component and secondary elements is derived from a four-state thermodynamic cycle. One set of parallel legs in the cycle describes the “work function,” or the free energy required to activate the principal component. The second are “lever operations” activating linked elements. The experimental embodiment of this linkage cycle is a plot of work function versus secondary force, whose asymptotes are a function of the parameters (displacements and interaction energies) of an allosteric network. Two essential work functions play a role in evaluating data from voltage-clamp experiments. The first is the conductance Hill energy WH[g], which is a “local” work function for pore activation, and is defined as kT times the Hill transform of the conductance (G-V) curve. The second is the electrical capacitance energy WC[q], representing “global” gating charge displacement, and is equal to the product of total gating charge per channel times the first moment (VM) of normalized capacitance (slope of Q-V curve). Plots of WH[g] and WC[q] versus voltage and Ca2+ potential can be used to measure thermodynamic parameters in a model-independent fashion of the core gating constituents (pore, voltage-sensor, and Ca2+-binding domain) of BK channel. The method is easily generalized for use in studying other allosterically regulated ion channels. The feasibility of performing linkage analysis from patch-clamp data were explored by simulating gating and ionic currents of a 17-particle model BK channel in response to a slow voltage ramp, which yielded interaction energies deviating from their given values in the range of 1.3 to 7.2%. PMID:23250867

Interdisciplinary linkage of community psychology and cross-cultural psychology: history, values, and an illustrative research and action project on intimate partner violence.

PubMed

Mankowski, Eric S; Galvez, Gino; Glass, Nancy

2011-03-01

An analysis of the respective organizational histories, missions, and scholarly activity of the International Association for Cross-Cultural Psychology and the Society for Community Research and Action was conducted in order to inform the development of interdisciplinary linkages between members of the two organizations. The analysis revealed many points of shared values and actions, as well as some important differences. Both scholarly organizations developed out of a similar historical and cultural zeitgeist in the late 1960s and early 1970s. The missions emphasize the role of culture/diversity in psychological phenomena, adopting an interdisciplinary orientation, the value of collaboration, the importance of research method and ethics, and the value of action research. However, community psychology generally lacks an adequate treatment of cultural phenomena while cross-cultural psychology often fails to draw on community and participatory methods useful for understanding culture in context. These common roots and differences are examined. Finally, we describe a community based, participatory research and intervention project to address intimate partner violence among Latinos and European-Americans living in Oregon. Analysis of the research process and on some of our initial findings illustrates challenges and potential benefits of an interdisciplinary, cultural community psychology.

Testing for linkage disequilibrium in the New Zealand radiata pine breeding population

Treesearch

S. Kumar; Craig Echt; P.L. Wilcox; T.E. Richardson

2004-01-01

Linkage analysis is commonly uscd to find marker-trait associations within the full-sib families of forest tree and other species. Study of marker-trait associations at the population level is termed linkage-disequilibrium (LD) mapping. A female-tester design comprising 200 full-sib families generated by crossing 40 pollen parents with five female parents was used to...

Linkages to Public Land Framework: toward embedding humans in ecosystem analyses by using “inside-out social assessment.”

Treesearch

Joanna Endter-Wada; Dale J. Blahna

2011-01-01

This article presents the " Linkages to Public Land" (LPL) Framework, a general but comprehensive data-gathering and analysis approach aimed at informing citizen and agency decision making about the social environment of public land. This social assessment and planning approach identifies and categorizes various types of linkages that people have to public...

Network analysis to detect common strategies in Italian foreign direct investment

NASA Astrophysics Data System (ADS)

De Masi, G.; Giovannetti, G.; Ricchiuti, G.

2013-03-01

In this paper we reconstruct and discuss the network of Italian firms investing abroad, exploiting information from complex network analysis. This method, detecting the key nodes of the system (both in terms of firms and countries of destination), allows us to single out the linkages among firms without ex-ante priors. Moreover, through the examination of affiliates’ economic activity, it allows us to highlight different internationalization strategies of “leaders” in different manufacturing sectors.

Education-Work Linkage and Policy: A Cross-National Analysis of Contextual Influences on School to Work Transition.

ERIC Educational Resources Information Center

Wiseman, Alexander W.; Alromi, Naif

A cross-national analysis was conducted to identify contextual influences that shape policies regarding the school-to-work transition and education-work linkages. The study's theoretical framework included principles based on technical-rational perspectives and neo-institutional perspectives. The study tested the following hypotheses: (1) schools…

Linkage analysis of the Nail-patella syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Campeau, E.; Watkins, D.; Rouleau, G.A.

1995-01-01

Nail-patella syndrome (NPS) is an autosomal dominant disorder characterized by dysplasia of nails and patella, decreased mobility of the elbow, iliac horns, and, in some cases, nephropathy. The disorder has been mapped to the long arm of chromosome 9, but the precise localization and identity of the NPS gene are unknown. Linkage analysis in three NPS families, using highly informative dinucleotide repeat polymorphisms on 9q33-q34, confirmed linkage of NPS to this chromosome. Recombinations were detected, by two-point linkage analysis, between NPS and the centromeric markers D9S60 and the gelsolin gene and the telomeric markers D9S64 and D9S66, in one ofmore » the families. Haplotype analysis suggested an additional recombination between NPS and the argininosuccinate synthetase (ASS) gene. These results localize the NPS gene to an interval on 9q34.1, distal to D9S60 an proximal to ASS, comprising a genetic distance of {approximately}9 cM. This represents a significant refinement in the localization of the NPS gene. 25 refs., 2 figs., 1 tab.« less

Tests for linkage and association in nuclear families.

PubMed Central

Martin, E R; Kaplan, N L; Weir, B S

1997-01-01

The transmission/disequilibrium test (TDT) originally was introduced to test for linkage between a genetic marker and a disease-susceptibility locus, in the presence of association. Recently, the TDT has been used to test for association in the presence of linkage. The motivation for this is that linkage analysis typically identifies large candidate regions, and further refinement is necessary before a search for the disease gene is begun, on the molecular level. Evidence of association and linkage may indicate which markers in the region are closest to a disease locus. As a test of linkage, transmissions from heterozygous parents to all of their affected children can be included in the TDT; however, the TDT is a valid chi2 test of association only if transmissions to unrelated affected children are used in the analysis. If the sample contains independent nuclear families with multiple affected children, then one procedure that has been used to test for association is to select randomly a single affected child from each sibship and to apply the TDT to those data. As an alternative, we propose two statistics that use data from all of the affected children. The statistics give valid chi2 tests of the null hypothesis of no association or no linkage and generally are more powerful than the TDT with a single, randomly chosen, affected child from each family. PMID:9311750

Testing association and linkage using affected-sib-parent study designs.

PubMed

Millstein, Joshua; Siegmund, Kimberly D; Conti, David V; Gauderman, W James

2005-11-01

We have developed a method for jointly testing linkage and association using data from affected sib pairs and their parents. We specify a conditional logistic regression model with two covariates, one that quantifies association (either direct association or indirect association via linkage disequilibrium), and a second that quantifies linkage. The latter covariate is computed based on expected identity-by-descend (ibd) sharing of marker alleles between siblings. In addition to a joint test of linkage and association, our general framework can be used to obtain a linkage test comparable to the mean test (Blackwelder and Elston [1985] Genet. Epidemiol. 2:85-97), and an association test comparable to the Family-Based Association Test (FBAT; Rabinowitz and Laird [2000] Hum. Hered. 50:211-223). We present simulation results demonstrating that our joint test can be more powerful than some standard tests of linkage or association. For example, with a relative risk of 2.7 per variant allele at a disease locus, the estimated power to detect a nearby marker with a modest level of LD was 58.1% by the mean test (linkage only), 69.8% by FBAT, and 82.5% by our joint test of linkage and association. Our model can also be used to obtain tests of linkage conditional on association and association conditional on linkage, which can be helpful in fine mapping. Copyright 2005 Wiley-Liss, Inc.

A Genomewide Linkage Scan of Cocaine Dependence and Major Depressive Episode in Two Populations

PubMed Central

Yang, Bao-Zhu; Han, Shizhong; Kranzler, Henry R; Farrer, Lindsay A; Gelernter, Joel

2011-01-01

Cocaine dependence (CD) and major depressive episode (MDE) frequently co-occur with poorer treatment outcome and higher relapse risk. Shared genetic risk was affirmed; to date, there have been no reports of genomewide linkage scans (GWLSs) surveying the susceptibility regions for comorbid CD and MDE (CD–MDE). We aimed to identify chromosomal regions and candidate genes susceptible to CD, MDE, and CD–MDE in African Americans (AAs) and European Americans (EAs). A total of 1896 individuals were recruited from 384 AA and 355 EA families, each with at least a sibling-pair with CD and/or opioid dependence. Array-based genotyping of about 6000 single-nucleotide polymorphisms was completed for all individuals. Parametric and non-parametric genomewide linkage analyses were performed. We found a genomewide-significant linkage peak on chromosome 7 at 183.4 cM for non-parametric analysis of CD–MDE in AAs (lod=3.8, genomewide empirical p=0.016; point-wise p=0.00001). A nearly genomewide significant linkage was identified for CD–MDE in EAs on chromosome 5 at 14.3 cM (logarithm of odds (lod)=2.95, genomewide empirical p=0.055; point-wise p=0.00012). Parametric analysis corroborated the findings in these two regions and improved the support for the peak on chromosome 5 so that it reached genomewide significance (heterogeneity lod=3.28, genomewide empirical p=0.046; point-wise p=0.00053). This is the first GWLS for CD–MDE. The genomewide significant linkage regions on chromosomes 5 and 7 harbor four particularly promising candidate genes: SRD5A1, UBE3C, PTPRN2, and VIPR2. Replication of the linkage findings in other populations is warranted, as is a focused analysis of the genes located in the linkage regions implicated here. PMID:21849985

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

PubMed Central

Simpson, Claire L; Cropp, Cheryl D; Wahlfors, Tiina; George, Asha; Jones, MaryPat S; Harper, Ursula; Ponciano-Jackson, Damaris; Tammela, Teuvo; Schleutker, Johanna; Bailey-Wilson, Joan E

2013-01-01

Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (ΔLOD=3.193, empirical P=0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD=2.541, ΔLOD=1.651, P=0.03) and 22q11.1-q11.21 (OSA LOD=2.395, ΔLOD=2.36, P=0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families. PMID:22948022

Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14

PubMed Central

Etain, Bruno; Mathieu, Flavie; Rietschel, Marcella; Maier, Wolfgang; Albus, Margot; Mckeon, Patrick; Roche, S.; Kealey, Carmel; Blackwood, Douglas; Muir, Walter; Bellivier, Franc; Henry, C.; Dina, Christian; Gallina, Sophie; Gurling, H.; Malafosse, Alain; Preisig, Martin; Ferrero, François; Cichon, Sven; Schumacher, J.; Ohlraun, Stéphanie; Borrmann-Hassenbach, M.; Propping, Peter; Abou Jamra, Rami; Schulze, Thomas G.; Marusic, Andrej; Dernovsek, Mojca Z.; Giros, Bruno; Bourgeron, Thomas; Lemainque, Arnaud; Bacq, Delphine; Betard, Christine; Charon, Céline; Nöthen, Markus M.; Lathrop, Mark; Leboyer, Marion

2006-01-01

Summary Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (age at onset of 21 years or below). Non parametric multi-point analysis suggested eight regions of linkage with p-values <0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide p-value estimated over 10.000 simulated replicates of 0.015 [0.01–0.02]). After genome-wide search analysis, we performed additional linkage analyses with increase marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non parametric linkage score increased from 3.51 to 3.83. This study is the first to use early onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families. PMID:16534504

Linkage analysis of juvenile myoclonic epilepsy and microsatellite loci spanning 61 cM of human chromosome 6p in 19 nuclear pedigrees provides no evidence for a susceptibility locus in this region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elmslie, F.V.; Williamson, M.P.; Rees, M.

1996-09-01

Linkage analysis in separately ascertained families of probands with juvenile myoclonic epilepsy (JME) has previously provided evidence both for and against the existence of a locus (designated {open_quotes}EJM1{close_quotes}), on chromosome 6p, predisposing to a trait defined as either clinical JME, its associated electroencephalographic abnormality, or idiopathic generalized epilepsy. Linkage analysis was performed in 19 families in which a proband and at least one first- or two second-degree relatives have clinical JME. Family members were typed for seven highly polymorphic microsatellite markers on chromosome 6p: D6S260, D6S276, D6S291, D6S271, D6S465, D6S257, and D6S254. Pairwise and multipoint linkage analysis was carried outmore » under the assumptions of autosomal dominant inheritance at 70% and 50% penetrance and autosomal recessive inheritance at 70% and 50% penetrance. No significant evidence in favor of linkage to the clinical trait of JME was obtained for any locus. The region formally excluded (LOD score <-2) by using multipoint analysis varies depending on the assumptions made concerning inheritance parameters and the proportion of linked families, {alpha} - that is, the degree of locus heterogeneity. Further analysis either classifying all unaffected individuals as unknown or excluding a subset of four families in which pyknoleptic absence seizures were present in one or more individuals did not alter these conclusions. 24 refs., 4 figs., 1 tab.« less

Linkage mechanisms in the vertebrate skull: Structure and function of three-dimensional, parallel transmission systems.

PubMed

Olsen, Aaron M; Westneat, Mark W

2016-12-01

Many musculoskeletal systems, including the skulls of birds, fishes, and some lizards consist of interconnected chains of mobile skeletal elements, analogous to linkage mechanisms used in engineering. Biomechanical studies have applied linkage models to a diversity of musculoskeletal systems, with previous applications primarily focusing on two-dimensional linkage geometries, bilaterally symmetrical pairs of planar linkages, or single four-bar linkages. Here, we present new, three-dimensional (3D), parallel linkage models of the skulls of birds and fishes and use these models (available as free kinematic simulation software), to investigate structure-function relationships in these systems. This new computational framework provides an accessible and integrated workflow for exploring the evolution of structure and function in complex musculoskeletal systems. Linkage simulations show that kinematic transmission, although a suitable functional metric for linkages with single rotating input and output links, can give misleading results when applied to linkages with substantial translational components or multiple output links. To take into account both linear and rotational displacement we define force mechanical advantage for a linkage (analogous to lever mechanical advantage) and apply this metric to measure transmission efficiency in the bird cranial mechanism. For linkages with multiple, expanding output points we propose a new functional metric, expansion advantage, to measure expansion amplification and apply this metric to the buccal expansion mechanism in fishes. Using the bird cranial linkage model, we quantify the inaccuracies that result from simplifying a 3D geometry into two dimensions. We also show that by combining single-chain linkages into parallel linkages, more links can be simulated while decreasing or maintaining the same number of input parameters. This generalized framework for linkage simulation and analysis can accommodate linkages of differing geometries and configurations, enabling novel interpretations of the mechanics of force transmission across a diversity of vertebrate feeding mechanisms and enhancing our understanding of musculoskeletal function and evolution. J. Morphol. 277:1570-1583, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

New Tools for Learning: A Case of Organizational Problem Analysis Derived from Debriefing Records in a Medical Center

ERIC Educational Resources Information Center

Holzmann, Vered; Mischari, Shoshana; Goldberg, Shoshana; Ziv, Amitai

2012-01-01

Purpose: This article aims to present a unique systematic and validated method for creating a linkage between past experiences and management of future occurrences in an organization. Design/methodology/approach: The study is based on actual data accumulated in a series of projects performed in a major medical center. Qualitative and quantitative…

A strabismus susceptibility locus on chromosome 7p

PubMed Central

Parikh, Vaishali; Shugart, Yin Yao; Doheny, Kimberly F.; Zhang, Jie; Li, Lan; Williams, John; Hayden, David; Craig, Brian; Capo, Hilda; Chamblee, Denise; Chen, Cathy; Collins, Mary; Dankner, Stuart; Fiergang, Dean; Guyton, David; Hunter, David; Hutcheon, Marcia; Keys, Marshall; Morrison, Nancy; Munoz, Michelle; Parks, Marshall; Plotsky, David; Protzko, Eugene; Repka, Michael X.; Sarubbi, Maria; Schnall, Bruce; Siatkowski, R. Michael; Traboulsi, Elias; Waeltermann, Joanne; Nathans, Jeremy

2003-01-01

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes. PMID:14519848

Short Communication: Genetic linkage map of Cucurbita maxima with molecular and morphological markers.

PubMed

Ge, Y; Li, X; Yang, X X; Cui, C S; Qu, S P

2015-05-22

Cucurbita maxima is one of the most widely cultivated vegetables in China and exhibits distinct morphological characteristics. In this study, genetic linkage analysis with 57 simple-sequence repeats, 21 amplified fragment length polymorphisms, 3 random-amplified polymorphic DNA, and one morphological marker revealed 20 genetic linkage groups of C. maxima covering a genetic distance of 991.5 cM with an average of 12.1 cM between adjacent markers. Genetic linkage analysis identified the simple-sequence repeat marker 'PU078072' 5.9 cM away from the locus 'Rc', which controls rind color. The genetic map in the present study will be useful for better mapping, tagging, and cloning of quantitative trait loci/gene(s) affecting economically important traits and for breeding new varieties of C. maxima through marker-assisted selection.

Genome scan for linkage to asthma using a linkage disequilibrium-lod score test.

PubMed

Jiang, Y; Slager, S L; Huang, J

2001-01-01

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.

A first AFLP-Based Genetic Linkage Map for Brine Shrimp Artemia franciscana and Its Application in Mapping the Sex Locus

PubMed Central

De Vos, Stephanie; Bossier, Peter; Van Stappen, Gilbert; Vercauteren, Ilse; Sorgeloos, Patrick; Vuylsteke, Marnik

2013-01-01

We report on the construction of sex-specific linkage maps, the identification of sex-linked markers and the genome size estimation for the brine shrimp Artemia franciscana. Overall, from the analysis of 433 AFLP markers segregating in a 112 full-sib family we identified 21 male and 22 female linkage groups (2n = 42), covering 1,041 and 1,313 cM respectively. Fifteen putatively homologous linkage groups, including the sex linkage groups, were identified between the female and male linkage map. Eight sex-linked AFLP marker alleles were inherited from the female parent, supporting the hypothesis of a WZ–ZZ sex-determining system. The haploid Artemia genome size was estimated to 0.93 Gb by flow cytometry. The produced Artemia linkage maps provide the basis for further fine mapping and exploring of the sex-determining region and are a possible marker resource for mapping genomic loci underlying phenotypic differences among Artemia species. PMID:23469207

Linkage analysis with multiplexed short tandem repeat polymorphisms using infrared fluorescence and M13 tailed primers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oetting, W.S.; Lee, H.K.; Flanders, D.J.

The use of short tandem repeat polymorphisms (STRPs) as marker loci for linkage analysis is becoming increasingly important due to their large numbers in the human genome and their high degree of polymorphism. Fluorescence-based detection of the STRP pattern with an automated DNA sequencer has improved the efficiency of this technique by eliminating the need for radioactivity and producing a digitized autoradiogram-like image that can be used for computer analysis. In an effort to simplify the procedure and to reduce the cost of fluorescence STRP analysis, we have developed a technique known as multiplexing STRPs with tailed primers (MSTP) usingmore » primers that have a 19-bp extension, identical to the sequence of an M13 sequencing primer, on the 5{prime} end of the forward primer in conjunction with multiplexing several primer pairs in a single polymerase chain reaction (PCR) amplification. The banding pattern is detected with the addition of the M13 primer-dye conjugate as the sole primer conjugated to the fluorescent dye, eliminating the need for direct conjugation of the infrared fluorescent dye to the STRP primers. The use of MSTP for linkage analysis greatly reduces the number of PCR reactions. Up to five primer pairs can be multiplexed together in the same reaction. At present, a set of 148 STRP markers spaced at an average genetic distance of 28 cM throughout the autosomal genome can be analyzed in 37 sets of multiplexed amplification reactions. We have automated the analysis of these patterns for linkage using software that both detects the STRP banding pattern and determines their sizes. This information can then be exported in a user-defined format from a database manager for linkage analysis. 15 refs., 2 figs., 4 tabs.« less

Genetic influences on bone loss in the San Antonio Family Osteoporosis Study

PubMed Central

Shaffer, John R.; Kammerer, Candace M.; Bruder, Jan M.; Cole, Shelley A.; Dyer, Thomas D.; Almasy, Laura; MacCluer, Jean W.; Blangero, John; Bauer, Richard L.; Mitchell, Braxton D.

2009-01-01

Summary The genetic contribution to age-related bone loss is not well understood. We estimated that genes accounted for 25–45% of variation in 5-year change in bone mineral density in men and women. An autosome-wide linkage scan yielded no significant evidence for chromosal regions implicated in bone loss. Introduction The contribution of genetics to acquisition of peak bone mass is well documented, but little is know about the influence of genes on subsequent bone loss with age. We therefore measured 5-year change in bone mineral density (BMD) in 300 Mexican Americans (>45 years of age) from the San Antonio Family Osteoporosis Study to identify genetic factors influencing bone loss. Methods Annualized change in BMD was calculated from measurements taken 5.5 years apart. Heritability (h2) of BMD change was estimated using variance components methods and autosome-wide linkage analysis was carried out using 460 microsatellite markers at a mean 7.6 cM interval density. Results Rate of BMD change was heritable at the forearm (h2=0.31, p=0.021), hip (h2 =0.44, p=0.017), spine (h2=0.42, p=0.005), but not whole body (h2=0.18, p=0.123). Covariates associated with rapid bone loss (advanced age, baseline BMD, female sex, low baseline weight, postmenopausal status, and interim weight loss) accounted for 10% to 28% of trait variation. No significant evidence of linkage was observed at any skeletal site. Conclusions This is one of the first studies to report significant heritability of BMD change for weight-bearing and non-weight-bearing bones in an unselected population and the first linkage scan for change in BMD. PMID:18414963

Genetic Alterations in Familial Breast Cancer: Mapping and Cloning Genes Other Than BRCAl

DTIC Science & Technology

1997-09-01

predisposition to breast cancer in families. The gene PTEN was successfully cloned by this project, and simultaneously by others (for a different ...with germline translocations’and breast cancer for the identification of tumor suppressor genes. 14. SUBJECT TERMS Breast cancer 17. SECURITY...would limit the statistical power of linkage analysis. Therefore, we decided to integrate linkage analysis with the analysis of germline chromosomal

Privacy-preserving record linkage using Bloom filters

PubMed Central

2009-01-01

Background Combining multiple databases with disjunctive or additional information on the same person is occurring increasingly throughout research. If unique identification numbers for these individuals are not available, probabilistic record linkage is used for the identification of matching record pairs. In many applications, identifiers have to be encrypted due to privacy concerns. Methods A new protocol for privacy-preserving record linkage with encrypted identifiers allowing for errors in identifiers has been developed. The protocol is based on Bloom filters on q-grams of identifiers. Results Tests on simulated and actual databases yield linkage results comparable to non-encrypted identifiers and superior to results from phonetic encodings. Conclusion We proposed a protocol for privacy-preserving record linkage with encrypted identifiers allowing for errors in identifiers. Since the protocol can be easily enhanced and has a low computational burden, the protocol might be useful for many applications requiring privacy-preserving record linkage. PMID:19706187

HLA is unlikely to be a major component of risk in familial inflammatory bowl disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mathew, C.G.; Naom, I.S.; Hodgson, S.V.

1994-09-01

Inflammatory bowel disease (IBD) is a chronic inflammation of the bowel which is confined to the colon in ulcerative colitis (UC) or may affect any part of the gastrointestinal tract in Crohn`s disease (CD). The cause of IBD is unknown, but a genetic component is suggested by a 10-fold increase in risk to first degree relatives, and a higher concordance of disease in MZ versus DZ twins. Distinct associations of HLA DR2 with UC and DR1/DQw5 with CD have been reported. We are searching for susceptibility genes in IBD by linkage analysis in a panel of 43 families with 3more » or more living affected members, which includes 12 families with CD, 17 with UC and 14 {open_quotes}mixed{close_quotes} families with UC and CD. In view of the reported HLA associations in IBD, we have analyzed 5 microsatellite markers from the major histocompatibility complex for linkage to IBD using both parametric and nonparametric methods. LOD scores were calculated for 4 different genetic models, including both dominant and recessive inheritance, and haplotype sharing was analyzed in affected siblings. LOD scores for the MHC locus were negative in the full data set, and in the 3 classes of family (UC,CD,mixed). Haplotype sharing in affected sibs was very close to that expected if no linkage was present. We conclude that genes from the HLA region are unlikely to be a major component of risk in familial IBD. Linkage analysis of genes which cause chronic colitis when disrupted in transgenic mice is in progress.« less

Are Cranial Biomechanical Simulation Data Linked to Known Diets in Extant Taxa? A Method for Applying Diet-Biomechanics Linkage Models to Infer Feeding Capability of Extinct Species

PubMed Central

Tseng, Zhijie Jack; Flynn, John J.

2015-01-01

Performance of the masticatory system directly influences feeding and survival, so adaptive hypotheses often are proposed to explain craniodental evolution via functional morphology changes. However, the prevalence of “many-to-one” association of cranial forms and functions in vertebrates suggests a complex interplay of ecological and evolutionary histories, resulting in redundant morphology-diet linkages. Here we examine the link between cranial biomechanical properties for taxa with different dietary preferences in crown clade Carnivora, the most diverse clade of carnivorous mammals. We test whether hypercarnivores and generalists can be distinguished based on cranial mechanical simulation models, and how such diet-biomechanics linkages relate to morphology. Comparative finite element and geometric morphometrics analyses document that predicted bite force is positively allometric relative to skull strain energy; this is achieved in part by increased stiffness in larger skull models and shape changes that resist deformation and displacement. Size-standardized strain energy levels do not reflect feeding preferences; instead, caniform models have higher strain energy than feliform models. This caniform-feliform split is reinforced by a sensitivity analysis using published models for six additional taxa. Nevertheless, combined bite force-strain energy curves distinguish hypercarnivorous versus generalist feeders. These findings indicate that the link between cranial biomechanical properties and carnivoran feeding preference can be clearly defined and characterized, despite phylogenetic and allometric effects. Application of this diet-biomechanics linkage model to an analysis of an extinct stem carnivoramorphan and an outgroup creodont species provides biomechanical evidence for the evolution of taxa into distinct hypercarnivorous and generalist feeding styles prior to the appearance of crown carnivoran clades with similar feeding preferences. PMID:25923776

Carbohydrate intake, obesity, metabolic syndrome and cancer risk? A two-part systematic review and meta-analysis protocol to estimate attributability

PubMed Central

Sartorius, B; Sartorius, K; Aldous, C; Madiba, T E; Stefan, C; Noakes, T

2016-01-01

Introduction Linkages between carbohydrates, obesity and cancer continue to demonstrate conflicting results. Evidence suggests inconclusive direct linkages between carbohydrates and specific cancers. Conversely, obesity has been strongly linked to a wide range of cancers. The purpose of the study is to explore linkages between carbohydrate intake and cancer types using a two-step approach. First the study will evaluate the linkages between carbohydrate intake and obesity, potentially stratified by metabolic syndrome status. Second, the estimated attributable fraction of obesity ascribed to carbohydrate intake will be multiplied against obesity attributable fractions for cancer types to give estimated overall attributable fraction for carbohydrate versus cancer type. Methods and analysis We will perform a comprehensive search to identify all possible published and unpublished studies that have assessed risk factors for obesity including dietary carbohydrate intake. Scientific databases, namely PubMed MEDLINE, EMBASE, EBSCOhost and ISI Web of Science will be searched. Following study selection, paper/data acquisition, and data extraction and synthesis, we will appraise the quality of studies and risk of bias, as well as assess heterogeneity. Meta-weighted attributable fractions of obesity due to carbohydrate intake will be estimated after adjusting for other potential confounding factors (eg, physical inactivity, other dietary intake). Furthermore, previously published systematic reviews assessing the cancer-specific risk associated with obesity will also be drawn. These estimates will be linked with the attributability of carbohydrate intake in part 1 to estimate the cancer-specific burden that can be attributed to dietary carbohydrates. This systematic review protocol has been developed according to the ‘Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) 2015’. Ethics and dissemination The current study will be based on published literature and data, and, as such, ethics approval is not required. The final results of this two part systematic review (plus multiplicative calculations) will be published in a relevant international peer-reviewed journal. Trial registration number PROSPERO CRD42015023257. PMID:26729382

Multifunctional Polymers and Composites for Self-Healing Applications

DTIC Science & Technology

2006-09-30

linkages (Chen et al. 2002), and a phase separated system based on polydimethylsiloxane (Cho et al. 2006). Self-healing occurs when monomer is released...WCI6 is shown in Figure 1.1a. The average particle sizes determined by analysis of SEM images for all three delivery methods are listed in Table 1.1...were then sieved and the beads smaller than 355 um were kept for further study. Elemental analysis of the wax beads revealed that the concentration of

Genetic evidence of multiple loci in dystocia - difficult labour

PubMed Central

2010-01-01

Background Dystocia, difficult labour, is a common but also complex problem during childbirth. It can be attributed to either weak contractions of the uterus, a large infant, reduced capacity of the pelvis or combinations of these. Previous studies have indicated that there is a genetic component in the susceptibility of experiencing dystocia. The purpose of this study was to identify susceptibility genes in dystocia. Methods A total of 104 women in 47 families were included where at least two sisters had undergone caesarean section at a gestational length of 286 days or more at their first delivery. Study of medical records and a telephone interview was performed to identify subjects with dystocia. Whole-genome scanning using Affymetrix genotyping-arrays and non-parametric linkage (NPL) analysis was made in 39 women exhibiting the phenotype of dystocia from 19 families. In 68 women re-sequencing was performed of candidate genes showing suggestive linkage: oxytocin (OXT) on chromosome 20 and oxytocin-receptor (OXTR) on chromosome 3. Results We found a trend towards linkage with suggestive NPL-score (3.15) on chromosome 12p12. Suggestive linkage peaks were observed on chromosomes 3, 4, 6, 10, 20. Re-sequencing of OXT and OXTR did not reveal any causal variants. Conclusions Dystocia is likely to have a genetic component with variations in multiple genes affecting the patient outcome. We found 6 loci that could be re-evaluated in larger patient cohorts. PMID:20587075

Motivation, Compensation, and Performance for Science and Technological Teachers

NASA Astrophysics Data System (ADS)

Abast, R. M.; Sangi, N. M.; Tumanduk, M. S. S. S.; Roring, R.

2018-02-01

This research is operationally aimed to obtain the result of analysis and interpretation about: relationship of achievement motive, compensation with performance at a junior high school in Manado, Indonesia. This research applies a quantitative approach with correlation analysis method. The research was conducted at one junior high school in Manado, Indonesia. The results showed achievement motive at the school teachers is quite high. This result means that, generally, the teachers of the school have a desire to improve achievement; the performance at the school is good enough. This result means that in general, the performance of teachers at the school is increasing, there is a linkage degree and determinative power between the achievement motive with the performance of teachers at the school amounted 0.773% or 77.3%, compensation for the school teachers in Manado is good enough. This result means that the compensation received is satisfactory, there is a linkage degree and determinative power between compensation and performance of the school teachers in Manado amounted to 0.582 or 58.2%.

The voluntary community health movement in India: a strengths, weaknesses, opportunities, and threats (SWOT) analysis.

PubMed

Sharma, M; Bhatia, G

1996-12-01

There has been a prolific growth of voluntary organizations in India since independence in 1947. One of the major areas of this growth has been in the field of community health. The purpose of this article is to historically trace the voluntary movement in community health in India, analyze the current status, and predict future trends of voluntary efforts. A review of the literature in the form of a Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis was the method of this study. Some of the key trends which emerged as the priority areas for progress and for strengthening voluntary organizations in the future were enhancing linkages between health and development; building upon collective force; greater utilization of participatory training; establishing egalitarian and effectual linkages for decision making at the international level; developing self-reliant community-based models; and the need for attaining holistic empowerment at individual, organizational, and community levels through "duty consciousness" as opposed to merely asking for rights.

Quantifying landscape linkages among giant panda subpopulations in regional scale conservation.

PubMed

Qi, Dunwu; Hu, Yibo; Gu, Xiaodong; Yang, Xuyi; Yang, Guang; Wei, Fuwen

2012-06-01

Understanding habitat requirements and identifying landscape linkages are essential for the survival of isolated populations of endangered species. Currently, some of the giant panda populations are isolated, which threatens their long-term survival, particularly in the Xiaoxiangling mountains. In the present study, we quantified niche requirements and then identified potential linkages of giant panda subpopulations in the most isolated region, using ecological niche factor analysis and a least-cost path model. Giant pandas preferred habitat with conifer forest and gentle slopes (>20 to ≤30°). Based on spatial distribution of suitable habitat, linkages were identified for the Yele subpopulation to 4 other subpopulations (Liziping, Matou, Xinmin and Wanba). Their lengths ranged from 15 to 54 km. The accumulated cost ranged from 693 to 3166 and conifer forest covered over 31%. However, a variety of features (e.g. major roads, human settlements and large unforested areas) might act as barriers along the linkages for giant panda dispersal. Our analysis quantified giant panda subpopulation connectivity to ensure long-term survival. © 2012 ISZS, Blackwell Publishing and IOZ/CAS.

Significant Linkage for Tourette Syndrome in a Large French Canadian Family

PubMed Central

Mérette, Chantal; Brassard, Andrée; Potvin, Anne; Bouvier, Hélène; Rousseau, François; Émond, Claudia; Bissonnette, Luc; Roy, Marc-André; Maziade, Michel; Ott, Jurg; Caron, Chantal

2000-01-01

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS. PMID:10986045

Methods of linking mothers and infants using health plan data for studies of pregnancy outcomes.

PubMed

Johnson, Karin E; Beaton, Sarah J; Andrade, Susan E; Cheetham, T Craig; Scott, Pamela E; Hammad, Tarek A; Dashevsky, Inna; Cooper, William O; Davis, Robert L; Pawloski, Pamala A; Raebel, Marsha A; Smith, David H; Toh, Sengwee; Li, De-Kun; Haffenreffer, Katherine; Dublin, Sascha

2013-07-01

Research on medication safety in pregnancy often utilizes health plan and birth certificate records. This study discusses methods used to link mothers with infants, a crucial step in such research. We describe how eight sites participating in the Medication Exposure in Pregnancy Risk Evaluation Program created linkages between deliveries, infants and birth certificates for the 2001-2007 birth cohorts. We describe linkage rates across sites, and for two sites, we compare the characteristics of populations linked using different methods. Of 299,260 deliveries, 256,563 (86%; range by site, 74-99%) could be linked to infants using a deterministic algorithm. At two sites, using birth certificate data to augment mother-infant linkage increased the representation of mothers who were Hispanic or non-White, younger, Medicaid recipients, or had low educational level. A total of 236,460 (92%; range by site, 82-100%) deliveries could be linked to a birth certificate. Tailored approaches enabled linking most deliveries to infants and to birth certificates, even when data systems differed. The methods used may affect the composition of the population identified. Linkages established with such methods can support sound pharmacoepidemiology studies of maternal drug exposure outside the context of a formal registry. Copyright © 2013 John Wiley & Sons, Ltd.

Determining the trophic guilds of fishes and macroinvertebrates in a seagrass food web

USGS Publications Warehouse

Luczkovich, J.J.; Ward, G.P.; Johnson, J.C.; Christian, R.R.; Baird, D.; Neckles, H.; Rizzo, W.M.

2002-01-01

We established trophic guilds of macroinvertebrate and fish taxa using correspondence analysis and a hierarchical clustering strategy for a seagrass food web in winter in the northeastern Gulf of Mexico. To create the diet matrix, we characterized the trophic linkages of macroinvertebrate and fish taxa present in Halodule wrightii seagrass habitat areas within the St. Marks National Wildlife Refuge (Florida) using binary data, combining dietary links obtained from relevant literature for macroinvertebrates with stomach analysis of common fishes collected during January and February of 1994. Heirarchical average-linkage cluster analysis of the 73 taxa of fishes and macroinvertebrates in the diet matrix yielded 14 clusters with diet similarity ??? 0.60. We then used correspondence analysis with three factors to jointly plot the coordinates of the consumers (identified by cluster membership) and of the 33 food sources. Correspondence analysis served as a visualization tool for assigning each taxon to one of eight trophic guilds: herbivores, detritivores, suspension feeders, omnivores, molluscivores, meiobenthos consumers, macrobenthos consumers, and piscivores. These trophic groups, cross-classified with major taxonomic groups, were further used to develop consumer compartments in a network analysis model of carbon flow in this seagrass ecosystem. The method presented here should greatly improve the development of future network models of food webs by providing an objective procedure for aggregating trophic groups.

Evaluation of hierarchical agglomerative cluster analysis methods for discrimination of primary biological aerosol

NASA Astrophysics Data System (ADS)

Crawford, I.; Ruske, S.; Topping, D. O.; Gallagher, M. W.

2015-11-01

In this paper we present improved methods for discriminating and quantifying primary biological aerosol particles (PBAPs) by applying hierarchical agglomerative cluster analysis to multi-parameter ultraviolet-light-induced fluorescence (UV-LIF) spectrometer data. The methods employed in this study can be applied to data sets in excess of 1 × 106 points on a desktop computer, allowing for each fluorescent particle in a data set to be explicitly clustered. This reduces the potential for misattribution found in subsampling and comparative attribution methods used in previous approaches, improving our capacity to discriminate and quantify PBAP meta-classes. We evaluate the performance of several hierarchical agglomerative cluster analysis linkages and data normalisation methods using laboratory samples of known particle types and an ambient data set. Fluorescent and non-fluorescent polystyrene latex spheres were sampled with a Wideband Integrated Bioaerosol Spectrometer (WIBS-4) where the optical size, asymmetry factor and fluorescent measurements were used as inputs to the analysis package. It was found that the Ward linkage with z-score or range normalisation performed best, correctly attributing 98 and 98.1 % of the data points respectively. The best-performing methods were applied to the BEACHON-RoMBAS (Bio-hydro-atmosphere interactions of Energy, Aerosols, Carbon, H2O, Organics and Nitrogen-Rocky Mountain Biogenic Aerosol Study) ambient data set, where it was found that the z-score and range normalisation methods yield similar results, with each method producing clusters representative of fungal spores and bacterial aerosol, consistent with previous results. The z-score result was compared to clusters generated with previous approaches (WIBS AnalysiS Program, WASP) where we observe that the subsampling and comparative attribution method employed by WASP results in the overestimation of the fungal spore concentration by a factor of 1.5 and the underestimation of bacterial aerosol concentration by a factor of 5. We suggest that this likely due to errors arising from misattribution due to poor centroid definition and failure to assign particles to a cluster as a result of the subsampling and comparative attribution method employed by WASP. The methods used here allow for the entire fluorescent population of particles to be analysed, yielding an explicit cluster attribution for each particle and improving cluster centroid definition and our capacity to discriminate and quantify PBAP meta-classes compared to previous approaches.

Determining the sample size for co-dominant molecular marker-assisted linkage detection for a monogenic qualitative trait by controlling the type-I and type-II errors in a segregating F2 population.

PubMed

Hühn, M; Piepho, H P

2003-03-01

Tests for linkage are usually performed using the lod score method. A critical question in linkage analyses is the choice of sample size. The appropriate sample size depends on the desired type-I error and power of the test. This paper investigates the exact type-I error and power of the lod score method in a segregating F(2) population with co-dominant markers and a qualitative monogenic dominant-recessive trait. For illustration, a disease-resistance trait is considered, where the susceptible allele is recessive. A procedure is suggested for finding the appropriate sample size. It is shown that recessive plants have about twice the information content of dominant plants, so the former should be preferred for linkage detection. In some cases the exact alpha-values for a given nominal alpha may be rather small due to the discrete nature of the sampling distribution in small samples. We show that a gain in power is possible by using exact methods.

Introductory guide to the statistics of molecular genetics.

PubMed

Eley, Thalia C; Rijsdijk, Frühling

2005-10-01

This introductory guide presents the main two analytical approaches used by molecular geneticists: linkage and association. Traditional linkage and association methods are described, along with more recent advances in methodologies such as those using a variance components approach. New methods are being developed all the time but the core principles of linkage and association remain the same. The basis of linkage is the transmission of a marker along with a disease within families, whereas association is based on the comparison of marker frequencies in case and control groups. It is becoming increasingly clear that effect sizes of individual markers on diseases and traits are likely to be very small. As such, much greater power is needed, and correspondingly greater sample sizes. Although non-replication is still a problem, molecular genetic studies in some areas such as attention deficit/hyperactivity disorder (ADHD) are starting to show greater convergence. Epidemiologists and other researchers with large well-characterized samples will be well placed to use these methods. Inter-disciplinary studies can then ask far more interesting questions such as those relating to developmental, multivariate and gene-environment interaction hypotheses.

Wildlife connectivity approaches and best practices in U.S. state wildlife action plans.

