bluuebunny/crossref_metadata_2025 huggingface dataset:
Fitting long‐tailed distribution to empirical data
Authors: Gil Joseph (Yossi) , Monni Cristina
Published: July 2017

Power laws can fit a variety of distributions coming from real data, so a systematic approach to the measurement of the accuracy of fitting algorithms is essential. We discuss the limits of the analysis of empirical fat‐tailed distributions, which can describe a variety of evolving systems, both natural and man‐made. An algorithm to fit fat‐tailed distributions is presented and tested against samplings of the power law, the Yule, the log‐normal, and Weibull distributions. We compute the parameters defining the shape of each distribution and test the results against simulations. We compare our method with another state‐of‐the‐art technique to estimate the parameters of empirical distributions. The accuracy of the estimations is discussed, and we conclude that our method based on a weighted iterated χ2 test performs better than the other. Our algorithm is general and can be applied to any numerical dataset.
What approaches for promoting shared decision‐making are used in child mental health? A scoping review
Authors: Cheng Helen , Hayes Daniel , Edbrooke‐Childs Julian , Martin Kate , Chapman Louise , Wolpert Miranda
Published: July 2017

Objective

Whilst the benefits of shared decision‐making (SDM) have been promoted across different health settings, its implementation is complex, particularly for children and young people with mental health difficulties. The aim of this scoping review was to identify and describe SDM approaches (tools, techniques, and technologies) used in child and youth mental health.

Method

Electronic databases and grey literature were searched. Papers were included if they satisfied these criteria: English language; described an SDM approach (tool, technique, or technology); included sufficient detail on the SDM approach for quality assessment; did not use only a questionnaire to provide feedback on SDM or related concepts (e.g., therapeutic alliance) without another SDM approach; child or adolescent population (up to 18 years); carers of children or adolescents; and mental health setting. Screening and data extraction were performed by two co‐authors, and each included record was quality assessed against a set of essential ingredients of SDM identified by previous studies.

Results

Of the 8,153 initial results, 22 were eligible for final inclusion. These could be grouped into six approaches: therapeutic techniques, psychoeducational information, decision aids, action planning or goal setting, discussion prompts, and mobilizing patients to engage. The quality of approaches identified ranged from one to seven of the nine essential elements of SDM.

Conclusion

Evidence suggests that a range of approaches are being developed to support SDM in child and youth mental health. Rigorous research evaluating the effectiveness of these approaches is urgently needed, particularly from the perspective of children and young people.
DUCR: Distributed unequal cluster‐based routing algorithm for heterogeneous wireless sensor networks
Authors: Mazumdar Nabajyoti , Om Hari
Published: July 2017

Designing energy efficient communication protocols for wireless sensor networks (WSNs) to conserve the sensors' energy is one of the prime concerns. Clustering in WSNs significantly reduces the energy consumption in which the nodes are organized in clusters, each having a cluster head (CH). The CHs collect data from their cluster members and transmit it to the base station via a single or multihop communication. The main issue in such mechanism is how to associate the nodes to CHs and how to route the data of CHs so that the overall load on CHs are balanced. Since the sensor nodes operate autonomously, the methods designed for WSNs should be of distributed nature, i.e., each node should run it using its local information only. Considering these issues, we propose a distributed multiobjective‐based clustering method to assign a sensor node to appropriate CH so that the load is balanced. We also propose an energy‐efficient routing algorithm to balance the relay load among the CHs. In case any CH dies, we propose a recovery strategy for its cluster members. All our proposed methods are completely distributed in nature. Simulation results demonstrate the efficiency of the proposed algorithm in terms of energy consumption and hence prolonging the network lifetime. We compare the performance of the proposed algorithm with some existing algorithms in terms of number of alive nodes, network lifetime, energy efficiency, and energy population.
Fine‐needle aspiration findings of a rare hematopoietic neoplasm presenting as obstructive jaundice
Authors: Tracht Jessica , Ahmed Ali M. , Rosenblum Donath Frida
Published: July 2017

A 51‐year‐old female who presented with obstructive jaundice was found to have masses in the pancreatic head and tail as well as suspicious liver and periaortic masses on imaging. Aspiration cytology of the pancreatic tail mass showed abundant large single cells with vacuolated eosinophilic cytoplasm, marked nuclear pleomorphism, large bizarre irregular nuclei, binucleation, and prominent nucleoli. Numerous cells also showed intracytoplasmic black to brown pigmentation. A cell block was obtained and extensive immunohistochemical staining was performed. S‐100, HMB‐45, Sox10, pancytokeratin, CK7, RCC antigen, synaptophysin, HepPar 1, inhibin, CD45, CD21, and CD123 were negative, making melanoma, epithelial malignancies, lymphoma, follicular dendritic and plasmacytoid dendritic cell neoplasms less likely. CD4 and CD56 showed partial positivity, and CD68, CD163, and CD14 were positive, supporting the diagnosis of histiocytic sarcoma. Surgical specimens and immunohistochemistry confirmed the cytologic findings. Histiocytic sarcoma is a rare aggressive malignancy of histiocytic origin with most cases presenting in adults in extranodal sites, most commonly the intestinal tract. Few cases are reported in the literature, presenting diagnostic challenges for cytopathologists when seen on fine‐needle aspiration. We present the first reported case of histiocytic sarcoma presenting as a pancreatic mass, diagnosed by endoscopic ultrasound guided fine‐needle aspiration (EUS‐FNA). This entity is rarely described on cytology and arose in a location in which EUS‐FNA is the diagnostic modality of choice. This case study highlights that cytopathologists should be aware of histiocytic sarcoma occurring in extranodal locations accessible by EUS‐FNA and be familiar with the cytomorphologic appearance.
Identifying coevolving loci using interspecific genetic correlations
Authors: Nuismer Scott L. , Jenkins Christina E. , Dybdahl Mark F.
Published: July 2017

