Linkage Analysis Software Research Articles

Design concepts for an integrated whiplash mitigating head restraint and seat

ABSTRACTThis paper presents design of a concept for an integrated head restraint and car seat system to mitigate whiplash in rear-end vehicle collisions. The main emphasis is on a concept, which combines a reactive head restraint with a reactive seat. The chosen concept is developed in the form of mechanical linkages using linkage analysis software, SAM 6.1. A human model positioned in a ‘good’ driving posture is used to show how the head restraint and seat would operate using a typical crash pulse used for dynamic sled testing of automotive seats. The head restraint system is capable of translating into an optimal position of 40 mm forwards and 60 mm upwards in 12 ms, before whiplash-induced injuries start to take place. The reactive seat is also capable of reclining 15 degrees. The combination of reducing the backset and reclining the seat to reduce the relative motion between the head and torso has the potential to reduce the whiplash-effect-related injuries in rear-end collisions.

Design concepts for an integrated whiplash mitigating head restraint and seat

ABSTRACTThis paper presents design of a concept for an integrated head restraint and car seat system to mitigate whiplash in rear-end vehicle collisions. The main emphasis is on a concept, which combines a reactive head restraint with a reactive seat. The chosen concept is developed in the form of mechanical linkages using linkage analysis software, SAM 6.1. A human model positioned in a ‘good’ driving posture is used to show how the head restraint and seat would operate using a typical crash pulse used for dynamic sled testing of automotive seats. The head restraint system is capable of translating into an optimal position of 40 mm forwards and 60 mm upwards in 12 ms, before whiplash-induced injuries start to take place. The reactive seat is also capable of reclining 15 degrees. The combination of reducing the backset and reclining the seat to reduce the relative motion between the head and torso has the potential to reduce the whiplash-effect-related injuries in rear-end collisions.

Gene Locater: Genetic linkage analysis software using three point testcross

Locating genes on a chromosome is important for understanding the gene function and its linkage and recombination. Knowledge of gene positions on chromosomes is necessary for annotation. The study is essential for disease genetics and genomics, among other aspects. Currently available software's for calculating recombination frequency is mostly limited to the range and flexibility of this type of analysis. GENE LOCATER is a fully customizable program for calculating recombination frequency, written in JAVA. Through an easy-to-use interface, GENE LOCATOR allows users a high degree of flexibility in calculating genetic linkage and displaying linkage group. Among other features, this software enables user to identify linkage groups with output visualized graphically. The program calculates interference and coefficient of coincidence with elevated accuracy in sample datasets.AvailabilityThe database is available for free at http://www.moperandib.com

A genome-wide search for linkage to allergic rhinitis in Danish sib-pair families

Allergic rhinitis (AR) is a complex disorder with a polygenic, multifactorial aetiology. Twin studies have found the genetic contribution to be substantial. We collected and clinically characterised a sample consisting of 127 Danish nuclear families with at least two siblings suffering from AR or allergic conjunctivitis including 540 individuals (286 children and 254 parents). A whole-genome linkage scan, using 424 microsatellite markers, was performed on both this sample and an earlier collected sample consisting of 130 families with atopic dermatitis and other atopic disorders. A third sib-pair family sample, which was previously collected and genotyped, was added to the analysis increasing the total sample size to 357 families consisting of 1508 individuals. In total, 190 families with AR was included. The linkage analysis software Genehunter NPL, Genehunter MOD, and Genehunter Imprinting were used to obtain nonparametric and parametric linkage results. Family-based association analysis of positional candidate SNPs was carried out using the FBAT program. We obtained genome-wide significant linkage to a novel AR locus at 1p13 and suggestive linkage to two novel regions at 1q31-q32 and 20p12, respectively. Family-based association analysis of SNPs in the candidate locus DNND1B/CRB1 at 1q31 showed no significant association and could not explain the linkage signal observed. Suggestive evidence of linkage was also obtained at three AR loci previously reported (2q14-q23, 2q23, and 12p13) and indication of linkage was observed at a number of additional loci. Likely maternal imprinting was observed at 2q23, and possible maternal imprinting at 3q28.

