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The advent of high-throughput sequencing technologies constituted a major advance in genomic studies, offering new prospects in a wide range of applications.We propose a rigorous and flexible algorithmic solution to mapping SOLiD color-space reads to a reference genome. The solution relies on an advanced method of seed design that uses a faithful probabilistic model of read matches and, on the other hand, a novel seeding principle especially adapted to read mapping. Our method can handle bothdoi:10.1155/2010/708501 pmid:20936175 pmcid:PMC2945724 fatcat:nahdomgtm5bfpf3pk2mrmifh2i
more »... ssy and lossless frameworks and is able to distinguish, at the level of seed design, between SNPs and reading errors. We illustrate our approach by several seed designs and demonstrate their efficiency.
Lecture Notes in Computer Science
The advent of high-throughput sequencing technologies constituted a major advance in genomic studies, offering new prospects in a wide range of applications. We propose a rigorous and flexible algorithmic solution to mapping SOLiD color-space reads to a reference genome. The solution relies on an advanced method of seed design that uses a faithful probabilistic model of read matches and, on the other hand, a novel seeding principle especially adapted to read mapping. Our method can handle bothdoi:10.1007/978-3-642-12683-3_25 fatcat:65fdkd7yjrgkrpcoujaeqjlw7y
more »... ossy and lossless frameworks and is able to distinguish, at the level of seed design, between SNPs and reading errors. We illustrate our approach by several seed designs and demonstrate their efficiency.
Lecture Notes in Computer Science
Frameshift mutations in protein-coding DNA sequences produce a drastic change in the resulting protein sequence, which prevents classic protein alignment methods from revealing the proteins' common origin. Moreover, when a large number of substitutions are additionally involved in the divergence, the homology detection becomes difficult even at the DNA level. To cope with this situation, we propose a novel method to infer distant homology relations of two proteins, that accounts for frameshiftdoi:10.1007/978-3-642-04241-6_10 fatcat:wawa3jrjtfclhnb6wb54o522b4
more »... nd point mutations that may have affected the coding sequences. We design a dynamic programming alignment algorithm over memory-efficient graph representations of the complete set of putative DNA sequences of each protein, with the goal of determining the two putative DNA sequences which have the best scoring alignment under a powerful scoring system designed to reflect the most probable evolutionary process. This allows us to uncover evolutionary information that is not captured by traditional alignment methods, which is confirmed by biologically significant examples.
It is becoming increasingly necessary to develop computerized methods for identifying the few disease-causing variants from hundreds discovered in each individual patient. This problem is especially relevant for Copy Number Variants (CNVs), which can be cheaply interrogated via low-cost hybridization arrays commonly used in clinical practice. We present a method to predict the disease relevance of CNVs that combines functional context and clinical phenotype to discover clinically harmful CNVsdoi:10.1371/journal.pone.0139656 pmid:26437450 pmcid:PMC4593641 fatcat:msxw5of6r5adpalxgq5fromffi
more »... nd likely causative genes) in patients with a variety of phenotypes. We compare several feature and gene weighing systems for classifying both genes and CNVs. We combined the best performing methodologies and parameters on over 2,500 Agilent CGH 180k Microarray CNVs derived from 140 patients. Our method achieved an F-score of 91.59%, with 87.08% precision and 97.00% recall. Our methods are freely available at https://github.com/compbio-UofT/cnvprioritization. Our dataset is included with the supplementary information.
Algorithms for Molecular Biology 2010, 5:6 http://www.almob.org/content/5/1/6 Gîrdea et al. ... Algorithms for Molecular Biology 2010, 5:6 http://www.almob.org/content/5/1/6 Page 7 of 15 Gîrdea et al. ...doi:10.1186/1748-7188-5-6 pmid:20047662 pmcid:PMC2821327 fatcat:xzr2xbglmncefdiy3qicl6mtj4
This paper proposes a technique for learning kernel functions that can be used in non-linear SVM classification. The technique uses genetic programming to evolve kernel functions as additive or multiplicative combinations of linear, polynomial and RBF kernels, while a procedure inspired from InfoBoost helps the evolved kernels concentrate on the most difficult objects to classify. The kernels obtained at each boosting round participate in the training of non-linear SVMs which are combined,doi:10.1109/synasc.2007.71 dblp:conf/synasc/GirdeaC07 fatcat:oneogk5vurepbngsaggus2l3by
more »... with their confidence coefficients, into a final classifier. We compared on several data sets the performance of the kernels obtained in this manner with the performance of classic RBF kernels and of kernels evolved using a pure GP method, and we concluded that the boosted GP kernels are generally better.