PubMed

Lacher, Iara; Wilkerson, Marit L

2014-02-01

As habitat loss and fragmentation threaten biodiversity on large geographic scales, creating and maintaining connectivity of wildlife populations is an increasingly common conservation objective. To assess the progress and success of large-scale connectivity planning, conservation researchers need a set of plans that cover large geographic areas and can be analyzed as a single data set. The state wildlife action plans (SWAPs) fulfill these requirements. We examined 50 SWAPs to determine the extent to which wildlife connectivity planning, via linkages, is emphasized nationally. We defined linkage as connective land that enables wildlife movement. For our content analysis, we identified and quantified 6 keywords and 7 content criteria that ranged in specificity and were related to linkages for wide-ranging terrestrial vertebrates and examined relations between content criteria and statewide data on focal wide-ranging species, spending, revenue, and conserved land. Our results reflect nationwide disparities in linkage conservation priorities and highlight the continued need for wildlife linkage planning. Only 30% or less of the 50 SWAPs fulfilled highly specific content criteria (e.g., identifying geographic areas for linkage placement or management). We found positive correlations between our content criteria and statewide data on percent conserved land, total focal species, and spending on parks and recreation. We supplemented our content analysis with interviews with 17 conservation professionals to gain specific information about state-specific context and future directions of linkage conservation. Based on our results, relevant literature, and interview responses, we suggest the following best practices for wildlife linkage conservation plans: collect ecologically meaningful background data; be specific; establish community-wide partnerships; and incorporate sociopolitical and socioeconomic information. © 2013 Society for Conservation Biology.

Wildlife connectivity approaches and best practices in U.S. state wildlife action plans

USGS Publications Warehouse

Lacher, Iara; Wilkerson, Marit L.

2014-01-01

As habitat loss and fragmentation threaten biodiversity on large geographic scales, creating and maintaining connectivity of wildlife populations is an increasingly common conservation objective. To assess the progress and success of large-scale connectivity planning, conservation researchers need a set of plans that cover large geographic areas and can be analyzed as a single data set. The state wildlife action plans (SWAPs) fulfill these requirements. We examined 50 SWAPs to determine the extent to which wildlife connectivity planning, via linkages, is emphasized nationally. We defined linkage as connective land that enables wildlife movement. For our content analysis, we identified and quantified 6 keywords and 7 content criteria that ranged in specificity and were related to linkages for wide-ranging terrestrial vertebrates and examined relations between content criteria and statewide data on focal wide-ranging species, spending, revenue, and conserved land. Our results reflect nationwide disparities in linkage conservation priorities and highlight the continued need for wildlife linkage planning. Only 30% or less of the 50 SWAPs fulfilled highly specific content criteria (e.g., identifying geographic areas for linkage placement or management). We found positive correlations between our content criteria and statewide data on percent conserved land, total focal species, and spending on parks and recreation. We supplemented our content analysis with interviews with 17 conservation professionals to gain specific information about state-specific context and future directions of linkage conservation. Based on our results, relevant literature, and interview responses, we suggest the following best practices for wildlife linkage conservation plans: collect ecologically meaningful background data; be specific; establish community-wide partnerships; and incorporate sociopolitical and socioeconomic information.

Localization of a gene responsible for nonspecific mental retardation (MRX9) to the pericentromeric region of the X chromosome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Willems, P.; Vits, L.; Buntinx, I.

1993-11-01

Nonspecific X-linked mental retardation (MRX) includes several distinct entities with mental retardation but without additional distinguishing features. The MRX family reported here has been classified previously as MRX9. In this study, the authors performed linkage analysis of MRX9 with a panel of 43 polymorphic DNA markers dispersed over chromosome X. Two-point linkage analysis revealed lod scores of 3.52 and 3.82 at 0% recombination for OATL1 and MAOA, both located in Xp11.2-p11.4. Lod scores for linkage with PGK1P1, DXS106, and DXS132, all located in Xq11-q13, were 3.83, 3.82, and 3.52, respectively, all at 0% recombination. Multipoint linkage analysis showed two peaksmore » with MAOA and DXS132/DXS106, respectively. Analysis of recombinational events indicated a position of the MRX9 gene between DXS164 and DXS453. These findings are compatible with a location of the MRX9 gene in the pericentromeric region of the X chromosome at Xp21-q13. 26 refs., 3 figs., 2 tabs.« less

Genomewide significant linkage to recurrent, early-onset major depressive disorder on chromosome 15q.

PubMed

Holmans, Peter; Zubenko, George S; Crowe, Raymond R; DePaulo, J Raymond; Scheftner, William A; Weissman, Myrna M; Zubenko, Wendy N; Boutelle, Sandra; Murphy-Eberenz, Kathleen; MacKinnon, Dean; McInnis, Melvin G; Marta, Diana H; Adams, Philip; Knowles, James A; Gladis, Madeleine; Thomas, Jo; Chellis, Jennifer; Miller, Erin; Levinson, Douglas F

2004-06-01

A genome scan was performed on the first phase sample of the Genetics of Recurrent Early-Onset Depression (GenRED) project. The sample consisted of 297 informative families containing 415 independent affected sibling pairs (ASPs), or, counting all possible pairs, 685 informative affected relative pairs (555 ASPs and 130 other pair types). Affected cases had recurrent major depressive disorder (MDD) with onset before age 31 years for probands or age 41 years for other affected relatives; the mean age at onset was 18.5 years, and the mean number of depressive episodes was 7.3. The Center for Inherited Disease Research genotyped 389 microsatellite markers (mean spacing of 9.3 cM). The primary linkage analysis considered allele sharing in all possible affected relative pairs with the use of the Z(lr) statistic computed by the ALLEGRO program. A secondary logistic regression analysis considered the effect of the sex of the pair as a covariate. Genomewide significant linkage was observed on chromosome 15q25.3-26.2 (Zlr=4.14, equivalent LOD = 3.73, empirical genomewide P=.023). The linkage was not sex specific. No other suggestive or significant results were observed in the primary analysis. The secondary analysis produced three regions of suggestive linkage, but these results should be interpreted cautiously because they depended primarily on the small subsample of 42 male-male pairs. Chromosome 15q25.3-26.2 deserves further study as a candidate region for susceptibility to MDD.

Identification of Sex-determining Loci in Pacific White Shrimp Litopeneaus vannamei Using Linkage and Association Analysis.

PubMed

Yu, Yang; Zhang, Xiaojun; Yuan, Jianbo; Wang, Quanchao; Li, Shihao; Huang, Hao; Li, Fuhua; Xiang, Jianhai

2017-06-01

The Pacific white shrimp Litopenaeus vannamei is a predominant aquaculture shrimp species in the world. Like other animals, the L. vannamei exhibited sexual dimorphism in growth trait. Mapping of the sex-determining locus will be very helpful to clarify the sex determination system and further benefit the shrimp aquaculture industry towards the production of mono-sex stocks. Based on the data used for high-density linkage map construction, linkage-mapping analysis was conducted. The sex determination region was mapped in linkage group (LG) 18. A large region from 0 to 21.205 cM in LG18 showed significant association with sex. However, none of the markers in this region showed complete association with sex in the other populations. So an association analysis was designed using the female parent, pool of female progenies, male parent, and pool of male progenies. Markers were de novo developed and those showing significant differences between female and male pools were identified. Among them, three sex-associated markers including one fully associated marker were identified. Integration of linkage and association analysis showed that the sex determination region was fine-mapped in a small region along LG18. The identified sex-associated marker can be used for the sex detection of this species at genetic level. The fine-mapped sex-determining region will contribute to the mapping of sex-determining gene and help to clarify sex determination system for L. vannamei.

[Linkage analysis of a family with familial hypertriglyceridemia].

PubMed

Tang, Xin; Lin, Ying; Liu, Bing; Ma, Shi; Yang, Yang; Yang, Zheng-lin

2009-10-01

To perform linkage analysis and mutation screening in a Chinese family with familial hpertriglyceridemia (FHTG). Thirty-two family members including 12 hypertriglyceridemia patients participated in the study. Genotyping and haplotype analysis for 22 subjects were performed using short tandem repeat (STR) microsatellite polymorphism markers on 16 candidate genes and/or loci related to lipid metabolism. Two of the sixteen known candidate genes, APOA2 and USF1 were screened for mutation by direct DNA sequencing. No linkage was found between the candidate genes/loci of APOA5, LIPI, RP1, APOC2, ABC1, LMF1, APOA1-APOC3-APOA4, LPL, APOB, CETP, LCAT, LDLR, APOE and the phenotype in this family. The two-point Lod scores (theta =0) were all less than-1.0 for all the markers tested. Linkage analysis suggested linkage to chromosome 1q23.3-24.2 between the disease phenotype and STR marker D1S194 with a two-point maximum Lod score of 2.44 at theta =0. Fine mapping indicated that the disease gene was localized to a 5.87 cM interval between D1S104 and D1S196. No disease-causing mutation was detected in the APOA2 and USF1 genes. The above mentioned candidate genes were excluded as the disease causing genes for this family. The results implied that there might be a novel gene/locus for FHTG on chromosome 1q23.3-1q24.2.

Moving Toward Improved Acquisition Outcomes: The Interrelationships Between Culture, Commitment, and Leadership

DTIC Science & Technology

2011-04-01

structure modeling . Psychological Methods, 1, 130–149. Mowday, R. T., Porter , L. W., & Steers, R. M. (1982). Organizational linkages: The psychology of...Leadership, Structural Equation Modeling , Analysis of Moment Structures (AMOS), Organizational Productivity MOVING TOWARD IMPROVED ACQUISITION OUTCOMES...greater than the sum of their individual elements. A conceptual model was identified and used as the foundation for building hypotheses. Structural

Quantitative trait locus linkage analysis in a large Amish pedigree identifies novel candidate loci for erythrocyte traits

PubMed Central

Hinckley, Jesse D; Abbott, Diana; Burns, Trudy L; Heiman, Meadow; Shapiro, Amy D; Wang, Kai; Di Paola, Jorge

2013-01-01

We characterized a large Amish pedigree and, in 384 pedigree members, analyzed the genetic variance components with covariate screen as well as genome-wide quantitative trait locus (QTL) linkage analysis of red blood cell count (RBC), hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet count (PLT), and white blood cell count (WBC) using SOLAR. Age and gender were found to be significant covariates in many CBC traits. We obtained significant heritability estimates for RBC, MCV, MCH, MCHC, RDW, PLT, and WBC. We report four candidate loci with Logarithm of the odds (LOD) scores above 2.0: 6q25 (MCH), 9q33 (WBC), 10p12 (RDW), and 20q13 (MCV). We also report eleven candidate loci with LOD scores between 1.5 and <2.0. Bivariate linkage analysis of MCV and MCH on chromosome 20 resulted in a higher maximum LOD score of 3.14. Linkage signals on chromosomes 4q28, 6p22, 6q25, and 20q13 are concomitant with previously reported QTL. All other linkage signals reported herein represent novel evidence of candidate QTL. Interestingly rs1800562, the most common causal variant of hereditary hemochromatosis in HFE (6p22) was associated with MCH and MCHC in this family. Linkage studies like the one presented here will allow investigators to focus the search for rare variants amidst the noise encountered in the large amounts of data generated by whole-genome sequencing. PMID:24058921

Refined genetic mapping of X-linked Charcot-Marie-Tooth neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fain, P.R.; Barker, D.F.; Chance, P.F.

1994-02-01

Genetic linkage studies were conducted in four multigenerational families with X-linked Charcot-Marie-Tooth disease (CMTX), using 12 highly polymorphic short-tandem-repeat markers for the pericentromeric region of the X Chromosome. Pairwise linkage analysis with individual markers confirmed tight linkage of CMTX to the pericentromeric region in each family. Multipoint analyses strongly support the order DXS337-CMTX-DXS441-(DXS56, PGK1). 38 refs., 2 figs., 1 tab.

Genome‐wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica

PubMed Central

Hersh, Craig P; Soto‐Quirós, Manuel E; Avila, Lydiana; Lake, Stephen L; Liang, Catherine; Fournier, Eduardo; Spesny, Mitzi; Sylvia, Jody S; Lazarus, Ross; Hudson, Thomas; Verner, Andrei; Klanderman, Barbara J; Freimer, Nelson B; Silverman, Edwin K; Celedón, Juan C

2007-01-01

Background Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma‐related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans. Methods Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV1) and FEV1/ forced vital capacity (FVC; both pre‐bronchodilator and post‐bronchodilator) and BDR were performed in these eight families (pre‐bronchodilator spirometry, n = 640; post‐bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking. Results Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV1 (post‐bronchodilator) was found on chromosome 7q34–35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV1/FVC (pre‐bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near‐significant evidence of linkage to FEV1/FVC (post‐bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV1 on chromosomes 3q (pre‐bronchodilator, LOD = 2.74) and 4q (post‐bronchodilator, LOD = 2.66). Conclusions In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV1 on chromosome 7q34–35. In these families, FEV1/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p. PMID:17099076

Use of linkage to improve the completeness of the SIM and SINASC in the Brazilian capitals

PubMed Central

Maia, Lívia Teixeira de Souza; de Souza, Wayner Vieira; Mendes, Antonio da Cruz Gouveia; da Silva, Aline Galdino Soares

2017-01-01

ABSTRACT OBJECTIVE To analyze the contribution of linkage between databases of live births and infant mortality to improve the completeness of the variables common to the Mortality Information System (SIM) and the Live Birth Information System (SINASC) in Brazilian capitals in 2012. METHODS We studied 9,001 deaths of children under one year registered in the SIM in 2012 and 1,424,691 live births present in the SINASC in 2011 and 2012. The databases were related with linkage in two steps – deterministic and probabilistic. We calculated the percentage of incompleteness of the variables common to the SIM and SINASC before and after using the technique. RESULTS We could relate 90.8% of the deaths to their respective declarations of live birth, most of them paired deterministically. We found a higher percentage of pairs in Porto Alegre, Curitiba, and Campo Grande. In the capitals of the North region, the average of pairs was 84.2%; in the South region, this result reached 97.9%. The 11 variables common to the SIM and SINASC had 11,278 incomplete fields cumulatively, and we could recover 91.4% of the data after linkage. Before linkage, five variables presented excellent completeness in the SINASC in all Brazilian capitals, but only one variable had the same status in the SIM. After applying this technique, all 11 variables of the SINASC became excellent, while this occurred in seven variables of the SIM. The city of birth was significantly associated with the death component in the quality of the information. CONCLUSIONS Despite advances in the coverage and quality of the SIM and SINASC, problems in the completeness of the variables can still be identified, especially in the SIM. In this perspective, linkage can be used to qualify important information for the analysis of infant mortality. PMID:29211201

Analyzing the Relative Linkages of Land Use and Hydrologic Variables with Urban Surface Water Quality using Multivariate Techniques

NASA Astrophysics Data System (ADS)

Ahmed, S.; Abdul-Aziz, O. I.

2015-12-01

We used a systematic data-analytics approach to analyze and quantify relative linkages of four stream water quality indicators (total nitrogen, TN; total phosphorus, TP; chlorophyll-a, Chla; and dissolved oxygen, DO) with six land use and four hydrologic variables, along with the potential external (upstream in-land and downstream coastal) controls in highly complex coastal urban watersheds of southeast Florida, U.S.A. Multivariate pattern recognition techniques of principle component and factor analyses, in concert with Pearson correlation analysis, were applied to map interrelations and identify latent patterns of the participatory variables. Relative linkages of the in-stream water quality variables with their associated drivers were then quantified by developing dimensionless partial least squares (PLS) regression model based on standardized data. Model fitting efficiency (R2=0.71-0.87) and accuracy (ratio of root-mean-square error to the standard deviation of the observations, RSR=0.35-0.53) suggested good predictions of the water quality variables in both wet and dry seasons. Agricultural land and groundwater exhibited substantial controls on surface water quality. In-stream TN concentration appeared to be mostly contributed by the upstream water entering from Everglades in both wet and dry seasons. In contrast, watershed land uses had stronger linkages with TP and Chla than that of the watershed hydrologic and upstream (Everglades) components for both seasons. Both land use and hydrologic components showed strong linkages with DO in wet season; however, the land use linkage appeared to be less in dry season. The data-analytics method provided a comprehensive empirical framework to achieve crucial mechanistic insights into the urban stream water quality processes. Our study quantitatively identified dominant drivers of water quality, indicating key management targets to maintain healthy stream ecosystems in complex urban-natural environments near the coast.

Genome-wide linkage scan for maximum and length-dependent knee muscle strength in young men: significant evidence for linkage at chromosome 14q24.3

PubMed Central

De Mars, G; Windelinckx, A; Huygens, W; Peeters, M W; Beunen, G P; Aerssens, J; Vlietinck, R; Thomis, M A I

2008-01-01

Background: Maintenance of high muscular fitness is positively related to bone health, functionality in daily life and increasing insulin sensitivity, and negatively related to falls and fractures, morbidity and mortality. Heritability of muscle strength phenotypes ranges between 31% and 95%, but little is known about the identity of the genes underlying this complex trait. As a first attempt, this genome-wide linkage study aimed to identify chromosomal regions linked to muscle and bone cross-sectional area, isometric knee flexion and extension torque, and torque–length relationship for knee flexors and extensors. Methods: In total, 283 informative male siblings (17–36 years old), belonging to 105 families, were used to conduct a genome-wide SNP-based multipoint linkage analysis. Results: The strongest evidence for linkage was found for the torque–length relationship of the knee flexors at 14q24.3 (LOD  = 4.09; p<10−5). Suggestive evidence for linkage was found at 14q32.2 (LOD  = 3.00; P = 0.005) for muscle and bone cross-sectional area, at 2p24.2 (LOD  = 2.57; p = 0.01) for isometric knee torque at 30° flexion, at 1q21.3, 2p23.3 and 18q11.2 (LOD  = 2.33, 2.69 and 2.21; p<10−4 for all) for the torque–length relationship of the knee extensors and at 18p11.31 (LOD  = 2.39; p = 0.0004) for muscle-mass adjusted isometric knee extension torque. Conclusions: We conclude that many small contributing genes rather than a few important genes are involved in causing variation in different underlying phenotypes of muscle strength. Furthermore, some overlap in promising genomic regions were identified among different strength phenotypes. PMID:18178634

Sexual selection and sex linkage.

PubMed

Kirkpatrick, Mark; Hall, David W

2004-04-01

Some animal groups, such as birds, seem prone to extreme forms of sexual selection. One contributing factor may be sex linkage of genes affecting male displays and female preferences. Here we show that sex linkage can have substantial effects on the genetic correlation between these traits and consequently for Fisher's runaway and the good-genes mechanisms of sexual selection. Under some kinds of sex linkage (e.g. Z-linked preferences), a runaway is more likely than under autosomal inheritance, while under others (e.g., X-linked preferences and autosomal displays), the good-genes mechanism is particularly powerful. These theoretical results suggest empirical tests based on the comparative method.

Linkage of Bardet-Biedl syndrome to chromosome 16q and evidence for non-allelic genetic heterogeneity.

PubMed

Kwitek-Black, A E; Carmi, R; Duyk, G M; Buetow, K H; Elbedour, K; Parvari, R; Yandava, C N; Stone, E M; Sheffield, V C

1993-12-01

Bardet-Biedl syndrome is an autosomal recessive disorder characterized by mental retardation, obesity, retinitis pigmentosa, polydactyly and hypogonadism. Other findings include hypertension, diabetes mellitus and renal and cardiovascular anomalies. We have performed a genome-wide search for linkage in a large inbred Bedouin family. Pairwise analysis established linkage with the locus D16S408 with no recombination and a lod score of 4.2. A multilocus lod score of 5.3 was observed. By demonstrating homozygosity, in all affected individuals, for the same allele of marker D16S408, further support for linkage is found, and the utility of homozygosity mapping using inbred families is demonstrated. In a second family, linkage was excluded at this locus, suggesting non-allelic genetic heterogeneity in this disorder.

Genetic linkage analysis of schizophrenia using chromosome 11q13-24 markers in Israeli pedigrees

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mulcrone, J.; Marchblanks, R.; Whatley, S.A.

It is generally agreed that there is a genetic component in the etiology of schizophrenia which may be tested by the application of linkage analysis to multiply-affected families. One genetic region of interest is the long arm of chromosome 11 because of previously reported associations of genetic variation in this region with schizophrenia, and because of the fact that it contains the locus for the dopamine D2 receptor gene. In this study we have examined the segregation of schizophrenia with microsatellite dinucleotide repeat DNA markers along chromosome 11q in 5 Israeli families multiply-affected for schizophrenia. The hypothesis of linkage undermore » genetic homogeneity of causation was tested under a number of genetic models. Linkage analysis provided no evidence for significant causal mutations within the region bounded by INT and D11S420 on chromosome 11q. It is still possible, however, that a gene of major effect exists in this region, either with low penetrance or with heterogeneity. 32 refs., 2 figs., 4 tabs.« less

Linkage analysis in Usher syndrome type I (USH1) families from Spain.

PubMed Central

Espinós, C; Nájera, C; Millán, J M; Ayuso, C; Baiget, M; Pérez-Garrigues, H; Rodrigo, O; Vilela, C; Beneyto, M

1998-01-01

Usher syndrome (USH) is an autosomal recessive hereditary disorder characterised by congenital sensorineural hearing loss and gradual visual impairment secondary to retinitis pigmentosa (RP). The disorder is clinically and genetically heterogeneous. With regard to Usher type I (USH1), several subtypes have been described, the most frequent being USH1B located on chromosome 11q13.5. Of 18 USH1 families studied by linkage analysis, 12 (67%) showed significant lod score values for locus D11S527 (Zmax=14.032, theta=0.000) situated on chromosome 11q. Our findings suggest considerable genetic heterogeneity in the Spanish USH1 population. It is important to note that one of our families linked to the USH1B locus shows interesting intrafamilial clinical variability. As regards the remaining six USH1 families, the linkage analysis did not provide conclusive data, although two of them show slight linkage to markers located on chromosome 3q (Zmax=1.880, theta=0.000 for D3S1279), the same location that had previously been assigned to some USH3 families. Images PMID:9610802

[The Willingness to Consent to the Linkage of Primary and Secondary Data: An Analysis Based on a Survey of Patients with Primary Breast Cancer in Northrhine Westfalia].

PubMed

Scholten, N; Pfaff, H; Raabe, N; Kowalski, C

2017-03-01

Introduction: By linking data it is possible to merge, for example, survey data with routine data from statutory health insurance (GKV), to gain benefit from the advantages of both. As personal data is involved, it is necessary to obtain consent. Previous studies show that willingness to release this kind of data for scientific research is limited. This fact restricts the number of participants and can cause selection bias. The aim of our study was to analyze willingness to consent to the linkage of survey data with statutory health insurance data in patients with primary breast cancer. Associations between approval and socio-demographic characteristics were explored. Method: In the annual survey of patients with primary breast cancer in certified breast centers in North Rhine-Westphalia, all included patients were questioned concerning their willingness to consent to data linkage. We distinguished between patients insured by AOK Rhineland/Hamburg and all other patients: based on cooperation with AOK Rhineland/Hamburg, we obtained consent to actually link the data for all patients insured there. All other patients were questioned in terms of their insurance and their willingness to consent in general. Results: A total of 2,387 questionnaires were returned, giving a return rate of 49.3%. For the AOK Rhineland/Hamburg-insured patients, the consent rate was at 89.6%. At 75.7%, positive attitudes towards data linkage turned out to be a bit lower for patients with other insurers. Under the assumption that all non-responders disapprove data linkage, still 38.1% of patients showed a positive attitude towards data linkage. As a result of the multivariable model, insurance status (private vs. statutory) and first language turned out to be the only significant factors influencing the response. The consent of patients insured by AOK Rhineland/Hamburg is not significantly influenced by any of the measured socio-demographic factors. Conclusion: Currently, there is not much knowledge on the acceptance of data linkage in patients suffering from an acute illness. Although our results are restricted to breast cancer patients, they are able to uncover problems and chances concerning data linkage. © Georg Thieme Verlag KG Stuttgart · New York.

Unravelling Glucan Recognition Systems by Glycome Microarrays Using the Designer Approach and Mass Spectrometry*

PubMed Central

Palma, Angelina S.; Liu, Yan; Zhang, Hongtao; Zhang, Yibing; McCleary, Barry V.; Yu, Guangli; Huang, Qilin; Guidolin, Leticia S.; Ciocchini, Andres E.; Torosantucci, Antonella; Wang, Denong; Carvalho, Ana Luísa; Fontes, Carlos M. G. A.; Mulloy, Barbara; Childs, Robert A.; Feizi, Ten; Chai, Wengang

2015-01-01

Glucans are polymers of d-glucose with differing linkages in linear or branched sequences. They are constituents of microbial and plant cell-walls and involved in important bio-recognition processes, including immunomodulation, anticancer activities, pathogen virulence, and plant cell-wall biodegradation. Translational possibilities for these activities in medicine and biotechnology are considerable. High-throughput micro-methods are needed to screen proteins for recognition of specific glucan sequences as a lead to structure–function studies and their exploitation. We describe construction of a “glucome” microarray, the first sequence-defined glycome-scale microarray, using a “designer” approach from targeted ligand-bearing glucans in conjunction with a novel high-sensitivity mass spectrometric sequencing method, as a screening tool to assign glucan recognition motifs. The glucome microarray comprises 153 oligosaccharide probes with high purity, representing major sequences in glucans. Negative-ion electrospray tandem mass spectrometry with collision-induced dissociation was used for complete linkage analysis of gluco-oligosaccharides in linear “homo” and “hetero” and branched sequences. The system is validated using antibodies and carbohydrate-binding modules known to target α- or β-glucans in different biological contexts, extending knowledge on their specificities, and applied to reveal new information on glucan recognition by two signaling molecules of the immune system against pathogens: Dectin-1 and DC-SIGN. The sequencing of the glucan oligosaccharides by the MS method and their interrogation on the microarrays provides detailed information on linkage, sequence and chain length requirements of glucan-recognizing proteins, and are a sensitive means of revealing unsuspected sequences in the polysaccharides. PMID:25670804

Lack of genetic linkage evidence for a trans-acting factor having a large effect on plasma lipoprotein[a] levels in African Americans.

PubMed

Barkley, Ruth Ann; Brown, Andrew C; Hanis, Craig L; Kardia, Sharon L; Turner, Stephen T; Boerwinkle, Eric

2003-07-01

The distribution of plasma lipoprotein[a] (Lp[a]) concentrations, a risk factor for cardiovascular disease, varies greatly among racial groups, with African Americans having values that are shifted toward higher levels than those of whites. The underlying cause of this heterogeneity is unknown, but a role for "trans-acting" factors has been hypothesized. This study used genetic linkage analysis to localize genetic factors influencing Lp[a] levels in African Americans that were absent in other populations; linkage results were analyzed separately in non-Hispanic whites, Hispanic whites, and African Americans. As expected, all three samples showed highly significant linkage at the approximate location of the lysophosphatidic acid locus. The white populations also independently had regions of significant linkage on chromosome 19 (LOD 3.80) and suggestive linkage on chromosomes 12 (LOD 1.60), 14 (LOD 2.56), and 19 (LOD 2.52). No linkage evidence was found to support the hypothesis of another single gene with large effects specifically segregating in African Americans that may account for their elevated Lp[a] levels.

Validation of an instrument to measure inter-organisational linkages in general practice.

PubMed

Amoroso, Cheryl; Proudfoot, Judith; Bubner, Tanya; Jayasinghe, Upali W; Holton, Christine; Winstanley, Julie; Beilby, Justin; Harris, Mark F

2007-12-03

Linkages between general medical practices and external services are important for high quality chronic disease care. The purpose of this research is to describe the development, evaluation and use of a brief tool that measures the comprehensiveness and quality of a general practice's linkages with external providers for the management of patients with chronic disease. In this study, clinical linkages are defined as the communication, support, and referral arrangements between services for the care and assistance of patients with chronic disease. An interview to measure surgery-level (rather than individual clinician-level) clinical linkages was developed, piloted, reviewed, and evaluated with 97 Australian general practices. Two validated survey instruments were posted to patients, and a survey of locally available services was developed and posted to participating Divisions of General Practice (support organisations). Hypotheses regarding internal validity, association with local services, and patient satisfaction were tested using factor analysis, logistic regression and multilevel regression models. The resulting General Practice Clinical Linkages Interview (GP-CLI) is a nine-item tool with three underlying factors: referral and advice linkages, shared care and care planning linkages, and community access and awareness linkages. Local availability of chronic disease services has no affect on the comprehensiveness of services with which practices link, however, comprehensiveness of clinical linkages has an association with patient assessment of access, receptionist services, and of continuity of care in their general practice. The GP-CLI may be useful to researchers examining comparable health care systems for measuring the comprehensiveness and quality of linkages at a general practice-level with related services, possessing both internal and external validity. The tool can be used with large samples exploring the impact, outcomes, and facilitators of high quality clinical linkages in general practice.

Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for HIV prevention in people who inject drugs: a cost-effectiveness modelling study.

PubMed

Uyei, Jennifer; Fiellin, David A; Buchelli, Marianne; Rodriguez-Santana, Ramon; Braithwaite, R Scott

2017-03-01

In the USA, an epidemic of opioid overdose deaths is occurring, many of which are from heroin. Combining naloxone distribution with linkage to addiction treatment or pre-exposure prophylaxis (PrEP) for HIV prevention through syringe service programmes has the potential to save lives and be cost-effective. We estimated the outcomes and cost-effectiveness of five alternative strategies: no additional intervention, naloxone distribution, naloxone distribution plus linkage to addiction treatment, naloxone distribution plus PrEP, and naloxone distribution plus linkage to addiction treatment and PrEP. We developed a decision analytical Markov model to simulate opioid overdose, HIV incidence, overdose-related deaths, and HIV-related deaths in people who inject drugs in Connecticut, USA. Model input parameters were derived from published sources. We compared each strategy with no intervention, as well as simultaneously considering all strategies. Sensitivity analysis was done for all variables. Linkage to addiction treatment was referral to an opioid treatment programme for methadone. Endpoints were survival, life expectancy, quality-adjusted life-years (QALYs), number and percentage of overdose deaths averted, number of HIV-related deaths averted, total costs (in 2015 US$) associated with each strategy, and incremental cost per QALY gained. In the base-case analysis, compared with no additional intervention, the naloxone distribution strategy yielded an incremental cost-effectiveness ratio (ICER) of $323 per QALY, and naloxone distribution plus linkage to addiction treatment was cost saving compared with no additional intervention (greater effectiveness and less expensive). The most efficient strategies (ie, those conferring the greatest health benefit for a particular budget) were naloxone distribution combined with linkage to addiction treatment (cost saving), and naloxone distribution combined with PrEP and linkage to addiction treatment (ICER $95 337 per QALY) at a willingness-to-pay threshold of $100 000. In probabilistic sensitivity analysis, the combination of naloxone distribution, PrEP, and linkage to addiction treatment was the optimal strategy in 37% of iterations and the combination of naloxone distribution and linkage to addiction treatment was the optimal strategy in 34% of iterations. Naloxone distribution through syringe service programmes is cost-effective compared with syringe distribution alone, but when combined with linkage to addiction treatment is cost saving compared with no additional services. A strategy that combines naloxone distribution, PrEP, and linkage to addiction treatment results in greater health benefits in people who inject drugs and is also cost-effective. State of Connecticut Department of Public Health and the National Institute of Mental Health. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.

Application of finite-element methods to dynamic analysis of flexible spatial and co-planar linkage systems, part 2

NASA Technical Reports Server (NTRS)

Dubowsky, Steven

1989-01-01

An approach is described to modeling the flexibility effects in spatial mechanisms and manipulator systems. The method is based on finite element representations of the individual links in the system. However, it should be noted that conventional finite element methods and software packages will not handle the highly nonlinear dynamic behavior of these systems which results form their changing geometry. In order to design high-performance lightweight systems and their control systems, good models of their dynamic behavior which include the effects of flexibility are required.

Significant Admixture Linkage Disequilibrium across 30 cM around the FY Locus in African Americans

PubMed Central

Lautenberger, James A.; Stephens, J. Claiborne; O'Brien, Stephen J.; Smith, Michael W.

2000-01-01

Scientists, to understand the importance of allelic polymorphisms on phenotypes that are quantitative and environmentally interacting, are now turning to population-association screens, especially in instances in which pedigree analysis is difficult. Because association screens require linkage disequilibrium between markers and disease loci, maximizing the degree of linkage disequilibrium increases the chances of discovering functional gene-marker associations. One theoretically valid approach—mapping by admixture linkage disequilibrium (MALD), using recently admixed African Americans—is empirically evaluated here by measurement of marker associations with 15 short tandem repeats (STRs) and an insertion/deletion polymorphism of the AT3 locus in a 70-cM segment at 1q22-23, around the FY (Duffy) locus. The FY polymorphism (−46T→C) disrupts the GATA promoter motif, specifically blocking FY erythroid expression and has a nearly fixed allele-frequency difference between European Americans and native Africans that is likely a consequence of a selective advantage of FY−/− in malaria infections. Analysis of linkage disequilibrium around the FY gene has indicated that there is strong and consistent linkage disequilibrium between FY and three flanking loci (D1S303, SPTA1, and D1S484) spanning 8 cM. We observed significant linkage-disequilibrium signals over a 30-cM region from −4.4 to 16.3 cM (from D1S2777 to D1S196) for STRs and at 26.4 cM (AT3), which provided quantitative estimates of centimorgan limits, by MALD assessment in African American population-association analyses, of 5–10 cM. PMID:10712211

Effective Linkages of Continuum of Care for Improving Neonatal, Perinatal, and Maternal Mortality: A Systematic Review and Meta-Analysis

PubMed Central

Kikuchi, Kimiyo; Enuameh, Yeetey; Yasuoka, Junko; Nanishi, Keiko; Shibanuma, Akira; Gyapong, Margaret; Owusu-Agyei, Seth; Oduro, Abraham Rexford; Asare, Gloria Quansah; Hodgson, Abraham; Jimba, Masamine

2015-01-01

Background Continuum of care has the potential to improve maternal, newborn, and child health (MNCH) by ensuring care for mothers and children. Continuum of care in MNCH is widely accepted as comprising sequential time (from pre-pregnancy to motherhood and childhood) and space dimensions (from community-family care to clinical care). However, it is unclear which linkages of care could have a greater effect on MNCH outcomes. The objective of the present study is to assess the effectiveness of different continuum of care linkages for reducing neonatal, perinatal, and maternal mortality in low- and middle-income countries. Methods We searched for randomized and quasi-randomized controlled trials that addressed two or more linkages of continuum of care and attempted to increase mothers’ uptake of antenatal care, skilled birth attendance, and postnatal care. The outcome variables were neonatal, perinatal, and maternal mortality. Results Out of the 7,142 retrieved articles, we selected 19 as eligible for the final analysis. Of these studies, 13 used packages of intervention that linked antenatal care, skilled birth attendance, and postnatal care. One study each used packages that linked antenatal care and skilled birth attendance or skilled birth attendance and postnatal care. Four studies used an intervention package that linked antenatal care and postnatal care. Among the packages that linked antenatal care, skilled birth attendance, and postnatal care, a significant reduction was observed in combined neonatal, perinatal, and maternal mortality risks (RR 0.83; 95% CI 0.77 to 0.89, I2 79%). Furthermore, this linkage reduced combined neonatal, perinatal, and maternal mortality when integrating the continuum of care space dimension (RR 0.85; 95% CI 0.77 to 0.93, I2 81%). Conclusions Our review suggests that continuous uptake of antenatal care, skilled birth attendance, and postnatal care is necessary to improve MNCH outcomes in low- and middle-income countries. The review was conclusive for the reduction of neonatal and perinatal deaths. Although maternal deaths were not significantly reduced, composite measures of all mortality were. Thus, the evidence is sufficient to scale up this intervention package for the improvement of MNCH outcomes. PMID:26422685

High-Resolution Detection of Identity by Descent in Unrelated Individuals

PubMed Central

Browning, Sharon R.; Browning, Brian L.

2010-01-01

Detection of recent identity by descent (IBD) in population samples is important for population-based linkage mapping and for highly accurate genotype imputation and haplotype-phase inference. We present a method for detection of recent IBD in population samples. Our method accounts for linkage disequilibrium between SNPs to enable full use of high-density SNP data. We find that our method can detect segments of a length of 2 cM with moderate power and negligible false discovery rate in Illumina 550K data in Northwestern Europeans. We compare our method with GERMLINE and PLINK, and we show that our method has a level of resolution that is significantly better than these existing methods, thus extending the usefulness of recent IBD in analysis of high-density SNP data. We survey four genomic regions in a sample of UK individuals of European descent and find that on average, at a given location, our method detects IBD in 2.7 per 10,000 pairs of individuals in Illumina 550K data. We also present methodology and results for detection of homozygosity by descent (HBD) and survey the whole genome in a sample of 1373 UK individuals of European descent. We detect HBD in 4.7 individuals per 10,000 on average at a given location. Our methodology is implemented in the freely available BEAGLE software package. PMID:20303063

X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping.

PubMed

Dressman, Devin; Ahearn, Mary Ellen; Yariz, Kemal O; Basterrecha, Hugo; Martínez, Francisco; Palau, Francesc; Barmada, M Michael; Clark, Robin Dawn; Meindl, Alfons; Wirth, Brunhilde; Hoffman, Eric P; Baumbach-Reardon, Lisa

2007-01-01

X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have previously reported a single family with XL-SMA that mapped to Xp11.3-q11.2. Here we report further clinical description of XL-SMA plus an additional seven unrelated (XL-SMA) families from North America and Europe that show linkage data consistent with the same region. We first investigated linkage to the candidate disease gene region using microsatellite repeat markers. We further saturated the candidate disease gene region using polymorphic microsatellite repeat markers and single nucleotide polymorphisms in an effort to narrow the critical region. Two-point and multipoint linkage analysis was performed using the Allegro software package. Linkage analysis of all XL-SMA families displayed linkage consistent with the original XL-SMA region. The addition of new families and new markers has narrowed the disease gene interval for a XL-SMA locus between SNP FLJ22843 near marker DXS 8080 and SNP ARHGEF9 which is near DXS7132 (Xp11.3-Xq11.1).

Association and linkage studies of candidate genes involved in GABAergic neurotransmission in lithium-responsive bipolar disorder.

PubMed Central

Duffy, A; Turecki, G; Grof, P; Cavazzoni, P; Grof, E; Joober, R; Ahrens, B; Berghöfer, A; Müller-Oerlinghausen, B; Dvoráková, M; Libigerová, E; Vojtĕchovský, M; Zvolský, P; Nilsson, A; Licht, R W; Rasmussen, N A; Schou, M; Vestergaard, P; Holzinger, A; Schumann, C; Thau, K; Robertson, C; Rouleau, G A; Alda, M

2000-01-01

OBJECTIVE: To test for genetic linkage and association with GABAergic candidate genes in lithium-responsive bipolar disorder. DESIGN: Polymorphisms located in genes that code for GABRA3, GABRA5 and GABRB3 subunits of the GABAA receptor were investigated using association and linkage strategies. PARTICIPANTS: A total of 138 patients with bipolar 1 disorder with a clear response to lithium prophylaxis, selected from specialized lithium clinics in Canada and Europe that are part of the International Group for the Study of Lithium-Treated Patients, and 108 psychiatrically healthy controls. Families of 24 probands were suitable for linkage analysis. OUTCOME MEASURES: The association between the candidate genes and patients with bipolar disorder versus that of controls and genetic linkage within families. RESULTS: There was no significant association or linkage found between lithium-responsive bipolar disorder and the GABAergic candidate genes investigated. CONCLUSIONS: This study does not support a major role for the GABAergic candidate genes tested in lithium-responsive bipolar disorder. PMID:11022400

Action of transglucosidase from Aspergillus niger on maltoheptaose and [U-(13)C]maltose.

PubMed

Ota, Masafumi; Okamoto, Takeshi; Wakabayashi, Hidehiko

2009-03-10

Oligosaccharides synthesized from a mixture of maltoheptaose and [U-(13)C]maltose with transglucosidase [EC 2.4.1.24] from Aspergillus niger were investigated. When the reaction mixture was incubated at 15 degrees C for 1h, several types of oligosaccharides with DP (degree of polymerization) 2 to DP8 containing alpha-D-Glcp-(1-->6)-maltoheptaose were detected by liquid chromatography-mass spectrometry (LC-MS) and methylation analysis. Most of these compounds consisted of alpha-(1-->4) linkages in the main chain and alpha-(1-->6) linkages at the non-reducing ends. However, when the reaction mixture was incubated for 96h, most of these products were converted into oligosaccharides with DP2 to DP5 consisting of only alpha-(1-->6) linkages. These results suggested that A. niger transglucosidase rapidly transferred glucosyl residues to maltooligosaccharides, and gradually hydrolyzed both alpha-(1-->4) linkages and alpha-(1-->6) linkages at the non-reducing end, and transformed these into smaller molecules of mainly alpha-(1-->6) linkages.

The potential for meta-analysis to support decision analysis in ecology.