Haplo2Ped: a tool using haplotypes as markers for linkage analysis

BackgroundGenerally, SNPs are abundant in the genome; however, they display low power in linkage analysis because of their limited heterozygosity. Haplotype markers, on the other hand, which are composed of many SNPs, greatly increase heterozygosity and have superiority in linkage statistics.ResultsHere we developed Haplo2Ped to automatically transform SNP data into haplotype markers and then to compute the logarithm (base 10) of odds (LOD) scores of regional haplotypes that are homozygous within the disease co-segregation haploid group. The results are reported as a hypertext file and a 3D figure to help users to obtain the candidate linkage regions. The hypertext file contains parameters of the disease linked regions, candidate genes, and their links to public databases. The 3D figure clearly displays the linkage signals in each chromosome. We tested Haplo2Ped in a simulated SNP dataset and also applied it to data from a real study. It successfully and accurately located the causative genomic regions. Comparison of Haplo2Ped with other existing software for linkage analysis further indicated the high effectiveness of this software.ConclusionsHaplo2Ped uses haplotype fragments as mapping markers in whole genome linkage analysis. The advantages of Haplo2Ped over other existing software include straightforward output files, increased accuracy and superior ability to deal with pedigrees showing incomplete penetrance. Haplo2Ped is freely available at: http://bighapmap.big.ac.cn/software.html.

How accurate are the marker orders in crop linkage maps generated from large marker datasets?

Marker ordering during linkage map construction is a critical component of QTL mapping research. In recent years, high-throughput genotyping methods have become widely used, and these methods may generate hundreds of markers for a single mapping population. This poses problems for linkage analysis software because the number of possible marker orders increases exponentially as the number of markers increases. In this paper, we tested the accuracy of linkage analyses on simulated recombinant inbred line data using the commonly used Map Manager QTX (Manly et al. 2001: Mammalian Genome 12, 930–932) software and RECORD (Van Os et al. 2005: Theoretical and Applied Genetics 112, 30–40). Accuracy was measured by calculating two scores: % correct marker positions, and a novel, weighted rank-based score derived from the sum of absolute values of true minus observed marker ranks divided by the total number of markers. The accuracy of maps generated using Map Manager QTX was considerably lower than those generated using RECORD. Differences in linkage maps were often observed when marker ordering was performed several times using the identical dataset. In order to test the effect of reducing marker numbers on the stability of marker order, we pruned marker datasets focusing on regions consisting of tightly linked clusters of markers, which included redundant markers. Marker pruning improved the accuracy and stability of linkage maps because a single unambiguous marker order was produced that was consistent across replications of analysis. Marker pruning was also applied to a real barley mapping population and QTL analysis was performed using different map versions produced by the different programs. While some QTLs were identified with both map versions, there were large differences in QTL mapping results. Differences included maximum LOD and R2 values at QTL peaks and map positions, thus highlighting the importance of marker order for QTL mapping.

Calculation of IBD probabilities with dense SNP or sequence data

The probabilities that two individuals share 0, 1, or 2 alleles identical by descent (IBD) at a given genotyped marker locus are quantities of fundamental importance for disease gene and quantitative trait mapping and in family-based tests of association. Until recently, genotyped markers were sufficiently sparse that founder haplotypes could be modelled as having been drawn from a population in linkage equilibrium for the purpose of estimating IBD probabilities. However, with the advent of high-throughput single nucleotide polymorphism genotyping assays, this is no longer a reasonable assumption. Indeed, the imminent arrival of individual sequencing will enable high-density single nucleotide polymorphism genotyping on a scale for which current algorithms are not equipped. In this paper, we present a simple new model in which founder haplotypes are modelled as a Markov chain. Another important innovation is that genotyping errors are explicitly incorporated into the model. We compare results obtained using the new model to those obtained using the popular genetic linkage analysis package Merlin, with and without using the cluster model of linkage disequilibrium that is incorporated into that program. We find that the new model results in accuracy approaching that of Merlin with haplotype blocks, but achieves this with orders of magnitude faster run times. Moreover, the new algorithm scales linearly with number of markers, irrespective of density, whereas Merlin scales supralinearly. We also confirm a previous finding that ignoring linkage disequilibrium in founder haplotypes can cause errors in the calculation of IBD probabilities.

FLOSS: flexible ordered subset analysis for linkage mapping of complex traits

The FLOSS software package is a flexible framework for ordered subset analysis. FLOSS is specifically designed for use with the Merlin linkage analysis package, but FLOSS can be used with any linkage analysis software package that reports NPL Z-scores for each locus and family. When FLOSS is used with the Merlin linkage analysis package, one can use either non-parametric Z-scores or Kong and Cox linear allele sharing model LOD scores. Monte Carlo P-values are calculated using a permutation test with an efficient Besag-Clifford sequential stopping rule. FLOSS also has a flexible tool for assigning family covariate scores from Merlin input files. FLOSS includes user documentation and is written in Java for easy portability. The FLOSS source code is documented and designed to be extensible.

