Linkage Analysis System Research Articles

Molecular Genetic Analysis of the Autosomal Recessive Non-Syndromic Inherited Retinitis Pigmentosa.

90% of visually impaired people live in developing countries. There are various types of vision impairment, but the focus of the current study is retinitis pigmentosa (RP). Up to now, 150 mutations have been reported that are linked with RP. Healthy and affected members from two Pakistani families (RP01 and RP02) segregating autosomal recessive RP were selected for DNA extraction. PCR was conducted, and the amplified PCR products were analyzed using Polyacrylamide Gel Electrophoresis (PAGE) andvisualized in the Gel Doc systemfor linkage analysis.The Gene Hunter 2.1r5 tool in the Simple Linkage v5.052 beta software suite was used to conduct multipoint parametric linkage analysis on the two consanguineous families examined on the 6K Illumina array. Exons and intron-exon borders of all known arRP genes found in homozygous areas were sequenced in the matching probands using a 3130 automated sequencer and the Big Dye Terminator Cycle Sequencing Kit v3.1. The mutation study was carried out using the AlaMut 1.5 program. In both families, linkage analysis was performed using microsatellite marker DIS422 for genecrumbs homolog 1 (CRB1)and microsatellite marker D8S2332 for geneRetinitis Pigmentosa 1 (RP1). Multipoint linkage analysis identifies genomic regions that could potentially contain the genetic defect. In family RP01, only a single peak with a maximal multipoint LOD score of 3.00 was identified on chromosome 1, whereas in family RP02, multiple peaks with multipoint LOD scores of 1.80 were identified on chromosome 8. Analysis of theCRB1gene revealed a homozygous substitution of glycine for valine (c.1152T>G; p.V243G), whereas theRP1gene demonstrated that leucine was substituted for proline as a result of cytosine to thymine transfer (c.3419C>T; p. P1035L). Conclusion: Homozygosity mapping is a powerful method for finding genetic abnormalities that are both precise and comprehensive for identifying harmful variations in consanguineous families. This method is invaluable for providing accurate clinical diagnostic and genetic advice in remote regions of Pakistanwhile also increasing knowledge about autosomal recessive diseases and the dangers of mixing.

The utility of the Violent Crime Linkage Analysis System for conducting comparative case analysis

PurposeThe Violent Crime Linkage Analysis System (ViCLAS) is a computerised database which is used by law enforcement in several countries to find potential links between serial violent crimes. In 2012, Bennell, Snook, MacDonald, House and Taylor identified a number of assumptions that must be valid for these computerised systems to be effective.Design/methodology/approachThis paper revisits and expands on these assumptions with specific reference to the use of ViCLAS, looking at research that has been conducted since this 2012 review and outlining where research is still outstanding.FindingsThe importance of evaluating ViCLAS is highlighted in this paper.Practical implicationsParticularly, the research agenda highlights how the practice of comparative case analysis when using ViCLAS could be improved.Originality/valueTo the best of the authors’ knowledge, this is the first review of the research dedicated specifically to the evaluation of ViCLAS.

Study on Economic Activity Analysis based on the Interaction of “Operation, Value and Performance”

In order to meet external regulation and challenges, and improve the quality of internal economic activity analysis, this study establishes a linkage analysis system from corporate strategy to strategic objectives to financial indicators to business indicators by building 3 independent and interrelated analysis models. One of them is the model of influencing factors of change of operating efficiency index, one of them is the traceability analysis model of the sales of electricity and electricity price, and the last one is an investment performance traceability analysis model. In this study, the actual data of a unit is used as an example. With the help of big data analysis, we fully tap the value of the company’s big data, accurately locate the weak links and risk points of management. By doing this we finely promote economic activity analysis system more comprehensive, more real-time, more dynamic and more intelligent, and thus improve the efficiency of business decision-making. The practicality of economic activity analysis based on “operation, value and performance” is confirmed.