PubMed

Mengersen, Kerrie; MacNeil, M Aaron; Caley, M Julian

2015-06-01

Meta-analysis and decision analysis are underpinned by well-developed methods that are commonly applied to a variety of problems and disciplines. While these two fields have been closely linked in some disciplines such as medicine, comparatively little attention has been paid to the potential benefits of linking them in ecology, despite reasonable expectations that benefits would be derived from doing so. Meta-analysis combines information from multiple studies to provide more accurate parameter estimates and to reduce the uncertainty surrounding them. Decision analysis involves selecting among alternative choices using statistical information that helps to shed light on the uncertainties involved. By linking meta-analysis to decision analysis, improved decisions can be made, with quantification of the costs and benefits of alternate decisions supported by a greater density of information. Here, we briefly review concepts of both meta-analysis and decision analysis, illustrating the natural linkage between them and the benefits from explicitly linking one to the other. We discuss some examples in which this linkage has been exploited in the medical arena and how improvements in precision and reduction of structural uncertainty inherent in a meta-analysis can provide substantive improvements to decision analysis outcomes by reducing uncertainty in expected loss and maximising information from across studies. We then argue that these significant benefits could be translated to ecology, in particular to the problem of making optimal ecological decisions in the face of uncertainty. Copyright © 2013 John Wiley & Sons, Ltd.

Linkage and association analysis of obesity traits reveals novel loci and interactions with dietary n-3 fatty acids in an Alaska Native (Yup'ik) population.

PubMed

Vaughan, Laura Kelly; Wiener, Howard W; Aslibekyan, Stella; Allison, David B; Havel, Peter J; Stanhope, Kimber L; O'Brien, Diane M; Hopkins, Scarlett E; Lemas, Dominick J; Boyer, Bert B; Tiwari, Hemant K

2015-06-01

To identify novel genetic markers of obesity-related traits and to identify gene-diet interactions with n-3 polyunsaturated fatty acid (n-3 PUFA) intake in Yup'ik people. We measured body composition, plasma adipokines and ghrelin in 982 participants enrolled in the Center for Alaska Native Health Research (CANHR) Study. We conducted a genome-wide SNP linkage scan and targeted association analysis, fitting additional models to investigate putative gene-diet interactions. Finally, we performed bioinformatic analysis to uncover likely candidate genes within the identified linkage peaks. We observed evidence of linkage for all obesity-related traits, replicating previous results and identifying novel regions of interest for adiponectin (10q26.13-2) and thigh circumference (8q21.11-13). Bioinformatic analysis revealed DOCK1, PTPRE (10q26.13-2) and FABP4 (8q21.11-13) as putative candidate genes in the newly identified regions. Targeted SNP analysis under the linkage peaks identified associations between three SNPs and obesity-related traits: rs1007750 on chromosome 8 and thigh circumference (P=0.0005), rs878953 on chromosome 5 and thigh skinfold (P=0.0004), and rs1596854 on chromosome 11 for waist circumference (P=0.0003). Finally, we showed that n-3 PUFA modified the association between obesity related traits and two additional variants (rs2048417 on chromosome 3 for adiponectin, P for interaction=0.0006 and rs730414 on chromosome 11 for percentage body fat, P for interaction=0.0004). This study presents evidence of novel genomic regions and gene-diet interactions that may contribute to the pathophysiology of obesity-related traits among Yup'ik people. Copyright © 2015 Elsevier Inc. All rights reserved.

Genome-wide Linkage Scan of Antisocial Behavior, Depression and Impulsive Substance Use in the UCSF Family Alcoholism Study

PubMed Central

Gizer, Ian R.; Ehlers, Cindy L.; Vieten, Cassandra; Feiler, Heidi S.; Gilder, David A.; Wilhelmsen, Kirk C.

2012-01-01

OBJECTIVE Epidemiological and clinical studies suggest that rates of antisocial behavior, depression, and impulsive substance use are increased among individuals diagnosed with alcohol dependence relative to those who are not. Thus, the present study conducted genome-wide linkage scans of antisocial behavior, depression, and impulsive substance use in the University of California at San Francisco Family Alcoholism Study. METHODS Antisocial behavior, depressive symptoms, and impulsive substance use were assessed using three scales from the MMPI-2, the Antisocial Practices content scale (ASP), the Depression content scale (DEP), and the revised MacAndrew Alcoholism scale (MAC-R). Linkage analyses were conducted using a variance components approach. RESULTS Suggestive evidence of linkage to three genomic regions independent of alcohol and cannabis dependence diagnostic status was observed: the ASP scale showed evidence of linkage to chromosome 13 at 11 cM, the MAC-R scale showed evidence of linkage to chromosome 15 at 47 cM, and all 3 scales showed evidence of linkage to chromosome 17 at 57–58 cM. CONCLUSIONS Each of these regions has shown prior evidence of linkage and association to substance dependence as well as other psychiatric disorders such as mood and anxiety disorders, ADHD, and schizophrenia thus suggesting potentially broad relations between these regions and psychopathology. PMID:22517380

Genetic linkage analysis using pooled DNA and infrared detection of tailed STRP primer patterns

NASA Astrophysics Data System (ADS)

Oetting, William S.; Wildenberg, Scott C.; King, Richard A.

1996-04-01

The mapping of a disease locus to a specific chromosomal region is an important step in the eventual isolation and analysis of a disease causing gene. Conventional mapping methods analyze large multiplex families and/or smaller nuclear families to find linkage between the disease and a chromosome marker that maps to a known chromosomal region. This analysis is time consuming and tedious, typically requiring the determination of 30,000 genotypes or more. For appropriate populations, we have instead utilized pooled DNA samples for gene mapping which greatly reduces the amount of time necessary for an initial chromosomal screen. This technique assumes a common founder for the disease locus of interest and searches for a region of a chromosome shared between affected individuals. Our analysis involves the PCR amplification of short tandem repeat polymorphisms (STRP) to detect these shared regions. In order to reduce the cost of genotyping, we have designed unlabeled tailed PCR primers which, when combined with a labeled universal primer, provides for an alternative to synthesizing custom labeled primers. The STRP pattern is visualized with an infrared fluorescence based automated DNA sequencer and the patterns quantitated by densitometric analysis of the allele pattern. Differences in the distribution of alleles between pools of affected and unaffected individuals, including a reduction in the number of alleles in the affected pool, indicate the sharing of a region of a chromosome. We have found this method effective for markers 10 - 15 cM away from the disease locus for a recessive genetic disease.

An Autosomal Genetic Linkage Map of the Sheep Genome

PubMed Central

Crawford, A. M.; Dodds, K. G.; Ede, A. J.; Pierson, C. A.; Montgomery, G. W.; Garmonsway, H. G.; Beattie, A. E.; Davies, K.; Maddox, J. F.; Kappes, S. W.; Stone, R. T.; Nguyen, T. C.; Penty, J. M.; Lord, E. A.; Broom, J. E.; Buitkamp, J.; Schwaiger, W.; Epplen, J. T.; Matthew, P.; Matthews, M. E.; Hulme, D. J.; Beh, K. J.; McGraw, R. A.; Beattie, C. W.

1995-01-01

We report the first extensive ovine genetic linkage map covering 2070 cM of the sheep genome. The map was generated from the linkage analysis of 246 polymorphic markers, in nine three-generation fullsib pedigrees, which make up the AgResearch International Mapping Flock. We have exploited many markers from cattle so that valuable comparisons between these two ruminant linkage maps can be made. The markers, used in the segregation analyses, comprised 86 anonymous microsatellite markers derived from the sheep genome, 126 anonymous microsatellites from cattle, one from deer, and 33 polymorphic markers of various types associated with known genes. The maximum number of informative meioses within the mapping flock was 222. The average number of informative meioses per marker was 140 (range 18-209). Linkage groups have been assigned to all 26 sheep autosomes. PMID:7498748

A Genome Scan Conducted in a Multigenerational Pedigree with Convergent Strabismus Supports a Complex Genetic Determinism

PubMed Central

Georges, Anouk; Cambisano, Nadine; Ahariz, Naïma; Karim, Latifa; Georges, Michel

2013-01-01

A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree. PMID:24376720

A genome scan conducted in a multigenerational pedigree with convergent strabismus supports a complex genetic determinism.

PubMed

Georges, Anouk; Cambisano, Nadine; Ahariz, Naïma; Karim, Latifa; Georges, Michel

2013-01-01

A genome-wide linkage scan was conducted in a Northern-European multigenerational pedigree with nine of 40 related members affected with concomitant strabismus. Twenty-seven members of the pedigree including all affected individuals were genotyped using a SNP array interrogating > 300,000 common SNPs. We conducted parametric and non-parametric linkage analyses assuming segregation of an autosomal dominant mutation, yet allowing for incomplete penetrance and phenocopies. We detected two chromosome regions with near-suggestive evidence for linkage, respectively on chromosomes 8 and 18. The chromosome 8 linkage implied a penetrance of 0.80 and a rate of phenocopy of 0.11, while the chromosome 18 linkage implied a penetrance of 0.64 and a rate of phenocopy of 0. Our analysis excludes a simple genetic determinism of strabismus in this pedigree.

Highly efficient solid phase synthesis of oligonucleotide analogs containing phosphorodithioate linkages.

PubMed

Capaldi, D C; Cole, D L; Ravikumar, V T

2000-05-01

A triester method for the synthesis of deoxynucleoside phosphorodithioate dimers is described. The phosphorodithioate linkage is introduced using a new dithiophosphorylating reagent DPSE-SP(S)Cl(2)where DPSE = 2-diphenylmethylsilylethyl. This group is removed quickly using tetra-butylammonium fluoride leading to the quantitative formation of phosphorodithioate diesters uncontaminated with the corresponding phosphorothioates. The utility of this group is demonstrated by the synthesis of a penta-decathymidylic acid, [T(PS(2))T(PO(2))](7)T, which contains alternating phosphorodithioate/phosphate diester internucleotide linkages.

Planning and environment linkages program : a guide to measuring progress in linking transportation planning and environmental analysis

DOT National Transportation Integrated Search

2009-12-01

Transportation agencies use a variety of metrics to document progress toward achieving specific goals and objectives. This guide, developed by Federal Highway Administration (FHWA) Planning and Environmental Linkages (PEL) program, is intended to hel...

Dynamic linkages among the gold market, US dollar and crude oil market

NASA Astrophysics Data System (ADS)

Mo, Bin; Nie, He; Jiang, Yonghong

2018-02-01

This paper aims to examine the dynamic linkages among the gold market, US dollar and crude oil market. The analysis also delves more deeply into the effect of the global financial crisis on the short-term relationship. We use fractional cointegration to analyze the long-term memory feature of these volatility processes to investigate whether they are tied through a common long-term equilibrium. The DCC-MGARCH model is employed to investigate the time-varying long-term linkages among these markets. The Krystou-Labys non-linear asymmetric Granger causality method is used to examine the effect of the financial crisis. We find that (i) there is clearly a long-term dependence among these markets; (ii) the dynamic gold-oil relationship is always positive and the oil-dollar relationship is always negative; and (iii) after the crisis, we can observe evidence of a positive non-linear causal relationship from gold to US dollar and US dollar to crude oil, and a negative non-linear causal relationship from US dollar to gold. Investors who want to construct their optimal portfolios and policymakers who aim to make effective macroeconomic policies should take these findings into account.

Genes, age, and alcoholism: analysis of GAW14 data.

PubMed

Apprey, Victor; Afful, Joseph; Harrell, Jules P; Taylor, Robert E; Bonney, George E

2005-12-30

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.

U.S. Maternally Linked Birth Records May Be Biased for Hispanics and Other Population Groups

PubMed Central

LEISS, JACK K.; GILES, DENISE; SULLIVAN, KRISTIN M.; MATHEWS, RAHEL; SENTELLE, GLENDA; TOMASHEK, KAY M.

2010-01-01

Purpose To advance understanding of linkage error in U.S. maternally linked datasets, and how the error may affect results of studies based on the linked data. Methods North Carolina birth and fetal death records for 1988-1997 were maternally linked (n=1,030,029). The maternal set probability, defined as the probability that all records assigned to the same maternal set do in fact represent events to the same woman, was used to assess differential maternal linkage error across race/ethnic groups. Results Maternal set probabilities were lower for records specifying Asian or Hispanic race/ethnicity, suggesting greater maternal linkage error. The lower probabilities for Hispanics were concentrated in women of Mexican origin who were not born in the United States. Conclusions Differential maternal linkage error may be a source of bias in studies using U.S. maternally linked datasets to make comparisons between Hispanics and other groups or among Hispanic subgroups. Methods to quantify and adjust for this potential bias are needed. PMID:20006273

An Analysis of the Joint Modular Intermodal Distribution System

DTIC Science & Technology

2007-06-01

the differing airframes. “Two methods are available to move a CROP-load of ammunition: 1. Reconfigure the load from the CROP onto multiple 463L...used among the services lack: • Transportability across different modes without re-handling/packaging • Quick reconfiguration for onward movement...numerous linkages among different channels of distribution. In the world of integrated logistics, that means that ground, rail, air, and sea modes of

The effect of missing data on linkage disequilibrium mapping and haplotype association analysis in the GAW14 simulated datasets

PubMed Central

McCaskie, Pamela A; Carter, Kim W; McCaskie, Simon R; Palmer, Lyle J

2005-01-01

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. PMID:16451612

Meta-analysis of genome-wide linkage studies in BMI and obesity.

PubMed

Saunders, Catherine L; Chiodini, Benedetta D; Sham, Pak; Lewis, Cathryn M; Abkevich, Victor; Adeyemo, Adebowale A; de Andrade, Mariza; Arya, Rector; Berenson, Gerald S; Blangero, John; Boehnke, Michael; Borecki, Ingrid B; Chagnon, Yvon C; Chen, Wei; Comuzzie, Anthony G; Deng, Hong-Wen; Duggirala, Ravindranath; Feitosa, Mary F; Froguel, Philippe; Hanson, Robert L; Hebebrand, Johannes; Huezo-Dias, Patricia; Kissebah, Ahmed H; Li, Weidong; Luke, Amy; Martin, Lisa J; Nash, Matthew; Ohman, Miina; Palmer, Lyle J; Peltonen, Leena; Perola, Markus; Price, R Arlen; Redline, Susan; Srinivasan, Sathanur R; Stern, Michael P; Stone, Steven; Stringham, Heather; Turner, Stephen; Wijmenga, Cisca; Collier, David A

2007-09-01

The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.

Evidence for bivariate linkage of obesity and HDL-C levels in the Framingham Heart Study.

PubMed

Arya, Rector; Lehman, Donna; Hunt, Kelly J; Schneider, Jennifer; Almasy, Laura; Blangero, John; Stern, Michael P; Duggirala, Ravindranath

2003-12-31

Epidemiological studies have indicated that obesity and low high-density lipoprotein (HDL) levels are strong cardiovascular risk factors, and that these traits are inversely correlated. Despite the belief that these traits are correlated in part due to pleiotropy, knowledge on specific genes commonly affecting obesity and dyslipidemia is very limited. To address this issue, we first conducted univariate multipoint linkage analysis for body mass index (BMI) and HDL-C to identify loci influencing variation in these phenotypes using Framingham Heart Study data relating to 1702 subjects distributed across 330 pedigrees. Subsequently, we performed bivariate multipoint linkage analysis to detect common loci influencing covariation between these two traits. We scanned the genome and identified a major locus near marker D6S1009 influencing variation in BMI (LOD = 3.9) using the program SOLAR. We also identified a major locus for HDL-C near marker D2S1334 on chromosome 2 (LOD = 3.5) and another region near marker D6S1009 on chromosome 6 with suggestive evidence for linkage (LOD = 2.7). Since these two phenotypes have been independently mapped to the same region on chromosome 6q, we used the bivariate multipoint linkage approach using SOLAR. The bivariate linkage analysis of BMI and HDL-C implicated the genetic region near marker D6S1009 as harboring a major gene commonly influencing these phenotypes (bivariate LOD = 6.2; LODeq = 5.5) and appears to improve power to map the correlated traits to a region, precisely. We found substantial evidence for a quantitative trait locus with pleiotropic effects, which appears to influence both BMI and HDL-C phenotypes in the Framingham data.

Extending the Fellegi-Sunter probabilistic record linkage method for approximate field comparators.

PubMed

DuVall, Scott L; Kerber, Richard A; Thomas, Alun

2010-02-01

Probabilistic record linkage is a method commonly used to determine whether demographic records refer to the same person. The Fellegi-Sunter method is a probabilistic approach that uses field weights based on log likelihood ratios to determine record similarity. This paper introduces an extension of the Fellegi-Sunter method that incorporates approximate field comparators in the calculation of field weights. The data warehouse of a large academic medical center was used as a case study. The approximate comparator extension was compared with the Fellegi-Sunter method in its ability to find duplicate records previously identified in the data warehouse using different demographic fields and matching cutoffs. The approximate comparator extension misclassified 25% fewer pairs and had a larger Welch's T statistic than the Fellegi-Sunter method for all field sets and matching cutoffs. The accuracy gain provided by the approximate comparator extension grew as less information was provided and as the matching cutoff increased. Given the ubiquity of linkage in both clinical and research settings, the incremental improvement of the extension has the potential to make a considerable impact.

Construction of a genetic linkage map and analysis of quantitative trait loci associated with the agronomically important traits of Pleurotus eryngii

Treesearch

Chak Han Im; Young-Hoon Park; Kenneth E. Hammel; Bokyung Park; Soon Wook Kwon; Hojin Ryu; Jae-San Ryu

2016-01-01

Breeding new strains with improved traits is a long-standing goal of mushroom breeders that can be expedited by marker-assisted selection (MAS). We constructed a genetic linkage map of Pleurotus eryngii based on segregation analysis of markers in postmeiotic monokaryons from KNR2312. In total, 256 loci comprising 226 simple sequence-repeat (SSR) markers, 2 mating-type...

Genetics and epidemiology, congenital anomalies and cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Friedman, J.M.

1997-03-01

Many of the basic statistical methods used in epidemiology - regression, analysis of variance, and estimation of relative risk, for example - originally were developed for the genetic analysis of biometric data. The familiarity that many geneticists have with this methodology has helped geneticists to understand and accept genetic epidemiology as a scientific discipline. It worth noting, however, that most of the work in genetic epidemiology during the past decade has been devoted to linkage and other family studies, rather than to population-based investigations of the type that characterize much of mainstream epidemiology. 30 refs., 2 tabs.

Dynamic analysis of space structures including elastic, multibody, and control behavior

NASA Technical Reports Server (NTRS)

Pinson, Larry; Soosaar, Keto

1989-01-01

The problem is to develop analysis methods, modeling stategies, and simulation tools to predict with assurance the on-orbit performance and integrity of large complex space structures that cannot be verified on the ground. The problem must incorporate large reliable structural models, multi-body flexible dynamics, multi-tier controller interaction, environmental models including 1g and atmosphere, various on-board disturbances, and linkage to mission-level performance codes. All areas are in serious need of work, but the weakest link is multi-body flexible dynamics.

A Genetic Linkage Map for Cattle

PubMed Central

Bishop, M. D.; Kappes, S. M.; Keele, J. W.; Stone, R. T.; Sunden, SLF.; Hawkins, G. A.; Toldo, S. S.; Fries, R.; Grosz, M. D.; Yoo, J.; Beattie, C. W.

1994-01-01

We report the most extensive physically anchored linkage map for cattle produced to date. Three-hundred thirteen genetic markers ordered in 30 linkage groups, anchored to 24 autosomal chromosomes (n = 29), the X and Y chromosomes, four unanchored syntenic groups and two unassigned linkage groups spanning 2464 cM of the bovine genome are summarized. The map also assigns 19 type I loci to specific chromosomes and/or syntenic groups and four cosmid clones containing informative microsatellites to chromosomes 13, 25 and 29 anchoring syntenic groups U11, U7 and U8, respectively. This map provides the skeletal framework prerequisite to development of a comprehensive genetic map for cattle and analysis of economic trait loci (ETL). PMID:7908653

ECOTOXICOGENOMICS: LINKAGES BETWEEN EXPOSURE AND EFFECTS IN ASSESSING RISKS OF AQUATIC CONTAMINANTS TO FISH (JOURNAL ARTICLE)

EPA Science Inventory

Understanding the biological effects of exposures to chemicals in the environment relies on classical methods and emerging technologies in the areas of genomics, proteomics, and metabonomics. Linkages between the historical and newer toxicological tools are currently being devel...

Rapid genotyping by low-coverage resequencing to construct genetic linkage maps of fungi: a case study in Lentinula edodes

PubMed Central

2013-01-01

Background Genetic linkage maps are important tools in breeding programmes and quantitative trait analyses. Traditional molecular markers used for genotyping are limited in throughput and efficiency. The advent of next-generation sequencing technologies has facilitated progeny genotyping and genetic linkage map construction in the major grains. However, the applicability of the approach remains untested in the fungal system. Findings Shiitake mushroom, Lentinula edodes, is a basidiomycetous fungus that represents one of the most popular cultivated edible mushrooms. Here, we developed a rapid genotyping method based on low-coverage (~0.5 to 1.5-fold) whole-genome resequencing. We used the approach to genotype 20 single-spore isolates derived from L. edodes strain L54 and constructed the first high-density sequence-based genetic linkage map of L. edodes. The accuracy of the proposed genotyping method was verified experimentally with results from mating compatibility tests and PCR-single-strand conformation polymorphism on a few known genes. The linkage map spanned a total genetic distance of 637.1 cM and contained 13 linkage groups. Two hundred sequence-based markers were placed on the map, with an average marker spacing of 3.4 cM. The accuracy of the map was confirmed by comparing with previous maps the locations of known genes such as matA and matB. Conclusions We used the shiitake mushroom as an example to provide a proof-of-principle that low-coverage resequencing could allow rapid genotyping of basidiospore-derived progenies, which could in turn facilitate the construction of high-density genetic linkage maps of basidiomycetous fungi for quantitative trait analyses and improvement of genome assembly. PMID:23915543

Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q.

PubMed

Luciano, M; Wright, M J; Duffy, D L; Wainwright, M A; Zhu, G; Evans, D M; Geffen, G M; Montgomery, G W; Martin, N G

2006-01-01

A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The sample included 361 families comprising 2-5 siblings who ranged in age from 15.7 to 22.2 years; genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score>2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any individual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.

An Enhanced Linkage Map of the Sheep Genome Comprising More Than 1000 Loci

PubMed Central

Maddox, Jillian F.; Davies, Kizanne P.; Crawford, Allan M.; Hulme, Dennis J.; Vaiman, Daniel; Cribiu, Edmond P.; Freking, Bradley A.; Beh, Ken J.; Cockett, Noelle E.; Kang, Nina; Riffkin, Christopher D.; Drinkwater, Roger; Moore, Stephen S.; Dodds, Ken G.; Lumsden, Joanne M.; van Stijn, Tracey C.; Phua, Sin H.; Adelson, David L.; Burkin, Heather R.; Broom, Judith E.; Buitkamp, Johannes; Cambridge, Lisa; Cushwa, William T.; Gerard, Emily; Galloway, Susan M.; Harrison, Blair; Hawken, Rachel J.; Hiendleder, Stefan; Henry, Hannah M.; Medrano, Juan F.; Paterson, Korena A.; Schibler, Laurent; Stone, Roger T.; van Hest, Beryl

2001-01-01

A medium-density linkage map of the ovine genome has been developed. Marker data for 550 new loci were generated and merged with the previous sheep linkage map. The new map comprises 1093 markers representing 1062 unique loci (941 anonymous loci, 121 genes) and spans 3500 cM (sex-averaged) for the autosomes and 132 cM (female) on the X chromosome. There is an average spacing of 3.4 cM between autosomal loci and 8.3 cM between highly polymorphic [polymorphic information content (PIC) ≥ 0.7] autosomal loci. The largest gap between markers is 32.5 cM, and the number of gaps of >20 cM between loci, or regions where loci are missing from chromosome ends, has been reduced from 40 in the previous map to 6. Five hundred and seventy-three of the loci can be ordered on a framework map with odds of >1000 : 1. The sheep linkage map contains strong links to both the cattle and goat maps. Five hundred and seventy-two of the loci positioned on the sheep linkage map have also been mapped by linkage analysis in cattle, and 209 of the loci mapped on the sheep linkage map have also been placed on the goat linkage map. Inspection of ruminant linkage maps indicates that the genomic coverage by the current sheep linkage map is comparable to that of the available cattle maps. The sheep map provides a valuable resource to the international sheep, cattle, and goat gene mapping community. PMID:11435411

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets.

PubMed

Saeed, Mohammad

2017-05-01

Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes.

Analysis of precipitation data in Bangladesh through hierarchical clustering and multidimensional scaling

NASA Astrophysics Data System (ADS)

Rahman, Md. Habibur; Matin, M. A.; Salma, Umma

2017-12-01

The precipitation patterns of seventeen locations in Bangladesh from 1961 to 2014 were studied using a cluster analysis and metric multidimensional scaling. In doing so, the current research applies four major hierarchical clustering methods to precipitation in conjunction with different dissimilarity measures and metric multidimensional scaling. A variety of clustering algorithms were used to provide multiple clustering dendrograms for a mixture of distance measures. The dendrogram of pre-monsoon rainfall for the seventeen locations formed five clusters. The pre-monsoon precipitation data for the areas of Srimangal and Sylhet were located in two clusters across the combination of five dissimilarity measures and four hierarchical clustering algorithms. The single linkage algorithm with Euclidian and Manhattan distances, the average linkage algorithm with the Minkowski distance, and Ward's linkage algorithm provided similar results with regard to monsoon precipitation. The results of the post-monsoon and winter precipitation data are shown in different types of dendrograms with disparate combinations of sub-clusters. The schematic geometrical representations of the precipitation data using metric multidimensional scaling showed that the post-monsoon rainfall of Cox's Bazar was located far from those of the other locations. The results of a box-and-whisker plot, different clustering techniques, and metric multidimensional scaling indicated that the precipitation behaviour of Srimangal and Sylhet during the pre-monsoon season, Cox's Bazar and Sylhet during the monsoon season, Maijdi Court and Cox's Bazar during the post-monsoon season, and Cox's Bazar and Khulna during the winter differed from those at other locations in Bangladesh.

Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity

PubMed Central

Jalali, Ali; Aldinger, Kimberly A.; Chary, Ajit; Mclone, David G.; Bowman, Robin M.; Le, Luan Cong; Jardine, Phillip; Newbury-Ecob, Ruth; Mallick, Andrew; Jafari, Nadereh; Russell, Eric J.; Curran, John; Nguyen, Pam; Ouahchi, Karim; Lee, Charles; Dobyns, William B.; Millen, Kathleen J.; Pina-Neto, Joao M.; Kessler, John A.; Bassuk, Alexander G.

2010-01-01

We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage analysis of the Vietnamese-American family identified the ADDWOC causative locus on chromosome 2q36.1 with a multipoint parametric LOD score of 3.3, while haplotype analysis refined the locus to 1.1 Mb. Sequencing of the five known genes in this locus did not identify any protein-altering mutations. However, a terminal deletion of chromosome 2 in a patient with an isolated case of Dandy-Walker malformation also encompassed the 2q36.1 chromosomal region. The Brazilian pedigree did not show linkage to this 2q36.1 region. Taken together, these results demonstrate a locus for ADDWOC on 2q36.1 and also suggest locus heterogeneity for ADDWOC. PMID:18204864

Identification of a herpes simplex labialis susceptibility region on human chromosome 21.

PubMed

Hobbs, Maurine R; Jones, Brandt B; Otterud, Brith E; Leppert, Mark; Kriesel, John D

2008-02-01

Most of the United States population is infected with either herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2, or both. Reactivations of HSV-1 infection cause herpes simplex labialis (HSL; cold sores or fever blisters), which is the most common recurring viral infection in humans. To investigate the possibility of a human genetic component conferring resistance or susceptibility to cold sores (i.e., a HSL susceptibility gene), we conducted a genetic linkage analysis that included serotyping and phenotyping 421 individuals from 39 families enrolled in the Utah Genetic Reference Project. Linkage analysis identified a 2.5-Mb nonrecombinant region of interest on the long arm of human chromosome 21, with a multipoint logarithm of odds score of 3.9 noted near marker abmc65 (D21S409). Nonparametric linkage analysis of the data also provided strong evidence for linkage (P = .0005). This region of human chromosome 21 contains 6 candidate genes for herpes susceptibility. The development of frequent cold sores is associated with a region on the long arm of human chromosome 21. This region contains several candidate genes that could influence the frequency of outbreaks of HSL.

Determining the trophic guilds of fishes and macroinvertebrates in a seagrass food web

USGS Publications Warehouse

Luczkovich, J.J.; Ward, G.P.; Johnson, J.C.; Christian, R.R.; Baird, D.; Neckles, H.; Rizzo, W.M.

2002-01-01

We established trophic guilds of macroinvertebrate and fish taxa using correspondence analysis and a hierarchical clustering strategy for a seagrass food web in winter in the northeastern Gulf of Mexico. To create the diet matrix, we characterized the trophic linkages of macroinvertebrate and fish taxa. present in Hatodule wrightii seagrass habitat areas within the St. Marks National Wildlife Refuge (Florida) using binary data, combining dietary links obtained from relevant literature for macroinvertebrates with stomach analysis of common fishes collected during January and February of 1994. Heirarchical average-linkage cluster analysis of the 73 taxa of fishes and macroinvertebrates in the diet matrix yielded 14 clusters with diet similarity greater than or equal to 0.60. We then used correspondence analysis with three factors to jointly plot the coordinates of the consumers (identified by cluster membership) and of the 33 food sources. Correspondence analysis served as a visualization tool for assigning each taxon to one of eight trophic guilds: herbivores, detritivores, suspension feeders, omnivores, molluscivores, meiobenthos consumers, macrobenthos consumers, and piscivores. These trophic groups, cross-classified with major taxonomic groups, were further used to develop consumer compartments in a network analysis model of carbon flow in this seagrass ecosystem. The method presented here should greatly improve the development of future network models of food webs by providing an objective procedure for aggregating trophic groups.

Evaluation of record linkage of two large administrative databases in a middle income country: stillbirths and notifications of dengue during pregnancy in Brazil.

PubMed

Paixão, Enny S; Harron, Katie; Andrade, Kleydson; Teixeira, Maria Glória; Fiaccone, Rosemeire L; Costa, Maria da Conceição N; Rodrigues, Laura C

2017-07-17

Due to the increasing availability of individual-level information across different electronic datasets, record linkage has become an efficient and important research tool. High quality linkage is essential for producing robust results. The objective of this study was to describe the process of preparing and linking national Brazilian datasets, and to compare the accuracy of different linkage methods for assessing the risk of stillbirth due to dengue in pregnancy. We linked mothers and stillbirths in two routinely collected datasets from Brazil for 2009-2010: for dengue in pregnancy, notifications of infectious diseases (SINAN); for stillbirths, mortality (SIM). Since there was no unique identifier, we used probabilistic linkage based on maternal name, age and municipality. We compared two probabilistic approaches, each with two thresholds: 1) a bespoke linkage algorithm; 2) a standard linkage software widely used in Brazil (ReclinkIII), and used manual review to identify further links. Sensitivity and positive predictive value (PPV) were estimated using a subset of gold-standard data created through manual review. We examined the characteristics of false-matches and missed-matches to identify any sources of bias. From records of 678,999 dengue cases and 62,373 stillbirths, the gold-standard linkage identified 191 cases. The bespoke linkage algorithm with a conservative threshold produced 131 links, with sensitivity = 64.4% (68 missed-matches) and PPV = 92.5% (8 false-matches). Manual review of uncertain links identified an additional 37 links, increasing sensitivity to 83.7%. The bespoke algorithm with a relaxed threshold identified 132 true matches (sensitivity = 69.1%), but introduced 61 false-matches (PPV = 68.4%). ReclinkIII produced lower sensitivity and PPV than the bespoke linkage algorithm. Linkage error was not associated with any recorded study variables. Despite a lack of unique identifiers for linking mothers and stillbirths, we demonstrate a high standard of linkage of large routine databases from a middle income country. Probabilistic linkage and manual review were essential for accurately identifying cases for a case-control study, but this approach may not be feasible for larger databases or for linkage of more common outcomes.

Evaluation of identifier field agreement in linked neonatal records.

PubMed

Hall, E S; Marsolo, K; Greenberg, J M

2017-08-01

To better address barriers arising from missing and unreliable identifiers in neonatal medical records, we evaluated agreement and discordance among traditional and non-traditional linkage fields within a linked neonatal data set. The retrospective, descriptive analysis represents infants born from 2013 to 2015. We linked children's hospital neonatal physician billing records to newborn medical records originating from an academic delivery hospital and evaluated rates of agreement, discordance and missingness for a set of 12 identifier field pairs used in the linkage algorithm. We linked 7293 of 7404 physician billing records (98.5%), all of which were deemed valid upon manual review. Linked records contained a mean of 9.1 matching and 1.6 non-matching identifier pairs. Only 4.8% had complete agreement among all 12 identifier pairs. Our approach to selection of linkage variables and data formatting preparatory to linkage have generalizability, which may inform future neonatal and perinatal record linkage efforts.

An autosomal genetic linkage map of the sheep genome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crawford, A.M.; Ede, A.J.; Pierson, C.A.

1995-06-01

We report the first extensive ovine genetic linkage map covering 2070 cM of the sheep genome. The map was generated from the linkage analysis of 246 polymorphic markers, in nine three-generation full-sib pedigrees, which make up the AgResearch International Mapping Flock. We have exploited many markers from cattle so that valuable comparisons between these two ruminant linkage maps can be made. The markers, used in the segregation analyses, comprised 86 anonymous microsatellite markers derived from the sheep genome, 126 anonymous microsatellites from cattle, one from deer, and 33 polymorphic markers of various types associated with known genes. The maximum numbermore » of informative meioses within the mapping flock was 22. The average number of informative meioses per marker was 140 (range 18-209). Linkage groups have been assigned to all 26 sheep autosomes. 102 refs., 8 figs., 5 tabs.« less

A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population.

PubMed

Liu, Fan; Arias-Vásquez, Alejandro; Sleegers, Kristel; Aulchenko, Yurii S; Kayser, Manfred; Sanchez-Juan, Pascual; Feng, Bing-Jian; Bertoli-Avella, Aida M; van Swieten, John; Axenovich, Tatiana I; Heutink, Peter; van Broeckhoven, Christine; Oostra, Ben A; van Duijn, Cornelia M

2007-07-01

Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes.

Discrimination of candidate subgenome-specific loci by linkage map construction with an S1 population of octoploid strawberry (Fragaria × ananassa).

PubMed

Nagano, Soichiro; Shirasawa, Kenta; Hirakawa, Hideki; Maeda, Fumi; Ishikawa, Masami; Isobe, Sachiko N

2017-05-12

The strawberry, Fragaria × ananassa, is an allo-octoploid (2n = 8x = 56) and outcrossing species. Although it is the most widely consumed berry crop in the world, its complex genome structure has hindered its genetic and genomic analysis, and thus discrimination of subgenome-specific loci among the homoeologous chromosomes is needed. In the present study, we identified candidate subgenome-specific single nucleotide polymorphism (SNP) and simple sequence repeat (SSR) loci, and constructed a linkage map using an S 1 mapping population of the cultivar 'Reikou' with an IStraw90 Axiom® SNP array and previously published SSR markers. The 'Reikou' linkage map consisted of 11,574 loci (11,002 SNPs and 572 SSR loci) spanning 2816.5 cM of 31 linkage groups. The 11,574 loci were located on 4738 unique positions (bin) on the linkage map. Of the mapped loci, 8999 (8588 SNPs and 411 SSR loci) showed a 1:2:1 segregation ratio of AA:AB:BB allele, which suggested the possibility of deriving loci from candidate subgenome-specific sequences. In addition, 2575 loci (2414 SNPs and 161 SSR loci) showed a 3:1 segregation of AB:BB allele, indicating they were derived from homoeologous genomic sequences. Comparative analysis of the homoeologous linkage groups revealed differences in genome structure among the subgenomes. Our results suggest that candidate subgenome-specific loci are randomly located across the genomes, and that there are small- to large-scale structural variations among the subgenomes. The mapped SNPs and SSR loci on the linkage map are expected to be seed points for the construction of pseudomolecules in the octoploid strawberry.

A Narrow and Highly Significant Linkage Signal for Severe Bipolar Disorder in the Chromosome 5q33 Region in Latin American Pedigrees

PubMed Central

Jasinska, A.J.; Service, S.; Jawaheer, D.; DeYoung, J.; Levinson, M.; Zhang, Z.; Kremeyer, B.; Muller, H.; Aldana, I.; Garcia, J.; Restrepo, G.; Lopez, C.; Palacio, C.; Duque, C.; Parra, M.; Vega, J.; Ortiz, D.; Bedoya, G.; Mathews, C.; Davanzo, P.; Fournier, E.; Bejarano, J.; Ramirez, M.; Ortiz, C. Araya; Araya, X.; Molina, J.; Sabatti, C.; Reus, V.; Ospina, J.; Macaya, G.; Ruiz-Linares, A.; Freimer, N.B.

2016-01-01

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees. PMID:19319892

On computation of p-values in parametric linkage analysis.

PubMed

Kurbasic, Azra; Hössjer, Ola

2004-01-01

Parametric linkage analysis is usually used to find chromosomal regions linked to a disease (phenotype) that is described with a specific genetic model. This is done by investigating the relations between the disease and genetic markers, that is, well-characterized loci of known position with a clear Mendelian mode of inheritance. Assume we have found an interesting region on a chromosome that we suspect is linked to the disease. Then we want to test the hypothesis of no linkage versus the alternative one of linkage. As a measure we use the maximal lod score Z(max). It is well known that the maximal lod score has asymptotically a (2 ln 10)(-1) x (1/2 chi2(0) + 1/2 chi2(1)) distribution under the null hypothesis of no linkage when only one point (one marker) on the chromosome is studied. In this paper, we show, both by simulations and theoretical arguments, that the null hypothesis distribution of Zmax has no simple form when more than one marker is used (multipoint analysis). In fact, the distribution of Zmax depends on the number of families, their structure, the assumed genetic model, marker denseness, and marker informativity. This means that a constant critical limit of Zmax leads to tests associated with different significance levels. Because of the above-mentioned problems, from the statistical point of view the maximal lod score should be supplemented by a p-value when results are reported. Copyright (c) 2004 S. Karger AG, Basel.

Microsatellite-based fine mapping of the Van der Woude syndrome locus to an interval of 4.1 cM between D1S245 and D1S414

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sander, A.; Schmelzle, R.; Murray, J.C.

1995-01-01

Van der Woude syndrome (VWS) is an autosomal dominant craniofacial disorder characterized by lip pits, clefting of the primary or secondary palate, and hypodontia. The gene has been localized, by RFLP-based linkage studies, to region 1q32-41 between D1S65-REN and D1S65-TGFB2. In this study we report the linkage analysis of 15 VWS families, using 18 microsatellite markers. Multipoint linkage analysis places the gene, with significant odds of 2,344:1, in a 4.1-cM interval flanked by D1S245 and D1S414. Two-point linkage analysis demonstrates close linkage of VWS with D1S205 (lod score [Z] = 24.41 at {theta} = .00) and with D1S491 (Z =more » 21.23 at {theta} = .00). The results revise the previous assignment of the VWS locus and show in an integrated map of the region 1q32-42 that the VWS gene resides more distally than previously suggested. When information about heterozygosity of the closely linked marker D1S491 in the affected members of the VWS family with a microdeletion is taken into account, the VWS critical region can be further narrowed, to the 3.6-cM interval between D1S491 and D1S414. 38 refs., 3 figs., 2 tabs.« less

Caucasian Families Exhibit Significant Linkage of Myopia to Chromosome 11p.

PubMed

Musolf, Anthony M; Simpson, Claire L; Moiz, Bilal A; Long, Kyle A; Portas, Laura; Murgia, Federico; Ciner, Elise B; Stambolian, Dwight; Bailey-Wilson, Joan E

2017-07-01

Myopia is a common visual disorder caused by eye overgrowth, resulting in blurry vision. It affects one in four Americans, and its prevalence is increasing. The genetic mechanisms that underpin myopia are not completely understood. Here, we use genotype data and linkage analyses to identify high-risk genetic loci that are significantly linked to myopia. Individuals from 56 Caucasian families with a history of myopia were genotyped on an exome-based array, and the single nucleotide polymorphism (SNP) data were merged with microsatellite genotype data. Refractive error measures on the samples were converted into binary phenotypes consisting of affected, unaffected, or unknown myopia status. Parametric linkage analyses assuming an autosomal dominant model with 90% penetrance and 10% phenocopy rate were performed. Single variant two-point analyses yielded three significantly linked SNPs at 11p14.1 and 11p11.2; a further 45 SNPs at 11p were found to be suggestive. No other chromosome had any significant SNPs or more than seven suggestive linkages. Two of the significant SNPs were located in BBOX1-AS1 and one in the intergenic region between ORA47 and TRIM49B. Collapsed haplotype pattern two-point analysis and multipoint analyses also yielded multiple suggestively linked genes at 11p. Multipoint analysis also identified suggestive evidence of linkage on 20q13. We identified three genome-wide significant linked variants on 11p for myopia in Caucasians. Although the novel specific signals still need to be replicated, 11p is a promising region that has been identified by other linkage studies with a number of potentially interesting candidate genes. We hope that the identification of these regions on 11p as potential causal regions for myopia will lead to more focus on these regions and maybe possible replication of our specific linkage peaks in other studies. We further plan targeted sequencing on 11p for our most highly linked families to more clearly understand the source of the linkage in this region.