Comparative linkage analysis and visualization of high-density oligonucleotide SNP array data

BackgroundThe identification of disease-associated genes using single nucleotide polymorphisms (SNPs) has been increasingly reported. In particular, the Affymetrix Mapping 10 K SNP microarray platform uses one PCR primer to amplify the DNA samples and determine the genotype of more than 10,000 SNPs in the human genome. This provides the opportunity for large scale, rapid and cost-effective genotyping assays for linkage analysis. However, the analysis of such datasets is nontrivial because of the large number of markers, and visualizing the linkage scores in the context of genome maps remains less automated using the current linkage analysis software packages. For example, the haplotyping results are commonly represented in the text format.ResultsHere we report the development of a novel software tool called CompareLinkage for automated formatting of the Affymetrix Mapping 10 K genotype data into the "Linkage" format and the subsequent analysis with multi-point linkage software programs such as Merlin and Allegro. The new software has the ability to visualize the results for all these programs in dChip in the context of genome annotations and cytoband information. In addition we implemented a variant of the Lander-Green algorithm in the dChipLinkage module of dChip software (V1.3) to perform parametric linkage analysis and haplotyping of SNP array data. These functions are integrated with the existing modules of dChip to visualize SNP genotype data together with LOD score curves. We have analyzed three families with recessive and dominant diseases using the new software programs and the comparison results are presented and discussed.ConclusionsThe CompareLinkage and dChipLinkage software packages are freely available. They provide the visualization tools for high-density oligonucleotide SNP array data, as well as the automated functions for formatting SNP array data for the linkage analysis programs Merlin and Allegro and calling these programs for linkage analysis. The results can be visualized in dChip in the context of genes and cytobands. In addition, a variant of the Lander-Green algorithm is provided that allows parametric linkage analysis and haplotyping.

Pelican: pedigree editor for linkage computer analysis.

Linkage analysis software requires an input text file that describes the structure of the pedigrees to be analysed. Manual creation of these files is tedious and error-prone, and a graphical input tool is desirable. This is currently only available in commercial packages that include much greater functionality. We have therefore developed Pelican, a lightweight graphical pedigree editor for rapid construction of linkage pedigree files and diagrams. The software runs on any Java-enabled machine (version 1.2 or higher). A Java Web Start launch, class files, a demonstration applet, source code and documentation are freely available at http://www.rfcgr.mrc.ac.uk/Software/PELICAN/

Linkage Analysis Using Single Nucleotide Polymorphisms

We performed multipoint linkage analysis using 83 markers from the SNP Consortium (TSC) SNP linkage map in 3 regions covering 190 cM previously scanned with microsatellite markers and found to be linked to type 2 diabetes. Since the average linkage disequilibrium present in the TSC SNP marker clusters is relatively low, we assumed the intracluster genetic distances were a reasonable small nonzero distance (0.03 cM) and performed linkage analysis using GENEHUNTER PLUS and ASM linkage analysis software. We found that for the pedigree structures and missing data patterns in our samples the average information content in all three regions and the LOD score curves in two regions obtained from the TSC SNP markers were similar to results obtained from microsatellite marker maps with 10 cM average spacing. We also give an algorithm which extends the Lander-Green algorithm to permit multipoint linkage analysis of clusters of tightly linked markers with arbitrarily high levels of intracluster linkage disequilibrium.

Parallel Genehunter: implementation of a linkage analysis package for distributed-memory architectures

We present a parallel algorithm for performing multipoint linkage analysis of genetic marker data on large family pedigrees. The algorithm effectively distributes both the computation and memory requirements of the analysis. We discuss an implementation of the algorithm in the Genehunter linkage analysis package (version 2.1), enabling Genehunter to run on distributed-memory platforms for the first time. Our preliminary benchmarks indicate reasonable scalability of the algorithm even for fixed-size problems, with parallel efficiencies of 75% or more on up to 128 processors. In addition, we have extended the hard-coded limit of 16 non-founding individuals in Genehunter 2.1 to a new limit of 32 non-founding individuals.

A survey of current software for linkage analysis.

There is now a wide choice of software available for linkage analysis. The most well known packages are briefly reviewed here. The package with the most extensive range of analyses is GENEHUNTER, but for many of its functions there are other programs with better performance. These include FASTLINK and VITESSE for parametric analysis ALLEGRO and MERLIN for non-parametric analysis and SOLAR for variance components analysis. The computational limits of current approaches can be improved with SIMWALK2 and the promising new SUPERLINK program. Directions for future work include improved user interfaces and consensus formats for data input and exchange.

MapChart: software for the graphical presentation of linkage maps and QTLs.