Linkage and exome analysis implicate multiple genes in non-syndromic intellectual disability in a large Swedish family

BackgroundNon-syndromic intellectual disability is genetically heterogeneous with dominant, recessive and complex forms of inheritance. We have performed detailed genetic studies in a large multi-generational Swedish family, including several members diagnosed with non-syndromic intellectual disability. Linkage analysis was performed on 22 family members, nine affected with mild to moderate intellectual disability and 13 unaffected family members.MethodsFamily members were analyzed with Affymetrix Genome-Wide Human SNP Array 6.0 and the genetic data was used to detect copy number variation and to perform genome wide linkage analysis with the SNP High Throughput Linkage analysis system and the Merlin software. For the exome sequencing, the samples were prepared using the Sure Select Human All Exon Kit (Agilent Technologies, Santa Clara, CA, USA) and sequenced using the Ion Proton™ System. Validation of identified variants was performed with Sanger sequencing.ResultsThe linkage analysis results indicate that intellectual disability in this family is genetically heterogeneous, with suggestive linkage found on chromosomes 1q31-q41, 4q32-q35, 6p25 and 14q24-q31 (LOD scores of 2.4, simulated p-value of 0.000003 and a simulated genome-wide p-value of 0.06). Exome sequencing was then performed in 14 family members and 7 unrelated individuals from the same region. The analysis of coding variation revealed a pathogenic and candidate variants in different branches of the family. In three patients we find a known homozygous pathogenic mutation in the Homo sapiens solute carrier family 17 member 5 (SLC17A5), causing Salla disease. We also identify a deletion overlapping KDM3B and a duplication overlapping MAP3K4 and AGPAT4, both overlapping variants previously reported in developmental disorders.ConclusionsDNA samples from the large family analyzed in this study were initially collected based on a hypothesis that affected members shared a major genetic risk factor. Our results show that a complex phenotype such as mild intellectual disability in large families from genetically isolated populations may show considerable genetic heterogeneity.

Mass murders in Germany – classification of surviving offenders based on the examination of court files

ABSTRACTPersonality, psychopathology, and motives of 44 surviving offenders committing mass murder in Germany over 25 years (1984–2009) were analyzed using court files and psychiatric expertises. Initially, 123 mass murders in Germany were detected in the time period 1980–2010 (inclusive deceased offenders). Using a data entry form based on ViCLAS (Violent Crime Linkage Analysis System), we categorized the 44 surviving mass murderers into three prototypes using the ‘TwoStep Cluster’-method (separation of the offenders in different groups depending on their similarity of specific items): 1. Narcissistic or aggressive men suffering from addiction or affective disorder, committing mass murder out of rage/hate when being intoxicated by alcohol, 2. Psychotic offenders with schizophrenia and comorbid substance abuse. 3. Aggressive, narcissistic or anxious adolescents, half of them suffering from affective disorder or ADHD, committing mass murder out of rage/hate. Not included are such events where the offenders died and therefore no court files or psychiatric expertises were available. Classification and subtyping of the offenders’ personalities and psychopathological conditions might help to improve the chances for an early detection of persons at risk.

The environmental variables that impact human decomposition in terrestrially exposed contexts within Canada

Little is known about the nature and trajectory of human decomposition in Canada. This study involved the examination of 96 retrospective police death investigation cases selected using the Canadian ViCLAS (Violent Crime Linkage Analysis System) and sudden death police databases. A classification system was designed and applied based on the latest visible stages of autolysis (stages 1–2), putrefaction (3–5) and skeletonisation (6–8) observed. The analysis of the progression of decomposition using time (Post Mortem Interval (PMI) in days) and temperature accumulated-degree-days (ADD) score found considerable variability during the putrefaction and skeletonisation phases, with poor predictability noted after stage 5 (post bloat). The visible progression of decomposition outdoors was characterized by a brown to black discolouration at stage 5 and remnant desiccated black tissue at stage 7. No bodies were totally skeletonised in under one year. Mummification of tissue was rare with earlier onset in winter as opposed to summer, considered likely due to lower seasonal humidity. It was found that neither ADD nor the PMI were significant dependent variables for the decomposition score with correlations of 53% for temperature and 41% for time. It took almost twice as much time and 1.5 times more temperature (ADD) for the set of cases exposed to cold and freezing temperatures (4°C or less) to reach putrefaction compared to the warm group. The amount of precipitation and/or clothing had a negligible impact on the advancement of decomposition, whereas the lack of sun exposure (full shade) had a small positive effect. This study found that the poor predictability of onset and the duration of late stage decomposition, combined with our limited understanding of the full range of variables which influence the speed of decomposition, makes PMI estimations for exposed terrestrial cases in Canada unreliable, but also calls in question PMI estimations elsewhere.