Formation of contact active antimicrobial surfaces by covalent grafting of quaternary ammonium compounds.

PubMed

Elena, Poverenov; Miri, Klein

2018-05-16

Different synthetic strategies for the formation of contact active antimicrobial materials utilizing covalent linkage of quaternary ammonium compounds (QACs) were reviewed. There is a demand to find methods that will prevent bacterial fouling without the release of antimicrobial agents, because biocides cause environment pollution and promote the development of bacteria resistance mechanisms. The contact active antimicrobial surfaces may provide a useful tool for this purpose. The covalent surface grafting of QACs seems to be a feasible and promising approach for the formation of safe and effective antimicrobial materials that could be utilized for medical devices, food industry, water treatment systems and other applications. This manuscript reviews covalent attachment of QACs to form contact active antimicrobial materials based on glass, metals, synthetic and natural polymers. The review emphasizes the description of different synthetic methods that are used for the covalent linkage. Direct covalent linkage of QACs to the material surfaces, a linkage via auxiliary nanoparticles (NPs), or spacers, controlled radical polymerization techniques and a linkage to pre-activated surfaces are discussed. The physico-chemical properties and biological activity of the modified surfaces are also described. This review does not cover non-covalent grafting of QACs and incorporation of QACs into a bulk material. Copyright © 2018 Elsevier B.V. All rights reserved.

Genotyping by Sequencing in Almond: SNP Discovery, Linkage Mapping, and Marker Design

PubMed Central

Goonetilleke, Shashi N.; March, Timothy J.; Wirthensohn, Michelle G.; Arús, Pere; Walker, Amanda R.; Mather, Diane E.

2017-01-01

In crop plant genetics, linkage maps provide the basis for the mapping of loci that affect important traits and for the selection of markers to be applied in crop improvement. In outcrossing species such as almond (Prunus dulcis Mill. D. A. Webb), application of a double pseudotestcross mapping approach to the F1 progeny of a biparental cross leads to the construction of a linkage map for each parent. Here, we report on the application of genotyping by sequencing to discover and map single nucleotide polymorphisms in the almond cultivars “Nonpareil” and “Lauranne.” Allele-specific marker assays were developed for 309 tag pairs. Application of these assays to 231 Nonpareil × Lauranne F1 progeny provided robust linkage maps for each parent. Analysis of phenotypic data for shell hardness demonstrated the utility of these maps for quantitative trait locus mapping. Comparison of these maps to the peach genome assembly confirmed high synteny and collinearity between the peach and almond genomes. The marker assays were applied to progeny from several other Nonpareil crosses, providing the basis for a composite linkage map of Nonpareil. Applications of the assays to a panel of almond clones and a panel of rootstocks used for almond production demonstrated the broad applicability of the markers and provide subsets of markers that could be used to discriminate among accessions. The sequence-based linkage maps and single nucleotide polymorphism assays presented here could be useful resources for the genetic analysis and genetic improvement of almond. PMID:29141988

Structural analysis and taste evaluation of γ-glutamyl peptides comprising sulfur-containing amino acids.

PubMed

Amino, Yusuke; Wakabayashi, Hidehiko; Akashi, Satoko; Ishiwatari, Yutaka

2018-03-01

The structures, flavor-modifying effects, and CaSR activities of γ-glutamyl peptides comprising sulfur-containing amino acids were investigated. The chemical structures, including the linkage mode of the N-terminal glutamic acid, of γ-L-glutamyl-S-(2-propenyl)-L-cysteine (γ-L-glutamyl-S-allyl-L-cysteine) and its sulfoxide isolated from garlic were established by comparing their NMR spectra with those of authentic peptides prepared using chemical methods. Mass spectrometric analysis also enabled determination of the linkage modes in the glutamyl dipeptides by their characteristic fragmentation. In sensory evaluation, these peptides exhibited flavor-modifying effects (continuity) in umami solutions less pronounced but similar to that of glutathione. Furthermore, the peptides exhibited intrinsic flavor due to the sulfur-containing structure, which may be partially responsible for their flavor-modifying effects. In CaSR assays, γ-L-glutamyl-S-methyl-L-cysteinylglycine was most active, which indicates that the presence of a medium-sized aliphatic substituent at the second amino acid residue in γ-glutamyl peptides enhances CaSR activity.

Linkage analysis of primary open-angle glaucoma excludes the juvenile glaucoma region on chromosome 1q

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wirtz, M.K.; Acott, T.S.; Samples, J.R.

1994-09-01

The gene for one form of juvenile glaucoma has been mapped to chromosome 1q21-q31. This raises the possibility of primary open-angle glaucoma (POAG) also mapping to this region if the same defective gene causes both diseases. To ask this question linkage analysis was performed on a large POAG kindred. Blood samples or skin biopsies were obtained from 40 members of this family. Individuals were diagnosed as having POAG if they met two or more of the following criteria: (1) Visual field defects compatible with glaucoma on automated perimetry; (2) Optic nerve head and/or nerve fiber layer analysis compatible with glaucomatousmore » damage; (3) high intraocular pressures (> 20 mm Hg). Patients were considered glaucoma suspects if they only met one criterion. These individuals were excluded from the analysis. Of the 40 members, seven were diagnosed with POAG; four were termed suspects. The earliest age of onset was 38 years old, while the average age of onset was 65 years old. We performed two-point and multipoint linkage analysis, using five markers which encompass the region 1q21-q31; specifically, D1S194, D1S210, D1S212, D1S191 and LAMB2. Two-point lod scores excluded tight linkage with all markers except D1S212 (maximum lod score of 1.07 at theta = 0.0). In the multipoint analysis, including D1S210-D1S212-LAMB2 and POAG, the entire 11 cM region spanned by these markers was excluded for linkage with POAG; that is, lod scores were < -2.0. In conclusion, POAG in this family does not map to chromosome 1q21-q31 and, thus, they carry a gene that is distinct from the juvenile glaucoma gene.« less

A simple linear regression method for quantitative trait loci linkage analysis with censored observations.

PubMed

Anderson, Carl A; McRae, Allan F; Visscher, Peter M

2006-07-01

Standard quantitative trait loci (QTL) mapping techniques commonly assume that the trait is both fully observed and normally distributed. When considering survival or age-at-onset traits these assumptions are often incorrect. Methods have been developed to map QTL for survival traits; however, they are both computationally intensive and not available in standard genome analysis software packages. We propose a grouped linear regression method for the analysis of continuous survival data. Using simulation we compare this method to both the Cox and Weibull proportional hazards models and a standard linear regression method that ignores censoring. The grouped linear regression method is of equivalent power to both the Cox and Weibull proportional hazards methods and is significantly better than the standard linear regression method when censored observations are present. The method is also robust to the proportion of censored individuals and the underlying distribution of the trait. On the basis of linear regression methodology, the grouped linear regression model is computationally simple and fast and can be implemented readily in freely available statistical software.

Genetic analysis of familial non-syndromic primary failure of eruption

PubMed Central

Frazier-Bowers, S.; Simmons, D; Koehler, K; Zhou, J

2009-01-01

Objectives While some eruption disorders occur as part of a medical syndrome, primary failure of eruption (PFE) – defined as a localized failure of secondary tooth eruption -exists without systemic involvement. Recent studies support that heredity may play an important role in the pathogenesis of PFE. The objective of our human genetic study is to investigate the genetic contribution to PFE. Materials and Methods Four candidate genes POSTN, RUNX2, AMELX, and AMBN) were investigated due to their relationship to tooth eruption or putative relationship to each other. Families and individuals were ascertained based on the clinical diagnosis of PFE. Pedigrees were constructed and analyzed by inspection to determine the mode of inheritance in 4 families. The candidate genes were directly sequenced for both unrelated affected individuals and unaffected individuals. A genome wide scan using 500 microsatellite markers followed by linkage analysis was carried out for one family. Results Pedigree analysis of families suggests an autosomal dominant inheritance pattern with complete penetrance and variable expressivity. Sequence analysis revealed 2 non-functional polymorphisms in the POSTN gene and no other sequence variations in the remaining candidate genes. Genotyping and linkage analysis of one family yielded a LOD score of 1.51 for markers D13S272; D15S118 and D17S831 on chromosomes 13, 15 and 17 respectively. Conclusions While LOD scores were not significant evidence of linkage, extension of current pedigrees and novel SNP chip technology holds great promise for identification of a causative locus for PFE. Clinical Relevance When the process of normal tooth eruption fails, it may result in a clinically guarded or hopeless prognosis. Our studies aim to understand the etiological basis of Primary Failure of Eruption (PFE) toward the development of future orthodontic or pharmocologic interventions that will successfully treat this problem. PMID:19419450

An instrumented spatial linkage for measuring knee joint kinematics.

PubMed

Rosvold, Joshua M; Atarod, Mohammad; Frank, Cyril B; Shrive, Nigel G

2016-01-01

In this study, the design and development of a highly accurate instrumented spatial linkage (ISL) for kinematic analysis of the ovine stifle joint is described. The ovine knee is a promising biomechanical model of the human knee joint. The ISL consists of six digital rotational encoders providing six degrees of freedom (6-DOF) to its motion. The ISL makes use of the complete and parametrically continuous (CPC) kinematic modeling method to describe the kinematic relationship between encoder readings and the relative positions and orientation of its two ends. The CPC method is useful when calibrating the ISL, because a small change in parameters corresponds to a small change in calculated positions and orientations and thus a smaller optimization error, compared to other kinematic models. The ISL is attached rigidly to the femur and the tibia for motion capture, and the CPC kinematic model is then employed to transform the angle sensor readings to relative motion of the two ends of the linkage, and thereby, the stifle joint motion. The positional accuracy for ISL after calibration and optimization was 0.3±0.2mm (mean +/- standard deviation). The ISL was also evaluated dynamically to ensure that accurate results were maintained, and achieved an accuracy of 0.1mm. Compared to the traditional motion capture methods, this system provides increased accuracy, reduced processing time, and ease of use. Future work will be on the application of the ISL to the ovine gait and determination of in vivo joint motions and tissue loads. Accurate measurement of knee joint kinematics is essential in understanding injury mechanisms and development of potential preventive or treatment strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haines, J.L.; Worster, T.; Ter-Minassian, M.

The loci for juvenile (CLN3) and infantile (CLN1) neuronal ceroid lipofuscinosis (NCL) types have been mapped by genetic linkage analysis to chromosome arms 16p and 1p, respectively. The late-infantile defect CLN2 has not yet been mapped, although linkage analysis with tightly linked markers excludes it from both the JNCL and INCL loci. We have initiated a genome-wide search for the LNCL gene, taking advantage of the large collection of highly polymorphic markers that has been developed through the Human Genome Initiative. The high degree of heterozygosity of these markers makes it possible to carry out successful linkage analysis in smallmore » nuclear families, such as found in LNCL. Our current collection of LNCL pedigrees includes 19 US families and 11 Costa Rican families. To date, we have completed typing with over 50 markers on chromosomes 2, 9, 13, and 18-22. The results of this analysis formally exclude about 10% of the human genome as the location of the LNCL gene. 14 refs., 3 tabs.« less

Robustness of linkage strategy that leads to large-scale cooperation.

PubMed

Inaba, Misato; Takahashi, Nobuyuki; Ohtsuki, Hisashi

2016-11-21

One of the most well-known models to characterize cooperation among unrelated individuals is Social dilemma (SD). However there is no consensus about how to solve the SD by itself. Since SDs are often embedded in other social interactions, including indirect reciprocity games (IR), human can coordinate their behaviors across multiple games. Such coordination is called 'linkage'. Recently linkage has been considered as a promising solution to resolve SDs, since excluding SD defectors (i.e. those who defected in SD) from indirectly reciprocal relationships functions as a costless sanction. A previous study performed mathematical modeling and revealed that a linkage strategy, which cooperates in SD and engages in the Standing strategy in IR based on the recipients' behaviors in both SD and IR, was an ESS against a non-linkage strategy which defects in SD and engages in the Standing strategy in IR based on recipients' behaviors only in IR (Panchanathan and Boyd, 2004). In order to investigate the robustness of the linkage strategy, we devised a non-linkage strategy, which cooperates in SD but does not link two games. First, we conducted a mathematical analysis and demonstrated that the linkage strategy was not an ESS against cooperating non-linkage strategy. Second, we conducted a series of agent-based computer simulations to examine how the strategies perform in situations in which various types of errors can occur. Our results showed that the linkage strategy was an ESS only when there are implementation errors in SD. However, the equilibrium of the linkage strategy was unstable when there are perception errors. Since we know that humans are not free from perception errors in their social life, future studies will need to show how perception errors can be overcome in order to provide support for the conclusion that linkage is a plausible solution to SDs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Association Analysis in Rice: From Application to Utilization

PubMed Central

Zhang, Peng; Zhong, Kaizhen; Shahid, Muhammad Qasim; Tong, Hanhua

2016-01-01

Association analysis based on linkage disequilibrium (LD) is an efficient way to dissect complex traits and to identify gene functions in rice. Although association analysis is an effective way to construct fine maps for quantitative traits, there are a few issues which need to be addressed. In this review, we will first summarize type, structure, and LD level of populations used for association analysis of rice, and then discuss the genotyping methods and statistical approaches used for association analysis in rice. Moreover, we will review current shortcomings and benefits of association analysis as well as specific types of future research to overcome these shortcomings. Furthermore, we will analyze the reasons for the underutilization of the results within association analysis in rice breeding. PMID:27582745

Highly efficient solid phase synthesis of oligonucleotide analogs containing phosphorodithioate linkages

PubMed Central

Capaldi, Daniel C.; Cole, Douglas L.; Ravikumar, Vasulinga T.

2000-01-01

A triester method for the synthesis of deoxynucleoside phosphorodithioate dimers is described. The phosphorodithioate linkage is introduced using a new dithiophosphorylating reagent DPSE-SP(S)Cl2 where DPSE = 2-diphenylmethylsilylethyl. This group is removed quickly using tetra-butylammonium fluoride leading to the quantitative formation of phosphorodithioate diesters uncontaminated with the corresponding phosphorothioates. The utility of this group is demonstrated by the synthesis of a pentadecathymidylic acid, [T(PS2)T(PO2)]7T, which contains alternating phosphorodithioate/phosphate diester internucleotide linkages. PMID:10756207

Targeted mapping and linkage analysis of morphological isozyme, and RAPD markers in peach.

PubMed

Chaparro, J X; Werner, D J; O'Malley, D; Sederoff, R R

1994-02-01

Nine different F2 families of peach [Prunus persica (L.) Batsch] were analyzed for linkage relationships between 14 morphological and two isozyme loci. Linkage was detected between weeping (We) and white flower (W), 33 cM; double flower (Dl) and pillar (Br), 10 cM; and flesh color (Y) and malate dehydrogenase (Mdh1), 26 cM. A leaf variant phenotypically distinct from the previously reported wavy-leaf (Wa) mutant in peach was found in progeny of 'Davie II'. The new willow-leaf character (designated Wa2) was closely linked (0.4 cM) to a new dwarf phenotype (designated Dw3). Two families derived from the pollen-fertile cultivar 'White Glory' segregated for pollen sterility, but segregation did not follow a 3∶1 ratio. Evidence is presented suggesting that 'White Glory' possesses a pollen-sterility gene (designated Ps2) that is non-allelic to the previously reported pollen-sterility gene (Ps) in peach. Ps2 was linked to both weeping (We-Ps2, 15.5 cM) and white flower (Ps2-W, 25.3 cM). A genomic map of peach containing 83 RAPD, one isozyme, and four morphological markers was generated using an F2 family obtained by selfing an NC174RL x 'Pillar' F1. A total of 83 RAPD markers were assigned to 15 linkage groups. Various RAPD markers were linked to morphological traits. Bulked segregant analysis was used to identify RAPD markers flanking the red-leaf (Gr) and Mdh1 loci in the NC174RL x 'Pillar' and 'Marsun' x 'White Glory' F2 families, respectively. Three markers flanking Mdh1 and ten markers flanking Gr were identified. The combination of RAPD markers and bulked segregant analysis provides an efficient method of identifying markers flanking traits of interest. Markers linked to traits that can only be scored late in development are potentially useful for marker-aided selection in trees. Alternatives for obtaining additional map order information for repulsion-phase markers in large F2 populations are proposed.

Nested association mapping of stem rust resistance in wheat using genotyping by sequencing

USDA-ARS?s Scientific Manuscript database

Nested association mapping is an approach to map trait loci in which families within populations are interconnected by a common parent. By implementing joint-linkage association analysis, this approach is able to map causative loci with higher power and resolution compared to biparental linkage mapp...

University-Industry Linkages in Developing Countries: Perceived Effect on Innovation

ERIC Educational Resources Information Center

Vaaland, Terje I.; Ishengoma, Esther

2016-01-01

Purpose: The purpose of this paper is to assess the perceptions of both universities and the resource-extractive companies on the influence of university-industry linkages (UILs) on innovation in a developing country. Design/Methodology/Approach: A total of 404 respondents were interviewed. Descriptive analysis and multinomial logistic regression…

Mutations in DSTYK and Dominant Urinary Tract Malformations

PubMed Central

Sanna-Cherchi, Simone; Nees, Shannon N.; Perry, Brittany J.; Choi, Murim; Bodria, Monica; Liu, Yan; Weng, Patricia L.; Lozanovski, Vladimir J.; Verbitsky, Miguel; Lugani, Francesca; Sterken, Roel; Paragas, Neal; Caridi, Gianluca; Carrea, Alba; Dagnino, Monica; Materna-Kiryluk, Anna; Santamaria, Giuseppe; Murtas, Corrado; Ristoska-Bojkovska, Nadica; Izzi, Claudia; Kacak, Nilgun; Bianco, Beatrice; Giberti, Stefania; Gigante, Maddalena; Piaggio, Giorgio; Gesualdo, Loreto; Vukic, Durdica Kosuljandic; Vukojevic, Katarina; Saraga-Babic, Mirna; Saraga, Marijan; Gucev, Zoran; Allegri, Landino; Latos-Bielenska, Anna; Casu, Domenica; State, Matthew; Scolari, Francesco; Ravazzolo, Roberto; Kiryluk, Krzysztof; Al-Awqati, Qais; D'Agati, Vivette D.; Drummond, Iain A.; Tasic, Velibor; Lifton, Richard P.; Ghiggeri, Gian Marco; Gharavi, Ali G.

2013-01-01

BACKGROUND Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine–threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.) PMID:23862974

Linkage-specific sialic acid derivatization for MALDI-TOF-MS profiling of IgG glycopeptides.

PubMed

de Haan, Noortje; Reiding, Karli R; Haberger, Markus; Reusch, Dietmar; Falck, David; Wuhrer, Manfred

2015-08-18

Glycosylation is a common co- and post-translational protein modification, having a large influence on protein properties like conformation and solubility. Furthermore, glycosylation is an important determinant of efficacy and clearance of biopharmaceuticals such as immunoglobulin G (IgG). Matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS) shows potential for the site-specific glycosylation analysis of IgG at the glycopeptide level. With this approach, however, important information about glycopeptide sialylation is not duly covered because of in-source and metastable decay of the sialylated species. Here, we present a highly repeatable sialic acid derivatization method to allow subclass-specific MALDI-TOF-MS analysis of tryptic IgG glycopeptides. The method, employing dimethylamidation with the carboxylic acid activator 1-ethyl-3-(3-dimethylamino)propyl)carbodiimide (EDC) and the catalyst 1-hydroxybenzotriazole (HOBt), results in different masses for the functionally divergent α2,3- and α2,6-linked sialic acids. Respective lactonization and dimethylamidation leads to their direct discrimination in MS and importantly, both glycan and peptide moieties reacted in a controlled manner. In addition, stabilization allowed the acquisition of fragmentation spectra informative with respect to glycosylation and peptide sequence. This was in contrast to fragmentation spectra of underivatized samples, which were dominated by sialic acid loss. The method allowed the facile discrimination and relative quantitation of IgG Fc sialylation in therapeutic IgG samples. The method has considerable potential for future site- and sialic acid linkage-specific glycosylation profiling of therapeutic antibodies, as well as for subclass-specific biomarker discovery in clinical IgG samples derived from plasma.

Narrowing the position of the Treacher Collins syndrome locus to a small interval between three new microsatellite markers at 5q32-33. 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dixon, M.J.; Dixon, J.; Houseal, T.

Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCOF1 locus has been localized to chromosome 5q32-33.2. In the present study the authors have used the combined techniques of genetic linkage analysis and fluorescence in situ hybridization (FISH) to more accurately define the TCOF1 critical region. Cosmids IG90 and SPARC, which map to distal 5q, encompass two and one hypervariable microsatellite markers, respectively. The heterozygosity values of these three markers range from .72 to .81. Twenty-two unrelated TCOF1 families have been analyzed for linkage tomore » these markers. There is strong evidence demonstrating linkage to all three markers, the strongest support for positive linkage being provided by haplotyping those markers at the locus encompassed by the cosmid IG90 (Z[sub max]= 19.65; 0 = .010). FISH to metaphase chromosomes and interphase nuclei established that IG90 lies centromeric to SPARC. This information combined with the data generated by genetic linkage analysis demonstrated that the TCOF1 locus is closely flanked proximally by IG90 and distally by SPARC. 30 refs., 2 figs., 4 tabs.« less

Wood degradation under UV irradiation: A lignin characterization.

PubMed

Cogulet, Antoine; Blanchet, Pierre; Landry, Véronic

2016-05-01

The photodegradation of white spruce by artificial ageing was studied by several techniques: colourimetry, FTIR-ATR and FT-Raman spectroscopy. Samples were exposed at a xenon lamp for 2000h. Two distinct colour changes were found by colourimetric analysis, yellowing and silvering. These colour modifications indicate the formation of chromophoric structures which supports previous FTIR-ATR experiments. The degradation of lignin to generate the first chromophoric group for yellowing and then the appearance of surface layer cellulose. New carbonyl compounds conjugated with double bond at 1615cm(-1) are probably the second chromophoric group. The crystallinity index was also calculated and showed an increase of cellulose crystallinity by prior degradation of amorphous cellulose. The FT-Raman analysis confirms the wood sensitivity to photodegradation but the most remarkable results is the increase of fluorescence as a function of time. In softwood lignin, the compound able to produce fluorescence is a free rotating 5-5' linkage of one biphenyl structure. At native state these linkages are not free rotating, this phenomenon means the release of 5-5' linkage of lignin structure by cleavage of both α carbon linkages (Norrish type I reaction). These data confirm also the photosensitivity of α and β carbon in lignin and the resistance of 5-5' linkages. Copyright © 2016 Elsevier B.V. All rights reserved.

The Effect of Pinyin Input Experience on the Link Between Semantic and Phonology of Chinese Character in Digital Writing.

PubMed

Chen, Jingjun; Luo, Rong; Liu, Huashan

2017-08-01

With the development of ICT, digital writing is becoming much more common in people's life. Differently from keyboarding alphabets directly to input English words, keyboarding Chinese character is always through typing phonetic alphabets and then identify the glyph provided by Pinyin input-method software while in this process which do not need users to produce orthography spelling, thus it is different from traditional written language production model based on handwriting process. Much of the research in this domain has found that using Pinyin input method is beneficial to Chinese characters recognition, but only a small part explored the effects of individual's Pinyin input experience on the Chinese characters production process. We ask whether using Pinyin input-method will strengthen the semantic-phonology linkage or semantic-orthography linkage in Chinese character mental lexicon. Through recording the RT and accuracy of participants completing semantic-syllable and semantic-glyph consistency judgments, the results found the accuracy of semantic-syllable consistency judgments in high Pinyin input experienced group was higher than that in low-experienced group, and RT was reversed. There were no significant differences on semantic-glyph consistency judgments between the two groups. We conclude that using Pinyin input method in Chinese digital writing can strengthen the semantic-phonology linkage while do not weakening the semantic-orthography linkage in mental lexicon at the same time, which means that Pinyin input method is beneficial to lexical processing involving Chinese cognition.

Genome survey and high-density genetic map construction provide genomic and genetic resources for the Pacific White Shrimp Litopenaeus vannamei

PubMed Central

Yu, Yang; Zhang, Xiaojun; Yuan, Jianbo; Li, Fuhua; Chen, Xiaohan; Zhao, Yongzhen; Huang, Long; Zheng, Hongkun; Xiang, Jianhai

2015-01-01

The Pacific white shrimp Litopenaeus vannamei is the dominant crustacean species in global seafood mariculture. Understanding the genome and genetic architecture is useful for deciphering complex traits and accelerating the breeding program in shrimp. In this study, a genome survey was conducted and a high-density linkage map was constructed using a next-generation sequencing approach. The genome survey was used to identify preliminary genome characteristics and to generate a rough reference for linkage map construction. De novo SNP discovery resulted in 25,140 polymorphic markers. A total of 6,359 high-quality markers were selected for linkage map construction based on marker coverage among individuals and read depths. For the linkage map, a total of 6,146 markers spanning 4,271.43 cM were mapped to 44 sex-averaged linkage groups, with an average marker distance of 0.7 cM. An integration analysis linked 5,885 genome scaffolds and 1,504 BAC clones to the linkage map. Based on the high-density linkage map, several QTLs for body weight and body length were detected. This high-density genetic linkage map reveals basic genomic architecture and will be useful for comparative genomics research, genome assembly and genetic improvement of L. vannamei and other penaeid shrimp species. PMID:26503227

Mobility and Position Error Analysis of a Complex Planar Mechanism with Redundant Constraints

NASA Astrophysics Data System (ADS)

Sun, Qipeng; Li, Gangyan

2018-03-01

Nowadays mechanisms with redundant constraints have been created and attracted much attention for their merits. The mechanism of the redundant constraints in a mechanical system is analyzed in this paper. A analysis method of Planar Linkage with a repetitive structure is proposed to get the number and type of constraints. According to the difference of applications and constraint characteristics, the redundant constraints are divided into the theoretical planar redundant constraints and the space-planar redundant constraints. And the calculation formula for the number of redundant constraints and type of judging method are carried out. And a complex mechanism with redundant constraints is analyzed of the influence about redundant constraints on mechanical performance. With the combination of theoretical derivation and simulation research, a mechanism analysis method is put forward about the position error of complex mechanism with redundant constraints. It points out the direction on how to eliminate or reduce the influence of redundant constraints.

Drought susceptibility of modern rice varieties: an effect of linkage of drought tolerance with undesirable traits

PubMed Central

Vikram, Prashant; Swamy, B. P. Mallikarjuna; Dixit, Shalabh; Singh, Renu; Singh, Bikram P.; Miro, Berta; Kohli, Ajay; Henry, Amelia; Singh, N. K.; Kumar, Arvind

2015-01-01

Green Revolution (GR) rice varieties are high yielding but typically drought sensitive. This is partly due to the tight linkage between the loci governing plant height and drought tolerance. This linkage is illustrated here through characterization of qDTY1.1, a QTL for grain yield under drought that co-segregates with the GR gene sd1 for semi-dwarf plant height. We report that the loss of the qDTY1.1 allele during the GR was due to its tight linkage in repulsion with the sd1 allele. Other drought-yield QTLs (qDTY) also showed tight linkage with traits rejected in GR varieties. Genetic diversity analysis for 11 different qDTY regions grouped GR varieties separately from traditional drought-tolerant varieties, and showed lower frequency of drought tolerance alleles. The increased understanding and breaking of the linkage between drought tolerance and undesirable traits has led to the development of high-yielding drought-tolerant dwarf lines with positive qDTY alleles and provides new hope for extending the benefits of the GR to drought-prone rice-growing regions. PMID:26458744

Mapping of a quantitative trait locus for resistance against infectious salmon anaemia in Atlantic salmon (Salmo Salar): comparing survival analysis with analysis on affected/resistant data

PubMed Central

Moen, Thomas; Sonesson, Anna K; Hayes, Ben; Lien, Sigbjørn; Munck, Hege; Meuwissen, Theo HE

2007-01-01

Background Infectious Salmon Anaemia (ISA) is a viral disease affecting farmed Atlantic salmon (Salmo salar) worldwide. The identification of Quantitative Trait Loci (QTL) affecting resistance to the disease could improve our understanding of the genetics underlying the trait and provide a means for Marker-Assisted Selection. We previously performed a genome scan on commercial Atlantic salmon families challenge tested for ISA resistance, identifying several putative QTL. In the present study, we set out to validate the strongest of these QTL in a larger family material coming from the same challenge test, and to determine the position of the QTL by interval mapping. We also wanted to explore different ways of performing QTL analysis within a survival analysis framework (i.e. using time-to-event data), and to compare results using survival analysis with results from analysis on the dichotomous trait 'affected/resistant'. Results The QTL, located on Atlantic salmon linkage group 8 (following SALMAP notation), was confirmed in the new data set. Its most likely position was at a marker cluster containing markers BHMS130, BHMS170 and BHMS553. Significant segregation distortion was observed in the same region, but was shown to be unrelated to the QTL. A maximum likelihood procedure for identifying QTL, based on the Cox proportional hazard model, was developed. QTL mapping was also done using the Haley-Knott method (affected/resistant data), and within a variance-component framework (affected/resistant data and time-to-event data). In all cases, analysis using affected/resistant data gave stronger evidence for a QTL than did analysis using time-to-event data. Conclusion A QTL for resistance to Infectious Salmon Anaemia in Atlantic salmon was validated in this study, and its more precise location on linkage group eight was determined. The QTL explained 6% of the phenotypic variation in resistance to the disease. The linkage group also displayed significant segregation distortion. Survival models proved in this case not to be more suitable than models based on the dichotomous trait 'affected/resistant' for analysing the data. PMID:17697344

Genetic analysis of abdominal aortic aneurysms (AAA)

DOE Office of Scientific and Technical Information (OSTI.GOV)

St. Jean, P.L.; Hart, B.K.; Zhang, X.C.

1994-09-01

The association between AAA and gender, smoking (SM), hypertension (HTN) and inguinal herniation (IH) was examined in 141 AAA probands and 139 of their 1st degree relatives with aortic exam (36 affected, 103 unaffected). There was no significant difference between age at diagnosis of affecteds and age at exam of unaffecteds. Of 181 males, 142 had AAA; of 99 females, 35 had AAA. Using log-linear modeling AAA was significantly associated at the 5% level with gender, SM and HTN but not IH. The association of AAA with SM and HTN held when males and females were analyzed separately. HTN wasmore » -1.5 times more common in both affected males and females, while SM was 1.5 and 2 times more common in affected males and females, respectively. Tests of association and linkage analyses were performed with relevant candidate genes: 3 COL3A1 polymorphisms (C/T, ALA/THR, AvaII), 2 ELN polymorphisms (SER/GLY, (CA)n), FBN1(TAAA)n, 2 APOB polymorphisms (Xbal,Ins/Del), CLB4B (CA)n, PI and markers D1S243 (CA)n, HPR (CA)n and MFD23(CA)n. The loci were genotyped in > 100 AAA probands and > 95 normal controls. No statistically significant evidence of association at the 5% level was obtained for any of the loci using chi-square test of association. 28 families with 2 or more affecteds were analyzed using the affected pedigree member method (APM) and lod-score analyses. There was no evidence for linkage with any loci using APM. Lod-score analysis under an autosomal recessive model resulted in excluding linkage (lod score < -2) of all loci to AAA at {theta}=0.0. Under an autosomal dominant model, linkage was excluded at {theta}=0.0 to ELN, APOB, CLG4B, D1S243, HPR and MFD23. The various genes previously proposed in AAA pathogenesis are neither associated nor casually related in our study population.« less

The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Chang-En; Nemens, E.; Olson, J.M.

1994-04-01

The chromosome 19 apolipoprotein E/CI/CII gene cluster was examined for evidence of linkage to a familial Alzheimer disease (FAD) locus. The family groups studied were Volga German (VG), early-onset non-VG (ENVG; mean age at onset <60 years), and late-onset families. A genetic association was observed between apolipoprotein E (ApoE) allele E4 and FAD in late-onset families; the E4 allele frequency was .51 in affected subjects, .37 in at-risk subjects, .11 in spouses, and .19 in unrelated controls. The differences between the E4 frequencies in affected subjects versus controls and in at-risk subjects versus controls were highly significant. No association betweenmore » the E4 allele and FAD was observed in the ENVG or VG groups. A statistically significant allelic association between E4 and AD was also observed in a group of unrelated subjects; the E4 frequency was .26 in affected subjects, versus .19 in controls (Z[sub SND] = 2.20, P < .03). Evidence of linkage of ApoE and ApoCII to FAD was examined by maximum-likelihood methods, using three models and assuming autosomal dominant inheritance: (1) age-dependent penetrance, (2) extremely low (1%) penetrance, and (3) age-dependent penetrance corrected for sporadic Alzheimer disease (AD). For ApoCII in late-onset families, results for close linkage were negative, and only small positive lod-score-statistic (Z) values were obtained. For ApoE in late-onset kindreds, positive Z values were obtained when either allele frequencies from controls or allele frequencies from the families were used. When linkage disequilibrium was incorporated into the analysis, the Z values increased. For the ENVG group, results for ApoE and ApoCII were uniformly negative. Affected-pedigree-member analysis gave significant results for the late-onset kindreds, for ApoE, when control allele frequencies were used but not when allele frequencies were derived from the families. 58 refs., 6 tabs.« less

Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kamino, K.; Anderson, L.; O'dahl, S.

1992-11-01

A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in amore » Glu[yields]Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu[yields]Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambigously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond [theta] = .10 for the Volga German kindreds, [theta] = .20 for early-onset non-Volga Germans, and [theta] = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. 49 refs., 6 figs., 4 tabs.« less

A thioacidolysis method tailored for higher‐throughput quantitative analysis of lignin monomers

PubMed Central

Foster, Cliff; Happs, Renee M.; Doeppke, Crissa; Meunier, Kristoffer; Gehan, Jackson; Yue, Fengxia; Lu, Fachuang; Davis, Mark F.

2016-01-01

Abstract Thioacidolysis is a method used to measure the relative content of lignin monomers bound by β‐O‐4 linkages. Current thioacidolysis methods are low‐throughput as they require tedious steps for reaction product concentration prior to analysis using standard GC methods. A quantitative thioacidolysis method that is accessible with general laboratory equipment and uses a non‐chlorinated organic solvent and is tailored for higher‐throughput analysis is reported. The method utilizes lignin arylglycerol monomer standards for calibration, requires 1–2 mg of biomass per assay and has been quantified using fast‐GC techniques including a Low Thermal Mass Modular Accelerated Column Heater (LTM MACH). Cumbersome steps, including standard purification, sample concentrating and drying have been eliminated to help aid in consecutive day‐to‐day analyses needed to sustain a high sample throughput for large screening experiments without the loss of quantitation accuracy. The method reported in this manuscript has been quantitatively validated against a commonly used thioacidolysis method and across two different research sites with three common biomass varieties to represent hardwoods, softwoods, and grasses. PMID:27534715

A thioacidolysis method tailored for higher-throughput quantitative analysis of lignin monomers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harman-Ware, Anne E.; Foster, Cliff; Happs, Renee M.

Thioacidolysis is a method used to measure the relative content of lignin monomers bound by β-O-4 linkages. Current thioacidolysis methods are low-throughput as they require tedious steps for reaction product concentration prior to analysis using standard GC methods. A quantitative thioacidolysis method that is accessible with general laboratory equipment and uses a non-chlorinated organic solvent and is tailored for higher-throughput analysis is reported. The method utilizes lignin arylglycerol monomer standards for calibration, requires 1-2 mg of biomass per assay and has been quantified using fast-GC techniques including a Low Thermal Mass Modular Accelerated Column Heater (LTM MACH). Cumbersome steps, includingmore » standard purification, sample concentrating and drying have been eliminated to help aid in consecutive day-to-day analyses needed to sustain a high sample throughput for large screening experiments without the loss of quantitation accuracy. As a result, the method reported in this manuscript has been quantitatively validated against a commonly used thioacidolysis method and across two different research sites with three common biomass varieties to represent hardwoods, softwoods, and grasses.« less

A thioacidolysis method tailored for higher-throughput quantitative analysis of lignin monomers

DOE PAGES

Harman-Ware, Anne E.; Foster, Cliff; Happs, Renee M.; ...

2016-09-14

Thioacidolysis is a method used to measure the relative content of lignin monomers bound by β-O-4 linkages. Current thioacidolysis methods are low-throughput as they require tedious steps for reaction product concentration prior to analysis using standard GC methods. A quantitative thioacidolysis method that is accessible with general laboratory equipment and uses a non-chlorinated organic solvent and is tailored for higher-throughput analysis is reported. The method utilizes lignin arylglycerol monomer standards for calibration, requires 1-2 mg of biomass per assay and has been quantified using fast-GC techniques including a Low Thermal Mass Modular Accelerated Column Heater (LTM MACH). Cumbersome steps, includingmore » standard purification, sample concentrating and drying have been eliminated to help aid in consecutive day-to-day analyses needed to sustain a high sample throughput for large screening experiments without the loss of quantitation accuracy. As a result, the method reported in this manuscript has been quantitatively validated against a commonly used thioacidolysis method and across two different research sites with three common biomass varieties to represent hardwoods, softwoods, and grasses.« less

Initial Reactivity of Linkages and Monomer Rings in Lignin Pyrolysis Revealed by ReaxFF Molecular Dynamics.

PubMed

Zhang, Tingting; Li, Xiaoxia; Guo, Li

2017-10-24

The initial conversion pathways of linkages and their linked monomer units in lignin pyrolysis were investigated comprehensively by ReaxFF MD simulations facilitated by the unique VARxMD for reaction analysis. The simulated molecular model contains 15 920 atoms and was constructed on the basis of Adler's softwood lignin model. The simulations uncover the initial conversion ratio of various linkages and their linked aryl monomers. For linkages and their linked monomer aryl rings of α-O-4, β-O-4 and α-O-4 & β-5, the C α /C β ether bond cracking dominates the initial pathway accounting for at least up to 80% of their consumption. For the linkage of β-β & γ-O-α, both the C α -O ether bond cracking and its linked monomer aryl ring opening are equally important. Ring-opening reactions dominate the initial consumption of other 4-O-5, 5-5, β-1, β-2, and β-5 linkages and their linked monomers. The ether bond cracking of C α -O and C β -O occurs at low temperature, and the aryl ring-opening reactions take place at relatively high temperature. The important intermediates leading to the stable aryl ring opening are the phenoxy radicals, the bridged five-membered and three-membered rings and the bridged six-membered and three-membered rings. In addition, the reactivity of a linkage and its monomer aryl ring may be affected by other linkages. The ether bond cracking of α-O-4 and β-O-4 linkages can activate its neighboring linkage or monomer ring through the formed phenoxy radicals as intermediates. The important intermediates revealed in this article should be of help in deepening the understanding of the controlling mechanism for producing aromatic chemicals from lignin pyrolysis.

Linkage of A-to-I RNA Editing in Metazoans and the Impact on Genome Evolution

PubMed Central

Duan, Yuange; Dou, Shengqian; Zhang, Hong; Wu, Changcheng; Wu, Mingming

2018-01-01

Abstract The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution. Nevertheless, in worms and humans, we only detected modest proportions of linked editing events, the majority of which were not conserved. Furthermore, the linkage of editing in coding regions of worms and humans might be overall deleterious, which drives the evolution of DNA sites to escape promiscuous editing. Altogether, our results suggest that the linkage landscape of A-to-I editing has evolved during metazoan evolution. This present study also suggests that linkage of editing should be considered in elucidating the functional consequences of RNA editing. PMID:29048557

A procedure for linking psychosocial job characteristics data to health surveys.

PubMed Central

Schwartz, J E; Pieper, C F; Karasek, R A

1988-01-01

A system is presented for linking information about psychosocial characteristics of job situations to national health surveys. Job information can be imputed to individuals on surveys that contain three-digit US Census occupation codes. Occupational mean scores on psychosocial job characteristics-control over task situation (decision latitude), psychological work load, physical exertion, and other measures-for the linkage system are derived from US national surveys of working conditions (Quality of Employment Surveys 1969, 1972, and 1977). This paper discusses a new method for reducing the biases in multivariate analyses that are likely to arise when utilizing linkage systems based on mean scores. Such biases are reduced by modifying the linkage system to adjust imputed individual scores for demographic factors such as age, education, race, marital status and, implicitly, sex (since men and women have separate linkage data bases). Statistics on the linkage system's efficiency and reliability are reported. All dimensions have high inter-survey reproducibility. Despite their psychosocial nature, decision latitude and physical exertion can be more efficiently imputed with the linkage system than earnings (a non-psychosocial job characteristic). The linkage system presented here is a useful tool for initial epidemiological studies of the consequences of psychosocial job characteristics and constitutes the methodological basis for the subsequent paper. PMID:3389426

Accuracy of Definitions for Linkage to Care in Persons Living with HIV

PubMed Central

KELLER, Sara C.; YEHIA, Baligh R.; EBERHART, Michael G.; BRADY, Kathleen A.