Over the last 15 years a wealth of linkage maps and quantitative trait loci (QTL) mapping results have become available. The pace of generating this genetic information is accelerating owing to advances in molecular marker technology and the development of software for linkage analysis and QTL mapping. A graphical presentation of this information is often needed, both for publication purposes and for easy and intuitive interpretation. However, the development of tools for the graphical presentation of linkage maps and QTLs has lagged behind. DrawMap (Van Ooijen 1994) was an early program capable of drawing genetic linkage maps. However, the output of this program was not very well suited for use in modern word processors and presentation software. Authors in this field have therefore, of necessity, resorted to the use of general graphics software to compose charts of their linkage and QTL maps. This is always a laborious process, with sometimes disappointing results. Also, each time a map is recalculated when new data become available, this process has to be repeated. For this reason I developed MapChart, a software package that takes as input the linkage and QTL data and generates charts of linkage maps and QTLs. These charts can easily be exported to word processing or presentation software. The charts are exported as vector graphics (Windows enhanced metafiles) rather than bitmaps, which makes them easy to rescale and to edit further if desired.

Drawbacks of GENEHUNTER for larger pedigrees: Application to panic disorder

Large pedigrees can pose a problem for GENEHUNTER linkage analysis software. Differences in two-point and multipoint lodscores were observed when comparing GENEHUNTER to other linkage software. Careful consideration must be given when selecting linkage analysis programs. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:781–783, 2000. © 2000 Wiley-Liss, Inc.

Drawbacks of GENEHUNTER for larger pedigrees: Application to panic disorder

Large pedigrees can pose a problem for GENEHUNTER linkage analysis software. Differences in two-point and multipoint lodscores were observed when comparing GENEHUNTER to other linkage software. Careful consideration must be given when selecting linkage analysis programs. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:781-783, 2000.

Parametric kinematic tolerance analysis of planar mechanisms

We present an efficient algorithm for worst-case and statistical kinematic tolerance analysis of mechanisms with parametric part tolerances. The algorithm derives the kinematic variation directly from the part geometry, the part degrees of freedom, and the allowable parameter variations. It first derives a geometric representation of the kinematic variation as parametric surfaces in the mechanism configuration space. It then performs sensitivity analysis on the surfaces and combines the results. In addition to traditional quantitative variations, the results reveal qualitative variations, such as play, undercutting, interference, and jamming. Our implementation handles planar mechanisms with one degree of freedom per part, including ones with higher pairs and multiple contacts. It is fast enough to be practical for full parametric models of complex mechanisms and for parametric representations of geometric tolerances, such as offsets, which typically require many parameters. The algorithm extends to linkage mechanisms when coupled with linkage analysis software. We demonstrate the implementation on a 26 parameter model of a Geneva pair and on an 82 parameter model of a camera shutter mechanism.

Assistant Software for Linkage Analysis

Assistant Software for Linkage Analysis

A Conceptual Database Model for Genomic Research

We describe a conceptual model for genome databases that facilitates the process of building, maintaining, and disseminating physically anchored genetic linkage maps. The model has been implemented as a relational database at the Roman L. Hruska U.S. Meat Animal Research Center (MARC). Development of consensus maps using disparate data from different reference pedigrees or laboratories is supported. The model is of use to quantitative and population geneticists interested in loci that affect phenotypes and marker-assisted selection, and it is sufficiently flexible for centralized, species genome databases facilitating comparative mapping. The MARC genome database is used to assemble, maintain, and disseminate physically anchored genetic linkage maps for cattle, swine, and sheep currently based on more than 100,000 genotypes from 1,000 markers. Integrated with linkage analysis software, this database permits frequent updates of physically anchored genetic linkage maps.

A user-friendly Hypercard interface for human linkage analysis.

The availability of a large number of highly informative genetic markers has made human linkage analysis faster and easier to perform. However, current linkage analysis software does not provide an organizational database into which a large body of linkage data can be easily stored and manipulated. This manual entry and editing of linkage data is often time consuming and prone to typing errors. In addition, the large number of alleles in many of these markers must be reduced in order to perform linkage analysis with multiple loci across large genetic distances. This reduction in allele number is often difficult and confusing, especially in large pedigrees. We have taken advantage of the Macintosh-based Hypercard program to develop an interface with which linkage data can be easily stored, retrieved and edited. For each family, the components of the pedigree, including ID numbers, sex and affection status, only need to be entered once. The program (Linkage Interface) retrieves this information each time the data from a new polymorphic marker is entered. Linkage Interface has flexible editing capabilities that allow the user to change any portion of the pedigree, including the addition or deletion of family members, without affecting previously entered genotype data. Linkage Interface can also analyze both the pedigree and marker data and will detect any inconsistencies in inheritance patterns. In addition, the program can reduce the number of alleles for a polymorphic marker. Linkage Interface will then compare the 'reduced' data to the original marker data and assists in maintaining all informative meioses by pointing out which meioses have become non-informative.(ABSTRACT TRUNCATED AT 250 WORDS)