Evaluating the importance of coevolution for a wide range of evolutionary questions, such as the role parasites play in the evolution of sexual reproduction, requires that we understand the genetic basis of coevolutionary interactions. Despite its importance, little progress has been made identifying the genetic basis of coevolution, largely because we lack tools designed specifically for this purpose. Instead, coevolutionary studies are often forced to re‐purpose single species techniques. Here, we propose a novel approach for identifying the genes mediating locally adapted coevolutionary interactions that relies on spatial correlations between genetic marker frequencies in the interacting species. Using individual‐based multi‐locus simulations, we quantify the performance of our approach across a range of coevolutionary genetic models. Our results show that when one species is strongly locally adapted to the other and a sufficient number of populations can be sampled, our approach accurately identifies functionally coupled host and parasite genes. Although not a panacea, the approach we outline here could help to focus the search for coevolving genes in a wide variety of well‐studied systems for which substantial local adaptation has been demonstrated.
Phenotypic differentiation of the Solidago virgaurea complex along an elevational gradient: Insights from a common garden experiment and population genetics
Authors: Hirano Masaaki , Sakaguchi Shota , Takahashi Koichi
Published: July 2017

Plant species distributed along wide elevational or latitudinal gradients show phenotypic variation due to their heterogeneous habitats. This study investigated whether phenotypic variation in populations of the Solidago virgaurea complex along an elevational gradient is caused by genetic differentiation. A common garden experiment was based on seeds collected from nine populations of the S. virgaurea complex growing at elevations from 1,597 m to 2,779 m a.s.l. on Mt. Norikura in central Japan. Population genetic analyses with microsatellite markers were used to infer the genetic structure and levels of gene flow between populations. Leaf mass per area was lower, while leaf nitrogen and chlorophyll concentrations were greater for higher elevations at which seeds were originally collected. For reproductive traits, plants derived from higher elevations had larger flower heads on shorter stems and flowering started earlier. These elevational changes in morphology were consistent with the clines in the field, indicating that phenotypic variation along the elevational gradient would have been caused by genetic differentiation. However, population genetic analysis using 16 microsatellite loci suggested an extremely low level of genetic differentiation of neutral genes among the nine populations. Analysis of molecular variance also indicated that most genetic variation was partitioned into individuals within a population, and the genetic differentiation among the populations was not significant. This study suggests that genome regions responsible for adaptive traits may differ among the populations despite the existence of gene flow and that phenotypic variation of the S. virgaurea complex along the elevational gradient is maintained by strong selection pressure.
Fitness landscapes and life‐table response experiments predict the importance of local areas to population dynamics
Authors: Kane Kristin , Sedinger James S. , Gibson Daniel , Blomberg Erik , Atamian Michael
Published: July 2017

Animal resource requirements differ among life‐history stages, and thus, habitat is most appropriately thought of as specific to a particular life stage. Accordingly, different habitats may vary in their significance as functions of (1) the sensitivity of population growth to the life stage for which the habitat is most important, (2) spatial association of each habitat to other habitats, and (3) the abundance of the habitat in question. We used an analogy to a life‐table response experiment to develop spatial models linking key habitats to rates of population increase in Greater Sage‐grouse. We parameterized models linking demographic rates to vegetation and physical attributes of habitats, including spatial association of some habitats to others, using a decade‐long study of Greater Sage‐grouse in central Nevada. We modeled the contribution of each pixel in the landscape to regional λ (finite rate of population increase) using functional relationships between demographic rates and the attributes of that pixel, and the sensitivity of λ to each demographic rate. We incorporated the following demographic rates into our model: female nesting success, survival of chicks from hatching to 45 d, and adult female annual survival. We also incorporated the probability a site was used for nesting. Chick survival (62%) and nest site selection (21%) explained most of the variance in lambda. We found that only ~8% of all habitat for Greater Sage‐grouse contributed to λ > 1. Habitat supporting population growth occurred in mid‐high elevation areas with moderate slopes, and a high percent cover of sagebrush, and in nesting areas close to late‐brood habitat. Our models indicate that a relatively small proportion of habitat available to Greater Sage‐grouse in central Nevada is responsible for maintenance of the population in our study system. We suggest that the general approach we describe here can be used to improve understanding of habitats most likely to regulate populations in other systems, providing an important tool in ecology and conservation.
Summer and winter drought drive the initiation and spread of spruce beetle outbreak
Authors: Hart Sarah J. , Veblen Thomas T. , Schneider Dominik , Molotch Noah P.
Published: July 2017