2013-01-01

Objective To compare the accuracy of linkage to care metrics for patients diagnosed with HIV using retention in care and virologic suppression as the gold standards of effective linkage. Design A retrospective cohort study of patients aged 18 and over with newly-diagnosed HIV infection in the City of Philadelphia, 2007 to 2008. Methods Times from diagnosis to clinic visits or laboratory testing were used as linkage measures. Outcome variables included being retained in care and achieving virologic suppression, 366-730 days after diagnosis. Positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) for each linkage measure and retention and virologic suppression outcomes are described. Results Of the 1781 patients in the study, 503 (28.2%) were retained in care in the Ryan White system and 418 (23.5%) achieved virologic suppression 366-730 days after diagnosis. The linkage measure with the highest PPV for retention was having two clinic visits within 365 days of diagnosis, separated by 90 days (74.2%). Having a clinic visit between 21 and 365 days after diagnosis had both the highest NPV for retention (94.5%) and the highest adjusted AUC for retention (0.872). Having two tests within 365 days of diagnosis, separated by 90 days, had the highest adjusted AUC for virologic suppression (0.780). Conclusions Linkage measures associated with clinic visits had higher PPV and NPV for retention, while linkage measures associated with laboratory testing had higher PPV and NPV for retention. Linkage measures should be chosen based on the outcome of interest. PMID:23614992

Postadoption and Guardianship: An Evaluation of the Adoption Preservation, Assessment, and Linkage Program

ERIC Educational Resources Information Center

Liao, Minli; Testa, Mark

2016-01-01

Objectives: This study evaluated the effects of the Adoption Preservation, Assessment, and Linkage (APAL) postpermanency program. Method: A quasi-experimental, posttest-only design was used to estimate the program's effects on youth discharged from foster care to adoption or legal guardianship. A random sample was surveyed (female = 44.7%; African…

Allelic loss and linkage studies in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, D.R.; Bale, A.E.; Lytton, B.

1994-09-01

Prostate cancer is the most common malignancy in U.S. males. Many examples of familial aggregation have been reported, and segregration analysis suggests that an autosomal dominant gene with a penetrance of 88% by age 85 accounts for 9% of all cases. Because many dominant cancer predisposition syndromes are related to germline mutations in tumor suppressor genes, we analyzed a series of sporadic and hereditary tumors for allelic loss. High grade sporadic, paraffin-embedded, primary prostate tumors were obtained from the archival collection in the Department of Pathology at Yale and hereditary tumors from three families were obtained by an advertisement inmore » the New York Times and from referrals by urologists. PCR analysis showed loss in 4/7 informative sporadic prostate tumors with NEFL (8p21), in 8/22 informative tumors with D10S169 (10q26-qter), in 2/8 informative tumors with D10S108 (10q) and in 4/23 informative tumors with D10S89 (10p) in agreement with previous studies. PYGM on chromosome 11 and D9S127 on chromosome 9 showed no loss. Linkage analysis with NEFL in 3 prostate cancer families gave strongly negative results for close linkage (Z=-2.1 at {theta}=0.01) but LOD scores were very dependent on parameters, e.g. gene frequency, phenocopy rate, and penetrance. Linkage analysis with chromosome 10 markers and systematic analysis of the genome for other area of allelic loss are underway.« less

Saturation of an Intra-Gene Pool Linkage Map: Towards a Unified Consensus Linkage Map for Fine Mapping and Synteny Analysis in Common Bean

PubMed Central

Galeano, Carlos H.; Fernandez, Andrea C.; Franco-Herrera, Natalia; Cichy, Karen A.; McClean, Phillip E.; Vanderleyden, Jos; Blair, Matthew W.

2011-01-01

Map-based cloning and fine mapping to find genes of interest and marker assisted selection (MAS) requires good genetic maps with reproducible markers. In this study, we saturated the linkage map of the intra-gene pool population of common bean DOR364×BAT477 (DB) by evaluating 2,706 molecular markers including SSR, SNP, and gene-based markers. On average the polymorphism rate was 7.7% due to the narrow genetic base between the parents. The DB linkage map consisted of 291 markers with a total map length of 1,788 cM. A consensus map was built using the core mapping populations derived from inter-gene pool crosses: DOR364×G19833 (DG) and BAT93×JALO EEP558 (BJ). The consensus map consisted of a total of 1,010 markers mapped, with a total map length of 2,041 cM across 11 linkage groups. On average, each linkage group on the consensus map contained 91 markers of which 83% were single copy markers. Finally, a synteny analysis was carried out using our highly saturated consensus maps compared with the soybean pseudo-chromosome assembly. A total of 772 marker sequences were compared with the soybean genome. A total of 44 syntenic blocks were identified. The linkage group Pv6 presented the most diverse pattern of synteny with seven syntenic blocks, and Pv9 showed the most consistent relations with soybean with just two syntenic blocks. Additionally, a co-linear analysis using common bean transcript map information against soybean coding sequences (CDS) revealed the relationship with 787 soybean genes. The common bean consensus map has allowed us to map a larger number of markers, to obtain a more complete coverage of the common bean genome. Our results, combined with synteny relationships provide tools to increase marker density in selected genomic regions to identify closely linked polymorphic markers for indirect selection, fine mapping or for positional cloning. PMID:22174773

[Construction of genetic linkage map and localization of NBS-LRR like resistance gene analogues in cauliflower (Brassica oleracea var. botrytis)].

PubMed

Gu, Yu; Zhao, Qian-Cheng; Sun, De-Ling; Song, Wen-Qin

2007-06-01

Nucleotide binding site (NBS) profiling, a new method was used to map resistance gene analogues (RGAs) in cauliflower (Brassica oleracea var. botrytis). This method allows amplification and the mapping of genetic markers anchored in the conserved NBS encoding domain of plant disease resistance genes. AFLP was also performed to construct the cauliflower intervarietal genetic map. The aim of constructing genetic map was to identify potential molecular markers linked to important agronomic traits that would be particularly useful for development and improving the species. Using 17 AFLP primer combinations and two degeneration primer/enzyme combinations, a total of 234 AFLP markers and 21 NBS markers were mapped in the F2 population derived from self-pollinating a single F1 plant of the cross AD White Flower x C-8. The markers were mapped in 9 of major linkage groups spanning 668.4 cM, with an average distance of 2.9 cM between adjacent mapped markers. The AFLP markers were well distributed throughout the linkage groups. The linkage groups contained from 12 to 47 loci each and the distance between two consecutive loci ranged from 0 to 14.9 cM. NBS markers were mapped on 8 of the 9 linkage groups of the genetic map. Most of these markers were organized in clusters. This result demonstrates the feasibility of the NBS-profiling method for generating NBS markers for resistance loci in cauliflower. The clustering of the markers mapped in this study adds to the evidence that most of them could be real RGAs.

Linkage analysis with chromosome 9 markers in hereditary essential tremor.

PubMed

Conway, D; Bain, P G; Warner, T T; Davis, M B; Findley, L J; Thompson, P D; Marsden, C D; Harding, A E

1993-07-01

Hereditary essential tremor (ET) is an autosomal dominant disorder with variable expression and reduced penetrance. A tremor indistinguishable from ET may be observed in patients with autosomal dominant idiopathic torsion dystonia (ITD), in which the disease locus has been mapped to 9q32-34 in some kindreds, tightly linked to the argininosuccinate synthetase (ASS) locus. We performed linkage analysis in 15 families with ET containing 60 definitely affected individuals, using dinucleotide repeat polymorphisms at the ASS locus and the Abelson locus (ABL). Cumulative lod scores were -19.5 for ASS and -10.8 for ABL at a recombination fraction of 0.01, and tight linkage to ASS was excluded individually in 11 of the families. These data indicate that the ET gene is not allelic to that causing ITD.

TSPmap, a tool making use of traveling salesperson problem solvers in the efficient and accurate construction of high-density genetic linkage maps.

PubMed

Monroe, J Grey; Allen, Zachariah A; Tanger, Paul; Mullen, Jack L; Lovell, John T; Moyers, Brook T; Whitley, Darrell; McKay, John K

2017-01-01

Recent advances in nucleic acid sequencing technologies have led to a dramatic increase in the number of markers available to generate genetic linkage maps. This increased marker density can be used to improve genome assemblies as well as add much needed resolution for loci controlling variation in ecologically and agriculturally important traits. However, traditional genetic map construction methods from these large marker datasets can be computationally prohibitive and highly error prone. We present TSPmap , a method which implements both approximate and exact Traveling Salesperson Problem solvers to generate linkage maps. We demonstrate that for datasets with large numbers of genomic markers (e.g. 10,000) and in multiple population types generated from inbred parents, TSPmap can rapidly produce high quality linkage maps with low sensitivity to missing and erroneous genotyping data compared to two other benchmark methods, JoinMap and MSTmap . TSPmap is open source and freely available as an R package. With the advancement of low cost sequencing technologies, the number of markers used in the generation of genetic maps is expected to continue to rise. TSPmap will be a useful tool to handle such large datasets into the future, quickly producing high quality maps using a large number of genomic markers.

Dosage Transmission Disequilibrium Test (dTDT) for Linkage and Association Detection

PubMed Central

Zhang, Zhehao; Wang, Jen-Chyong; Howells, William; Lin, Peng; Agrawal, Arpana; Edenberg, Howard J.; Tischfield, Jay A.; Schuckit, Marc A.; Bierut, Laura J.; Goate, Alison; Rice, John P.

2013-01-01

Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to “infer” the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data. PMID:23691058

Empirical research in medical ethics: how conceptual accounts on normative-empirical collaboration may improve research practice.

PubMed

Salloch, Sabine; Schildmann, Jan; Vollmann, Jochen

2012-04-13

The methodology of medical ethics during the last few decades has shifted from a predominant use of normative-philosophical analyses to an increasing involvement of empirical methods. The articles which have been published in the course of this so-called 'empirical turn' can be divided into conceptual accounts of empirical-normative collaboration and studies which use socio-empirical methods to investigate ethically relevant issues in concrete social contexts. A considered reference to normative research questions can be expected from good quality empirical research in medical ethics. However, a significant proportion of empirical studies currently published in medical ethics lacks such linkage between the empirical research and the normative analysis. In the first part of this paper, we will outline two typical shortcomings of empirical studies in medical ethics with regard to a link between normative questions and empirical data: (1) The complete lack of normative analysis, and (2) cryptonormativity and a missing account with regard to the relationship between 'is' and 'ought' statements. Subsequently, two selected concepts of empirical-normative collaboration will be presented and how these concepts may contribute to improve the linkage between normative and empirical aspects of empirical research in medical ethics will be demonstrated. Based on our analysis, as well as our own practical experience with empirical research in medical ethics, we conclude with a sketch of concrete suggestions for the conduct of empirical research in medical ethics. High quality empirical research in medical ethics is in need of a considered reference to normative analysis. In this paper, we demonstrate how conceptual approaches of empirical-normative collaboration can enhance empirical research in medical ethics with regard to the link between empirical research and normative analysis.

Empirical research in medical ethics: How conceptual accounts on normative-empirical collaboration may improve research practice

PubMed Central

2012-01-01

Background The methodology of medical ethics during the last few decades has shifted from a predominant use of normative-philosophical analyses to an increasing involvement of empirical methods. The articles which have been published in the course of this so-called 'empirical turn' can be divided into conceptual accounts of empirical-normative collaboration and studies which use socio-empirical methods to investigate ethically relevant issues in concrete social contexts. Discussion A considered reference to normative research questions can be expected from good quality empirical research in medical ethics. However, a significant proportion of empirical studies currently published in medical ethics lacks such linkage between the empirical research and the normative analysis. In the first part of this paper, we will outline two typical shortcomings of empirical studies in medical ethics with regard to a link between normative questions and empirical data: (1) The complete lack of normative analysis, and (2) cryptonormativity and a missing account with regard to the relationship between 'is' and 'ought' statements. Subsequently, two selected concepts of empirical-normative collaboration will be presented and how these concepts may contribute to improve the linkage between normative and empirical aspects of empirical research in medical ethics will be demonstrated. Based on our analysis, as well as our own practical experience with empirical research in medical ethics, we conclude with a sketch of concrete suggestions for the conduct of empirical research in medical ethics. Summary High quality empirical research in medical ethics is in need of a considered reference to normative analysis. In this paper, we demonstrate how conceptual approaches of empirical-normative collaboration can enhance empirical research in medical ethics with regard to the link between empirical research and normative analysis. PMID:22500496

A SSR-based composite genetic linkage map for the cultivated peanut (Arachis hypogaea L.) genome

PubMed Central

2010-01-01

Background The construction of genetic linkage maps for cultivated peanut (Arachis hypogaea L.) has and continues to be an important research goal to facilitate quantitative trait locus (QTL) analysis and gene tagging for use in a marker-assisted selection in breeding. Even though a few maps have been developed, they were constructed using diploid or interspecific tetraploid populations. The most recently published intra-specific map was constructed from the cross of cultivated peanuts, in which only 135 simple sequence repeat (SSR) markers were sparsely populated in 22 linkage groups. The more detailed linkage map with sufficient markers is necessary to be feasible for QTL identification and marker-assisted selection. The objective of this study was to construct a genetic linkage map of cultivated peanut using simple sequence repeat (SSR) markers derived primarily from peanut genomic sequences, expressed sequence tags (ESTs), and by "data mining" sequences released in GenBank. Results Three recombinant inbred lines (RILs) populations were constructed from three crosses with one common female parental line Yueyou 13, a high yielding Spanish market type. The four parents were screened with 1044 primer pairs designed to amplify SSRs and 901 primer pairs produced clear PCR products. Of the 901 primer pairs, 146, 124 and 64 primer pairs (markers) were polymorphic in these populations, respectively, and used in genotyping these RIL populations. Individual linkage maps were constructed from each of the three populations and a composite map based on 93 common loci were created using JoinMap. The composite linkage maps consist of 22 composite linkage groups (LG) with 175 SSR markers (including 47 SSRs on the published AA genome maps), representing the 20 chromosomes of A. hypogaea. The total composite map length is 885.4 cM, with an average marker density of 5.8 cM. Segregation distortion in the 3 populations was 23.0%, 13.5% and 7.8% of the markers, respectively. These distorted loci tended to cluster on LG1, LG3, LG4 and LG5. There were only 15 EST-SSR markers mapped due to low polymorphism. By comparison, there were potential synteny, collinear order of some markers and conservation of collinear linkage groups among the maps and with the AA genome but not fully conservative. Conclusion A composite linkage map was constructed from three individual mapping populations with 175 SSR markers in 22 composite linkage groups. This composite genetic linkage map is among the first "true" tetraploid peanut maps produced. This map also consists of 47 SSRs that have been used in the published AA genome maps, and could be used in comparative mapping studies. The primers described in this study are PCR-based markers, which are easy to share for genetic mapping in peanuts. All 1044 primer pairs are provided as additional files and the three RIL populations will be made available to public upon request for quantitative trait loci (QTL) analysis and linkage map improvement. PMID:20105299

Nested association mapping for dissecting complex traits using Peanut 58K SNP array

USDA-ARS?s Scientific Manuscript database

Genome-wide association studies (GWAS) and linkage mapping have been the two most predominant strategies to dissect complex traits, but are limited by the occurrence of false positives reported for GWAS, and low resolution in the case of linkage analysis. This has led to the development of a joint a...

Religious Attendance and Physiological Problems in Late Life.

PubMed

Das, Aniruddha; Nairn, Stephanie

2016-03-01

This study queried linkages of older adults' religious attendance with their physiological health. Data were from the 2005-2006 National Social Life, Health, and Aging Project, nationally representative of U.S. adults aged 57-85 years. Analyses examined associations of religious attendance with biological states, potential gender variations in these linkages, and attenuation by this factor of health effects of spousal loss. Religious attendance was negatively associated with a system of physiological issues, consistent with mitigation of multisystemic "weathering." Linkages were relatively uniform with inflammatory and cardiovascular but not metabolic states and were not significantly different for women than men. Effects of spousal loss on the 2 former subsystems were attenuated by regular religious attendance-in combined-gender analysis and among women, but not men. Religious attendance may buffer older adults from physiological problems and the health effects of life events such as spousal loss. More intensive analysis is needed to explain differential linkages with specific biological subsystems. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Patterns of linkage disequilibrium at PARK16 may explain variances in genetic association studies.

PubMed

Li, Huihua; Teo, Yik-Ying; Tan, Eng-King

2015-09-01

Reproducing genomewide association studies findings in different populations is challenging, because the reproducibility fundamentally relies on the similar patterns of linkage disequilibrium between the unknown causal variants and the genotyped single-nucleotide polymorphisms (SNPs). The PARK16 locus was reported to alter the risk of Parkinson's disease (PD) in genomewide association studies in Japanese and Caucasians. We evaluated the regional linkage disequilibrium pattern at PARK16 locus in Caucasians, Japanese, and Chinese from HapMap and Chinese, Malays, and Indians from the Singapore Genome Variation Project, using the traditional heatmaps and targeted analysis of PARK16 gene via Monte Carlo simulation through varLD scores of these ethnic groups. One hundred SNPs in Caucasians, 95 SNPs in Chinese, 78 SNPs in Japanese from HapMap, 86 SNPs in Chinese, 99 SNPs in Indians, and 97 SNPs in Malays from the Singapore Genome Variation Project were included. Our targeted analysis showed that the linkage disequilibrium pattern of SNPs close to rs947211 was similar in Caucasians and Asians, including Chinese, Japanese, and Malay (all P > 0.0001), whereas different linkage disequilibrium patterns around rs823128, rs823156, and rs708730 were found between Caucasians and these Asian groups (all P < 0.0001). Our study suggests a higher chance to detect the association between rs947211 and PD in Chinese, Malay, and other Caucasian groups because of the similar linkage disequilibrium pattern around rs947211. The associations between rs823128/rs823156/rs708730 and PD are more likely to be replicated in Chinese and Malay populations. © 2015 International Parkinson and Movement Disorder Society.

Analysis of quantitative lipid traits in the genetics of NIDDM (GENNID) study.

PubMed

Malhotra, Alka; Wolford, Johanna K

2005-10-01

Coronary heart disease (CHD) is the leading cause of death among individuals with type 2 diabetes. Dyslipidemia contributes significantly to CHD in diabetic patients, in whom lipid abnormalities include hypertriglyceridemia, low HDL cholesterol, and increased levels of small, dense LDL particles. To identify genes for lipid-related traits, we performed genome-wide linkage analyses for levels of triglycerides and HDL, LDL, and total cholesterol in Caucasian, Hispanic, and African-American families from the Genetics of NIDDM (GENNID) study. Most lipid traits showed significant estimates of heritability (P < 0.001) with the exception of triglycerides and the triglyceride/HDL ratio in African Americans. Variance components analysis identified linkage on chromosome 3p12.1-3q13.31 for the triglyceride/HDL ratio (logarithm of odds [LOD] = 3.36) and triglyceride (LOD = 3.27) in Caucasian families. Statistically significant evidence for linkage was identified for the triglyceride/HDL ratio (LOD = 2.45) on 11p in Hispanic families in a region that showed suggestive evidence for linkage (LOD = 2.26) for triglycerides in this population. In African Americans, the strongest evidence for linkage (LOD = 2.26) was found on 19p13.2-19q13.42 for total cholesterol. Our findings provide strong support for previous reports of linkage for lipid-related traits, suggesting the presence of genes on 3p12.1-3q13.31, 11p15.4-11p11.3, and 19p13.2-19q13.42 that may influence traits underlying lipid abnormalities associated with type 2 diabetes.

Genotyping by Sequencing in Almond: SNP Discovery, Linkage Mapping, and Marker Design.

PubMed

Goonetilleke, Shashi N; March, Timothy J; Wirthensohn, Michelle G; Arús, Pere; Walker, Amanda R; Mather, Diane E

2018-01-04

In crop plant genetics, linkage maps provide the basis for the mapping of loci that affect important traits and for the selection of markers to be applied in crop improvement. In outcrossing species such as almond ( Prunus dulcis Mill. D. A. Webb), application of a double pseudotestcross mapping approach to the F 1 progeny of a biparental cross leads to the construction of a linkage map for each parent. Here, we report on the application of genotyping by sequencing to discover and map single nucleotide polymorphisms in the almond cultivars "Nonpareil" and "Lauranne." Allele-specific marker assays were developed for 309 tag pairs. Application of these assays to 231 Nonpareil × Lauranne F 1 progeny provided robust linkage maps for each parent. Analysis of phenotypic data for shell hardness demonstrated the utility of these maps for quantitative trait locus mapping. Comparison of these maps to the peach genome assembly confirmed high synteny and collinearity between the peach and almond genomes. The marker assays were applied to progeny from several other Nonpareil crosses, providing the basis for a composite linkage map of Nonpareil. Applications of the assays to a panel of almond clones and a panel of rootstocks used for almond production demonstrated the broad applicability of the markers and provide subsets of markers that could be used to discriminate among accessions. The sequence-based linkage maps and single nucleotide polymorphism assays presented here could be useful resources for the genetic analysis and genetic improvement of almond. Copyright © 2018 Goonetilleke et al.

Genetic counseling in Usher syndrome: linkage and mutational analysis of 10 Colombian families.

PubMed

Tamayo, M L; Lopez, G; Gelvez, N; Medina, D; Kimberling, W J; Rodríguez, V; Tamayo, G E; Bernal, J E

2008-01-01

Usher Syndrome (US), an autosomal recessive disease, is characterized by retinitis pigmentosa (RP), vestibular dysfunction, and congenital sensorineural deafness. There are three recognized clinical types of the disorder. In order to improve genetic counseling for affected families, we conducted linkage analysis and DNA sequencing in 10 Colombian families with confirmed diagnosis of US (4 type I and 6 type II). Seventy-five percent of the US1 families showed linkage to locus USH1B, while the remaining 25% showed linkage to loci USH1B and USH1C. Among families showing linkage to USH1B we found two different mutations in the MYO7A gene: IVS42-26insTTGAG in exon 43 (heterozygous state) and R634X (CGA-TGA) in exon 16 (homozygous state). All six US2 families showed linkage to locus USH2A. Of them, 4 had c.2299delG mutation (1 homozygote state and 3 heterozygous); in the remaining 2 we did not identify any pathologic DNA variant. USH2A individuals with a 2299delG mutation presented a typical and homogeneous retinal phenotype with bilateral severe hearing loss, except for one individual with a heterozygous 2299delG mutation, whose hearing loss was asymmetric, but more profound than in the other cases. The study of these families adds to the genotype-phenotype characterization of the different types and subtypes of US and facilitates genetic counseling in these families. We would like to emphasize the need to perform DNA studies as a prerequisite for genetic counseling in affected families.

Linkage analyses of chromosome 6 loci, including HLA, in familial aggregations of Crohn disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hugot, J.P.; Laurent-Puig, P.; Gower-Rousseau, C.

1994-08-15

Segregation analyses of familial aggregations of Crohn disease have provided consistent results pointing to the involvement of a predisposing gene with a recessive mode of inheritance. Although extensively investigated, the role played by human leucocyte antigen (HLA) genes in this inflammatory bowel disease remains elusive and the major histocompatibility complex is a candidate region for the mapping of the Crohn disease susceptibility gene. A total of 25 families with multiple cases of Crohn disease was genotyped for HLA DRB1 and for 16 highly polymorphic loci evenly distributed on chromosome 6. The data were subjected to linkage analysis using the lodmore » score method. Neither individual nor combined lod scores for any family and for any locus tested reached values suggesting linkage or genetic heterogeneity. The Crohn disease predisposing locus was excluded from the whole chromosome 6 with lod scores less than -2. It was excluded from the major histocompatibility complex and from 91% of the chromosome 6 genetic map with lod scores less than -4. The major recessive gene involved in genetic predisposition to Crohn disease does not reside on the major histocompatibility complex nor on any locus mapping to chromosome 6. 37 refs., 2 figs., 2 tabs.« less

Linkage results on 11q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maziade, M.; Raymond, V.; Cliche, D.

The 11q21-22 region is of interest for schizophrenia because several candidate genes are located in this section of the genome. The 11q21-22 region, including DRD2, was surveyed by linkage analysis in a sample (N = 242) made of four large multigenerational pedigrees densely affected by schizophrenia (SZ) and eight others by bipolar disorder (BP). These pedigrees were ascertained in a large area of Eastern Quebec and Northern New Brunswick and are still being extended. Family members were administered a {open_quotes}consensus best-estimate diagnosis procedure{close_quotes} (DSM-III-R criteria) blind to probands and relatives` diagnosis and to pedigree assignment (SZ or BP). For linkagemore » analysis, 11 microsatellite polymorphism (CA repeat) markers, located at 11q21-22, and comprising DRD2, were genotyped. Results show no evidence of a major gene for schizophrenia. However, a maximum lod score of 3.41 at the D11S35 locus was observed in an affected-only analysis of one large SZ family, pedigree 255. Whether or not the positive linkage trend in pedigree 255 reflects a true linkage for a small proportion of SZ needs to be confirmed through the extension of this kindred and through replication. 36 refs., 2 tabs.« less

Genetic mapping of the gene for Usher syndrome: linkage analysis in a large Samaritan kindred.

PubMed

Bonné-Tamir, B; Korostishevsky, M; Kalinsky, H; Seroussi, E; Beker, R; Weiss, S; Godel, V

1994-03-01

Usher syndrome is a group of autosomal recessive disorders associated with congenital sensorineural deafness and progressive visual loss due to retinitis pigmentosa. Sixteen members of the small inbred Samaritan isolate with autosomal recessive deafness were studied in 10 related sibships. DNA samples from 59 individuals including parents and affected and nonaffected sibs were typed for markers on chromosomes 1q and 11q for which linkage has recently been established for Usher syndrome types II and I. Statistically significant linkage was observed with four markers on 11q (D11S533, D11S527, OMP, and INT2) with a maximum six-point location score of 11.61 at the D11S533 locus. Analysis of haplotypes supports the notion that the mutation arose only once in an ancestral chromosome carrying a specific haplotype. The availability of markers closely linked to the disease locus allows indirect genotype analysis and identifies all carriers of the gene within the community. Furthermore, the detection of complete linkage disequilibrium between the D11S533 marker and the Usher gene suggests that these loci are either identical or adjacent and narrows the critical region to which physical mapping efforts are currently directed.

Genetic heterogeneity of Usher syndrome type II.

PubMed Central

Pieke Dahl, S; Kimberling, W J; Gorin, M B; Weston, M D; Furman, J M; Pikus, A; Möller, C

1993-01-01

Usher syndrome is an autosomal recessive disorder characterised by retinitis pigmentosa and congenital sensorineural hearing loss. A gene for Usher syndrome type II (USH2) has been localised to chromosome 1q32-q41. DNA from a family with four of seven sibs affected with clinical characteristics of Usher syndrome type II was genotyped using markers spanning the 1q32-1q41 region. These included D1S70 and D1S81, which are believed to flank USH2. Genotypic results and subsequent linkage analysis indicated non-linkage of this family to these markers. The A test analysis for heterogeneity with this family and 32 other Usher type II families was statistically significant at p < 0.05. Further clinical evaluation of this family was done in light of the linkage results to determine if any phenotypic characteristics would allow for clinical identification of the unlinked type. No clear phenotypic differences were observed; however, this unlinked family may represent a previously unreported subtype of Usher type II characterised by a milder form of retinitis pigmentosa and mild vestibular abnormalities. Heterogeneity of Usher syndrome type II complicates efforts to isolate and clone Usher syndrome genes using linkage analysis and limits the use of DNA markers in early detection of Usher type II. Images PMID:7901420

Precise Estimation of Allele Frequencies of Single-Nucleotide Polymorphisms by a Quantitative SSCP Analysis of Pooled DNA

PubMed Central

Sasaki, Tomonari; Tahira, Tomoko; Suzuki, Akari; Higasa, Koichiro; Kukita, Yoji; Baba, Shingo; Hayashi, Kenshi

2001-01-01

We show that single-nucleotide polymorphisms (SNPs) of moderate to high heterozygosity (minor allele frequencies >10%) can be efficiently detected, and their allele frequencies accurately estimated, by pooling the DNA samples and applying a capillary-based SSCP analysis. In this method, alleles are separated into peaks, and their frequencies can be reliably and accurately quantified from their peak heights (SD <1.8%). We found that as many as 40% of publicly available SNPs that were analyzed by this method have widely differing allele frequency distributions among groups of different ethnicity (parents of Centre d'Etude Polymorphisme Humaine families vs. Japanese individuals). These results demonstrate the effectiveness of the present pooling method in the reevaluation of candidate SNPs that have been collected by examination of limited numbers of individuals. The method should also serve as a robust quantitative technique for studies in which a precise estimate of SNP allele frequencies is essential—for example, in linkage disequilibrium analysis. PMID:11083945

X Linkage of AP3A, a Homolog of the Y-Linked MADS-Box Gene AP3Y in Silene latifolia and S. dioica

PubMed Central

Penny, Rebecca H.; Montgomery, Benjamin R.; Delph, Lynda F.

2011-01-01

Background The duplication of autosomal genes onto the Y chromosome may be an important element in the evolution of sexual dimorphism.A previous cytological study reported on a putative example of such a duplication event in a dioecious tribe of Silene (Caryophyllaceae): it was inferred that the Y-linked MADS-box gene AP3Y originated from a duplication of the reportedly autosomal orthologAP3A. However, a recent study, also using cytological methods, indicated that AP3A is X-linked in Silenelatifolia. Methodology/Principal Findings In this study, we hybridized S. latifolia and S. dioicato investigate whether the pattern of X linkage is consistent among distinct populations, occurs in both species, and is robust to genetic methods. We found inheritance patterns indicative of X linkage of AP3A in widely distributed populations of both species. Conclusions/Significance X linkage ofAP3A and Y linkage of AP3Yin both species indicates that the genes' ancestral progenitor resided on the autosomes that gave rise to the sex chromosomesand that neither gene has moved between chromosomes since species divergence.Consequently, our results do not support the contention that inter-chromosomal gene transfer occurred in the evolution of SlAP3Y from SlAP3A. PMID:21533056

Linkage analysis of chromosome 22q12-13 in a United Kingdom/Icelandic sample of 23 multiplex schizophrenia families

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kalsi, G.; Read, T.; Butler, R.

A possible linkage to a genetic subtype of schizophrenia and related disorders has been reported on the long arm of chromosome 22 at q12-13. However formal statistical tests in a combined sample could not reject homogeneity and prove that there was linked subgroup of families. We have studied 23 schizophrenia pedigrees to test whether some multiplex schizophrenia families may be linked to the microsatellite markers D22S274 and D22S283 which span the 22q12-13 region. Two point followed by multipoint lod and non-parametric linkage analyses under the assumption of heterogeneity provided no evidence for linkage over the relevant region. 16 refs., 4more » tabs.« less

Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results

PubMed Central

Dorfman, Ruslan; Li, Weili; Sun, Lei; Lin, Fan; Wang, Yongqian; Sandford, Andrew; Paré, Peter D.; McKay, Karen; Kayserova, Hana; Piskackova, Tereza; Macek, Milan; Czerska, Kamila; Sands, Dorota; Tiddens, Harm; Margarit, Sonia; Repetto, Gabriela; Sontag, Marci K.; Accurso, Frank J.; Blackman, Scott; Cutting, Garry R.; Tsui, Lap-Chee; Corey, Mary; Durie, Peter; Zielenski, Julian; Strug, Lisa J.

2010-01-01

Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up. PMID:19662435

Momentum-Based Dynamics for Spacecraft with Chained Revolute Appendages

NASA Technical Reports Server (NTRS)

Queen, Steven; London, Ken; Gonzalez, Marcelo

2005-01-01

An efficient formulation is presented for a sub-class of multi-body dynamics problems that involve a six degree-of-freedom base body and a chain of N rigid linkages connected in series by single degree-of-freedom revolute joints. This general method is particularly well suited for simulations of spacecraft dynamics and control that include the modeling of an orbiting platform with or without internal degrees of freedom such as reaction wheels, dampers, and/or booms. In the present work, particular emphasis is placed on dynamic simulation of multi-linkage robotic manipulators. The differential equations of motion are explicitly given in terms of linear and angular momentum states, which can be evaluated recursively along a serial chain of linkages for an efficient real-time solution on par with the best of the O(N3) methods.

Electrodes including a polyphosphazene cyclomatrix, methods of forming the electrodes, and related electrochemical cells

DOEpatents

Gering, Kevin L; Stewart, Frederick F; Wilson, Aaron D; Stone, Mark L

2014-10-28

An electrode comprising a polyphosphazene cyclomatrix and particles within pores of the polyphosphazene cyclomatrix. The polyphosphazene cyclomatrix comprises a plurality of phosphazene compounds and a plurality of cross-linkages. Each phosphazene compound of the plurality of phosphazene compounds comprises a plurality of phosphorus-nitrogen units, and at least one pendant group bonded to each phosphorus atom of the plurality of phosphorus-nitrogen units. Each phosphorus-nitrogen unit is bonded to an adjacent phosphorus-nitrogen unit. Each cross-linkage of the plurality of cross-linkages bonds at least one pendant group of one phosphazene compound of the plurality of phosphazene compounds with the at least one pendant group of another phosphazene compound of the plurality of phosphazene compounds. A method of forming a negative electrode and an electrochemical cell are also described.

Genetic linkage analysis in 26 families with Bardet-Biedl syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wright, A.F.; Bruford, E.A.; Mansfield, D.C.

Bardet-Biedl syndrome is an autosomal recessive disorder characterized by polydactyly, obesity, hypogonadism, retinitis pigmentosa, renal anomalies and mental retardation. Clinical heterogeneity is quite marked both within and between families. Linkage has been reported between Bardet-Biedl syndrome and the D16408 marker in chromosomal region 16q21 in an extended Bedouin kindred and, more recently, in a subset of 17 out of 31 families using the PYGM/D11S913 markers in chromosomal region 11q13. We have analyzed linkage to the 16q21 and 11q13 regions and used markers covering chromosomes 2, 3, 17 and 18 in a set of 26 Bardet-Biedl families, each containing at leastmore » two affected individuals, with a total of 57 affected members. Evidence of linkage to the D11S527 locus has been identified assuming linkage homogeneity with a lod score of 2.72 at a recombination fraction of 0.11 (95% limits 0.03-0.25).« less

Genomic Characterization of DArT Markers Based on High-Density Linkage Analysis and Physical Mapping to the Eucalyptus Genome

PubMed Central

Petroli, César D.; Sansaloni, Carolina P.; Carling, Jason; Steane, Dorothy A.; Vaillancourt, René E.; Myburg, Alexander A.; da Silva, Orzenil Bonfim; Pappas, Georgios Joannis; Kilian, Andrzej; Grattapaglia, Dario

2012-01-01

Diversity Arrays Technology (DArT) provides a robust, high throughput, cost-effective method to query thousands of sequence polymorphisms in a single assay. Despite the extensive use of this genotyping platform for numerous plant species, little is known regarding the sequence attributes and genome-wide distribution of DArT markers. We investigated the genomic properties of the 7,680 DArT marker probes of a Eucalyptus array, by sequencing them, constructing a high density linkage map and carrying out detailed physical mapping analyses to the Eucalyptus grandis reference genome. A consensus linkage map with 2,274 DArT markers anchored to 210 microsatellites and a framework map, with improved support for ordering, displayed extensive collinearity with the genome sequence. Only 1.4 Mbp of the 75 Mbp of still unplaced scaffold sequence was captured by 45 linkage mapped but physically unaligned markers to the 11 main Eucalyptus pseudochromosomes, providing compelling evidence for the quality and completeness of the current Eucalyptus genome assembly. A highly significant correspondence was found between the locations of DArT markers and predicted gene models, while most of the 89 DArT probes unaligned to the genome correspond to sequences likely absent in E. grandis, consistent with the pan-genomic feature of this multi-Eucalyptus species DArT array. These comprehensive linkage-to-physical mapping analyses provide novel data regarding the genomic attributes of DArT markers in plant genomes in general and for Eucalyptus in particular. DArT markers preferentially target the gene space and display a largely homogeneous distribution across the genome, thereby providing superb coverage for mapping and genome-wide applications in breeding and diversity studies. Data reported on these ubiquitous properties of DArT markers will be particularly valuable to researchers working on less-studied crop species who already count on DArT genotyping arrays but for which no reference genome is yet available to allow such detailed characterization. PMID:22984541

Linking product-elicited emotional associations and sensory perceptions through a circumplex model based on valence and arousal: Five consumer studies.

PubMed

Jaeger, Sara R; Spinelli, Sara; Ares, Gastón; Monteleone, Erminio

2018-07-01

Sensory product characterisation by consumers is increasingly supplemented by measurement of emotional associations. However, studies that link products' sensory perception and emotional associations are still scarce. Five consumer studies were conducted using cashew nuts, peanuts, chocolate, fruit and processed tomatoes as the product categories. Consumers (n = 685) completed check-all-that-apply (CATA) questions to obtain sensory product perceptions and associations with emotion words. The latter were conceptualised and interpreted through a circumplex emotion model spanned by the dimensions of valence (pleasure to displeasure) and arousal (activation to deactivation). Through regression analysis, sensory terms were mapped to the circumplex model to represent statistical linkages with emotion words. Within a were interpretable. The most notable finding was the highly study-specific nature of the linkages, which was mainly attributed to the influence of product category. Methodological choices may also have been partly responsible for the differences. Three studies used a general emotion vocabulary (EsSense Profile®) and an identical number of sensory terms (n = 39). The less complete coverage of the emotional circumplex and the presence of synonymous sensory terms could have diminished the ability to interpret the results. Conversely, two studies used fewer emotion words and sensory terms and these, furthermore, were purposefully selected for the focal sets of samples. The linkages in these latter studies were more interpretable and this could suggest that customised vocabularies of modest length may be desirable when seeking to establish linkages between emotional associations and sensory characteristics of food/beverage stimuli. Purposeful inclusion of emotion words that fully span the circumplex emotion model may also be desirable. Overall, the research represents a new method for establishing linkages between the sensory properties and emotional association to food and beverage products. Copyright © 2018 Elsevier Ltd. All rights reserved.

Linkage analysis of alternative anxiety phenotypes in multiply affected panic disorder families

PubMed Central

Fyer, Abby J.; Costa, Ramiro; Haghighi, Fatemeh; Logue, Mark W.; Knowles, James A.; Weissman, Myrna M.; Hodge, Susan E.; Hamilton, Steven P.

2013-01-01

Background The choice of phenotype definitions for genetic studies of panic and phobic disorders is complicated by family, twin and neurobiological data indicating both distinct and shared risk factors as well as heterogeneity within categories. We previously reported a genome scan in 120 multiplex panic disorder (PD) families using a phenotype that closely adhered to the DSM IV PD definition. Here we extend this work by conducting exploratory linkage analyses in this same pedigree set using ten additional literature- based panic and phobia-related phenotypes that take into account aspects of these hypothesized complexities. Methods Multiply affected families (> 2 individuals with PD) were recruited from clinical and non-clinical sources, evaluated by clinician administered semi-structured interview and subsequent blind consensus best estimate procedure. Each phenotype was analyzed under dominant and recessive models using parametric 2-point (homogeneity and heterogeneity), multipoint, and non-parametric methods. Empirically based permutations were used to estimate model specific and global (across all phenotypes) p-values. Results The highest score was a 2-point lod (4.27, global p < 0.08) on chromosome 13 (D13S793, 76cM) for the phenotype “specific or social phobia” under a recessive model and conditions of homogeneity. There was minimal support for linkage to any of the remaining nine phenotypes. Conclusions Though interpretation of findings is limited by sample size and the large number of phenotypes and models analyzed these data suggest a region on chromosome 13 as a potential site for further exploration in relation to risk for specific and social phobias. PMID:22525237

Valorization of Lignin to Simple Phenolic Compounds over Tungsten Carbide: Impact of Lignin Structure.