The clinical use of whole-genome sequencing (WGS) is expected to alter pediatric medical management. The study aimed to describe the type and cost of healthcare activities following pediatric WGS compared to chromosome microarray (CMA). Healthcare activities prompted by WGS and CMA were ascertained for 101 children with developmental delay over 1 year. Activities following receipt of non-diagnostic CMA were compared to WGS diagnostic and non-diagnostic results. Activities were costed in 2016doi:10.1038/s41431-017-0020-3 pmid:29158552 fatcat:tauljtcgabckxbf4wajx6icloy
more »... adian dollars (CDN). Ongoing care accounted for 88.6% of post-test activities. The mean number of lab tests was greater following CMA than WGS (0.55 vs. 0.09; p = 0.007). The mean number of specialist visits was greater following WGS than CMA (0.41 vs. 0; p = 0.016). WGS results (diagnostic vs. non-diagnostic) modified the effect of test type on mean number of activities (p < 0.001). The cost of activities prompted by diagnostic WGS exceeded $557CDN for 10% of cases. In complex pediatric care, CMA prompted additional diagnostic investigations while WGS prompted tailored care guided by genotypic variants. Costs for prompted activities were low for the majority and constitute a small proportion of total test costs. Optimal use of WGS depends on robust evaluation of downstream care and cost consequences.
The discovery of disease-causing mutations typically requires confirmation of the variant or gene in multiple unrelated individuals, and a large number of rare genetic diseases remain unsolved due to difficulty identifying second families. To enable the secure sharing of case records by clinicians and rare disease scientists, we have developed the PhenomeCentral portal (https:// phenomecentral.org). Each record includes a phenotypic description and relevant genetic information (exome ordoi:10.1002/humu.22851 pmid:26251998 pmcid:PMC5467641 fatcat:wt3uvlhaxze55h54byafspg3d4
more »... e genes). PhenomeCentral identifies similar patients in the database based on semantic similarity between clinical features, automatically prioritized genes from whole-exome data, and candidate genes entered by the users, enabling both hypothesis-free and hypothesis-driven matchmaking. Users can then contact other submitters to follow up on
The National Institutes of Health Undiagnosed Diseases Program (NIH UDP) applies translational research systematically to diagnose patients with undiagnosed diseases. The challenge is to implement an information system enabling scalable translational research. The authors hypothesized that similar complex problems are resolvable through process management and the distributed cognition of communities. The team, therefore, built the NIH UDP integrated collaboration system (UDPICS) to form virtualdoi:10.3389/fmed.2016.00039 pmid:27785453 pmcid:PMC5060938 fatcat:wfom55rpzzhohelp5l2w6yhtte
more »... collaborative multidisciplinary research networks or communities. UDPICS supports these communities through integrated process management, ontology-based phenotyping, biospecimen management, cloud-based genomic analysis, and an electronic laboratory notebook. UDPICS provided a mechanism for efficient, transparent, and scalable translational research and thereby addressed many of the complex and diverse research and logistical problems of the NIH UDP. Full definition of the strengths and deficiencies of UDPICS will require formal qualitative and quantitative usability and process improvement measurement.
Marta Girdea, from the University of Toronto, Ontario, spoke for the Finding of Rare Diseases Genes in Canada (FORGE Canada) on ways to ensure accurate phenotyping data is captured in her talk "Easy phenotyping ...doi:10.1002/humu.22293 pmid:23401191 pmcid:PMC4130157 fatcat:olvqoha4mrcstgbq23cpufuhka
Genetics in Medicine
There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happendoi:10.1002/humu.22858 pmid:26295439 pmcid:PMC4610002 fatcat:f5r4wjy3rjcyngkpnfuvbqaeey
more »... learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. Research Chair in Law and Medicine; Public Population Project in Genomics and Society (P3G). C 2015 WILEY PERIODICALS, INC. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow. Hum Mutat 36:915-921, 2015. C 2015 Wiley Periodicals, Inc.
The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and welldefined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability withdoi:10.1093/nar/gkt1026 pmid:24217912 pmcid:PMC3965098 fatcat:p2ubynvoprbopaeyoboloexzcq
more »... resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online.
npj Genomic Medicine
The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yielddoi:10.1038/npjgenmed.2015.12 pmid:28567303 pmcid:PMC5447450 fatcat:kyib3zsflrfnfcm75lxxaen3me
more »... mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%; P value = 1.42E − 05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%; P value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.
This study starts from certain observation of some clinical features regarding the subjective symptoms in connection with the specific pathology of the temporomandibular dysfunction (TMD). The observations were made on a sample of adolescent with orthodontic appliances, so that having different dento-maxillary anomalies. They had to fill in four questionnaires with closed and combined final in order to evaluate the subjective simptomatology of the potential dysfunction of the temporomandibularfatcat:oevi4hcuh5dgfcvhr367f475sy
more »... oint (TMJ). On the other hand it was searched for a potential correlation that might be between a sort of a dento-maxillary anomaly and the incidence of the TMD simptomatol-ogy.
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