This study used Landsat‐based detection of spruce beetle (Dendroctonus rufipennis) outbreak over the years 2000–2014 across the Southern Rocky Mountain Ecoregion to examine the spatiotemporal patterns of outbreak and assess the influence of temperature, drought, forest characteristics, and previous spruce beetle activity on outbreak development. During the 1999–2013 period, time series of spruce beetle activity were highly spatially correlated (r > 0.5) at distances <5 km, but remained weakly correlated (r = 0.08) at distances >400 km. Furthermore, cluster analysis on time series of outbreak activity revealed the outbreak developed at multiple incipient locations and spread to unaffected forest, highlighting the importance of both local‐scale dispersal and regional‐scale drivers in synchronizing spruce beetle outbreak. Spatial overlay analysis and Random Forest modeling of outbreak development show that outbreaks initiate in areas characterized by summer, winter, and multi‐year drought and that outbreak spread is strongly linked to the proximity and extent of nearby outbreak, but remains associated with drought. Notably, we find that spruce beetle outbreak is associated with low peak snow water equivalent, not just summer drought. As such, future alterations to both winter and summer precipitation regimes are likely to drive important changes in subalpine forests.
Development of Aldehyde‐Based Fluorescent Probes for Highly Selective Recognition of 1,3‐Diaminopropane
Authors: Xu Yimang , Shi Dan , Wang Xinjing , Yu Shanshan , Yu Xiaoqi , Pu Lin
Published: July 2017

The 1,1′‐bi‐2‐naphthol (BINOL)‐based aldehydes 5 and 6 are synthesized. It is found that 1,3‐diaminopropane (DAP) can greatly enhance the fluorescence of these compounds in methanol, but other monoamines and diamines cause much smaller fluorescent response under the same conditions. 1H NMR analyses show that 6 reacts with DAP to form a six‐membered ring aminal as the major product but other amines and diamines can only generate the corresponding imines. A molecular modelling study indicates that formation of the aminal product can inhibit the photoinduced electron transfer of the BINOL‐based aldehydes, which leads to the observed selective fluorescence enhancement. These molecules represent the first highly selective fluorescent probes for the recognition of DAP and their further development should be useful for the study of the biological functions of the polyamines.
Serum N‐glycans outperform CA19‐9 in diagnosis of extrahepatic cholangiocarcinoma
Authors: Wang Mengmeng , Fang Meng , Zhu Jianhui , Feng Huijuan , Warner Elisa , Yi Changhong , Ji Jun , Gu Xing , Gao Chunfang
Published: July 2017

Extensive efforts have been devoted to improve the diagnosis of extrahepatic cholangiocarcinoma (ECCA) due to its silent clinical character and lack of effective diagnostic biomarkers. Specific alterations in N‐glycosylation of glycoproteins are considered a key component in cancer progression, which can serve as a distinct molecular signature for cancer detection. This study aims to find potential serum N‐glycan markers for ECCA. In total, 255 serum samples from patients with ECCA (n = 106), benign bile tract disease (BBD, n = 60) and healthy controls (HC, n = 89) were recruited. Only 2 μL of serum from individual patients was used in this assay where the N‐glycome of serum glycoproteins was profiled by DNA sequencer‐assisted fluorophore‐assisted capillary electrophoresis (DSA‐FACE) technology. Multi‐parameter models were constructed by combining the N‐glycans and carbohydrate antigen 19‐9 (CA19‐9) which is currently used clinically. Quantitative analyses showed that among 13 N‐glycan structures, the bifucosylated triantennary N‐glycan (peak10, NA3F2) presented the best diagnostic performance for distinguishing ECCA from BBD and HC. Two diagnostic models (Glycotest1 and Glycotest2) performed better than single N‐glycan or CA19‐9. Additionally, two N‐glycan structures (peak9, NA3Fb; peak12, NA4Fb) were tightly related to lymph node metastasis in ECCA patients. In conclusion, sera of ECCA showed relatively specific N‐glycome profiling patterns. Serum N‐glycan markers and models are novel, valuable and noninvasive alternatives in ECCA diagnosis and progression monitoring.
System identification and modeling of a dynamically tested and gradually damaged 10‐story reinforced concrete building
Authors: Yousefianmoghadam Seyedsina , Behmanesh Iman , Stavridis Andreas , Moaveni Babak , Nozari Amin , Sacco Andrea
Published: July 2017

This paper discusses the dynamic tests, system identification, and modeling of a 10‐story reinforced concrete building. Six infill walls were demolished in 3 stages during the tests to introduce damage. In each damage stage, dynamic tests were conducted by using an eccentric‐mass shaker. Accelerometers were installed to record the torsional and translational responses of the building to the induced excitation, as well as its ambient vibration. The modal properties in all damage states are identified using 2 operational modal analysis methods that can capture the effect of the wall demolition. The modal identification is facilitated by a finite element model of the building. In turn, the model is validated through the comparison of the numerically and experimentally obtained modal parameters. The validated model is used in a parametric study to estimate the influence of structural and nonstructural elements on the dynamic properties of the building and to assess the validity of commonly used empirical formulas found in building codes. Issues related to the applicability and feasibility of system identification on complex structures, as well as considerations for the development of accurate, yet efficient, finite element models are also discussed.
Assessing Catastrophes—Dragon‐Kings, Black, and Gray Swans—for Science‐Policy
Authors: Ricci Paolo F. , Sheng Hua‐Xia
Published: July 2017