A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees

A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees

A system for exact and approximate genetic linkage analysis of SNP data in large pedigrees

The use of dense single nucleotide polymorphism (SNP) data in genetic linkage analysis of large pedigrees is impeded by significant technical, methodological and computational challenges. Here we describe Superlink-Online SNP, a new powerful online system that streamlines the linkage analysis of SNP data. It features a fully integrated flexible processing workflow comprising both well-known and novel data analysis tools, including SNP clustering, erroneous data filtering, exact and approximate LOD calculations and maximum-likelihood haplotyping. The system draws its power from thousands of CPUs, performing data analysis tasks orders of magnitude faster than a single computer. By providing an intuitive interface to sophisticated state-of-the-art analysis tools coupled with high computing capacity, Superlink-Online SNP helps geneticists unleash the potential of SNP data for detecting disease genes. Computations performed by Superlink-Online SNP are automatically parallelized using novel paradigms, and executed on unlimited number of private or public CPUs. One novel service is large-scale approximate Markov Chain-Monte Carlo (MCMC) analysis. The accuracy of the results is reliably estimated by running the same computation on multiple CPUs and evaluating the Gelman-Rubin Score to set aside unreliable results. Another service within the workflow is a novel parallelized exact algorithm for inferring maximum-likelihood haplotyping. The reported system enables genetic analyses that were previously infeasible. We demonstrate the system capabilities through a study of a large complex pedigree affected with metabolic syndrome. Superlink-Online SNP is freely available for researchers at http://cbl-hap.cs.technion.ac.il/superlink-snp. The system source code can also be downloaded from the system website. omerw@cs.technion.ac.il Supplementary data are available at Bioinformatics online.

The Violent Crime Linkage Analysis System

The interrater reliability of an internationally renowned crime linkage system—the Violent Crime Linkage Analysis System (ViCLAS)—was tested. Police officers ( N = 10) were presented with a case file and asked to complete a ViCLAS booklet. The level of occurrence agreement between each officer was calculated. Results showed a 30.77% level of agreement across the 106 variables examined. Agreement ranged from 2.36% for weapon variables to 62.87% for administration variables. Only 11 (10.38%) of the variables reached an acceptable level of agreement. Concerns pertaining to the validity of inferences produced using ViCLAS data are discussed, along with potential explanations for the findings, limitations of the study, and future research directions.

Hyperchlorhidrosis Caused by Homozygous Mutation in CA12, Encoding Carbonic Anhydrase XII

Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO₂ hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).

Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

A Description of Sexual Offending Committed by Canadian Teachers

The aim of this investigation was to describe teachers who sexually offend against youth and the circumstances related to these offenses. Archival Violent Crime Linkage Analysis System reports were obtained from the Royal Canadian Mounted Police, and demographic and criminal characteristics for the offender, as well as information about the victim and offense, were selected for analyses. A descriptive approach was used to analyze the qualitative reports for a group of 113 Canadian sexual offenders between 1995 and 2002. The results provide a description of adult male teachers who offended within their position of trust as well as offense and victim characteristics.

Japan spastic paraplegia research consortium (JASPAC)

Japan Spastic Paraplegia Research Consortium (JASPAC), a nationwide clinical and genetic survey of patients with HSP in Japan, was started from 2006 as a project of the Research Committee for Ataxic Diseases of the Ministry of Health, Labor and Welfare, Japan. To date (October 4, 2010), 321 index patients with HSP have been registered from 40 prefectures in Japan. We are now performing molecular testing for the HSP patients using direct sequencing (SPG4, SPG31, and ARSACS), comparative genomic hybridization (CGH) array (SPG1/2/3A/4/5/6/7/8/10/11/13/15/17/20/21/31/33/39/42/ABCD1/alsin/SACS), and resequencing microarray (SPG1/2/3A/4/5/6/7/8/10/11/13/17/20/21/31/33/ABCD1). In 144 Japanese ADHSP families, SPG4 was the most common form, accounting for 47%, followed by SPG31 (4%), SPG3A (3%), SPG8 (1%), and SPG10 (1%). The results of molecular testing will be applicable to patients in terms of improved positive diagnosis, follow-up, and genetic counseling. Since approximately 40% of ADHSP remain unknown, we will perform high-throughput linkage analyses using SNP HiTLink (SNP High Throughput Linkage analysis system) for the identification of loci for disease-associated genes. Meanwhile, preliminary data showed that SPG11 and ARSACS were common in Japanese ARHSP families. JASPAC will contribute to elucidate the spectrum of clinical features and mutations, genotype/phenotype correlations, pathophisiology in various HSP phenotypes.