PubMed

Guo, Haiwei; Zhang, Bo; Qi, Zaojuan; Li, Changzhi; Ji, Jianwei; Dai, Tao; Wang, Aiqin; Zhang, Tao

2017-02-08

Lignins isolated from representative hardwood, softwood, and grass materials were effectively hydrocracked to aromatics catalyzed by tungsten carbide over activated carbon (W 2 C/AC). The effects of botanical species and fractionation methods on lignin structure and the activity of W 2 C/AC were studied in detail. Gas permeation chromatography (GPC), FTIR, elemental analysis, and 2 D HSQC NMR showed that all the extracted samples shared the basic skeleton of lignin, whereas the fractionation method significantly affected the structure. The organosolv process provided lignin with a structure more similar to the native lignin, which was labile to be depolymerized by W 2 C/AC. Softwood lignins (i.e., spruce and pine) possessed higher molecular weights than hardwood lignins (i.e., poplar and basswood); whereas corn stalk lignin that has noncanonical subunits and exhibited the lowest molecular weight owing to its shorter growth period. β-O-4 bonds were the major linkages in all lignin samples, whereas softwood lignins contained more resistant linkages of β-5 and less β-β than corn stalk and hardwood lignins; as a result, lowest hydrocracking efficiency was obtained in softwood lignins, followed by corn stalk and hardwood lignins. 2 D HSQC NMR spectra of lignin and the liquid oil as well as the solid residue showed that W 2 C/AC exhibited high activity not only in β-O-4 cleavage, but also in deconstruction of other ether linkages between aromatic units, so that high yield of liquid oil was obtained from lignin. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Measuring anxiety after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Anxiety item bank and linkage with GAD-7.

PubMed

Kisala, Pamela A; Tulsky, David S; Kalpakjian, Claire Z; Heinemann, Allen W; Pohlig, Ryan T; Carle, Adam; Choi, Seung W

2015-05-01

To develop a calibrated item bank and computer adaptive test to assess anxiety symptoms in individuals with spinal cord injury (SCI), transform scores to the Patient Reported Outcomes Measurement Information System (PROMIS) metric, and create a statistical linkage with the Generalized Anxiety Disorder (GAD)-7, a widely used anxiety measure. Grounded-theory based qualitative item development methods; large-scale item calibration field testing; confirmatory factor analysis; graded response model item response theory analyses; statistical linking techniques to transform scores to a PROMIS metric; and linkage with the GAD-7. Setting Five SCI Model System centers and one Department of Veterans Affairs medical center in the United States. Participants Adults with traumatic SCI. Spinal Cord Injury-Quality of Life (SCI-QOL) Anxiety Item Bank Seven hundred sixteen individuals with traumatic SCI completed 38 items assessing anxiety, 17 of which were PROMIS items. After 13 items (including 2 PROMIS items) were removed, factor analyses confirmed unidimensionality. Item response theory analyses were used to estimate slopes and thresholds for the final 25 items (15 from PROMIS). The observed Pearson correlation between the SCI-QOL Anxiety and GAD-7 scores was 0.67. The SCI-QOL Anxiety item bank demonstrates excellent psychometric properties and is available as a computer adaptive test or short form for research and clinical applications. SCI-QOL Anxiety scores have been transformed to the PROMIS metric and we provide a method to link SCI-QOL Anxiety scores with those of the GAD-7.

Construction of a high-density linkage map and mapping quantitative trait loci for somatic embryogenesis using leaf petioles as explants in upland cotton (Gossypium hirsutum L.).

PubMed

Xu, Zhenzhen; Zhang, Chaojun; Ge, Xiaoyang; Wang, Ni; Zhou, Kehai; Yang, Xiaojie; Wu, Zhixia; Zhang, Xueyan; Liu, Chuanliang; Yang, Zuoren; Li, Changfeng; Liu, Kun; Yang, Zhaoen; Qian, Yuyuan; Li, Fuguang

2015-07-01

The first high-density linkage map was constructed to identify quantitative trait loci (QTLs) for somatic embryogenesis (SE) in cotton ( Gossypium hirsutum L.) using leaf petioles as explants. Cotton transformation is highly limited by only a few regenerable genotypes and the lack of understanding of the genetic and molecular basis of somatic embryogenesis (SE) in cotton (Gossypium hirsutum L.). To construct a more saturated linkage map and further identify quantitative trait loci (QTLs) for SE using leaf petioles as explants, a high embryogenesis frequency line (W10) from the commercial Chinese cotton cultivar CRI24 was crossed with TM-1, a genetic standard upland cotton with no embryogenesis frequency. The genetic map spanned 2300.41 cM in genetic distance and contained 411 polymorphic simple sequence repeat (SSR) loci. Of the 411 mapped loci, 25 were developed from unigenes identified for SE in our previous study. Six QTLs for SE were detected by composite interval mapping method, each explaining 6.88-37.07% of the phenotypic variance. Single marker analysis was also performed to verify the reliability of QTLs detection, and the SSR markers NAU3325 and DPL0209 were detected by the two methods. Further studies on the relatively stable and anchoring QTLs/markers for SE in an advanced population of W10 × TM-1 and other cross combinations with different SE abilities may shed light on the genetic and molecular mechanism of SE in cotton.

Identification and characterization of isomeric N-glycans of human alfa-acid-glycoprotein by stable isotope labelling and ZIC-HILIC-MS in combination with exoglycosidase digestion.

PubMed

Mancera-Arteu, Montserrat; Giménez, Estela; Barbosa, José; Sanz-Nebot, Victòria

2016-10-12

In this study, a ZIC-HILIC-MS methodology for the analysis of N-glycan isomers was optimized to obtain greater detection sensitivity and thus identify more glycan structures in hAGP. In a second step, this method was combined with glycan reductive isotope labelling (GRIL) through [(12)C6]/[(13)C6]-aniline and exoglycosidase digestion to characterize the different glycan isomers. The GRIL method allows the peak areas resulting from two different labelled samples to be compared, since neither retention time shifts nor variations in the ionization of glycans between these samples are obtained. First, sialic acid linkage assignations were performed for most hAGP glycan isomers with α2-3 sialidase digestion. Bi-, tri- and tetraantennary glycan isomers with different terminal sialic acid linkages to galactose (α2-3 or α2-6) were assigned, and the potential of this technique for the structural characterization of isobaric isomers was therefore demonstrated. Furthermore, fucose linkage isomers of hAGP glycans were also characterized using this isotope-labelling approach in combination with α1-3,4 fucosidase and β1-4 galactosidase digestion. α1-3 antennary fucoses and α1-6 core fucosylation were detected in hAGP fucosylated glycans. These established methodologies can be extremely useful for patho-glycomic studies to characterize glycoproteins of biomedical interest and find novel glycan isomers that could be used as biomarkers in cancer research. Copyright © 2016 Elsevier B.V. All rights reserved.

Piperazine-based nucleic acid analogs

DOEpatents

Schmidt, Jurgen; Silks, Louis A.; Michalczyk, Ryszard

2005-01-11

A novel nucleoside analog is disclosed which comprises a piperazine ring in the place of the ring ribose or deoxyribose sugar. Monomers utilizing a broad variety of nucleobases are disclosed, as well as oligomers comprising the monomers disclosed herein linked by a variety of linkages, including amide, phosphonamide, and sulfonamide linkages. A method of synthesizing the nucleoside analogs is also disclosed.

Describing the linkages of the immigration, refugees and citizenship Canada permanent resident data and vital statistics death registry to Ontario's administrative health database.

PubMed

Chiu, Maria; Lebenbaum, Michael; Lam, Kelvin; Chong, Nelson; Azimaee, Mahmoud; Iron, Karey; Manuel, Doug; Guttmann, Astrid

2016-10-21

Ontario, the most populous province in Canada, has a universal healthcare system that routinely collects health administrative data on its 13 million legal residents that is used for health research. Record linkage has become a vital tool for this research by enriching this data with the Immigration, Refugees and Citizenship Canada Permanent Resident (IRCC-PR) database and the Office of the Registrar General's Vital Statistics-Death (ORG-VSD) registry. Our objectives were to estimate linkage rates and compare characteristics of individuals in the linked versus unlinked files. We used both deterministic and probabilistic linkage methods to link the IRCC-PR database (1985-2012) and ORG-VSD registry (1990-2012) to the Ontario's Registered Persons Database. Linkage rates were estimated and standardized differences were used to assess differences in socio-demographic and other characteristics between the linked and unlinked records. The overall linkage rates for the IRCC-PR database and ORG-VSD registry were 86.4 and 96.2 %, respectively. The majority (68.2 %) of the record linkages in IRCC-PR were achieved after three deterministic passes, 18.2 % were linked probabilistically, and 13.6 % were unlinked. Similarly the majority (79.8 %) of the record linkages in the ORG-VSD were linked using deterministic record linkage, 16.3 % were linked after probabilistic and manual review, and 3.9 % were unlinked. Unlinked and linked files were similar for most characteristics, such as age and marital status for IRCC-PR and sex and most causes of death for ORG-VSD. However, lower linkage rates were observed among people born in East Asia (78 %) in the IRCC-PR database and certain causes of death in the ORG-VSD registry, namely perinatal conditions (61.3 %) and congenital anomalies (81.3 %). The linkages of immigration and vital statistics data to existing population-based healthcare data in Ontario, Canada will enable many novel cross-sectional and longitudinal studies to be conducted. Analytic techniques to account for sub-optimal linkage rates may be required in studies of certain ethnic groups or certain causes of death among children and infants.

A comprehensive screen for SNP associations on chromosome region 5q31-33 in Swedish/Norwegian celiac disease families.

PubMed

Amundsen, Silja Svanstrøm; Adamovic, Svetlana; Hellqvist, Asa; Nilsson, Staffan; Gudjónsdóttir, Audur H; Ascher, Henry; Ek, Johan; Larsson, Kristina; Wahlström, Jan; Lie, Benedicte A; Sollid, Ludvig M; Naluai, Asa Torinsson

2007-09-01

Celiac disease (CD) is a gluten-induced enteropathy, which results from the interplay between environmental and genetic factors. There is a strong human leukocyte antigen (HLA) association with the disease, and HLA-DQ alleles represent a major genetic risk factor. In addition to HLA-DQ, non-HLA genes appear to be crucial for CD development. Chromosomal region 5q31-33 has demonstrated linkage with CD in several genome-wide studies, including in our Swedish/Norwegian cohort. In a European meta-analysis 5q31-33 was the only region that reached a genome-wide level of significance except for the HLA region. To identify the genetic variant(s) responsible for this linkage signal, we performed a comprehensive single nucleotide polymorphism (SNP) association screen in 97 Swedish/Norwegian multiplex families who demonstrate linkage to the region. We selected tag SNPs from a 16 Mb region representing the 95% confidence interval of the linkage peak. A total of 1,404 SNPs were used for the association analysis. We identified several regions with SNPs demonstrating moderate single- or multipoint associations. However, the isolated association signals appeared insufficient to account for the linkage signal seen in our cohort. Collective effects of multiple risk genes within the region, incomplete genetic coverage or effects related to copy number variation are possible explanations for our findings.

Construction of an Integrated High Density Simple Sequence Repeat Linkage Map in Cultivated Strawberry (Fragaria × ananassa) and its Applicability

PubMed Central

Isobe, Sachiko N.; Hirakawa, Hideki; Sato, Shusei; Maeda, Fumi; Ishikawa, Masami; Mori, Toshiki; Yamamoto, Yuko; Shirasawa, Kenta; Kimura, Mitsuhiro; Fukami, Masanobu; Hashizume, Fujio; Tsuji, Tomoko; Sasamoto, Shigemi; Kato, Midori; Nanri, Keiko; Tsuruoka, Hisano; Minami, Chiharu; Takahashi, Chika; Wada, Tsuyuko; Ono, Akiko; Kawashima, Kumiko; Nakazaki, Naomi; Kishida, Yoshie; Kohara, Mitsuyo; Nakayama, Shinobu; Yamada, Manabu; Fujishiro, Tsunakazu; Watanabe, Akiko; Tabata, Satoshi

2013-01-01

The cultivated strawberry (Fragaria× ananassa) is an octoploid (2n = 8x = 56) of the Rosaceae family whose genomic architecture is still controversial. Several recent studies support the AAA′A′BBB′B′ model, but its complexity has hindered genetic and genomic analysis of this important crop. To overcome this difficulty and to assist genome-wide analysis of F. × ananassa, we constructed an integrated linkage map by organizing a total of 4474 of simple sequence repeat (SSR) markers collected from published Fragaria sequences, including 3746 SSR markers [Fragaria vesca expressed sequence tag (EST)-derived SSR markers] derived from F. vesca ESTs, 603 markers (F. × ananassa EST-derived SSR markers) from F. × ananassa ESTs, and 125 markers (F. × ananassa transcriptome-derived SSR markers) from F. × ananassa transcripts. Along with the previously published SSR markers, these markers were mapped onto five parent-specific linkage maps derived from three mapping populations, which were then assembled into an integrated linkage map. The constructed map consists of 1856 loci in 28 linkage groups (LGs) that total 2364.1 cM in length. Macrosynteny at the chromosome level was observed between the LGs of F. × ananassa and the genome of F. vesca. Variety distinction on 129 F. × ananassa lines was demonstrated using 45 selected SSR markers. PMID:23248204

Linkage to HIV, TB and Non-Communicable Disease Care from a Mobile Testing Unit in Cape Town, South Africa

PubMed Central

Govindasamy, Darshini; Kranzer, Katharina; van Schaik, Nienke; Noubary, Farzad; Wood, Robin; Walensky, Rochelle P.; Freedberg, Kenneth A.; Bassett, Ingrid V.; Bekker, Linda-Gail

2013-01-01

Background HIV counseling and testing may serve as an entry point for non-communicable disease screening. Objectives To determine the yield of newly-diagnosed HIV, tuberculosis (TB) symptoms, diabetes and hypertension, and to assess CD4 count testing, linkage to care as well as correlates of linkage and barriers to care from a mobile testing unit. Methods A mobile unit provided screening for HIV, TB symptoms, diabetes and hypertension in Cape Town, South Africa between March 2010 and September 2011. The yield of newly-diagnosed cases of these conditions was measured and clients were followed-up between January and November 2011 to assess linkage. Linkage to care was defined as accessing care within one, three or six months post-HIV diagnosis (dependent on CD4 count) and one month post-diagnosis for other conditions. Clinical and socio-demographic correlates of linkage to care were evaluated using Poisson regression and barriers to care were determined. Results Of 9,806 clients screened, the yield of new diagnoses was: HIV (5.5%), TB suspects (10.1%), diabetes (0.8%) and hypertension (58.1%). Linkage to care for HIV-infected clients, TB suspects, diabetics and hypertensives was: 51.3%, 56.7%, 74.1% and 50.0%. Only disclosure of HIV-positive status to family members or partners (RR=2.6, 95% CI: 1.04-6.3, p=0.04) was independently associated with linkage to HIV care. The main barrier to care reported by all groups was lack of time to access a clinic. Conclusion Screening for HIV, TB symptoms and hypertension at mobile units in South Africa has a high yield but inadequate linkage. After-hours and weekend clinics may overcome a major barrier to accessing care. PMID:24236170

Bronx Teens Connection's Clinic Linkage Model: Connecting Youth to Quality Sexual and Reproductive Health Care.

PubMed

O'Uhuru, Deborah J; Santiago, Vivian; Murray, Lauren E; Travers, Madeline; Bedell, Jane F

2017-03-01

Teen pregnancy and birth rates in the Bronx have been higher than in New York City, representing a longstanding health disparity. The New York City Department of Health and Mental Hygiene implemented a community-wide, multicomponent intervention to reduce unintended teen pregnancy, the Bronx Teens Connection. The Bronx Teens Connection Clinic Linkage Model sought to increase teens' access to and use of sexual and reproductive health care by increasing community partner capacity to link neighborhood clinics to youth-serving organizations, including schools. The Bronx Teens Connection Clinic Linkage Model used needs assessments, delineated the criteria for linkages, clarified roles and responsibilities of partners and staff, established trainings to support the staff engaged in linkage activities, and developed and used process evaluation methods. Early results demonstrated the strength and feasibility of the model over a 4-year period, with 31 linkages developed and maintained, over 11,300 contacts between clinic health educators and teens completed, and increasing adherence to the Centers for Disease Control and Prevention-defined clinical best practices for adolescent reproductive health. For those eight clinics that were able to provide data, there was a 25% increase in the number of teen clients seen over 4 years. There are many factors that relate to an increase in clinic utilization; some of this increase may have been a result of the linkages between schools and clinics. The Bronx Teens Connection Clinic Linkage Model is an explicit framework for clinical and youth-serving organizations seeking to establish formal linkage relationships that may be useful for other municipalities or organizations. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Linkage disequilibrium interval mapping of quantitative trait loci.

PubMed

Boitard, Simon; Abdallah, Jihad; de Rochambeau, Hubert; Cierco-Ayrolles, Christine; Mangin, Brigitte

2006-03-16

For many years gene mapping studies have been performed through linkage analyses based on pedigree data. Recently, linkage disequilibrium methods based on unrelated individuals have been advocated as powerful tools to refine estimates of gene location. Many strategies have been proposed to deal with simply inherited disease traits. However, locating quantitative trait loci is statistically more challenging and considerable research is needed to provide robust and computationally efficient methods. Under a three-locus Wright-Fisher model, we derived approximate expressions for the expected haplotype frequencies in a population. We considered haplotypes comprising one trait locus and two flanking markers. Using these theoretical expressions, we built a likelihood-maximization method, called HAPim, for estimating the location of a quantitative trait locus. For each postulated position, the method only requires information from the two flanking markers. Over a wide range of simulation scenarios it was found to be more accurate than a two-marker composite likelihood method. It also performed as well as identity by descent methods, whilst being valuable in a wider range of populations. Our method makes efficient use of marker information, and can be valuable for fine mapping purposes. Its performance is increased if multiallelic markers are available. Several improvements can be developed to account for more complex evolution scenarios or provide robust confidence intervals for the location estimates.

Allele-sharing models: LOD scores and accurate linkage tests.

PubMed

Kong, A; Cox, N J

1997-11-01

Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested.

Allele-sharing models: LOD scores and accurate linkage tests.

PubMed Central

Kong, A; Cox, N J

1997-01-01

Starting with a test statistic for linkage analysis based on allele sharing, we propose an associated one-parameter model. Under general missing-data patterns, this model allows exact calculation of likelihood ratios and LOD scores and has been implemented by a simple modification of existing software. Most important, accurate linkage tests can be performed. Using an example, we show that some previously suggested approaches to handling less than perfectly informative data can be unacceptably conservative. Situations in which this model may not perform well are discussed, and an alternative model that requires additional computations is suggested. PMID:9345087

Construction of a reference genetic linkage map for carnation (Dianthus caryophyllus L.)

PubMed Central

2013-01-01

Background Genetic linkage maps are important tools for many genetic applications including mapping of quantitative trait loci (QTLs), identifying DNA markers for fingerprinting, and map-based gene cloning. Carnation (Dianthus caryophyllus L.) is an important ornamental flower worldwide. We previously reported a random amplified polymorphic DNA (RAPD)-based genetic linkage map derived from Dianthus capitatus ssp. andrezejowskianus and a simple sequence repeat (SSR)-based genetic linkage map constructed using data from intraspecific F2 populations; however, the number of markers was insufficient, and so the number of linkage groups (LGs) did not coincide with the number of chromosomes (x = 15). Therefore, we aimed to produce a high-density genetic map to improve its usefulness for breeding purposes and genetic research. Results We improved the SSR-based genetic linkage map using SSR markers derived from a genomic library, expression sequence tags, and RNA-seq data. Linkage analysis revealed that 412 SSR loci (including 234 newly developed SSR loci) could be mapped to 17 linkage groups (LGs) covering 969.6 cM. Comparison of five minor LGs covering less than 50 cM with LGs in our previous RAPD-based genetic map suggested that four LGs could be integrated into two LGs by anchoring common SSR loci. Consequently, the number of LGs corresponded to the number of chromosomes (x = 15). We added 192 new SSRs, eight RAPD, and two sequence-tagged site loci to refine the RAPD-based genetic linkage map, which comprised 15 LGs consisting of 348 loci covering 978.3 cM. The two maps had 125 SSR loci in common, and most of the positions of markers were conserved between them. We identified 635 loci in carnation using the two linkage maps. We also mapped QTLs for two traits (bacterial wilt resistance and anthocyanin pigmentation in the flower) and a phenotypic locus for flower-type by analyzing previously reported genotype and phenotype data. Conclusions The improved genetic linkage maps and SSR markers developed in this study will serve as reference genetic linkage maps for members of the genus Dianthus, including carnation, and will be useful for mapping QTLs associated with various traits, and for improving carnation breeding programs. PMID:24160306

Construction of a reference genetic linkage map for carnation (Dianthus caryophyllus L.).

PubMed

Yagi, Masafumi; Yamamoto, Toshiya; Isobe, Sachiko; Hirakawa, Hideki; Tabata, Satoshi; Tanase, Koji; Yamaguchi, Hiroyasu; Onozaki, Takashi

2013-10-26

Genetic linkage maps are important tools for many genetic applications including mapping of quantitative trait loci (QTLs), identifying DNA markers for fingerprinting, and map-based gene cloning. Carnation (Dianthus caryophyllus L.) is an important ornamental flower worldwide. We previously reported a random amplified polymorphic DNA (RAPD)-based genetic linkage map derived from Dianthus capitatus ssp. andrezejowskianus and a simple sequence repeat (SSR)-based genetic linkage map constructed using data from intraspecific F2 populations; however, the number of markers was insufficient, and so the number of linkage groups (LGs) did not coincide with the number of chromosomes (x = 15). Therefore, we aimed to produce a high-density genetic map to improve its usefulness for breeding purposes and genetic research. We improved the SSR-based genetic linkage map using SSR markers derived from a genomic library, expression sequence tags, and RNA-seq data. Linkage analysis revealed that 412 SSR loci (including 234 newly developed SSR loci) could be mapped to 17 linkage groups (LGs) covering 969.6 cM. Comparison of five minor LGs covering less than 50 cM with LGs in our previous RAPD-based genetic map suggested that four LGs could be integrated into two LGs by anchoring common SSR loci. Consequently, the number of LGs corresponded to the number of chromosomes (x = 15). We added 192 new SSRs, eight RAPD, and two sequence-tagged site loci to refine the RAPD-based genetic linkage map, which comprised 15 LGs consisting of 348 loci covering 978.3 cM. The two maps had 125 SSR loci in common, and most of the positions of markers were conserved between them. We identified 635 loci in carnation using the two linkage maps. We also mapped QTLs for two traits (bacterial wilt resistance and anthocyanin pigmentation in the flower) and a phenotypic locus for flower-type by analyzing previously reported genotype and phenotype data. The improved genetic linkage maps and SSR markers developed in this study will serve as reference genetic linkage maps for members of the genus Dianthus, including carnation, and will be useful for mapping QTLs associated with various traits, and for improving carnation breeding programs.

Linkage of A-to-I RNA Editing in Metazoans and the Impact on Genome Evolution.

PubMed

Duan, Yuange; Dou, Shengqian; Zhang, Hong; Wu, Changcheng; Wu, Mingming; Lu, Jian

2018-01-01

The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution. Nevertheless, in worms and humans, we only detected modest proportions of linked editing events, the majority of which were not conserved. Furthermore, the linkage of editing in coding regions of worms and humans might be overall deleterious, which drives the evolution of DNA sites to escape promiscuous editing. Altogether, our results suggest that the linkage landscape of A-to-I editing has evolved during metazoan evolution. This present study also suggests that linkage of editing should be considered in elucidating the functional consequences of RNA editing. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

High-Density Genetic Linkage Map Construction and Quantitative Trait Locus Mapping for Hawthorn (Crataegus pinnatifida Bunge).

PubMed

Zhao, Yuhui; Su, Kai; Wang, Gang; Zhang, Liping; Zhang, Jijun; Li, Junpeng; Guo, Yinshan

2017-07-14

Genetic linkage maps are an important tool in genetic and genomic research. In this study, two hawthorn cultivars, Qiujinxing and Damianqiu, and 107 progenies from a cross between them were used for constructing a high-density genetic linkage map using the 2b-restriction site-associated DNA (2b-RAD) sequencing method, as well as for mapping quantitative trait loci (QTL) for flavonoid content. In total, 206,411,693 single-end reads were obtained, with an average sequencing depth of 57× in the parents and 23× in the progeny. After quality trimming, 117,896 high-quality 2b-RAD tags were retained, of which 42,279 were polymorphic; of these, 12,951 markers were used for constructing the genetic linkage map. The map contained 17 linkage groups and 3,894 markers, with a total map length of 1,551.97 cM and an average marker interval of 0.40 cM. QTL mapping identified 21 QTLs associated with flavonoid content in 10 linkage groups, which explained 16.30-59.00% of the variance. This is the first high-density linkage map for hawthorn, which will serve as a basis for fine-scale QTL mapping and marker-assisted selection of important traits in hawthorn germplasm and will facilitate chromosome assignment for hawthorn whole-genome assemblies in the future.

Purification and partial elucidation of the structure of an antioxidant carbohydrate biopolymer from the probiotic bacterium Bacillus coagulans RK-02.

PubMed

Kodali, Vidya P; Perali, Ramu S; Sen, R

2011-08-26

An exopolysaccharide (EPS) was isolated from Bacillus coagulans RK-02 and purified by size exclusion chromatography. The purified, homogeneous EPS had an average molecular weight of ∼3 × 10⁴ Da by comparison with FITC-labeled dextran standards. In vivo evaluations showed that, like other reported polysaccharides, this EPS displayed significant antioxidant activity. FTIR spectroscopy analysis showed the presence of hydroxy, carboxy, and α-glycosidic linkages and a mannose residue. GC analysis indicated that the EPS was a heteropolymer composed of glucose, mannose, galactose, glucosamine, and fucose as monomeric constituent units. Partial elucidation of the structure of the carbohydrate biopolymer based on GC-MS and NMR analysis showed the presence of two unique sets of tetrasaccharide repeating units that have 1→3 and 1→6 glycosidic linkages. This is also the first report of a Gram-positive bacterial polysaccharide with both fucose as a sugar monomer and 1→3 and 1→6 glycosidic linkages in the molecular backbone.

Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers.

PubMed

Levinson, Douglas F; Evgrafov, Oleg V; Knowles, James A; Potash, James B; Weissman, Myrna M; Scheftner, William A; Depaulo, J Raymond; Crowe, Raymond R; Murphy-Eberenz, Kathleen; Marta, Diana H; McInnis, Melvin G; Adams, Philip; Gladis, Madeline; Miller, Erin B; Thomas, Jo; Holmans, Peter

2007-02-01

The authors studied a dense map of single nucleotide polymorphism (SNP) DNA markers on chromosome 15q25-q26 to maximize the informativeness of genetic linkage analyses in a region where they previously reported suggestive evidence for linkage of recurrent early-onset major depressive disorder. In 631 European-ancestry families with multiple cases of recurrent early-onset major depressive disorder, 88 SNPs were genotyped, and multipoint allele-sharing linkage analyses were carried out. Marker-marker linkage disequilibrium was minimized, and a simulation study with founder haplotypes from these families suggested that linkage scores were not inflated by linkage disequilibrium. The dense SNP map increased the information content of the analysis from around 0.7 to over 0.9. The maximum evidence for linkage was the Z likelihood ratio score statistic of Kong and Cox (Z(LR))=4.69 at 109.8 cM. The exact p value was below the genomewide significance threshold. By contrast, in the genome scan with microsatellite markers at 9 cM spacing, the maximum Z(LR) for European-ancestry families was 3.43 (106.53 cM). It was estimated that the linked locus or loci in this region might account for a 20% or less populationwide increase in risk to siblings of cases. This region has produced modestly positive evidence for linkage to depression and related traits in other studies. These results suggest that DNA sequence variations in one or more genes in the 15q25-q26 region can increase susceptibility to major depression and that efforts are warranted to identify these genes.

Combined linkage and association analyses identify a novel locus for obesity near PROX1 in Asians.

PubMed

Kim, Hyun-Jin; Yoo, Yun Joo; Ju, Young Seok; Lee, Seungbok; Cho, Sung-Il; Sung, Joohon; Kim, Jong-Il; Seo, Jeong-Sun

2013-11-01

Although genome-wide association studies (GWAS) have substantially contributed to understanding the genetic architecture, unidentified variants for complex traits remain an issue. One of the efficient approaches is the improvement of the power of GWAS scan by weighting P values with prior linkage signals. Our objective was to identify the novel candidates for obesity in Asian populations by using genemapping strategies that combine linkage and association analyses. To obtain linkage information for body mass index (BMI) and waist circumference (WC), we performed a multipoint genome-wide linkage study in an isolated Mongolian sample of 1,049 individuals from 74 families. Next, a family-based GWAS, which integrates within- and between-family components, was performed using the genotype data of 756 individuals of the Mongolian sample, and P values for association were weighted using linkage information obtained previously. For both BMI (LOD = 3.3) and WC (LOD = 2.6), the highest linkage peak was discovered at chromosome 10q11.22. In family-based GWAS combined with linkage information, six single-nucleotide polymorphisms (SNPs) for BMI and five SNPs for WC reached a significant level of association (linkage weighted P < 1 × 10(-5) ). Of these, only one of the SNPs associated with WC (rs1704198) was replicated in 327 Korean families comprising 1,301 individuals. This SNP was located in the proximity of the prosperorelated homeobox 1 (PROX1) gene, the function of which was validated previously in a mouse model. Our powerful strategic analysis enabled the discovery of a novel candidate gene, PROX1, associated with WC in an Asian population. Copyright © 2012 The Obesity Society.

Autosomal Linkage Scan for Loci Predisposing to Comorbid Dependence on Multiple Substances

PubMed Central

Yang, Bao-Zhu; Han, Shizhong; Kranzler, Henry R.; Farrer, Lindsay A.; Elston, Robert C.; Gelernter, Joel

2014-01-01

Multiple substance dependence (MSD) trait comorbidity is common, and MSD patients are often severely affected clinically. While shared genetic risks have been documented, so far there has been no published report using the linkage scan approach to survey risk loci for MSD as a phenotype. A total of 1,758 individuals in 739 families [384 African American (AA) and 355 European American (EA) families] ascertained via affected sib-pairs with cocaine or opioid or alcohol dependence were genotyped using an array-based linkage panel of single-nucleotide polymorphism markers. Fuzzy clustering analysis was conducted on individuals with alcohol, cannabis, cocaine, opioid, and nicotine dependence for AAs and EAs separately, and linkage scans were conducted for the output membership coefficients using Merlin-regression. In EAs, we observed an autosome-wide significant linkage signal on chromosome 4 (peak lod = 3.31 at 68.3 cM; empirical autosome-wide P = 0.038), and a suggestive linkage signal on chromosome 21 (peak lod = 2.37 at 19.4 cM). In AAs, four suggestive linkage peaks were observed: two peaks on chromosome 10 (lod = 2.66 at 96.7 cM and lod = 3.02 at 147.6 cM] and the other two on chromosomes 3 (lod = 2.81 at 145.5 cM) and 9 (lod = 1.93 at 146.8 cM). Three particularly promising candidate genes, GABRA4, GABRB1, and CLOCK, are located within or very close to the autosome-wide significant linkage region for EAs on chromosome 4. This is the first linkage evidence supporting existence of genetic loci influencing risk for several comorbid disorders simultaneously in two major US populations. PMID:22354695

Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia

PubMed Central

Lewis, Cathryn M.; Levinson, Douglas F.; Wise, Lesley H.; DeLisi, Lynn E.; Straub, Richard E.; Hovatta, Iiris; Williams, Nigel M.; Schwab, Sibylle G.; Pulver, Ann E.; Faraone, Stephen V.; Brzustowicz, Linda M.; Kaufmann, Charles A.; Garver, David L.; Gurling, Hugh M. D.; Lindholm, Eva; Coon, Hilary; Moises, Hans W.; Byerley, William; Shaw, Sarah H.; Mesen, Andrea; Sherrington, Robin; O’Neill, F. Anthony; Walsh, Dermot; Kendler, Kenneth S.; Ekelund, Jesper; Paunio, Tiina; Lönnqvist, Jouko; Peltonen, Leena; O’Donovan, Michael C.; Owen, Michael J.; Wildenauer, Dieter B.; Maier, Wolfgang; Nestadt, Gerald; Blouin, Jean-Louis; Antonarakis, Stylianos E.; Mowry, Bryan J.; Silverman, Jeremy M.; Crowe, Raymond R.; Cloninger, C. Robert; Tsuang, Ming T.; Malaspina, Dolores; Harkavy-Friedman, Jill M.; Svrakic, Dragan M.; Bassett, Anne S.; Holcomb, Jennifer; Kalsi, Gursharan; McQuillin, Andrew; Brynjolfson, Jon; Sigmundsson, Thordur; Petursson, Hannes; Jazin, Elena; Zoëga, Tomas; Helgason, Tomas

2003-01-01

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (Ravg) and then weighted for sample size (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} \\begin{equation*}\\sqrt{N[affected cases]}\\end{equation*}\\end{document}). A permutation test was used to compute the probability of observing, by chance, each bin’s average rank (PAvgRnk) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (Pord). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both PAvgRnk and Pord<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with Pord<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations. PMID:12802786

Synthetic Methods for Ester Bond Formation and Conformational Analysis of Ester-Containing Carbohydrates

NASA Astrophysics Data System (ADS)

Hackbusch, Sven

This dissertation encompasses work related to synthetic methods for the formation of ester linkages in organic compounds, as well as the investigation of the conformational influence of the ester functional group on the flexibility of inter-saccharide linkages, specifically, and the solution phase structure of ester-containing carbohydrate derivatives, in general. Stereoselective reactions are an important part of the field of asymmetric synthesis and an understanding of their underlying mechanistic principles is essential for rational method development. Here, the exploration of a diastereoselective O-acylation reaction on a trans-2-substituted cyclohexanol scaffold is presented, along with possible reasons for the observed reversal of stereoselectivity dependent on the presence or absence of an achiral amine catalyst. In particular, this work establishes a structure-activity relationship with regard to the trans-2-substituent and its role as a chiral auxiliary in the reversal of diastereoselectivity. In the second part, the synthesis of various ester-linked carbohydrate derivatives, and their conformational analysis is presented. Using multidimensional NMR experiments and computational methods, the compounds' solution-phase structures were established and the effect of the ester functional group on the molecules' flexibility and three-dimensional (3D) structure was investigated and compared to ether or glycosidic linkages. To aid in this, a novel Karplus equation for the C(sp2)OCH angle in ester-linked carbohydrates was developed on the basis of a model ester-linked carbohydrate. This equation describes the sinusoidal relationship between the C(sp2)OCH dihedral angle and the corresponding 3JCH coupling constant that can be determined from a J-HMBC NMR experiment. The insights from this research will be useful in describing the 3D structure of naturally occurring and lab-made ester-linked derivatives of carbohydrates, as well as guiding the de novo-design of carbohydrate based compounds with specific shape constraints for its use as enzyme inhibitors or similar targets. In addition, the above project led to the development of a methodology for the synthesis of symmetrical ester molecules from primary alcohols using a mild oxidative esterification reaction, which proceeds in hydrous solvents using a nitrosyl radical catalyst. The reaction could be performed with a variety of alcohols and the resulting compounds are of interest in the fragrance and flavor industries.

Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study

PubMed Central

Gribble, Matthew O.; Voruganti, Venkata Saroja; Cole, Shelley A.; Haack, Karin; Balakrishnan, Poojitha; Laston, Sandra L.; Tellez-Plaza, Maria; Francesconi, Kevin A.; Goessler, Walter; Umans, Jason G.; Thomas, Duncan C.; Gilliland, Frank; North, Kari E.; Franceschini, Nora; Navas-Acien, Ana

2015-01-01

Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood. We examined urine arsenic species patterns measured by HPLC-ICPMS among 2189 Strong Heart Study participants 18 years of age and older with data on ∼400 genome-wide microsatellite markers spaced ∼10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA, and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenic metabolism gene AS3MT via conditional linkage analysis. We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic species individually. Some other loci were suggestive or significant for 1 geographical area but not overall across all areas, indicating possible locus heterogeneity. This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly. PMID:26209557

Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus.

PubMed

Mitchell, Anna L; Bøe Wolff, Anette; MacArthur, Katie; Weaver, Jolanta U; Vaidya, Bijay; Erichsen, Martina M; Darlay, Rebecca; Husebye, Eystein S; Cordell, Heather J; Pearce, Simon H S

2015-01-01

Autoimmune Addison's disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered. DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach. In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene. This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis.

Results of a SNP genome screen in a large Costa Rican pedigree segregating for severe bipolar disorder.

PubMed

Service, Susan; Molina, Julio; Deyoung, Joseph; Jawaheer, Damini; Aldana, Ileana; Vu, Thuy; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Fournier, Eduardo; Ramirez, Magui; Mathews, Carol A; Davanzo, Pablo; Macaya, Gabriel; Sandkuijl, Lodewijk; Sabatti, Chiara; Reus, Victor; Freimer, Nelson

2006-06-05

We have ascertained in the Central Valley of Costa Rica a new kindred (CR201) segregating for severe bipolar disorder (BP-I). The family was identified by tracing genealogical connections among eight persons initially independently ascertained for a genome wide association study of BP-I. For the genome screen in CR201, we trimmed the family down to 168 persons (82 of whom are genotyped), containing 25 individuals with a best-estimate diagnosis of BP-I. A total of 4,690 SNP markers were genotyped. Analysis of the data was hampered by the size and complexity of the pedigree, which prohibited using exact multipoint methods on the entire kindred. Two-point parametric linkage analysis, using a conservative model of transmission, produced a maximum LOD score of 2.78 on chromosome 6, and a total of 39 loci with LOD scores >1.0. Multipoint parametric and non-parametric linkage analysis was performed separately on four sections of CR201, and interesting (nominal P-value from either analysis <0.01), although not statistically significant, regions were highlighted on chromosomes 1, 2, 3, 12, 16, 19, and 22, in at least one section of the pedigree, or when considering all sections together. The difficulties of analyzing genome wide SNP data for complex disorders in large, potentially informative, kindreds are discussed.

A Targeted Capture Linkage Map Anchors the Genome of the Schistosomiasis Vector Snail, Biomphalaria glabrata.

PubMed

Tennessen, Jacob A; Bollmann, Stephanie R; Blouin, Michael S

2017-07-05

The aquatic planorbid snail Biomphalaria glabrata is one of the most intensively-studied mollusks due to its role in the transmission of schistosomiasis. Its 916 Mb genome has recently been sequenced and annotated, but it remains poorly assembled. Here, we used targeted capture markers to map over 10,000 B. glabrata scaffolds in a linkage cross of 94 F1 offspring, generating 24 linkage groups (LGs). We added additional scaffolds to these LGs based on linkage disequilibrium (LD) analysis of targeted capture and whole-genome sequences of 96 unrelated snails. Our final linkage map consists of 18,613 scaffolds comprising 515 Mb, representing 56% of the genome and 75% of genic and nonrepetitive regions. There are 18 large (> 10 Mb) LGs, likely representing the expected 18 haploid chromosomes, and > 50% of the genome has been assigned to LGs of at least 17 Mb. Comparisons with other gastropod genomes reveal patterns of synteny and chromosomal rearrangements. Linkage relationships of key immune-relevant genes may help clarify snail-schistosome interactions. By focusing on linkage among genic and nonrepetitive regions, we have generated a useful resource for associating snail phenotypes with causal genes, even in the absence of a complete genome assembly. A similar approach could potentially improve numerous poorly-assembled genomes in other taxa. This map will facilitate future work on this host of a serious human parasite. Copyright © 2017 Tennessen et al.

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

PubMed

Asherson, P; Zhou, K; Anney, R J L; Franke, B; Buitelaar, J; Ebstein, R; Gill, M; Altink, M; Arnold, R; Boer, F; Brookes, K; Buschgens, C; Butler, L; Cambell, D; Chen, W; Christiansen, H; Feldman, L; Fleischman, K; Fliers, E; Howe-Forbes, R; Goldfarb, A; Heise, A; Gabriëls, I; Johansson, L; Lubetzki, I; Marco, R; Medad, S; Minderaa, R; Mulas, F; Müller, U; Mulligan, A; Neale, B; Rijsdijk, F; Rabin, K; Rommelse, N; Sethna, V; Sorohan, J; Uebel, H; Psychogiou, L; Weeks, A; Barrett, R; Xu, X; Banaschewski, T; Sonuga-Barke, E; Eisenberg, J; Manor, I; Miranda, A; Oades, R D; Roeyers, H; Rothenberger, A; Sergeant, J; Steinhausen, H-C; Taylor, E; Thompson, M; Faraone, S V

2008-05-01

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

SNP Discovery and Linkage Map Construction in Cultivated Tomato

PubMed Central

Shirasawa, Kenta; Isobe, Sachiko; Hirakawa, Hideki; Asamizu, Erika; Fukuoka, Hiroyuki; Just, Daniel; Rothan, Christophe; Sasamoto, Shigemi; Fujishiro, Tsunakazu; Kishida, Yoshie; Kohara, Mitsuyo; Tsuruoka, Hisano; Wada, Tsuyuko; Nakamura, Yasukazu; Sato, Shusei; Tabata, Satoshi

2010-01-01

Few intraspecific genetic linkage maps have been reported for cultivated tomato, mainly because genetic diversity within Solanum lycopersicum is much less than that between tomato species. Single nucleotide polymorphisms (SNPs), the most abundant source of genomic variation, are the most promising source of polymorphisms for the construction of linkage maps for closely related intraspecific lines. In this study, we developed SNP markers based on expressed sequence tags for the construction of intraspecific linkage maps in tomato. Out of the 5607 SNP positions detected through in silico analysis, 1536 were selected for high-throughput genotyping of two mapping populations derived from crosses between ‘Micro-Tom’ and either ‘Ailsa Craig’ or ‘M82’. A total of 1137 markers, including 793 out of the 1338 successfully genotyped SNPs, along with 344 simple sequence repeat and intronic polymorphism markers, were mapped onto two linkage maps, which covered 1467.8 and 1422.7 cM, respectively. The SNP markers developed were then screened against cultivated tomato lines in order to estimate the transferability of these SNPs to other breeding materials. The molecular markers and linkage maps represent a milestone in the genomics and genetics, and are the first step toward molecular breeding of cultivated tomato. Information on the DNA markers, linkage maps, and SNP genotypes for these tomato lines is available at http://www.kazusa.or.jp/tomato/. PMID:21044984

DNA linkage studies of degenerative retinal diseases.