The threat of catastrophic incidents—from nonroutine events to extreme ones, such as Dragon‐Kings (DK), Black Swans (BS), and Gray Swans—induces precautionary initiatives that, before the fact, may encounter public resistance or after the fact recriminations. This study develops three aspects of these events: (1) generating mechanisms, (2) the statistical distributions of near and far‐term consequences, and (3) the aggregation of expert opinions about assumptions, mechanisms, and consequences that informs science‐policy. This study shows how causal analysis should account for the: (1) nonlinear catastrophic behaviors that generate predictions, (2) common and power‐law distributions of the consequences, (3) self‐organizing criticality and self‐similarity, and (4) feedbacks and couplings between mechanisms that produce snaps, crackles, and pops as precursor, warning signals. The distribution of the consequences associated with catastrophic incidents has longer and fatter right tails than those expected from failure analysis based on known nonroutine events. DK are extreme events that deviate from these fat tail distributions, have a much higher frequency than expected, and can be predicted unlike BS. This shows how to combine divergent expert individual beliefs over assumptions, causation, and results, and a paradox that affects agreements obtained by majority rule.
Pooling Data and Linkage Analysis in the Chromosome 5q Candidate Region for Asthma
Authors: Jacobs Kevin B. , Burton Paul R. , Iyengar Sudha K. , Elston Robert C. , Palmer Lyle J.
Published: July 2017

We investigated a variety of methods for pooling data from eight data sets (n = 5,424 subjects) to validate evidence for linkage of markers in the cytokine cluster on chromosome 5q31–33 to asthma and asthma‐associated phenotypes. Chromosome 5 markers were integrated into current genetic linkage and physical maps, and a consensus map was constructed to facilitate effective data pooling. To provide more informative phenotypes with better distributional properties, variance component models were fitted using Gibbs sampling methods in order to generate residual additive genetic effects, or sigma‐squared‐A‐random‐effects (SSARs), which were used as derived phenotypes in subsequent linkage analyses. Multipoint estimates of alleles shared identically by descent (IBD) were computed for all full sibling pairs. Linkage analyses were performed with a new Haseman‐Elston method that uses generalized‐least‐squares and a weighted combination of the mean‐corrected trait‐sum squared and trait‐difference squared as the dependent variable. Analyses were performed with all data sets pooled together, and also separately with the resulting linkage statistics pooled by several meta‐analytic methods. Our results provide no significant evidence that loci conferring susceptibility to asthma affection or atopy, as measured by total serum IgE levels, are present in the 5q31–33 region. This study has provided a clearer understanding of the significance, or lack of significance, of the 5q31–33 region in asthma genetics for the phenotypes studied. © 2001 Wiley‐Liss, Inc.
The Effect of Genotype and Pedigree Error on Linkage Analysis: Analysis of Three Asthma Genome Scans
Authors: Cherny Stacey S. , Abecasis Gonçalo R. , Cookson William O.C. , Sham Pak C. , Cardon Lon R.
Published: July 2017

The effects of genotype and relationship errors on linkage results arc evaluated in three of the Genetic Analysis Workshop 12 asthma genome scans. A number of errors are detected in the samples. While the evidence for linkage is not striking in any data set with or without error, in some cases the difference in test statistic could support different conclusions. The results provide empirical evidence for the predicted effects of genotype and relationship error and highlight the need for rigorous detection and elimination of data error in complex trait studies. © 2001 Wiley‐Liss, Inc.
Improved Evidence for Linkage on 6p and 5p with Retrospective Pooling of Data from Three Asthma Genome Screens
Authors: Iyengar Sudha K. , Jacobs Kevin B. , Palmer Lyle J.
Published: July 2017

To improve our ability to identify genes for complex diseases, evaluation of new methods that retrospectively pool genotype and phenotype data collected by multiple centers is important. Availability of three whole‐genome screens enabled us to compare two methods, pooling raw data and meta‐analysis. Multipoint linkage analyses were performed on two outcomes, total serum IgE levels and asthma affection status, using an improved Haseman‐Elston algorithm. Two regions showed stronger evidence for linkage using covariate‐adjusted pooled data, compared with any individual sample. Both methods for pooling data identified strong linkage to Z‐transformed logeIgE levels at a location between D6S1019 and D6S426, and to the asthma trait at D5S268. In conclusion, retrospective analysis of pooled genome scan data is a potentially powerful and useful method to examine both positive and negative evidence for linkage of quantitative and categorical phenotypes across populations. © 2001 Wiley‐Liss, Inc.
Weighting Schemes in Pooled Linkage Analysis
Authors: Loesgen Sabine , Dempfle Astrid , Golla Astrid , Bickeböller Heike
Published: July 2017

To identify susceptibility gene regions for complex diseases a combined linkage analysis of several genome scans might give additional insights to individual studies. In this article we consider different weighting schemes to combine the score statistics of individual studies to an overall statistic within multipoint nonparametric linkage analysis by GENEHUNTER/ALLEGRO. With the Genetic Analysis Workshop (GAW) 12 asthma data sets the weights are dominated by the large differences in the relevant sample sizes. © 2001 Wiley‐Liss, Inc.
Inclusion of Candidate Region Studies in Meta‐Analysis Using the Genome Screen Meta‐Analysis Method: Application to Asthma Data
Authors: Wise Lesley H.
Published: July 2017