Statistical modelling in the investigation of stranger rape

AbstractA sample of stranger rape offences (n = 271) registered in the Dutch Violence Crime Linkage Analysis System database in the Netherlands between 1997 and 2007 was studied with the objective of developing statistical models, which give an indication of the probability of basic offender characteristics. Observable crime characteristics concerning the modus operandi, interaction between the offender and the victim, violence, precautionary measures, and sexual behaviours were selected in the dataset. Offender characteristics were selected based on their usefulness for the police organisation in narrowing the scope of a criminal investigation. Spatial behaviour, criminal history, and living situation of the offender were selected. From the predictive models, four out of five achieved a correct rate of over 70%, and all models predicted better than the best guess method. The proposed models for distance and prior convictions for violence seem particularly promising. Both these models show an improvement of correctly predicted offender characteristics of more than 20 percentile points compared with that which could have been estimated based on the average in the total sample. The predictive value of the models needs to be tested further with ‘new offences’, which were not used to construct the model. In general, the current study supports the finding that crime characteristics can be used to get an indication of the probability of certain offender characteristics. Nevertheless, for an understanding of the relationship between the crime characteristics and offender characteristics, a further development of a theoretical framework is urgently necessary. Copyright © 2009 John Wiley & Sons, Ltd.

SNP HiTLink: a high-throughput linkage analysis system employing dense SNP data

BackgroundDuring this recent decade, microarray-based single nucleotide polymorphism (SNP) data are becoming more widely used as markers for linkage analysis in the identification of loci for disease-associated genes. Although microarray-based SNP analyses have markedly reduced genotyping time and cost compared with microsatellite-based analyses, applying these enormous data to linkage analysis programs is a time-consuming step, thus, necessitating a high-throughput platform.ResultsWe have developed SNP HiTLink (SNP High Throughput Linkage analysis system). In this system, SNP chip data of the Affymetrix Mapping 100 k/500 k array set and Genome-Wide Human SNP array 5.0/6.0 can be directly imported and passed to parametric or model-free linkage analysis programs; MLINK, Superlink, Merlin and Allegro. Various marker-selecting functions are implemented to avoid the effect of typing-error data, markers in linkage equilibrium or to select informative data.ConclusionThe results using the 100 k SNP dataset were comparable or even superior to those obtained from analyses using microsatellite markers in terms of LOD scores obtained. General personal computers are sufficient to execute the process, as runtime for whole-genome analysis was less than a few hours. This system can be widely applied to linkage analysis using microarray-based SNP data and with which one can expect high-throughput and reliable linkage analysis.

Investigating the Reliability of the Violent Crime Linkage Analysis System (ViCLAS) Crime Report

The Violent Crime Linkage Analysis System (ViCLAS) is a computerized investigative aid, developed by the Royal Canadian Mounted Police, which is used to increase information sharing and enable crime linkages in serious crime investigations. The current study examines the reliability of the ViCLAS Crime Report by calculating the level of agreement among two samples of police officers who received one of two fictitious crime scenarios; homicide (n = 116) or sexual assault (n = 121). Results from this study show that the observed inter-rater reliability among police officers completing the ViCLAS booklet was 79.30% for the homicide scenario, and 87.70% for the sexual assault scenario. Implications of the results are discussed.