PubMed

Daiger, S P; Heckenlively, J R; Lewis, R A; Pelias, M Z

1987-01-01

DNA linkage studies of human genetic diseases have led to rapid characterization of a number of otherwise intractable disease loci. Detection of a linked DNA marker, the first step in "reverse genetics", has permitted cloning of the genes for Duchenne muscular dystrophy, retinoblastoma and chronic granulomatosis disease, among others. Thus, the case for applying these techniques to retinitis pigmentosa and related diseases, and the urgency in capitalizing on molecular developments, is justified and compelling. The first major success regarding RP was in demonstrating linkage of the DNA marker DXS7 (L1.28) to XRP. For autosomal forms of the disease, conventional linkage studies have provided tentative evidence for linkage of ADRP to the Rh blood group on chromosome lp and for linkage of Usher's syndrome to Gc and 4q. These provisional assignments are, at least, an important starting point for DNA analysis. The Support Program for DNA Linkage Studies of Degenerative Retinal Diseases was established to provide access for the scientific community to appropriate families, using the resources of the Human Genetic Mutant Cell Repository to prepare, store and distribute lymphoblast lines. To date, two extensive, well-characterized families are included in the program: the autosomal dominant RP family UCLA-RP01, and the Usher's syndrome families LSU-US01. It is highly likely that rapid progress will be made in mapping and characterizing the inherited retinal dystrophies. We believe the support program will facilitate this progress.

Fine mapping on chromosome 13q32-34 and brain expression analysis implicates MYO16 in schizophrenia.

PubMed

Rodriguez-Murillo, Laura; Xu, Bin; Roos, J Louw; Abecasis, Gonçalo R; Gogos, Joseph A; Karayiorgou, Maria

2014-03-01

We previously reported linkage of schizophrenia and schizoaffective disorder to 13q32-34 in the European descent Afrikaner population from South Africa. The nature of genetic variation underlying linkage peaks in psychiatric disorders remains largely unknown and both rare and common variants may be contributing. Here, we examine the contribution of common variants located under the 13q32-34 linkage region. We used densely spaced SNPs to fine map the linkage peak region using both a discovery sample of 415 families and a meta-analysis incorporating two additional replication family samples. In a second phase of the study, we use one family-based data set with 237 families and independent case-control data sets for fine mapping of the common variant association signal using HapMap SNPs. We report a significant association with a genetic variant (rs9583277) within the gene encoding for the myosin heavy-chain Myr 8 (MYO16), which has been implicated in neuronal phosphoinositide 3-kinase signaling. Follow-up analysis of HapMap variation within MYO16 in a second set of Afrikaner families and additional case-control data sets of European descent highlighted a region across introns 2-6 as the most likely region to harbor common MYO16 risk variants. Expression analysis revealed a significant increase in the level of MYO16 expression in the brains of schizophrenia patients. Our results suggest that common variation within MYO16 may contribute to the genetic liability to schizophrenia.

Salmonid Chromosome Evolution as Revealed by a Novel Method for Comparing RADseq Linkage Maps

PubMed Central

Gosselin, Thierry; Normandeau, Eric; Lamothe, Manuel; Isabel, Nathalie; Audet, Céline; Bernatchez, Louis

2016-01-01

Whole genome duplication (WGD) can provide material for evolutionary innovation. Family Salmonidae is ideal for studying the effects of WGD as the ancestral salmonid underwent WGD relatively recently, ∼65 Ma, then rediploidized and diversified. Extensive synteny between homologous chromosome arms occurs in extant salmonids, but each species has both conserved and unique chromosome arm fusions and fissions. Assembly of large, outbred eukaryotic genomes can be difficult, but structural rearrangements within such taxa can be investigated using linkage maps. RAD sequencing provides unprecedented ability to generate high-density linkage maps for nonmodel species, but can result in low numbers of homologous markers between species due to phylogenetic distance or differences in library preparation. Here, we generate a high-density linkage map (3,826 markers) for the Salvelinus genera (Brook Charr S. fontinalis), and then identify corresponding chromosome arms among the other available salmonid high-density linkage maps, including six species of Oncorhynchus, and one species for each of Salmo, Coregonus, and the nonduplicated sister group for the salmonids, Northern Pike Esox lucius for identifying post-duplicated homeologs. To facilitate this process, we developed MapComp to identify identical and proximate (i.e. nearby) markers between linkage maps using a reference genome of a related species as an intermediate, increasing the number of comparable markers between linkage maps by 5-fold. This enabled a characterization of the most likely history of retained chromosomal rearrangements post-WGD, and several conserved chromosomal inversions. Analyses of RADseq-based linkage maps from other taxa will also benefit from MapComp, available at: https://github.com/enormandeau/mapcomp/ PMID:28173098

Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions

PubMed Central

Ombrello, Michael J.; Remmers, Elaine F.; Sun, Guangping; Freeman, Alexandra F.; Datta, Shrimati; Torabi-Parizi, Parizad; Subramanian, Naeha; Bunney, Tom D.; Baxendale, Rhona W.; Martins, Marta S.; Romberg, Neil; Komarow, Hirsh; Aksentijevich, Ivona; Kim, Hun Sik; Ho, Jason; Cruse, Glenn; Jung, Mi-Yeon; Gilfillan, Alasdair M.; Metcalfe, Dean D.; Nelson, Celeste; O'Brien, Michelle; Wisch, Laura; Stone, Kelly; Douek, Daniel C.; Gandhi, Chhavi; Wanderer, Alan A.; Lee, Hane; Nelson, Stanley F.; Shianna, Kevin V.; Cirulli, Elizabeth T.; Goldstein, David B.; Long, Eric O.; Moir, Susan; Meffre, Eric; Holland, Steven M.; Kastner, Daniel L.; Katan, Matilda; Hoffman, Hal M.; Milner, Joshua D.

2012-01-01

Background Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. Methods We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. Results Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cγ2 (PLCγ2), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. Conclusions Genomic deletions in PLCG2 cause gain of PLCγ2 function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.) PMID:22236196

Identification a novel MYOC gene mutation in a Chinese family with juvenile-onset open angle glaucoma.

PubMed

Zhao, Xin; Yang, Chaoshan; Tong, Yi; Zhang, Xiaohui; Xu, Liang; Li, Yang

2010-08-25

To describe the clinical and genetic findings in one Chinese family with juvenile-onset open angle glaucoma (JOAG). One family was examined clinically and a follow-up took place 5 years later. After informed consent was obtained, genomic DNA was extracted from the venous blood of all participants. Linkage analysis was performed with three microsatellite markers around the MYOC gene (D1S196, D1S2815, and D1S218) in the family. Mutation screening of all coding exons of MYOC was performed by direct sequencing of PCR-amplified DNA fragments and restriction fragment length polymorphism (RFLP) analysis. Bioinformatics analysis by the Garnier-Osguthorpe-Robson (GOR) method predicted the effects of variants detected on secondary structures of the MYOC protein. Clinical examination and pedigree analysis revealed a three- generation family with seven members diagnosed with JOAG, three with ocular hypertension, and five normal individuals. Through genotyping, the pedigree showed a linkage to the MYOC on chromosome 1q24-25. Mutation screening of MYOC in this family revealed an A-->T transition at position 1348 (p. N450Y) of the cDNA sequence. This missense mutation co-segregated with the disease phenotype of the family, but was not found in 100 normal controls. Secondary structure prediction of the p.N450Y by the GOR method revealed the replacement of a coil with a beta sheet at the amino acid 447. Early onset JOAG, with incomplete penetrance, is consistent with a novel mutation in MYOC. The finding provides pre-symptomatic molecular diagnosis for the members of this family and is useful for further genetic consultation.

Linkage and candidate gene analysis of X-linked familial exudative vitreoretinopathy.

PubMed

Shastry, B S; Hejtmancik, J F; Plager, D A; Hartzer, M K; Trese, M T

1995-05-20

Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disorder characterized by avascularity of the peripheral retina, retinal exudates, tractional detachment, and retinal folds. The disorder is most commonly transmitted as an autosomal dominant trait, but X-linked transmission also occurs. To initiate the process of identifying the gene responsible for the X-linked disorder, linkage analysis has been performed with three previously unreported three- or four-generation families. Two-point analysis showed linkage to MAOA (Zmax = 2.1, theta max = 0) and DXS228 (Zmax = 0.5, theta max = 0.11), and this was further confirmed by multipoint analysis with these same markers (Zmax = 2.81 at MAOA), which both lie near the gene causing Norrie disease. Molecular genetic analysis further reveals a missense mutation (R121W) in the third exon of the Norrie's disease gene that perfectly cosegregates with the disease through three generations in one family. This mutation was not detected in the unaffected family members and six normal unrelated controls, suggesting that it is likely to be the pathogenic mutation. Additionally, a polymorphic missense mutation (H127R) was detected in a severely affected patient.

An Exploratory Investigation of the Assessment Practices of Selected Association to Advance Collegiate Schools of Business--Accredited Business Programs and Linkages with General Education Outcomes

ERIC Educational Resources Information Center

Vitullo, Elizabeth; Jones, Elizabeth A.

2010-01-01

This research study investigated the assessment practices of five different undergraduate business programs. It examines the learning outcomes required for the business programs and their linkages with general education outcomes. Specific assessment methods, the results from assessments, and how business program faculty use assessment findings to…

Linking Scores from Tests of Similar Content Given in Different Languages: An Illustration Involving Methodological Alternatives

ERIC Educational Resources Information Center

Cascallar, Alicia S.; Dorans, Neil J.

2005-01-01

This study compares two methods commonly used (concordance and prediction) to establish linkages between scores from tests of similar content given in different languages. Score linkages between the Verbal and Math sections of the SAT I and the corresponding sections of the Spanish-language admissions test, the Prueba de Aptitud Academica (PAA),…

Linkage mapping in the oilseed crop Jatropha curcas L. reveals a locus controlling the biosynthesis of phorbol esters which cause seed toxicity

PubMed Central

King, Andrew J; Montes, Luis R; Clarke, Jasper G; Affleck, Julie; Li, Yi; Witsenboer, Hanneke; van der Vossen, Edwin; van der Linde, Piet; Tripathi, Yogendra; Tavares, Evanilda; Shukla, Parul; Rajasekaran, Thirunavukkarasu; van Loo, Eibertus N; Graham, Ian A

2013-01-01

Current efforts to grow the tropical oilseed crop Jatropha curcas L. economically are hampered by the lack of cultivars and the presence of toxic phorbol esters (PE) within the seeds of most provenances. These PE restrict the conversion of seed cake into animal feed, although naturally occurring ‘nontoxic’ provenances exist which produce seed lacking PE. As an important step towards the development of genetically improved varieties of J. curcas, we constructed a linkage map from four F2 mapping populations. The consensus linkage map contains 502 codominant markers, distributed over 11 linkage groups, with a mean marker density of 1.8 cM per unique locus. Analysis of the inheritance of PE biosynthesis indicated that this is a maternally controlled dominant monogenic trait. This maternal control is due to biosynthesis of the PE occurring only within maternal tissues. The trait segregated 3 : 1 within seeds collected from F2 plants, and QTL analysis revealed that a locus on linkage group 8 was responsible for phorbol ester biosynthesis. By taking advantage of the draft genome assemblies of J. curcas and Ricinus communis (castor), a comparative mapping approach was used to develop additional markers to fine map this mutation within 2.3 cM. The linkage map provides a framework for the dissection of agronomic traits in J. curcas, and the development of improved varieties by marker-assisted breeding. The identification of the locus responsible for PE biosynthesis means that it is now possible to rapidly breed new nontoxic varieties. PMID:23898859

Linkage mapping in the oilseed crop Jatropha curcas L. reveals a locus controlling the biosynthesis of phorbol esters which cause seed toxicity.

PubMed

King, Andrew J; Montes, Luis R; Clarke, Jasper G; Affleck, Julie; Li, Yi; Witsenboer, Hanneke; van der Vossen, Edwin; van der Linde, Piet; Tripathi, Yogendra; Tavares, Evanilda; Shukla, Parul; Rajasekaran, Thirunavukkarasu; van Loo, Eibertus N; Graham, Ian A

2013-10-01

Current efforts to grow the tropical oilseed crop Jatropha curcas L. economically are hampered by the lack of cultivars and the presence of toxic phorbol esters (PE) within the seeds of most provenances. These PE restrict the conversion of seed cake into animal feed, although naturally occurring 'nontoxic' provenances exist which produce seed lacking PE. As an important step towards the development of genetically improved varieties of J. curcas, we constructed a linkage map from four F₂ mapping populations. The consensus linkage map contains 502 codominant markers, distributed over 11 linkage groups, with a mean marker density of 1.8 cM per unique locus. Analysis of the inheritance of PE biosynthesis indicated that this is a maternally controlled dominant monogenic trait. This maternal control is due to biosynthesis of the PE occurring only within maternal tissues. The trait segregated 3 : 1 within seeds collected from F₂ plants, and QTL analysis revealed that a locus on linkage group 8 was responsible for phorbol ester biosynthesis. By taking advantage of the draft genome assemblies of J. curcas and Ricinus communis (castor), a comparative mapping approach was used to develop additional markers to fine map this mutation within 2.3 cM. The linkage map provides a framework for the dissection of agronomic traits in J. curcas, and the development of improved varieties by marker-assisted breeding. The identification of the locus responsible for PE biosynthesis means that it is now possible to rapidly breed new nontoxic varieties. © 2013 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

Genome-scan analysis for quantitative trait loci in an F2 tilapia hybrid.

PubMed

Cnaani, A; Zilberman, N; Tinman, S; Hulata, G; Ron, M

2004-09-01

We searched for genetic linkage between DNA markers and quantitative trait loci (QTLs) for innate immunity, response to stress, biochemical parameters of blood, and fish size in an F2 population derived from an interspecific tilapia hybrid (Oreochromis mossambicusx O. aureus). A family of 114 fish was scanned for 40 polymorphic microsatellite DNA markers and two polymorphic genes, covering approximately 80% of the tilapia genome. These fish had previously been phenotyped for seven immune-response traits and six blood parameters. Critical values for significance were P <0.05 with the false discovery rate (FDR) controlled at 40%. The genome-scan analysis resulted in 35 significant marker-trait associations, involving 26 markers in 16 linkage groups. In a second experiment, nine markers were re-sampled in a second family of 79 fish of the same species hybrid. Seven markers (GM180, GM553, MHC-I, UNH848, UNH868, UNH898 and UNH925) in five linkage groups (LG 1, 3, 4, 22 and 23) were associated with stress response traits. An additional six markers (GM47, GM552, UNH208, UNH881, UNH952, UNH998) in five linkage groups (LG 4, 16, 19, 20 and 23) were verified for their associations with immune response traits, by linkage to several different traits. The portion of variance explained by each QTL was 11% on average, with a maximum of 29%. The average additive effect of QTLs was 0.2 standard deviation units of stress response traits and fish size, with a maximum of 0.33. In three linkage groups (LG 1, 3 and 23) markers were associated with stress response, body weight and sex determination, confirming the location of QTLs reported by several other studies.

Barriers and facilitators of linkage to HIV care among HIV-infected young Chinese men who have sex with men: a qualitative study.

PubMed

Li, Haochu; Wei, Chongyi; Tucker, Joseph; Kang, Dianmin; Liao, Meizhen; Holroyd, Eleanor; Zheng, Jietao; Qi, Qian; Ma, Wei

2017-03-16

The Four Free and One Care Policy (HIV/AIDS-related free services) has been in place in China since 2004. However, linkage to human immunodeficiency virus (HIV) care is not yet achieved very well among people living with HIV. We conducted a qualitative study to explore individual and contextual factors that may influence a linkage to HIV care from the perspective of young HIV-infected men who have sex with men (MSM) in a highly centralized HIV care context of China. Purposive sampling was used to recruit 21 HIV-infected MSM in Shandong Province, with in-depth interviews conducted between March and July 2015. Thematic content analysis was subsequently used for data analysis. Key barriers and facilitators related to a linkage to HIV care emerged from participants' narratives. The barriers included perceived healthy status, low health literacy, and stigma associated with receiving HIV care. The facilitators included an awareness of responsibility, knowledge associated with health literacy, social support, and trusting and relying on services provided by the Center for Disease Control and Prevention (CDC) and the government. These were related to the quality of current HIV counselling and testing, service promotion, and the cost and placement of these HIV services. In order to improve the MSM linkage to HIV care in China, it is imperative to improve the quality of the current on-going counselling and testing. Further critical linkage support includes increasing supportive services among local CDC systems, designated hospitals and community-based organizations (CBOs), and more financial support for HIV/AIDS related testing, medical checkups and treatments.

Genetic Mapping and QTL Analysis of Growth-Related Traits in Pinctada fucata Using Restriction-Site Associated DNA Sequencing

PubMed Central

Li, Yaoguo; He, Maoxian

2014-01-01

The pearl oyster, Pinctada fucata (P. fucata), is one of the marine bivalves that is predominantly cultured for pearl production. To obtain more genetic information for breeding purposes, we constructed a high-density linkage map of P. fucata and identified quantitative trait loci (QTL) for growth-related traits. One F1 family, which included the two parents, 48 largest progeny and 50 smallest progeny, was sampled to construct a linkage map using restriction site-associated DNA sequencing (RAD-Seq). With low coverage data, 1956.53 million clean reads and 86,342 candidate RAD loci were generated. A total of 1373 segregating SNPs were used to construct a sex-average linkage map. This spanned 1091.81 centimorgans (cM), with 14 linkage groups and an average marker interval of 1.41 cM. The genetic linkage map coverage, Coa, was 97.24%. Thirty-nine QTL-peak loci, for seven growth-related traits, were identified using the single-marker analysis, nonparametric mapping Kruskal-Wallis (KW) test. Parameters included three for shell height, six for shell length, five for shell width, four for hinge length, 11 for total weight, eight for soft tissue weight and two for shell weight. The QTL peak loci for shell height, shell length and shell weight were all located in linkage group 6. The genotype frequencies of most QTL peak loci showed significant differences between the large subpopulation and the small subpopulation (P<0.05). These results highlight the effectiveness of RAD-Seq as a tool for generation of QTL-targeted and genome-wide marker data in the non-model animal, P. fucata, and its possible utility in marker-assisted selection (MAS). PMID:25369421

Detecting Recombination Hotspots from Patterns of Linkage Disequilibrium.

PubMed

Wall, Jeffrey D; Stevison, Laurie S

2016-08-09

With recent advances in DNA sequencing technologies, it has become increasingly easy to use whole-genome sequencing of unrelated individuals to assay patterns of linkage disequilibrium (LD) across the genome. One type of analysis that is commonly performed is to estimate local recombination rates and identify recombination hotspots from patterns of LD. One method for detecting recombination hotspots, LDhot, has been used in a handful of species to further our understanding of the basic biology of recombination. For the most part, the effectiveness of this method (e.g., power and false positive rate) is unknown. In this study, we run extensive simulations to compare the effectiveness of three different implementations of LDhot. We find large differences in the power and false positive rates of these different approaches, as well as a strong sensitivity to the window size used (with smaller window sizes leading to more accurate estimation of hotspot locations). We also compared our LDhot simulation results with comparable simulation results obtained from a Bayesian maximum-likelihood approach for identifying hotspots. Surprisingly, we found that the latter computationally intensive approach had substantially lower power over the parameter values considered in our simulations. Copyright © 2016 Wall and Stevison.

Heritability and linkage analysis of personality in bipolar disorder.

PubMed

Greenwood, Tiffany A; Badner, Judith A; Byerley, William; Keck, Paul E; McElroy, Susan L; Remick, Ronald A; Dessa Sadovnick, A; Kelsoe, John R

2013-11-01

The many attempts that have been made to identify genes for bipolar disorder (BD) have met with limited success, which may reflect an inadequacy of diagnosis as an informative and biologically relevant phenotype for genetic studies. Here we have explored aspects of personality as quantitative phenotypes for bipolar disorder through the use of the Temperament and Character Inventory (TCI), which assesses personality in seven dimensions. Four temperament dimensions are assessed: novelty seeking (NS), harm avoidance (HA), reward dependence (RD), and persistence (PS). Three character dimensions are also included: self-directedness (SD), cooperativeness (CO), and self-transcendence (ST). We compared personality scores between diagnostic groups and assessed heritability in a sample of 101 families collected for genetic studies of BD. A genome-wide SNP linkage analysis was then performed in the subset of 51 families for which genetic data was available. Significant group differences were observed between BD subjects, their first-degree relatives, and independent controls for all but RD and PS, and all but HA and RD were found to be significantly heritable in this sample. Linkage analysis of the heritable dimensions produced several suggestive linkage peaks for NS (chromosomes 7q21 and 10p15), PS (chromosomes 6q16, 12p13, and 19p13), and SD (chromosomes 4q35, 8q24, and 18q12). The relatively small size of our linkage sample likely limited our ability to reach genome-wide significance in this study. While not genome-wide significant, these results suggest that aspects of personality may prove useful in the identification of genes underlying BD susceptibility. © 2013 Elsevier B.V. All rights reserved.

Power of a Labrador Retriever-Greyhound pedigree for linkage analysis of hip dysplasia and osteoarthritis.

PubMed

Todhunter, Rory J; Casella, George; Bliss, Stuart P; Lust, George; Williams, Alma Jo; Hamilton, Samuel; Dykes, Nathan L; Yeager, Amy E; Gilbert, Robert O; Burton-Wurster, Nancy I; Mellersh, Cathryn C; Acland, Gregory M

2003-04-01

To estimate the number of dogs required to find linkage to heritable traits of hip dysplasia in dogs from an experimental pedigree. 147 Labrador Retrievers, Greyhounds, and their crossbreed offspring. Labrador Retrievers with hip dysplasia were crossed with unaffected Greyhounds. Age at detection of femoral capital ossification, distraction index (DI), hip joint dorsolateral subluxation (DLS) score, and hip joint osteoarthritis (OA) were recorded. Power to find linkage of a single marker to a quantitative trait locus (QTL) controlling 100% of the variation in a dysplastic trait in the backcross dogs was determined. For the DI at the observed effect size, recombination fraction of 0.05, and heterozygosity of 0.75, 35 dogs in the backcross of the F1 to the Greyhound generation would yield linkage at a power of 0.8. For the DLS score, 35 dogs in the backcross to the Labrador Retriever generation would be required for linkage at the same power. For OSS, 45 dogs in the backcross to the founding Labrador Retrievers would yield linkage at the same power. Fewer dogs were projected to be necessary to find linkage to hip OA. Testing for linkage to the DLS at 4 loci simultaneously, each controlling 25% of the phenotypic variation, yielded an overall power of 0.7 CONCLUSIONS AND CLINICAL SIGNIFICANCE: Based on this conservative single-marker estimate, this pedigree has the requisite power to find microsatellites linked to susceptibility loci for hip dysplasia and hip OA by breeding a reasonable number of backcross dogs.

Exome Sequencing and Linkage Analysis Identified Novel Candidate Genes in Recessive Intellectual Disability Associated with Ataxia.

PubMed

Jazayeri, Roshanak; Hu, Hao; Fattahi, Zohreh; Musante, Luciana; Abedini, Seyedeh Sedigheh; Hosseini, Masoumeh; Wienker, Thomas F; Ropers, Hans Hilger; Najmabadi, Hossein; Kahrizi, Kimia

2015-10-01

Intellectual disability (ID) is a neuro-developmental disorder which causes considerable socio-economic problems. Some ID individuals are also affected by ataxia, and the condition includes different mutations affecting several genes. We used whole exome sequencing (WES) in combination with homozygosity mapping (HM) to identify the genetic defects in five consanguineous families among our cohort study, with two affected children with ID and ataxia as major clinical symptoms. We identified three novel candidate genes, RIPPLY1, MRPL10, SNX14, and a new mutation in known gene SURF1. All are autosomal genes, except RIPPLY1, which is located on the X chromosome. Two are housekeeping genes, implicated in transcription and translation regulation and intracellular trafficking, and two encode mitochondrial proteins. The pathogenesis of these variants was evaluated by mutation classification, bioinformatic methods, review of medical and biological relevance, co-segregation studies in the particular family, and a normal population study. Linkage analysis and exome sequencing of a small number of affected family members is a powerful new technique which can be used to decrease the number of candidate genes in heterogenic disorders such as ID, and may even identify the responsible gene(s).

A Novel Multiobjective Evolutionary Algorithm Based on Regression Analysis

PubMed Central

Song, Zhiming; Wang, Maocai; Dai, Guangming; Vasile, Massimiliano

2015-01-01

As is known, the Pareto set of a continuous multiobjective optimization problem with m objective functions is a piecewise continuous (m − 1)-dimensional manifold in the decision space under some mild conditions. However, how to utilize the regularity to design multiobjective optimization algorithms has become the research focus. In this paper, based on this regularity, a model-based multiobjective evolutionary algorithm with regression analysis (MMEA-RA) is put forward to solve continuous multiobjective optimization problems with variable linkages. In the algorithm, the optimization problem is modelled as a promising area in the decision space by a probability distribution, and the centroid of the probability distribution is (m − 1)-dimensional piecewise continuous manifold. The least squares method is used to construct such a model. A selection strategy based on the nondominated sorting is used to choose the individuals to the next generation. The new algorithm is tested and compared with NSGA-II and RM-MEDA. The result shows that MMEA-RA outperforms RM-MEDA and NSGA-II on the test instances with variable linkages. At the same time, MMEA-RA has higher efficiency than the other two algorithms. A few shortcomings of MMEA-RA have also been identified and discussed in this paper. PMID:25874246

Identification of quantitative trait loci for fibrin clot phenotypes: The EuroCLOT study

PubMed Central

Williams, Frances MK; Carter, Angela M; Kato, Bernet; Falchi, Mario; Bathum, Lise; Surdulescu, Gabriela; Kyvik, Kirsten Ohm; Palotie, Aarno; Spector, Tim D; Grant, Peter J

2012-01-01

Objectives Fibrin makes up the structural basis of an occlusive arterial thrombus and variability in fibrin phenotype relates to cardiovascular risk. The aims of the current study from the EU consortium EuroCLOT were to 1) determine the heritability of fibrin phenotypes and 2) identify QTLs associated with fibrin phenotypes. Methods 447 dizygotic (DZ) and 460 monozygotic (MZ) pairs of healthy UK Caucasian female twins and 199 DZ twin pairs from Denmark were studied. D-dimer, an indicator of fibrin turnover, was measured by ELISA and measures of clot formation, morphology and lysis were determined by turbidimetric assays. Heritability estimates and genome-wide linkage analysis were performed. Results Estimates of heritability for d-dimer and turbidometric variables were in the range 17 - 46%, with highest levels for maximal absorbance which provides an estimate of clot density. Genome-wide linkage analysis revealed 6 significant regions with LOD>3 on 5 chromosomes (5, 6, 9, 16 and 17). Conclusions The results indicate a significant genetic contribution to variability in fibrin phenotypes and highlight regions in the human genome which warrant further investigation in relation to ischaemic cardiovascular disorders and their therapy. PMID:19150881

Methods for detecting additional genes underlying Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Locke, P.A.; Haines, J.L.; Ter-Minassian, M.

1994-09-01

Alzheimer`s disease (AD) is a complex inherited disorder with proven genetic heterogeneity. To date, genes on chromosome 21 (APP) and 14 (not yet identified) are associated with early-onset familial AD, while the APOE gene on chromosome 19 is associated with both late onset familial and sporadic AD and early onset sporadic AD. Although these genes likely account for the majority of AD, many familial cases cannot be traced to any of these genes. From a set of 127 late-onset multiplex families screened for APOE, 43 (34%) families have at least one affected individual with no APOE-4 allele, suggesting an alternativemore » genetic etiology. Simulation studies indicated that additional loci could be identified through a genomic screen with a 10 cM sieve on a subset of 21 well documented, non-APOE-4 families. Given the uncertainties in the mode of inheritance, reliance on a single analytical method could result in a missed linkage. Therefore, we have developed a strategy of using multiple overlapping yet complementary methods to detect linkage. These include sib-pair analysis and affected-pedigree-member analysis, neither of which makes assumptions about mode of inheritance, and lod score analysis (using two predefined genetic models). In order for a marker to qualify for follow-up, it must fit at least two of three criteria. These are nominal P values of 0.05 or less for the non-parametric methods, and/or a lod score greater than 1.0. Adjacent markers each fulfilling a single criterion also warrant follow-up. To date, we have screened 61 markers on chromosomes 1, 2, 3, 18, 19, 21, and 22. One marker, D2S163, generated a lod score of 1.06 ({theta} = 0.15) and an APMT statistic of 3.68 (P < 0.001). This region is currently being investigated in more detail. Updated results of this region plus additional screening data will be presented.« less

Intra-Facility Linkage of HIV-Positive Mothers and HIV-Exposed Babies into HIV Chronic Care: Rural and Urban Experience in a Resource Limited Setting

PubMed Central

Mugasha, Christine; Kigozi, Joanita; Kiragga, Agnes; Muganzi, Alex; Sewankambo, Nelson; Coutinho, Alex; Nakanjako, Damalie

2014-01-01

Introduction Linkage of HIV-infected pregnant women to HIV care remains critical for improvement of maternal and child outcomes through prevention of maternal-to-child transmission of HIV (PMTCT) and subsequent chronic HIV care. This study determined proportions and factors associated with intra-facility linkage to HIV care and Early Infant Diagnosis care (EID) to inform strategic scale up of PMTCT programs. Methods A cross-sectional review of records was done at 2 urban and 3 rural public health care facilities supported by the Infectious Diseases Institute (IDI). HIV-infected pregnant mothers, identified through routine antenatal care (ANC) and HIV-exposed babies were evaluated for enrollment in HIV clinics by 6 weeks post-delivery. Results Overall, 1,025 HIV-infected pregnant mothers were identified during ANC between January and June, 2012; 267/1,025 (26%) in rural and 743/1,025 (74%) in urban facilities. Of these 375/1,025 (37%) were linked to HIV clinics [67/267(25%) rural and 308/758(41%) urban]. Of 636 HIV-exposed babies, 193 (30%) were linked to EID. Linkage of mother-baby pairs to HIV chronic care and EID was 16% (101/636); 8/179 (4.5%)] in rural and 93/457(20.3%) in urban health facilities. Within rural facilities, ANC registration <28 weeks-of-gestation was associated with mothers' linkage to HIV chronic care [AoR, 2.0 95% CI, 1.1–3.7, p = 0.019] and mothers' multi-parity was associated with baby's linkage to EID; AoR 4.4 (1.3–15.1), p = 0.023. Stigma, long distance to health facilities and vertical PMTCT services affected linkage in rural facilities, while peer mothers, infant feeding services, long patient queues and limited privacy hindered linkage to HIV care in urban settings. Conclusion Post-natal linkage of HIV-infected mothers to chronic HIV care and HIV-exposed babies to EID programs was low. Barriers to linkage to HIV care vary in urban and rural settings. We recommend targeted interventions to rapidly improve linkage to antiretroviral therapy for elimination of MTCT. PMID:25546453

Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31-q32.1 in an inbred and genetically heterogeneous disease population

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van Soest, S.; Ingeborgh Van Den Born, L.; Bergen, A.A.B.

1994-08-01

Linkage analysis was carried out in a large family segregating for autosomal recessive retinitis pigmentosa (arRP), originating from a genetically isolated population in The Netherlands. Within the family, clinical heterogeneity was observed, with a major section of the family segregating arRP with characteristic para-arteriolar preservation of the retinal pigment epithelium (PPRPE). In the remainder of the arRP patients no PPRPE was found. Initially, all branches of the family were analyzed jointly, and linkage was found between the marker F13B, located at 1q31-q32.1, and RP12 ({Zeta}{sub max} = 4.99 at 8% recombination). Analysis of linkage heterogeneity between five branches of themore » family yielded significant evidence for nonallelic genetic heterogeneity within this family, coinciding with the observed clinical differences. Multipoint analysis, carried out in the branches that showed linkage, favored the locus order 1cen-D1S158-(F13B, RP12)-D1S53-1qter ({Zeta}{sub max} = 9.17). The finding of a single founder allele associated with the disease phenotype supports this localization. This study reveals that even in a large family, apparently segregating for a single disease entity, genetic heterogeneity can be detected and resolved successfully. 35 refs., 5 figs.« less

High-resolution melt analysis to identify and map sequence-tagged site anchor points onto linkage maps: a white lupin (Lupinus albus) map as an exemplar.

PubMed

Croxford, Adam E; Rogers, Tom; Caligari, Peter D S; Wilkinson, Michael J

2008-01-01

* The provision of sequence-tagged site (STS) anchor points allows meaningful comparisons between mapping studies but can be a time-consuming process for nonmodel species or orphan crops. * Here, the first use of high-resolution melt analysis (HRM) to generate STS markers for use in linkage mapping is described. This strategy is rapid and low-cost, and circumvents the need for labelled primers or amplicon fractionation. * Using white lupin (Lupinus albus, x = 25) as a case study, HRM analysis was applied to identify 91 polymorphic markers from expressed sequence tag (EST)-derived and genomic libraries. Of these, 77 generated STS anchor points in the first fully resolved linkage map of the species. The map also included 230 amplified fragment length polymorphisms (AFLP) loci, spanned 1916 cM (84.2% coverage) and divided into the expected 25 linkage groups. * Quantitative trait loci (QTL) analyses performed on the population revealed genomic regions associated with several traits, including the agronomically important time to flowering (tf), alkaloid synthesis and stem height (Ph). Use of HRM-STS markers also allowed us to make direct comparisons between our map and that of the related crop, Lupinus angustifolius, based on the conversion of RFLP, microsatellite and single nucleotide polymorphism (SNP) markers into HRM markers.

Genomewide Scan for Nonsyndromic Cleft Lip and Palate in Multigenerational Indian Families Reveals Significant Evidence of Linkage at 13q33.1-34

PubMed Central

Radhakrishna, Uppala; Ratnamala, Uppala; Gaines, Mathew; Beiraghi, Soraya; Hutchings, David; Golla, Jeffrey; Husain, Syed A.; Gambhir, Prakash S.; Sheth, Jayesh J.; Sheth, Frenny J.; Chetan, Ghati K.; Naveed, Mohammed; Solanki, Jitendra V.; Patel, Uday C.; Master, Dilipkumar C.; Memon, Rafiq; Antonarakis, Gregory S.; Antonarakis, Stylianos E.; Nath, Swapan K.

2006-01-01

Nonsyndromic cleft lip with or without cleft palate (CL-P) is a common congenital anomaly with incidence ranging from 1 in 300 to 1 in 2,500 live births. We analyzed two Indian pedigrees (UR017 and UR019) with isolated, nonsyndromic CL-P, in which the anomaly segregates as an autosomal dominant trait. The phenotype was variable, ranging from unilateral to bilateral CL-P. A genomewide linkage scan that used ∼10,000 SNPs was performed. Nonparametric linkage (NPL) analysis identified 11 genomic regions (NPL>3.5; P<.005) that could potentially harbor CL-P susceptibility variations. Among those, the most significant evidence was for chromosome 13q33.1-34 at marker rs1830756 (NPL=5.57; P=.00024). This was also supported by parametric linkage; MOD score (LOD scores maximized over genetic model parameters) analysis favored an autosomal dominant model. The maximum LOD score was 4.45, and heterogeneity LOD was 4.45 (α=100%). Haplotype analysis with informative crossovers enabled the mapping of the CL-P locus to a region of ∼20.17 cM (7.42 Mb) between SNPs rs951095 and rs726455. Thus, we have identified a novel genomic region on 13q33.1-34 that harbors a high-risk variant for CL-P in these Indian families. PMID:16909398

The Role of Natural Heritage in Rural Development: An Analysis of Economic Linkages in Scotland

ERIC Educational Resources Information Center

Courtney, Paul; Hill, Gary; Roberts, Deborah

2006-01-01

There is growing recognition of the important role played by natural heritage in rural economic development, but limited empirical work as yet to inform this debate. This paper examines the nature and strength of local economic linkages associated with the natural heritage in four case study areas in Scotland, differentiated in terms of their…

Linkage to HIV care after home-based HIV counselling and testing in sub-Saharan Africa: a systematic review.

PubMed

Ruzagira, Eugene; Baisley, Kathy; Kamali, Anatoli; Biraro, Samuel; Grosskurth, Heiner

2017-07-01

Home-based HIV counselling and testing (HBHCT) has the potential to increase HIV testing uptake in sub-Saharan Africa (SSA), but data on linkage to HIV care after HBHCT are scarce. We conducted a systematic review of linkage to care after HBHCT in SSA. Five databases were searched for studies published between 1st January 2000 and 19th August 2016 that reported on linkage to care among adults newly identified with HIV infection through HBHCT. Eligible studies were reviewed, assessed for risk of bias and findings summarised using the PRISMA guidelines. A total of 14 studies from six countries met the eligibility criteria; nine used specific strategies (point-of-care CD4 count testing, follow-up counselling, provision of transport funds to clinic and counsellor facilitation of HIV clinic visit) in addition to routine referral to facilitate linkage to care. Time intervals for ascertaining linkage ranged from 1 week to 12 months post-HBHCT. Linkage ranged from 8.2% [95% confidence interval (CI), 6.8-9.8%] to 99.1% (95% CI, 96.9-99.9%). Linkage was generally lower (<33%) if HBHCT was followed by referral only, and higher (>80%) if additional strategies were used. Only one study assessed linkage by means of a randomised trial. Five studies had data on cotrimoxazole (CTX) prophylaxis and 12 on ART eligibility and initiation. CTX uptake among those eligible ranged from 0% to 100%. The proportion of persons eligible for ART ranged from 16.5% (95% CI, 12.1-21.8) to 77.8% (95% CI, 40.0-97.2). ART initiation among those eligible ranged from 14.3% (95% CI, 0.36-57.9%) to 94.9% (95% CI, 91.3-97.4%). Additional linkage strategies, whilst seeming to increase linkage, were not associated with higher uptake of CTX and/or ART. Most of the studies were susceptible to risk of outcome ascertainment bias. A pooled analysis was not performed because of heterogeneity across studies with regard to design, setting and the key variable definitions. Only few studies from SSA investigated linkage to care among adults newly diagnosed with HIV through HBHCT. Linkage was often low after routine referral but higher if additional interventions were used to facilitate it. The effectiveness of linkage strategies should be confirmed through randomised controlled trials. © 2017 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.

Efficient Record Linkage Algorithms Using Complete Linkage Clustering.

PubMed

Mamun, Abdullah-Al; Aseltine, Robert; Rajasekaran, Sanguthevar

2016-01-01

Data from different agencies share data of the same individuals. Linking these datasets to identify all the records belonging to the same individuals is a crucial and challenging problem, especially given the large volumes of data. A large number of available algorithms for record linkage are prone to either time inefficiency or low-accuracy in finding matches and non-matches among the records. In this paper we propose efficient as well as reliable sequential and parallel algorithms for the record linkage problem employing hierarchical clustering methods. We employ complete linkage hierarchical clustering algorithms to address this problem. In addition to hierarchical clustering, we also use two other techniques: elimination of duplicate records and blocking. Our algorithms use sorting as a sub-routine to identify identical copies of records. We have tested our algorithms on datasets with millions of synthetic records. Experimental results show that our algorithms achieve nearly 100% accuracy. Parallel implementations achieve almost linear speedups. Time complexities of these algorithms do not exceed those of previous best-known algorithms. Our proposed algorithms outperform previous best-known algorithms in terms of accuracy consuming reasonable run times.

[Genetics of bipolar affective disorders. Current status of research for identification of susceptibility genes].