An extension to the genome screen meta‐analysis (GSMA) method is proposed that allows results from candidate region studies to be included in a meta‐analysis of genome‐wide search results. Quantitative linkage analyses for susceptibility loci linked to total IgE were performed for data from three genome‐wide searches and four candidate region studies from the Genetic Analysis Workshop 12 asthma data set. The GSMA and proposed extension were used to carry out a meta‐analysis of the results from these studies. The meta‐analysis indicates strong evidence for a susceptibility locus on the p‐arm of chromosome 6 and some evidence for susceptibility loci on chromosomes 2, 9, 10, and 15. There is no evidence from this meta‐analysis for a susceptibility locus for total IgE on chromosome 5. A method for assessing the possible effect of publication bias is also introduced. © 2001 Wiley‐Liss, Inc.
An Autosome‐Wide Search for Loci Underlying Wheezing Age of Onset in German Asthmatic Children Identifies a New Region of Interest on 6q24–q25
Authors: Alcaïs Alexandre , Plancoulaine Sabine , Abel Laurent
Published: July 2017

While numerous familial studies of asthma have identified several distinct chromosomal regions, no linkage studies have been performed taking into account the age of onset of disease. Here, we performed a genome‐wide scan to search for loci linked either to asthma or wheezing age of onset in a population of German asthmatic children by incorporating survival analysis techniques in the maximum‐likelihood‐binomial approach. In addition to several regions already reported in asthma, wheezing age of onset was found to be strongly linked to chromosome 6q24–q25 (lod score = 3.56). Interestingly, this region contains some candidates genes such as the gene coding for the IFN‐γ receptor ligand‐binding chain. © 2001 Wiley‐Liss, Inc.
Using Data Mining to Address Heterogeneity in the Southampton Data
Authors: Chang Chee Jen , Fann Cathy S.J.
Published: July 2017

When analyzing complex traits such as asthma, heterogeneity needs to be assumed. With this in mind, to identify a more homogeneous group of asthmatic patients, we analyzed the Southampton data using the data mining technique known as the regression tree method and the two most inheritable quantitative phenotypes (LnIgE and RAST) as the target variables. Two‐point and multipoint nonparametric linkage analyses were carried out using one of the subgroups as affected. In addition, we performed quantitative trait loci nonparametric linkage analysis using each phenotype as the outcome. The results from the affected‐sib‐pairs method and quantitative linkage analysis were compared. © 2001 Wiley‐Liss, Inc.
Triangle Test Statistic in Discordant Sib Pairs: Test of Genetic Heterogeneity of Asthma and Atopy in CSGA Families
Authors: Dizier Marie-Hélène , Babron Marie-Claude
Published: July 2017

The purpose of our study was to detect genetic heterogeneity (i.e., different genotype relative risks of genetic factor) between atopic and non‐atopic asthma and between atopy associated or independent of asthma. Genetic heterogeneity was tested in the Caucasian Collaborative Study on the Genetics of Asthma families using the TTS (triangle test statistic) and the predivided sample test. The ITS was proposed to detect both linkage and intra‐sib‐pair genetic heterogeneity; such heterogeneity may exist if the sibs differ for a factor on which the penetrances of the putative linked gene depend. The TTS has been applied to asthmatic pairs discordant for atopy and atopic sib pairs discordant for asthma. To confirm genetic heterogeneity detected by the ITS, the predivided sample test was also applied among concordant and discordant sib pairs. The analyses detected a genetic factor on chromosome 8p that could be involved in atopy with different genotype relative risks according to whether asthma is present. This would suggest a pleiotropic effect of this genetic factor in asthma and atopy. Two other regions located on chromosomes 8q and 20p were detected for genetic heterogeneity with asthma and atopy, respectively, but the factor of heterogeneity could be independent from the presence of atopy or asthma, respectively. It could be a characteristic of the disease such as the severity or the presence of an environmental factor. © 2001 Wiley‐Liss, Inc.
Linkage Analysis of Asthma and Atopy Including Models with Genomic Imprinting
Authors: Strauch Konstantin , Bogdanow Manuela , Fimmers Rolf , Baur Max P. , Wienker Thomas F.
Published: July 2017

Asthma and atopy are two closely related, common complex traits in which a number of genetic and environmental factors are suspected to play a role. We have performed parametric and nonparametric multi‐marker linkage analysis for the Busselton data set, which is part of problem 1 of Genetic Analysis Workshop 12. In particular, we have focused on the dichotomous trait atopy, as well as on dichotomized versions of the quantitative traits RASTI and loge slope. The lod score analysis with adequate modeling of a parent‐of‐origin effect, by use of the program GENEHUNTER‐IMPRINTING, was of special interest. The most prominent findings are a multipoint mod score of 3.12 at D13S153 for RASTI, and a multipoint mod score of 4.32 at the same locus for atopy, both with four‐penetrance imprinting models that point to a gene subject to maternal imprinting. In addition, there are marked differences between imprinting and non‐imprinting mod scores. These results corroborate earlier findings of linkage between atopy and D13S153, but add the aspect of paternal gene expression. Furthermore, suggestive evidence for linkage to atopy is found near D6S291, D7S530, and D14S74. The best‐fitting models for chromosome 6 and 14 may suggest that genomic imprinting takes place at these two loci as well. © 2001 Wiley‐Liss, Inc.
A Pedigree Partitioning Approach to Quantitative Trait Loci Mapping of IgE Serum Level in the GAW12 Hutterite Data
Authors: Pankratz V. Shane , Iturria Stephen J.
Published: July 2017