An Introduction to the Special Issue on Criminal Profiling

The frequency with which profilers are called on to assist in criminal investigations has increased dramatically from year to year over the past three decades. Unfortunately, as many people have pointed out, the amount of profiling research has increased at a much slower rate over the same time period. While things seem to be gradually improving in this regard, there are still many unanswered questions about profiling that need to be answered, many of which are crucial for the field. For example, debates are ongoing about what roles profilers should play in criminal investigations, how profiles should be constructed, delivered, and evaluated, whether the contributions made by profilers are valid and, if so, how, and whether there are new, potentially more productive approaches to profiling that could improve upon or even replace the methods that are currently being used. The list of unanswered question in this field goes on and on. Clearly it is not possible in one special issue to tackle all of these questions. Instead, the goal of this issue was to bring together high quality research, conducted by a range of individuals with different backgrounds and perspectives, that tackled a variety of important issues in the profiling field. My hope is that the papers included in this special issue will help in some small way to move the profiling field forward. I feel confident that police practitioners and profilers will see value in much of what is included in this special issue. I am also certain that researchers will be inspired by this collection of papers and continue to conduct quality research on the topic of criminal profiling so that the large gap that currently exists between profiling practice and profiling research can slowly be filled. In an attempt to fill a very important gap that currently exists in the profiling field, the first article in this special issue by Melissa Martineau and Shevaun Corey examines the degree to which crime descriptions can be coded reliably using the variables included in the Violent Crime Linkage Analysis System (ViCLAS). While the relevance of this article to the field of criminal profiling may not be obvious at first glance, when one considers that ViCLAS-type data forms the basis of much profiling research the importance of this article becomes obvious. Indeed, many researchers rely on ViCLAS-type data as the basis for their studies and rarely can these researchers speak to the reliability of that data. While the results of Martineau and Corey’s study clearly cannot be generalized from ViCLAS to other databases at this time, their study is the first publication that I am aware of to directly address the issue of coding reliability within such databases. Thus, this study represents a very important contribution to the profiling field. The second article by Brandy Doan and Brent Snook uses archival police data to empirically examine one of the fundamental assumptions underlying many forms of criminal profiling – the homology assumption. This assumption states that if two offenders commit similar crimes with respect to their crime scene behaviors they should exhibit similar background characteristics. While a crucial assumption in the profiling field, few studies have actually examined whether the assumption is valid. As argued by Doan and Snook, those studies that have examined the assumption fail to find strong empirical support for it. Their test of the homology assumption, which for the first time is based on Canadian data, generally supports previous research and raises some important questions about the validity of certain profiling practices. J Police Crim Psych (2008) 23:49–50 DOI 10.1007/s11896-008-9025-8

MLIP: using multiple processors to compute the posterior probability of linkage

BackgroundLocalization of complex traits by genetic linkage analysis may involve exploration of a vast multidimensional parameter space. The posterior probability of linkage (PPL), a class of statistics for complex trait genetic mapping in humans, is designed to model the trait model complexity represented by the multidimensional parameter space in a mathematically rigorous fashion. However, the method requires the evaluation of integrals with no functional form, making it difficult to compute, and thus further test, develop and apply. This paper describes MLIP, a multiprocessor two-point genetic linkage analysis system that supports statistical calculations, such as the PPL, based on the full parameter space implicit in the linkage likelihood.ResultsThe fundamental question we address here is whether the use of additional processors effectively reduces total computation time for a PPL calculation. We use a variety of data – both simulated and real – to explore the question "how close can we get?" to linear speedup. Empirical results of our study show that MLIP does significantly speed up two-point log-likelihood ratio calculations over a grid space of model parameters.ConclusionObserved performance of the program is dependent on characteristics of the data including granularity of the parameter grid space being explored and pedigree size and structure. While work continues to further optimize performance, the current version of the program can already be used to efficiently compute the PPL. Thanks to MLIP, full multidimensional genome scans are now routinely being completed at our centers with runtimes on the order of days, not months or years.

Child Care Providers Who Commit Sexual Offences

The aim of this investigation was to undertake an exploratory analysis of child care providers who sexually offend against children and adolescents and the circumstances related to these offences. Archival Violent Crime Linkage Analysis System (ViCLAS) reports were obtained from the Royal Canadian Mounted Police (RCMP), and demographic and criminal characteristics for the offender, as well as information about the victim and offence, were selected for analyses. A descriptive approach was used to analyze the qualitative reports for a group of 305 Canadian sexual offenders between 1995 and 2002. Adult male (N = 163) and female ( N = 14), along with juvenile male (N = 100) and female (N = 28) child care providers who were involved in a sexual offence against a child or adolescent are described. This article provides unique information about the crimes committed by child care providers in that it is focused on crime characteristics, rather than on personality or treatment variables. Furthermore, it represents a comprehensive examination of this type of offender by including understudied groups, namely juvenile and female offenders.

Maximum Likelihood Haplotyping for General Pedigrees

Haplotype data is valuable in mapping disease-susceptibility genes in the study of Mendelian and complex diseases. We present algorithms for inferring a most likely haplotype configuration for general pedigrees, implemented in the newest version of the genetic linkage analysis system SUPERLINK. In SUPERLINK, genetic linkage analysis problems are represented internally using Bayesian networks. The use of Bayesian networks enables efficient maximum likelihood haplotyping for more complex pedigrees than was previously possible. Furthermore, to support efficient haplotyping for larger pedigrees, we have also incorporated a novel algorithm for determining a better elimination order for the variables of the Bayesian network. The presented optimization algorithm also improves likelihood computations. We present experimental results for the new algorithms on a variety of real and semiartificial data sets, and use our software to evaluate MCMC approximations for haplotyping.