PubMed

Schumacher, J; Cichon, S; Rietschel, M; Nöthen, M M; Propping, P

2002-07-01

Bipolar affective disorder is a highly heritable condition, as evidenced by twin, family, and adoption studies. However, the mode of inheritance is complex and linkage findings have been difficult to replicate. Despite these limitations, consistent linkage findings have emerged for several chromosomes, notably 3p12-p14, 4p16, 10q25-q26, and 12q23-q24. Three additional areas, 13q32-q33, 18p11-q11, and 22q12-q13, have shown linkage in regions that appear to overlap with linkage findings in schizophrenia. These chromosomal regions might harbour genes that contribute to the development of bipolar affective disorder. Recent candidate gene studies include some positive results for the serotonin transporter gene (5-HTT) on 17q11-q12 and the catechol-O-methyltransferase gene (COMT) on 22q11. New methods are being developed for linkage disequilibrium mapping and candidate gene approaches. One can be optimistic that over the next few years bipolar susceptibility genes will be identified.

Efficient Record Linkage Algorithms Using Complete Linkage Clustering

PubMed Central

Mamun, Abdullah-Al; Aseltine, Robert; Rajasekaran, Sanguthevar

2016-01-01

Data from different agencies share data of the same individuals. Linking these datasets to identify all the records belonging to the same individuals is a crucial and challenging problem, especially given the large volumes of data. A large number of available algorithms for record linkage are prone to either time inefficiency or low-accuracy in finding matches and non-matches among the records. In this paper we propose efficient as well as reliable sequential and parallel algorithms for the record linkage problem employing hierarchical clustering methods. We employ complete linkage hierarchical clustering algorithms to address this problem. In addition to hierarchical clustering, we also use two other techniques: elimination of duplicate records and blocking. Our algorithms use sorting as a sub-routine to identify identical copies of records. We have tested our algorithms on datasets with millions of synthetic records. Experimental results show that our algorithms achieve nearly 100% accuracy. Parallel implementations achieve almost linear speedups. Time complexities of these algorithms do not exceed those of previous best-known algorithms. Our proposed algorithms outperform previous best-known algorithms in terms of accuracy consuming reasonable run times. PMID:27124604

An Interaction Landscape of Ubiquitin Signaling.

PubMed

Zhang, Xiaofei; Smits, Arne H; van Tilburg, Gabrielle B A; Jansen, Pascal W T C; Makowski, Matthew M; Ovaa, Huib; Vermeulen, Michiel

2017-03-02

Intracellular signaling via the covalent attachment of different ubiquitin linkages to protein substrates is fundamental to many cellular processes. Although linkage-selective ubiquitin interactors have been studied on a case-by-case basis, proteome-wide analyses have not been conducted yet. Here, we present ubiquitin interactor affinity enrichment-mass spectrometry (UbIA-MS), a quantitative interaction proteomics method that makes use of chemically synthesized diubiquitin to enrich and identify ubiquitin linkage interactors from crude cell lysates. UbIA-MS reveals linkage-selective diubiquitin interactions in multiple cell types. For example, we identify TAB2 and TAB3 as novel K6 diubiquitin interactors and characterize UCHL3 as a K27-linkage selective interactor that regulates K27 polyubiquitin chain formation in cells. Additionally, we show a class of monoubiquitin and K6 diubiquitin interactors whose binding is induced by DNA damage. We expect that our proteome-wide diubiquitin interaction landscape and established workflows will have broad applications in the ongoing efforts to decipher the complex language of ubiquitin signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Computerized analysis and duplication of mandibular motion.

PubMed

Knap, F J; Abler, J H; Richardson, B L

1975-05-01

A new digital system has been devised to analyze and duplicate jaw motion. The arrangement of the electronic system offers a range of versatility which includes graphic as well as numerical data analysis. The duplicator linkage is identical to the sensor linkage which, together with an accurate model transfer system, results in an encouraging level of accuracy in jaw-motion duplication. The data collected from normal subjects should offer some new knowledge in the normal motions of the mandible as well as establish a reference for comparison with abnormal masticatory function.

Individual specific DNA fingerprints from a hypervariable region probe: alpha-globin 3'HVR.

PubMed

Fowler, S J; Gill, P; Werrett, D J; Higgs, D R

1988-06-01

A probe detecting a hypervariable region (HVR) 3' to the alpha globin locus on chromosome 16 has been used to produce DNA fingerprints. Segregation analysis has revealed multiple, randomly dispersed DNA fragments inherited in a Mendelian fashion with minimal allelism and linkage. The fingerprints are highly polymorphic (probability of chance association between random individuals much less than 10(-14]. The probe is, therefore, a powerful discriminating tool: it is envisaged that this probe will have forensic applications, including paternity cases, and will be informative in linkage analysis.

Single nucleotide polymorphisms in an intergenic chromosome 2q region associated with tissue factor pathway inhibitor plasma levels and venous thromboembolism.

PubMed

Dennis, J; Truong, V; Aïssi, D; Medina-Rivera, A; Blankenberg, S; Germain, M; Lemire, M; Antounians, L; Civelek, M; Schnabel, R; Wells, P; Wilson, M D; Morange, P-E; Trégouët, D-A; Gagnon, F

2016-10-01

Essentials Tissue factor pathway inhibitor (TFPI) regulates the blood coagulation cascade. We replicated previously reported linkage of TFPI plasma levels to the chromosome 2q region. The putative causal locus, rs62187992, was associated with TFPI plasma levels and thrombosis. rs62187992 was marginally associated with TFPI expression in human aortic endothelial cells. Click to hear Ann Gil's presentation on new insights into thrombin activatable fibrinolysis inhibitor SUMMARY: Background Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial thromboembolism and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes. Objectives To replicate the finding of the linkage region in an independent sample, and to identify the causal locus. Methods We first performed a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study, and replicated the finding of the linkage peak on chromosome 2q (LOD = 3.06). We next defined a follow-up region that included 112 603 single nucleotide polymorphisms (SNPs) under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and the Marseille Thrombosis Association (MARTHA) Study, a study of 1033 unrelated VTE patients. SNPs with false discovery rate q-values of < 0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene Study. Results and Conclusions One SNP, rs62187992, was associated with TFPI plasma levels in all three samples (β = + 0.14 and P = 4.23 × 10 -6 combined; β = + 0.16 and P = 0.02 in the F5L Family Study; β = + 0.13 and P = 6.3 × 10 -4 in the MARTHA Study; β = + 0.17 and P = 0.03 in the AtheroGene Study), and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio 0.90, P = 0.03) in the INVENT Consortium of > 7000 cases and their controls, and was marginally associated with TFPI expression (β = + 0.19, P = 0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated. © 2016 International Society on Thrombosis and Haemostasis.

Development of gene-based markers for use in construction of the chickpea (Cicer arietinum L.) genetic linkage map and identification of QTLs associated with seed weight and plant height.

PubMed

Gupta, Shefali; Kumar, Tapan; Verma, Subodh; Bharadwaj, Chellapilla; Bhatia, Sabhyata

2015-11-01

Seed weight and plant height are important agronomic traits and contribute to seed yield. The objective of this study was to identify QTLs underlying these traits using an intra-specific mapping population of chickpea. A F11 population of 177 recombinant inbred lines derived from a cross between SBD377 (100-seed weight--48 g and plant height--53 cm) and BGD112 (100-seed weight--15 g and plant height--65 cm) was used. A total of 367 novel EST-derived functional markers were developed which included 187 EST-SSRs, 130 potential intron polymorphisms (PIPs) and 50 expressed sequence tag polymorphisms (ESTPs). Along with these, 590 previously published markers including 385 EST-based markers and 205 genomic SSRs were utilized. Of the 957 markers tested for analysis of parental polymorphism between the two parents of the mapping population, 135 (14.64%) were found to be polymorphic. Of these, 131 polymorphic markers could be mapped to the 8 linkage groups. The linkage map had a total length of 1140.54 cM with an average marker density of 8.7 cM. The map was further used for QTL identification using composite interval mapping method (CIM). Two QTLs each for seed weight, qSW-1 and qSW-2 (explaining 11.54 and 19.24% of phenotypic variance, respectively) and plant height, qPH-1 and qPH-2 (explaining 13.98 and 12.17% of phenotypic variance, respectively) were detected. The novel set of genic markers, the intra-specific linkage map and the QTLs identified in the present study will serve as valuable genomic resources in improving the chickpea seed yield using marker-assisted selection (MAS) strategies.

Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium

PubMed Central

Shete, Sanjay; Lau, Ching C; Houlston, Richard S; Claus, Elizabeth B; Barnholtz-Sloan, Jill; Lai, Rose; Il’yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Johansen, Christoffer; Bernstein, Jonine L; Olson, Sara H; Jenkins, Robert B; Yang, Ping; Vick, Nicholas A; Wrensch, Margaret; Davis, Faith G; McCarthy, Bridget J; Leung, Eastwood Hon-chiu; Davis, Caleb; Cheng, Rita; Hosking, Fay J; Armstrong, Georgina N; Liu, Yanhong; Yu, Robert K; Henriksson, Roger; Consortium, The Gliogene; Melin, Beatrice S; Bondy, Melissa L

2011-01-01

Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have demonstrated that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium SNPs, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P=0.0005) at 17q12–21.32 and the Z-score of 4.20 (P=0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P=0.008) and the Z-score of 1.47 (P=0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P=0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. PMID:22037877

Primary care physicians’ perspectives on facilitating older patients’ access to community support services

PubMed Central

Ploeg, Jenny; Denton, Margaret; Hutchison, Brian; McAiney, Carrie; Moore, Ainsley; Brazil, Kevin; Tindale, Joseph; Lam, Annie

2017-01-01

Abstract Objective To understand how family physicians facilitate older patients’ access to community support services (CSSs) and to identify similarities and differences across primary health care (PHC) models. Design Qualitative, multiple-case study design using semistructured interviews. Setting Four models of PHC delivery, specifically 2 family health teams (FHTs), 4 non-FHTs family health organizations, 4 fee-for-service practices, and 2 community health centres in urban Ontario. Participants Purposeful sampling of 23 family physicians in solo and small and large group practices within the 4 models of PHC. Methods A multiple-case study approach was used. Semistructured interviews were conducted and data were analyzed using within- and cross-case analysis. Case study tactics to ensure study rigour included memos and an audit trail, investigator triangulation, and the use of multiple, rather than single, case studies. Main findings Three main themes were identified: consulting and communicating with the health care team to create linkages; linking patients and families to CSSs; and relying on out-of-date resources and ineffective search strategies for information on CSSs. All participants worked with their team members; however, those in FHTs and community health centres generally had a broader range of health care providers available to assist them. Physicians relied on home-care case managers to help make linkages to CSSs. Physicians recommended the development of an easily searchable, online database containing available CSSs. Conclusion This study shows the importance of interprofessional teamwork in primary care settings to facilitate linkages of older patients to CSSs. The study also provides insight into the strategies physicians use to link older persons to CSSs and their recommendations for change. This understanding can be used to develop resources and approaches to better support physicians in making appropriate linkages to CSSs. PMID:28115458

Novel QTL at chromosome 6p22 for alcohol consumption: Implications for the genetic liability of alcohol use disorders

PubMed Central

Kos, Mark Z.; Glahn, David C.; Carless, Melanie A.; Olvera, Rene; McKay, D. Reese; Quillen, Ellen E.; Gelernter, Joel; Chen, Xiang-Ding; Deng, Hong-Wen; Kent, Jack W.; Dyer, Thomas D.; Göring, Harald H.H.; Curran, Joanne E.; Duggirala, Ravi; Blangero, John; Almasy, Laura

2014-01-01

Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hour period (abbreviated Max Drinks), a significantly heritable phenotype (h2 = 0.32 ± 0.05; P = 4.61 × 10−14) with a strong genetic correlation with AUD (ρg = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10−6) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10−3), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10−4), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific. PMID:24692236

The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders.

PubMed

Naluai, A T; Nilsson, S; Samuelsson, L; Gudjónsdóttir, A H; Ascher, H; Ek, J; Hallberg, B; Kristiansson, B; Martinsson, T; Nerman, O; Sollid, L M; Wahlström, J

2000-10-01

The effect of the gene region on chromosome 2q33 containing the CD28 and the cytotoxic T-lymphocyte associated (CTLA4) genes has been investigated in several diseases with chronic inflammatory nature. In addition to celiac disease (CD), type I diabetes, Grave's disease, rheumatoid arthritis and multiple sclerosis have all demonstrated associations to the A/G single nucleotide polymorphism (SNP) in exon 1, position +49 of the CTLA4 gene. The purpose of this study was to investigate this gene region in a genetically homogeneous population consisting of 107 Swedish and Norwegian families with CD using genetic association and linkage methods. We found a significant association with preferential transmission of the A-allele of the exon 1 +49 polymorphism by using the transmission disequilibrium test (TDT). Suggestive linkage of this region to CD was moreover demonstrated by non-parametric linkage (NPL) analysis giving a NPL-score of 2.1. These data strongly indicates that the CTLA4 region is a susceptibility region in CD. Interestingly, of the several chronic inflammatory diseases that exhibit associations to the CTLA4 +49 A/G dimorphism, CD appears to be the only disease associated to the A allele. This suggests that the +49 alleles of the CTLA4 gene are in linkage disequilibrium with two distinct disease predisposing alleles with separate effects. The peculiar association found in the gut disorder CD may possibly relate to the fact that the gastrointestinal immune system, in contrast to the rest of the immune system, aims to establish tolerance to foreign proteins.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tahvanainen, E.; Karila, E.; Kolehmainen, J.

We recently assigned a gene for autosomal recessive cornea plana congenita (CNA2; MIM No. 217300) by linkage analysis to the approximately 3-cM interval between markers D12S82 and D12S327. Here, we extended these studies by exploiting the haplotype and linkage disequilibrium information that can be derived from the genetically isolated Finnish population and its subpopulations. By testing 32 independent families with 10 polymorphic markers in the CNA2 interval, strong allelic association between CNA2 and a set of markers with a peak at marker D12S351 was detected. Based on linkage disequilibrium analysis, the critical region for CNA2 could be narrowed to onlymore » 0.04-0.3 cM from marker D12S351, thus defining a critical interval 0.08-0.60 cM in length. These results provide a basis for highly focused positional cloning of CNA2. 18 refs., 5 figs., 1 tab.« less

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

PubMed Central

Wright, Fred A.; Strug, Lisa J.; Doshi, Vishal K.; Commander, Clayton W.; Blackman, Scott M.; Sun, Lei; Berthiaume, Yves; Cutler, David; Cojocaru, Andreea; Collaco, J. Michael; Corey, Mary; Dorfman, Ruslan; Goddard, Katrina; Green, Deanna; Kent, Jack W.; Lange, Ethan M.; Lee, Seunggeun; Li, Weili; Luo, Jingchun; Mayhew, Gregory M.; Naughton, Kathleen M.; Pace, Rhonda G.; Paré, Peter; Rommens, Johanna M.; Sandford, Andrew; Stonebraker, Jaclyn R.; Sun, Wei; Taylor, Chelsea; Vanscoy, Lori L.; Zou, Fei; Blangero, John; Zielenski, Julian; O’Neal, Wanda K.; Drumm, Mitchell L.; Durie, Peter R.; Knowles, Michael R.; Cutting, Garry R.

2012-01-01

A combined genome-wide association and linkage study was used to identify loci causing variation in CF lung disease severity. A significant association (P=3. 34 × 10-8) near EHF and APIP (chr11p13) was identified in F508del homozygotes (n=1,978). The association replicated in F508del homozygotes (P=0.006) from a separate family-based study (n=557), with P=1.49 × 10-9 for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family-based study identified a significant QTL on chromosome 20q13.2 (LOD=5.03). Our findings provide insight into the causes of variation in lung disease severity in CF and suggest new therapeutic targets for this life-limiting disorder. PMID:21602797

Localization of an Ataxia-Telangiectasia Gene to an −500-kb Interval on Chromosome 11q23.1: Linkage Analysis of 176 Families by an International Consortium

PubMed Central

Lange, Ethan; Borresen, Anna-Lise; Chen, Xiaoguang; Chessa, Luciana; Chiplunkar, Sujata; Concannon, Patrick; Dandekar, Sugandha; Gerken, Steven; Lange, Kenneth; Liang, Teresa; McConville, Carmel; Polakow, Jeff; Porras, Oscar; Rotman, Galit; Sanal, Ozden; Sheikhavandi, Sepideh; Shiloh, Yosef; Sobel, Eric; Taylor, Malcolm; Telatar, Milhan; Teraoka, Sharon; Tolun, Aslihan; Udar, Nitin; Uhrhammer, Nancy; Vanagaite, Lina; Wang, Zhijun; Wapelhorst, Beth; Wright, Jocyndra; Yang, Huan-Ming; Yang, Lan; Ziv, Yael; Gatti, Richard A.

1995-01-01

We describe a 20-point linkage analysis map of chromosome 11q22-23 that is based on genotyping 249 families (59 CEPH and 190 A-T). Monte Carlo linkage analyses of 176 ataxia-telangiectasia (A-T) families localizes the major A-T locus to the region between S1819(A4) and S1818(A2). When seven nonlinking families were excluded from subsequent analyses, a 2-lod support interval of ∼500 kb was identified between S1819(A4) and S1294. No recombinants were observed between A-T and markers S384, B7, S535, or S1294. Only 17 of the international consortium families have been assigned to complementation groups. The available evidence favors either a cluster of A-T genes on chromosome 11 or intragenic defects in a single gene. PMID:7611279

Analysis of ethnic disparities in workers' compensation claims using data linkage.

PubMed

Friedman, Lee S; Ruestow, Peter; Forst, Linda

2012-10-01

The overall goal of this research project was to assess ethnic disparities in monetary compensation among construction workers injured on the job through the linkage of medical records and workers' compensation data. Probabilistic linkage of medical records with workers' compensation claim data. In the final multivariable robust regression model, compensation was $5824 higher (P = 0.030; 95% confidence interval: 551 to 11,097) for white non-Hispanic workers than for other ethnic groups when controlling for injury severity, affected body region, type of injury, average weekly wage, weeks of temporary total disability, percent permanent partial disability, death, or attorney use. The analysis indicates that white non-Hispanic construction workers are awarded higher monetary settlements despite the observation that for specific injuries the mean temporary total disability and permanent partial disability were equivalent to or lower than those in Hispanic and black construction workers.

African American church-based HIV testing and linkage to care: assets, challenges and needs.

PubMed

Stewart, Jennifer M; Thompson, Keitra; Rogers, Christopher

2016-01-01

The US National HIV AIDS strategy promotes the use of faith communities to lessen the burden of HIV in African American communities. One specific strategy presented is the use of these non-traditional venues for HIV testing and co-location of services. African American churches can be at the forefront of this endeavour through the provision of HIV testing and linkage to care. However, there are few interventions to promote the churches' involvement in both HIV testing and linkage to care. We conducted 4 focus groups (n = 39 participants), 4 interviews and 116 surveys in a mixed-methods study to examine the feasibility of a church-based HIV testing and linkage to care intervention in Philadelphia, PA, USA. Our objectives were to examine: (1) available assets, (2) challenges and barriers and (3) needs associated with church-based HIV testing and linkage to care. Analyses revealed several factors of importance, including the role of the church as an access point for testing in low-income neighbourhoods, challenges in openly discussing the relationship between sexuality and HIV, and buy-in among church leadership. These findings can support intervention development and necessitate situating African American church-based HIV testing and linkage to care interventions within a multi-level framework.

Grinding Method and Error Analysis of Eccentric Shaft Parts

NASA Astrophysics Data System (ADS)

Wang, Zhiming; Han, Qiushi; Li, Qiguang; Peng, Baoying; Li, Weihua

2017-12-01

RV reducer and various mechanical transmission parts are widely used in eccentric shaft parts, The demand of precision grinding technology for eccentric shaft parts now, In this paper, the model of X-C linkage relation of eccentric shaft grinding is studied; By inversion method, the contour curve of the wheel envelope is deduced, and the distance from the center of eccentric circle is constant. The simulation software of eccentric shaft grinding is developed, the correctness of the model is proved, the influence of the X-axis feed error, the C-axis feed error and the wheel radius error on the grinding process is analyzed, and the corresponding error calculation model is proposed. The simulation analysis is carried out to provide the basis for the contour error compensation.

Linkage localization of the thoraco-abdominal syndrome (TAS) gene to Xq25-26.

PubMed

Parvari, R; Weinstein, Y; Ehrlich, S; Steinitz, M; Carmi, R

1994-02-15

The thoraco-abdominal syndrome (TAS) presents a closure defect confined to the ventral midline, manifested as ventral hernia of various degrees in all affected individuals and antero-lateral diaphragmatic defect manifested almost exclusively in affected males. The syndrome is inherited as an X-linked dominant trait affecting blastogenesis (XLB mutation). We studied 27 members of the TAS family for linkage on the X chromosome. The best lod score of 5.5 at theta 0.04 was found for the HPRT locus on Xq26.1. A multilocus lod score of 12.4 was observed when the linkage analysis utilized additional markers in Xq25-26.

Biomechanical design of escalading lower limb exoskeleton with novel linkage joints.

PubMed

Zhang, Guoan; Liu, Gangfeng; Ma, Sun; Wang, Tianshuo; Zhao, Jie; Zhu, Yanhe

2017-07-20

In this paper, an obstacle-surmounting-enabled lower limb exoskeleton with novel linkage joints that perfectly mimicked human motions was proposed. Currently, most lower exoskeletons that use linear actuators have a direct connection between the wearer and the controlled part. Compared to the existing joints, the novel linkage joint not only fitted better into compact chasis, but also provided greater torque when the joint was at a large bend angle. As a result, it extended the angle range of joint peak torque output. With any given power, torque was prioritized over rotational speed, because instead of rotational speed, sufficiency of torque is the premise for most joint actions. With insufficient torque, the exoskeleton will be a burden instead of enhancement to its wearer. With optimized distribution of torque among the joints, the novel linkage method may contribute to easier exoskeleton movements.

Long-range evolutionary constraints reveal cis-regulatory interactions on the human X chromosome

PubMed Central

Naville, Magali; Ishibashi, Minaka; Ferg, Marco; Bengani, Hemant; Rinkwitz, Silke; Krecsmarik, Monika; Hawkins, Thomas A.; Wilson, Stephen W.; Manning, Elizabeth; Chilamakuri, Chandra S. R.; Wilson, David I.; Louis, Alexandra; Lucy Raymond, F.; Rastegar, Sepand; Strähle, Uwe; Lenhard, Boris; Bally-Cuif, Laure; van Heyningen, Veronica; FitzPatrick, David R.; Becker, Thomas S.; Roest Crollius, Hugues

2015-01-01

Enhancers can regulate the transcription of genes over long genomic distances. This is thought to lead to selection against genomic rearrangements within such regions that may disrupt this functional linkage. Here we test this concept experimentally using the human X chromosome. We describe a scoring method to identify evolutionary maintenance of linkage between conserved noncoding elements and neighbouring genes. Chromatin marks associated with enhancer function are strongly correlated with this linkage score. We test >1,000 putative enhancers by transgenesis assays in zebrafish to ascertain the identity of the target gene. The majority of active enhancers drive a transgenic expression in a pattern consistent with the known expression of a linked gene. These results show that evolutionary maintenance of linkage is a reliable predictor of an enhancer's function, and provide new information to discover the genetic basis of diseases caused by the mis-regulation of gene expression. PMID:25908307

A locus for isolated cataract on human Xp

PubMed Central

Francis, P; Berry, V; Hardcastle, A; Maher, E; Moore, A; Bhattacharya, S

2002-01-01

Purpose: To genetically map the gene causing isolated X linked cataract in a large European pedigree. Methods: Using the patient registers at Birmingham Women's Hospital, UK, we identified and examined 23 members of a four generation family with nuclear cataract. Four of six affected males also had complex congenital heart disease. Pedigree data were collated and leucocyte DNA extracted from venous blood. Linkage analysis by PCR based microsatellite marker genotyping was used to identify the disease locus and mutations within candidate genes screened by direct sequencing. Results: The disease locus was genetically refined to chromosome Xp22, within a 3 cM linkage interval flanked by markers DXS9902 and DXS999 (Zmax=3.64 at θ=0 for marker DXS8036). Conclusions: This is the first report of a locus for isolated inherited cataract on the X chromosome. The disease interval lies within the Nance-Horan locus suggesting allelic heterogeneity. The apparent association with congenital cardiac anomalies suggests a possible new oculocardiac syndrome. PMID:11836358

People’s Preferences of Urban Design Qualities for Walking on a Commercial Street

NASA Astrophysics Data System (ADS)

Ernawati, J.; Surjono; Sudarmo, B. S.

2018-03-01

This research aims to explore people’s preferences of urban design qualities for walking on a commercial street, with Kawi Street located in a commercial neighborhood in the town of Malang Indonesia as the case study. Based on a literature review, this study used eight urban design qualities, i.e., enclosure, legibility, human scale, transparency, complexity, coherence, linkage, and imageability. This study applied a survey research method using a self-administered paper-pencil questionnaire applying two measurement techniques: Likert scale was used to explore people’s evaluations of urban design qualities of the street, while multiple-rating scales were used to measure people’s preference for walking on the street. One hundred and ten people randomly selected as respondents. Regression analysis was employed to explore the influence of urban design qualities on people preference for walking. Results indicated four urban design qualities that affect people’s choice for walking on a commercial street, i.e., transparency, coherence, linkage, and imageability. Implications of the findings will be discussed in the paper.

A Genetic Linkage Map of the Male Goat Genome

PubMed Central

Vaiman, D.; Schibler, L.; Bourgeois, F.; Oustry, A.; Amigues, Y.; Cribiu, E. P.

1996-01-01

This paper presents a first genetic linkage map of the goat genome. Primers derived from the flanking sequences of 612 bovine, ovine and goat microsatellite markers were gathered and tested for amplification with goat DNA under standardized PCR conditions. This screen made it possible to choose a set of 55 polymorphic markers that can be used in the three species and to define a panel of 223 microsatellites suitable for the goat. Twelve half-sib paternal goat families were then used to build a linkage map of the goat genome. The linkage analysis made it possible to construct a meiotic map covering 2300 cM, i.e., >80% of the total estimated length of the goat genome. Moreover, eight cosmids containing microsatellites were mapped by fluorescence in situ hybridization in goat and sheep. Together with 11 microsatellite-containing cosmids previously mapped in cattle (and supposing conservation of the banding pattern between this species and the goat) and data from the sheep map, these results made the orientation of 15 linkage groups possible. Furthermore, 12 coding sequences were mapped either genetically or physically, providing useful data for comparative mapping. PMID:8878693

Linkage and Branch Analysis of High-Mannose Oligosaccharides Using Closed-Ring Labeling of 8-Aminopyrene-1,3,6-Trisulfonate and P-Aminobenzoic Ethyl Ester and Negative Ion Trap Mass Spectrometry

NASA Astrophysics Data System (ADS)

Chen, Shu-Ting; Her, Guor-Rong

2012-08-01

A strategy based on negative ion electrospray ionization tandem mass spectrometry and closed-ring labeling with both 8-aminopyrene-1,3,6-trisulfonate (APTS) and p-aminobenzoic acid ethyl ester (ABEE) was developed for linkage and branch determination of high-mannose oligosaccharides. X-type cross-ring fragment ions obtained from APTS-labeled oligosaccharides by charge remote fragmentation provided information on linkages near the non-reducing terminus. In contrast, A-type cross-ring fragment ions observed from ABEE-labeled oligosaccharides yielded information on linkages near the reducing terminus. This complementary information provided by APTS- and ABEE-labeled oligosaccharides was utilized to delineate the structures of the high-mannose oligosaccharides. As a demonstration of this approach, the linkages and branches of high-mannose oligosaccharides Man5GlcNAc2, Man6GlcNAc2, Man8GlcNAc2, and Man9GlcNAc2 cleaved from the ribonuclease B were assigned from MS2 spectra of ABEE- and APTS-labeled derivatives.

Linkage study of nonsyndromic cleft lip with or without cleft palate using candidate genes and mapped polymorphic markers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stein, J.D.; Nelson, L.D.; Conner, B.J.

1994-09-01

Nonsyndromic cleft lip with or without cleft palate (CL(P)) involves fusion or growth failure of facial primordia during development. Complex segregation analysis of clefting populations suggest that an autosomal dominant gene may play a role in this common craniofacial disorder. We have ascertained 16 multigenerational families with CL(P) and tested linkage to 29 candidate genes and 139 mapped short tandem repeat markers. The candidate genes were selected based on their expression in craniofacial development or were identified through murine models. These include: TGF{alpha}, TGF{beta}1, TGF{beta}2, TGF{beta}3, EGF, EGFR, GRAS, cMyc, FGFR, Jun, JunB, PDFG{alpha}, PDGF{beta}, IGF2R, GCR Hox7, Hox8, Hox2B,more » twirler, 5 collagen and 3 extracellular matrix genes. Linkage was tested assuming an autosomal dominant model with sex-specific decreased penetrance. Linkage to all of the candidate loci was excluded in 11 families. RARA was tested and was not informative. However, haplotype analysis of markers flanking RARA on 17q allowed exclusion of this candidate locus. We have previously excluded linkage to 61 STR markers in 11 families. Seventy-eight mapped short tandem repeat markers have recently been tested in 16 families and 30 have been excluded. The remaining are being analyzed and an exclusion map is being developed based on the entire study results.« less

Motor sequencing deficit as an endophenotype of speech sound disorder: a genome-wide linkage analysis in a multigenerational family.

PubMed

Peter, Beate; Matsushita, Mark; Raskind, Wendy H

2012-10-01

The aim of this pilot study was to investigate a measure of motor sequencing deficit as a potential endophenotype of speech sound disorder (SSD) in a multigenerational family with evidence of familial SSD. In a multigenerational family with evidence of a familial motor-based SSD, affectation status and a measure of motor sequencing during oral motor testing were obtained. To further investigate the role of motor sequencing as an endophenotype for genetic studies, parametric and nonparametric linkage analyses were carried out using a genome-wide panel of 404 microsatellites. In seven of the 10 family members with available data, SSD affectation status and motor sequencing status coincided. Linkage analysis revealed four regions of interest, 6p21, 7q32, 7q36, and 8q24, primarily identified with the measure of motor sequencing ability. The 6p21 region overlaps with a locus implicated in rapid alternating naming in a recent genome-wide dyslexia linkage study. The 7q32 locus contains a locus implicated in dyslexia. The 7q36 locus borders on a gene known to affect the component traits of language impairment. The results are consistent with a motor-based endophenotype of SSD that would be informative for genetic studies. The linkage results in this first genome-wide study in a multigenerational family with SSD warrant follow-up in additional families and with fine mapping or next-generation approaches to gene identification.

An ultra-high density linkage map and QTL mapping for sex and growth-related traits of common carp (Cyprinus carpio)

PubMed Central

Peng, Wenzhu; Xu, Jian; Zhang, Yan; Feng, Jianxin; Dong, Chuanju; Jiang, Likun; Feng, Jingyan; Chen, Baohua; Gong, Yiwen; Chen, Lin; Xu, Peng

2016-01-01

High density genetic linkage maps are essential for QTL fine mapping, comparative genomics and high quality genome sequence assembly. In this study, we constructed a high-density and high-resolution genetic linkage map with 28,194 SNP markers on 14,146 distinct loci for common carp based on high-throughput genotyping with the carp 250 K single nucleotide polymorphism (SNP) array in a mapping family. The genetic length of the consensus map was 10,595.94 cM with an average locus interval of 0.75 cM and an average marker interval of 0.38 cM. Comparative genomic analysis revealed high level of conserved syntenies between common carp and the closely related model species zebrafish and medaka. The genome scaffolds were anchored to the high-density linkage map, spanning 1,357 Mb of common carp reference genome. QTL mapping and association analysis identified 22 QTLs for growth-related traits and 7 QTLs for sex dimorphism. Candidate genes underlying growth-related traits were identified, including important regulators such as KISS2, IGF1, SMTLB, NPFFR1 and CPE. Candidate genes associated with sex dimorphism were also identified including 3KSR and DMRT2b. The high-density and high-resolution genetic linkage map provides an important tool for QTL fine mapping and positional cloning of economically important traits, and improving common carp genome assembly. PMID:27225429

First High-Density Linkage Map and Single Nucleotide Polymorphisms Significantly Associated With Traits of Economic Importance in Yellowtail Kingfish Seriola lalandi.

PubMed

Nguyen, Nguyen H; Rastas, Pasi M A; Premachandra, H K A; Knibb, Wayne

2018-01-01

The genetic resources available for the commercially important fish species Yellowtail kingfish (YTK) ( Seriola lalandi) are relative sparse. To overcome this, we aimed (1) to develop a linkage map for this species, and (2) to identify markers/variants associated with economically important traits in kingfish (with an emphasis on body weight). Genetic and genomic analyses were conducted using 13,898 single nucleotide polymorphisms (SNPs) generated from a new high-throughput genotyping by sequencing platform, Diversity Arrays Technology (DArTseq TM ) in a pedigreed population comprising 752 animals. The linkage analysis enabled to map about 4,000 markers to 24 linkage groups (LGs), with an average density of 3.4 SNPs per cM. The linkage map was integrated into a genome-wide association study (GWAS) and identified six variants/SNPs associated with body weight ( P < 5e -8 ) when a multi-locus mixed model was used. Two out of the six significant markers were mapped to LGs 17 and 23, and collectively they explained 5.8% of the total genetic variance. It is concluded that the newly developed linkage map and the significantly associated markers with body weight provide fundamental information to characterize genetic architecture of growth-related traits in this population of YTK S. lalandi .

Evaluation of Hydrologic and Meteorological Impacts on Dengue Fever Incidences in Southern Taiwan using Time- Frequency Method

NASA Astrophysics Data System (ADS)

Tsai, Christina; Yeh, Ting-Gu

2017-04-01

Extreme weather events are occurring more frequently as a result of climate change. Recently dengue fever has become a serious issue in southern Taiwan. It may have characteristic temporal scales that can be identified. Some researchers have hypothesized that dengue fever incidences are related to climate change. This study applies time-frequency analysis to time series data concerning dengue fever and hydrologic and meteorological variables. Results of three time-frequency analytical methods - the Hilbert Huang transform (HHT), the Wavelet Transform (WT) and the Short Time Fourier Transform (STFT) are compared and discussed. A more effective time-frequency analysis method will be identified to analyze relevant time series data. The most influential time scales of hydrologic and meteorological variables that are associated with dengue fever are determined. Finally, the linkage between hydrologic/meteorological factors and dengue fever incidences can be established.

Characterization of Isomeric Glycans by Reversed Phase Liquid Chromatography-Electronic Excitation Dissociation Tandem Mass Spectrometry

NASA Astrophysics Data System (ADS)

Tang, Yang; Wei, Juan; Costello, Catherine E.; Lin, Cheng

2018-04-01

The occurrence of numerous structural isomers in glycans from biological sources presents a severe challenge for structural glycomics. The subtle differences among isomeric structures demand analytical methods that can provide structural details while working efficiently with on-line glycan separation methods. Although liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful tool for mixture analysis, the commonly utilized collision-induced dissociation (CID) method often does not generate a sufficient number of fragments at the MS2 level for comprehensive structural characterization. Here, we studied the electronic excitation dissociation (EED) behaviors of metal-adducted, permethylated glycans, and identified key spectral features that could facilitate both topology and linkage determinations. We developed an EED-based, nanoscale, reversed phase (RP)LC-MS/MS platform, and demonstrated its ability to achieve complete structural elucidation of up to five structural isomers in a single LC-MS/MS analysis. [Figure not available: see fulltext.

Identifying Loci for the Overlap between Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Using a Genome-Wide QTL Linkage Approach

ERIC Educational Resources Information Center

Nijmeijer, Judith S.; Arias-Vasquez, Alejandro; Rommelse, Nanda N. J.; Altink, Marieke E.; Anney, Richard J. L.; Asherson, Philip; Banaschewski, Tobias; Buschgens, Cathelijne J. M.; Fliers, Ellen A.; Gill, Michael; Minderaa, Ruud B.; Poustka, Luise; Sergeant, Joseph A.; Buitelaar, Jan K.; Franke, Barbara; Ebstein, Richard P.; Miranda, Ana; Mulas, Fernando; Oades, Robert D.; Roeyers, Herbert; Rothenberger, Aribert; Sonuga-Barke, Edmund J. S.; Steinhausen, Hans-Christoph; Faraone, Stephen V.; Hartman, Catharina A.; Hoekstra, Pieter J.

2010-01-01

Objective: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. Method: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD and 1,453 siblings were analyzed. The total and…

Actuation for simultaneous motions and constraining efforts: an open chain example

NASA Astrophysics Data System (ADS)

Perreira, N. Duke

1997-06-01

A brief discussion on systems where simultaneous control of forces and velocities are desirable is given and an example linkage with revolute and prismatic joint is selected for further analysis. The Newton-Euler approach for dynamic system analysis is applied to the example to provide a basis of comparison. Gauge invariant transformations are used to convert the dynamic equations into invariant form suitable for use in a new dynamic system analysis method known as the motion-effort approach. This approach uses constraint elimination techniques based on singular value decompositions to recast the invariant form of dynamic system equations into orthogonal sets of motion and effort equations. Desired motions and constraining efforts are partitioned into ideally obtainable and unobtainable portions which are then used to determine the required actuation. The method is applied to the example system and an analytic estimate to its success is made.

Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics.

PubMed Central

Sobel, E.; Lange, K.

1996-01-01

The introduction of stochastic methods in pedigree analysis has enabled geneticists to tackle computations intractable by standard deterministic methods. Until now these stochastic techniques have worked by running a Markov chain on the set of genetic descent states of a pedigree. Each descent state specifies the paths of gene flow in the pedigree and the founder alleles dropped down each path. The current paper follows up on a suggestion by Elizabeth Thompson that genetic descent graphs offer a more appropriate space for executing a Markov chain. A descent graph specifies the paths of gene flow but not the particular founder alleles traveling down the paths. This paper explores algorithms for implementing Thompson's suggestion for codominant markers in the context of automatic haplotyping, estimating location scores, and computing gene-clustering statistics for robust linkage analysis. Realistic numerical examples demonstrate the feasibility of the algorithms. PMID:8651310

Xylanases, nucleic acids encoding them and methods for making and using them

DOEpatents

Gray, Kevin A; Dirmeier, Reinhard

2013-07-16

The invention relates to enzymes having xylanase, mannanase and/or glucanase activity, e.g., catalyzing hydrolysis of internal .beta.-1,4-xylosidic linkages or endo-.beta.-1,4-glucanase linkages; and/or degrading a linear polysaccharide beta-1,4-xylan into xylose. Thus, the invention provides methods and processes for breaking down hemicellulose, which is a major component of the cell wall of plants, including methods and processes for hydrolyzing hemicelluloses in any plant or wood or wood product, wood waste, paper pulp, paper product or paper waste or byproduct. In addition, methods of designing new xylanases, mannanases and/or glucanases and methods of use thereof are also provided. The xylanases, mannanases and/or glucanases have increased activity and stability at increased pH and temperature.

Xylanases, nucleic acids encoding them and methods for making and using them

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gray, Kevin A.; Dirmeier, Richard

The invention relates to enzymes having xylanase, mannanase and/or glucanase activity, e.g., catalyzing hydrolysis of internal .beta.-1,4-xylosidic linkages or endo-.beta.-1,4-glucanase linkages; and/or degrading a linear polysaccharide beta-1,4-xylan into xylose. Thus, the invention provides methods and processes for breaking down hemicellulose, which is a major component of the cell wall of plants, including methods and processes for hydrolyzing hemicelluloses in any plant or wood or wood product, wood waste, paper pulp, paper product or paper waste or byproduct. In addition, methods of designing new xylanases, mannanases and/or glucanases and methods of use thereof are also provided. The xylanases, mannanases and/or glucanasesmore » have increased activity and stability at increased pH and temperature.« less

Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.

PubMed

Bailey-Wilson, Joan E; Childs, Erica J; Cropp, Cheryl D; Schaid, Daniel J; Xu, Jianfeng; Camp, Nicola J; Cannon-Albright, Lisa A; Farnham, James M; George, Asha; Powell, Isaac; Carpten, John D; Giles, Graham G; Hopper, John L; Severi, Gianluca; English, Dallas R; Foulkes, William D; Mæhle, Lovise; Møller, Pål; Eeles, Rosalind; Easton, Douglas; Guy, Michelle; Edwards, Steve; Badzioch, Michael D; Whittemore, Alice S; Oakley-Girvan, Ingrid; Hsieh, Chih-Lin; Dimitrov, Latchezar; Stanford, Janet L; Karyadi, Danielle M; Deutsch, Kerry; McIntosh, Laura; Ostrander, Elaine A; Wiley, Kathleen E; Isaacs, Sarah D; Walsh, Patrick C; Thibodeau, Stephen N; McDonnell, Shannon K; Hebbring, Scott; Lange, Ethan M; Cooney, Kathleen A; Tammela, Teuvo L J; Schleutker, Johanna; Maier, Christiane; Bochum, Sylvia; Hoegel, Josef; Grönberg, Henrik; Wiklund, Fredrik; Emanuelsson, Monica; Cancel-Tassin, Geraldine; Valeri, Antoine; Cussenot, Olivier; Isaacs, William B

2012-06-19

Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.