We present a semi‐automatic method that uses principles from factor analysis to subdivide large pedigrees into smaller, non‐overlapping sub‐pedigrees. Application of our method to the Genetic Analysis Workshop 12 Hutterite pedigree yielded 12 sub‐pedigrees that were used to carry out a genome‐wide linkage scan for IgE serum level in SOLAR. Two‐point analyses resulted in strong evidence for linkage to two marker loci on chromosome 1, D1S3723 (lod = 3.70) and D1S534 (lod = 3.58). Multipoint analysis resulted in a maximum lod of 4.58 on chromosome 1 at 143 cM. After extending the two pedigrees that contributed the most evidence for linkage, the maximum lod score decreased to 4.18, with most of the evidence for linkage due to a single large sub‐pedigree. © 2001 Wiley‐Liss, Inc.
Family‐Based Tests of Association in the Presence and Absence of Known Linkage
Authors: Bertram Lars , Hayward Brooke , Lake Stephen L. , Falls Kathleen , Eerdewegh Paul Van , Blacker Deborah
Published: July 2017

Correlation among sibling marker genotypes may invalidate the results of family‐based tests of association in the presence of linkage. We apply an empirical variance estimation method, which is implemented in the program package FBAT, on Caucasian families with asthma in the presence and absence of linkage and compare the results with those obtained using the TDT (TDTEX‐PAIRS) on the same data sets. Our results indicate that both tests generally perform comparably in either setting. © 2001 Wiley‐Liss, Inc.
Transmission/Disequilibrium Test Analysis of Total Serum IgE Levels in the Hutterite and Collaborative Study on the Genetics of Asthma Data Sets
Authors: Jedrey Catherine M. , Chen Chien-Hsiun , Moser Kathy L. , Wedig Geoffrey C. , George Varghese , Tiwari Hemant K.
Published: July 2017

The Hutterite and Collaborative Study on the Genetics of Asthma data sets provided by Genetic Analysis Workshop 12 were analyzed using a regression‐based transmission/disequilibrium test that assesses linkage between a marker locus and quantitative trait locus when allelic association is present, as proposed by George et al. [Am J Hum Genet 65:236–45, 1999]. Because the same marker set and analytical technique was used, the results from these data sets are amenable for comparison. Statistically significant results common to both data sets were found on chromosomes 1 and 3. A noteworthy result, significant at p < 10‐4, was detected on chromosome 18 in the Hutterites. © 2001 Wiley‐Liss, Inc.
Tree‐Based Linkage and Association Analyses of Asthma
Authors: Zhang Heping , Tsai Chin-Pei , Yu Chang-Yung , Bonney George
Published: July 2017

Tree‐based linkage analyses and association studies are introduced and applied for two data sets on asthma from Genetic Analysis Workshop 12. Consistent and strong evidence of linkage and association to markers on chromosomes 1 and 11 is revealed. Linkage to chromosome 16 in one data set and association with D6S276 in the other data set are also detected. © 2001 Wiley‐Liss, Inc.
Association Analysis in a Variance Components Framework
Authors: Abecasis Gonçalo R. , Cardon Lon R. , Cookson William O.C. , Sham Pak C. , Cherny Stacey S.
Published: July 2017

Association analyses conducted in a variance components framework can include information from all available individuals but remain unbiased in the presence of familiality or linkage. Models that include both linkage and association parameters provide different estimates of the effect of a single locus and can be used to distinguish causal polymorphisms from other types of variation. We examine some of these models and their properties in a blind analysis of the simulated Genetic Analysis Workshop 12 data sets. © 2001 Wiley‐Liss, Inc.
Using Step‐Wise Linear Regression to Detect “Functional” Sequence Variants: Application to Simulated Data
Authors: Mitchell Braxton D. , Hsueh Wen-Chi , Schneider Jennifer L. , Blangero John
Published: July 2017

Step‐wise linear regression was used to detect the “functional” sequence variant in gene 6 responsible for phenotypic variation in traits Q1 and Q2. Prior to analysis, single‐nucleotide polymorphisms (SNPs) that were in complete or near complete linkage disequilibrium were binned. In total, we identified 11 separate alleles (or allelic bins). Analyses were performed on all 50 replicates. The “functional” allele variant in gene 6 (at position 5782) accounted for 24% of the variation in Q1 and 11% of the variation in Q2. We detected a significant association between this SNP and Q1 in 90% of the replicates (i.e., in 45 of 50 replicates) and between this SNP and Q2 in 78% of the replicates. Although significant associations were also observed with some nonfunctional SNPs, our results nevertheless suggest that simple step‐wise regression may play a useful role in analyzing sequence data. Some additional extensions to this approach are suggested. © 2001 Wiley‐Liss, Inc.
Combined Linkage and Association Analysis in Pedigrees
Authors: Siegmund Kimberly D. , Vora Hita , Gauderman W. James
Published: July 2017

We applied a combined linkage and association model for quantitative traits in pedigrees to identify possible functional polymorphisms and to test for association resulting from population stratification and admixture. Functional polymorphisms are identified as variants that are significantly associated with a trait (high x2 value) and showing no residual evidence of linkage (low lod score). Applying our model to the simulated data in the population isolate (replicate 1) we correctly identified the polymorphism in gene 6 (MG1) that affects Q1. Without modeling association the lod score for Q1 was 5.4. At the site of the functional variant (5782 bp) the association x2 was 88.1 on 1 df (p < 0.001) and the lod score was 0.003. We estimated a 3.7‐unit increase in the average Q1 for each extra copy of the polymorphism (95% CI = 2.95–4.41) and there was no evidence of population stratification or admixture (x2= 0.08 on 2 df). For Q5 and gene 2, modeling the sequence variants at 11 loci simultaneously identified multiple functional variants. Including the main effect of 11 marker genotypes reduced the lod score at gene 2 from 8.7 to 0.9. Again, no evidence of population stratification or admixture was found (all x2< 4.9 on 2 df; p > 0.05). © 2001 Wiley‐Liss, Inc.
Test of Association for Quantitative Traits in General Pedigrees: The Quantitative Pedigree Disequilibrium Test
Authors: Zhang Shuanglin , Zhang Kui , Li Jinming , Sun Fengzhu , Zhao Hongyu
Published: July 2017

Many statistical methods have been proposed in recent years to test for genetic linkage and association between genetic markers and traits of interest through unrelated nuclear families. However, most of these methods are not valid tests of association in the presence of linkage when some of the nuclear families are related. As a result, related nuclear families in large pedigrees cannot be included in a single analysis to test for linkage disequilibrium. Recently, Martin et al. [Am J Hum Genet 67:146–54, 2000] proposed the pedigree disequilibrium test (PDT) to test for linkage and association in general pedigrees for qualitative traits. In this article, we develop a similar quantitative pedigree disequilibrium test (QPDT) to test for linkage and association in general pedigrees for quantitative traits. We apply both the PDT and the QPDT to analyze the sequence data from the seven candidate genes in the simulated data sets in the Genetic Analysis Workshop 12. © 2001 Wiley‐Liss, Inc.
Modeling Complex Disease with Demographic and Environmental Covariates and a Candidate Gene Marker
Authors: Beyene Joseph , Fallah Shafagh , Bull Shelley B. , Tritchler David , Chan Viann , Knight Julia
Published: July 2017

We randomly chose replicates 28 and 29 of the simulated data sets of Genetic Analysis Workshop 12 to model the dependence of affection status on covariates, quantitative traits, and genes using all living pedigree members. First we explored the relationship of affection status to demographic and environmental factors using logistic regression and the Cox proportional hazards models. In the second stage of our analyses the generalized transmission disequilibrium test (GTDT) was applied to nuclear families with at least two affected siblings to select single markers and high‐risk alleles, which were tested in the population association analyses including all pedigree members. Multiple logistic regression models were fitted to investigate the joint contributions of genetic and nongenetic factors and a block‐recursive modeling approach was adopted to study inherent hierarchical dependence structure in the data. We found that allele 2 on marker 35 of chromosome 6 is associated with higher risk compared with the other 3 alleles of this marker. In addition to this significant genetic effect, age at exam and four of the five quantitative traits (QT1, QT2, QT4, and QT5) had a significant association with the disease. Our results were obtained without knowledge of the true disease generating models. © 2001 Wiley‐Liss, Inc.
Applying Data Mining Techniques to the Mapping of Complex Disease Genes
Authors: Czika W.A. , Weir B.S. , Edwards S.R. , Thompson R.W. , Nielsen D.M. , Brocklebank J.C. , Zinkus C. , Martin E.R. , Nobler K.E.
Published: July 2017

The simulated sequence data for the Genetic Analysis Workshop 12 were analyzed using data mining techniques provided by SAS ENTERPRISE MINERTM Release 4.0 in addition to traditional statistical tests for linkage and association of genetic markers with disease status. We examined two ways of combining these approaches to make use of the covariate data along with the genotypic data. The result of incorporating data mining techniques with more classical methods is an improvement in the analysis, both by correctly classifying the affection status of more individuals and by locating more single nucleotide polymorphisms related to the disease, relative to analyses that use classical methods alone. © 2001 Wiley‐Liss, Inc.
Homogeneity of Asthma Genome Scan Results
Authors: Babron Marie-Claude , Selinger-Leneman Hana , Dizier Marie-Hélène , Clerget-Darpoux Françoise
Published: July 2017

Three different samples of families with asthmatic patients, the German data set and the CSGA data set subdivided into Caucasian and African American groups, were analyzed using the maximum lod score statistic. Although different scores were obtained in each sample, the Wald's likelihood homogeneity test did not reveal any significant genetic heterogeneity. This may be due to the very large variance of the model‐free linkage statistics. © 2001 Wiley‐Liss, Inc.
Combining Multiple Phenotypic Traits Optimally for Detecting Linkage with Sib‐Pair Observations
Authors: Xu Xin , Palmer Lyle J. , Horvath Steve , Wei L.J.
Published: July 2017

A number of investigators have proposed regression methods for testing linkage between a phenotypic trait and a genetic marker with sib‐pair observations. Xu et al. [Am J Hum Genet 67:1025–8, 2000] studied a unified method for testing linkage, which tends to be more powerful than existing procedures. Often there are multiple traits, which are linked to a common set of genetic markers. In this paper, we present a simple generalization of the unified test to combine information from multiple traits optimally. We use the simulated Genetic Analysis Workshop 12 data to illustrate this methodology and show the advantage of using the combined tests over the single‐trait tests. For the four quantitative traits (Q1,...,Q4) studied, our linkage results suggest that major loci affecting Q1 and Q2 localize at or near markers D02G172, D19G032, and D09G122, while loci affecting Q3 and Q4 localize at or near markers D09G122 and D17G051. © 2001 Wiley‐Liss, Inc.
Life After the Screen: Making Sense of Many P‐Values
Authors: Schmidt Silke , Shao Yujun , Hauser Elizabeth R. , Slifer Susan H. , Martin Eden R. , Scott William K. , Speer Marcy C. , Pericak-Vance Margaret A.
Published: July 2017

A multiple analytic approach may be useful for analyzing complex traits since different methods extract both similar and distinct, but complementary pieces of information from genome screen data on extended pedigrees. We examined the usefulness of combining p‐values both across methods and across adjacent markers, taking into account the observed correlation structure among these p‐values. To this end, we employed the recently proposed truncated product method [Zaykin et al., Genet Epidemiol, in press]. It appears that this approach is helpful for visualizing priority regions for follow‐up analysis and reducing the number of false‐positive linkage signals. © 2001 Wiley‐Liss, Inc.
Maximum Identity Length Contrast: A Powerful Method For Susceptibility Gene Detection in Isolated Populations
Authors: Bourgain Catherine , Génin Emmanuelle , Margaritte-Jeannin Patricia , Clerget-Darpoux Françoise
Published: July 2017

We report the results of our analysis of the Genetic Analysis Workshop 12 simulated data set. Focusing on the isolated populations, we compare the efficiency of a new method, the maximum identity length contrast statistic (MILC) with the maximum likelihood score (MLS) in a genome screen strategy. MILC is a method based on the contrast of haplotype identity between transmitted and nontransmitted haplotypes in trios. It uses information on linkage and association. We found that MILC allows the detection of a risk factor corresponding to candidate gene 1 where the MLS fails, though the same population replicates were used. Interestingly, the association between this risk factor and the disease could not have been detected with the TDT at a genome‐wide level. © 2001 Wiley‐Liss, Inc.
Selection of Single Nucleotide Polymorphisms for Association Studies in Candidate Genes
Authors: Génin Emmanuelle
Published: July 2017

Comparison of polymorphic sites such as single nucleotide polymorphisms (SNPs) within a gene between cases and controls may be useful for establishing a role of this gene in disease susceptibility. The approach includes two steps: the first step is the discovery of the different SNPs within the candidate gene and the second step is the association testing per se that can be done on the entire set of sites discovered or on a subset of these sites only. Selecting a subset of sites may increase the power to detect the association with the candidate gene since a smaller number of tests would then be performed. We proposed a strategy to select sites within a candidate gene and applied it on the Genetic Analysis Workshop 12 candidate gene data. Using these selected sites, we detected an association with candidate genes 1 and 6. © 2001 Wiley‐Liss, Inc.
Linkage Disequilibrium Structure and Its Impact on the Localization of a Candidate Functional Mutation
Authors: Huang Qiqing , Morrison Alanna C. , Boerwinkle Eric
Published: July 2017

We have used the unblinded MG1/Q1 Genetic Analysis Workshop 12 simulated data as a model system for investigating the use of linkage disequilibrium structure and simple genotype‐phenotype associations to identify candidate functional mutations within a gene of interest. Analysis of the pattern of pair‐wise linkage disequilibrium indicated three groups of single‐nucleotide polymorphisms for which the linkage disequilibrium was high between sites within a group, but lower between sites of different groups. Using linear regression to predict levels of the trait Q1 showed that the known functional site, 5782, was usually not the best genetic predictor of Q1, but sites belonging to the same group as 5782 (i.e., group 2) were always included in the prediction model. In 49 out of the 50 replicates, the functional site was not the best predictor of the trait. Finally, more detailed analyses demonstrate that the relationship between the adjusted R2 for the marker in the prediction model and its disequilibrium with 5782 was linear with the intercept at the origin and terminating at the R2 value for the known functional mutation when the disequilibrium is maximal. These data indicate that simple association studies will not identify the functional mutation, but rather will identify candidate functional mutations that are in very tight linkage disequilibrium with the functional mutation. © 2001 Wiley‐Liss, Inc.
Analysis of Nucleotide Sequence Data Using Mixed Model Methodology
Authors: Rodriguez-Zas Sandra L. , Southey Bruce R.
Published: July 2017

Linear, logistic, and multivariate mixed model analyses were applied to simulated data of five quantitative traits and a binary liability trait to detect associations with sequence variants in seven genes. Infrequent site variants (<1%) were eliminated and conservative step‐wise procedures were used to reduce the number of variants fitted. Random effects accounting for additive genetic relationships between individuals and for common environment effects were fitted to reduce spurious significant results. Five sites in genes 1, 2, and 6 had significant effects (p < 0.0001) on the traits and were found in both replicates studied. Survival analysis using a Weibull model identified two significant sites for disease age at onset. Other less significant sites may be false positives or due to founder effects. This approach was effective in identifying putative sites while accounting for polygenic and environmental sources of variation. © 2001 Wiley‐Liss, Inc.
Markov Chain Monte Carlo Linkage Analysis of Complex Quantitative Phenotypes
Authors: Hinrichs Anthony , Reich Theodore
Published: July 2017

We report a Markov chain Monte Carlo analysis of the five simulated quantitative traits in Genetic Analysis Workshop 12 using the Loki software. Our objectives were to determine the efficacy of the Markov chain Monte Carlo method and to test a new scoring technique. Our initial blind analysis, on replicate 42 (the “best replicate”) successfully detected four out of the five disease loci and found no false positives. A power analysis shows that the software could usually detect 4 of the 10 trait/gene combinations at an empirical point‐wise p‐value of 1.5 x 10‐4. © 2001 Wiley‐Liss, Inc.