R Scott Winters

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (14)120.01 Total impact

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    ABSTRACT: Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E.
    American Journal of Medical Genetics Part A 05/2008; 146(7):952-64. · 2.30 Impact Factor
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    ABSTRACT: Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5' untranslated region (UTR) exons. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes). Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains.
    Investigative Ophthalmology &amp Visual Science 12/2007; 48(11):5007-12. · 3.44 Impact Factor
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    ABSTRACT: The proliferation of biomedical literature makes it increasingly difficult for researchers to find and manage relevant information. However, identifying research articles containing mutation data, a requisite first step in integrating large and complex mutation data sets, is currently tedious, time-consuming and imprecise. More effective mechanisms for identifying articles containing mutation information would be beneficial both for the curation of mutation databases and for individual researchers. We developed an automated method that uses information extraction, classifier, and relevance ranking techniques to determine the likelihood of MEDLINE abstracts containing information regarding genomic variation data suitable for inclusion in mutation databases. We targeted the CDKN2A (p16) gene and the procedure for document identification currently used by CDKN2A Database curators as a measure of feasibility. A set of abstracts was manually identified from a MEDLINE search as potentially containing specific CDKN2A mutation events. A subset of these abstracts was used as a training set for a maximum entropy classifier to identify text features distinguishing "relevant" from "not relevant" abstracts. Each document was represented as a set of indicative word, word pair, and entity tagger-derived genomic variation features. When applied to a test set of 200 candidate abstracts, the classifier predicted 88 articles as being relevant; of these, 29 of 32 manuscripts in which manual curation found CDKN2A sequence variants were positively predicted. Thus, the set of potentially useful articles that a manual curator would have to review was reduced by 56%, maintaining 91% recall (sensitivity) and more than doubling precision (positive predictive value). Subsequent expansion of the training set to 494 articles yielded similar precision and recall rates, and comparison of the original and expanded trials demonstrated that the average precision improved with the larger data set. Our results show that automated systems can effectively identify article subsets relevant to a given task and may prove to be powerful tools for the broader research community. This procedure can be readily adapted to any or all genes, organisms, or sets of documents.
    Human Mutation 10/2006; 27(9):957-64. · 5.21 Impact Factor
  • R. Scott Winters
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    ABSTRACT: Darwin. Niles Eldredge, curator. At the American Museum of Natural History, New York, through 29 May 2006;. Museum of Science, Boston, 2 December 2006 to 22 April 2007;. Field Museum, Chicago, 15 June 2007 to 1 January 2008;. Royal Ontario Museum, Toronto, 8 March 2008 to 4 August 2008;. Natural History Museum, London, October 2008 to March 2009. www.amnh.org/exhibitions/darwin Darwin. Discovering the Tree of Life. By Niles Eldredge. Norton, New York, 2005. 272 pp. $35. ISBN: 0-393-05966-9. An exhibit at the American Museum of Natural History in New York, "Origins" presents a comprehensive collection of artifacts and displays that illustrate the life of Charles Darwin and the intellectual formation of his theory of evolution.
    Science 01/2006; 311(5758):179-179. · 31.20 Impact Factor
  • R. Scott Winters
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    ABSTRACT: William Hodges 1744-1797 The Art of Exploration. Geoff Quilley, Curator. Organized by the National Maritime Museum, Greenwich, UK, and the Yale Center for British Art, New Haven, CT. At the Yale Center for British Art through 24 April 2005. http://ycba.yale.edu William Hodges 1744-1797 The Art of Exploration. Geoff Quilley and John Bonehill, Eds.. Yale University Press, New Haven, CT, 2004. 224 pp. $60, £40. ISBN 0-300-10376-X. This exhibit and the accompanying catalog offer a reappraisal of the work and reputation of the landscape painter who accompanied Cook's second voyage to the South Pacific.
    Science 03/2005; 307(5715):1565-1565. · 31.20 Impact Factor
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    ABSTRACT: A complex relation is any n-ary relation in which some of the arguments may be be unspecified. We present here a simple two-stage method for extracting complex relations between named entities in text. The first stage creates a graph from pairs of entities that are likely to be related, and the second stage scores maximal cliques in that graph as potential complex relation instances. We evaluate the new method against a standard baseline for extracting genomic variation relations from biomed- ical text.
    ACL 2005, 43rd Annual Meeting of the Association for Computational Linguistics, Proceedings of the Conference, 25-30 June 2005, University of Michigan, USA; 01/2005
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    ABSTRACT: VTag is an application for identifying the type, genomic location and genomic state-change of acquired genomic aberrations described in text. The application uses a machine learning technique called conditional random fields. VTag was tested with 345 training and 200 evaluation documents pertaining to cancer genetics. Our experiments resulted in 0.8541 precision, 0.7870 recall and 0.8192 F-measure on the evaluation set.
    Bioinformatics 12/2004; 20(17):3249-51. · 5.32 Impact Factor
  • R. Scott Winters
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    ABSTRACT: Gene(sis) Contemporary Art Explores Human Genomics. Robin Held, curator. Organized by the Henry Art Gallery, the University of Washington, Seattle, WA, in affiliation with the Berkeley Art Museum, Berkeley, CA. At the Mary and Leigh Block Museum of Art, Northwestern University, Evanston, IL, through 28 November 2004. www.gene-sis.net. CD-ROM catalogue, $24.95. The nearly 60 works, by 24 contemporary artists or ensembles, in this exhibit seek to promote considerations of the potential social, emotional, and ethical implications of the Human Genome Project.
    Science 10/2004; 306(5694):231-231. · 31.20 Impact Factor
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    ABSTRACT: Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant eye disease with a spectrum of clinical manifestations that may include bilateral corneal clouding, arcus lipoides, and anterior corneal crystalline cholesterol deposition. We have previously performed a genome-wide linkage analysis on two large Swede-Finn families and mapped the SCCD locus to a 16-cM interval between markers D1S2633 and D1S228 on chromosome 1p36. We have collected 11 additional families from Finland, Germany, Turkey, and USA to narrow the critical region for SCCD. Here, we have used haplotype analysis with densely spaced microsatellite markers in a total of 13 families to refine the candidate interval. A common disease haplotype was observed among the four Swede-Finn families indicating the presence of a founder effect. Recombination results from all 13 families refined the SCCD locus to 2.32 Mbp between markers D1S1160 and D1S1635. Within this interval, identity-by-state was present in all 13 families for two markers D1S244 and D1S3153, further refining the candidate region to 1.58 Mbp.
    Human Genetics 06/2004; 114(6):594-600. · 4.63 Impact Factor
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    ABSTRACT: We have adapted the originally described electronic PCR (e-PCR) algorithm to perform string searches more accurately and much more rapidly than previously possible. Our implementation [multithreaded e-PCR (me-PCR)] runs sufficiently fast to allow even desktop machines to query quickly large genomes with very large genomic element sets. In addition, me-PCR is multithreaded, interprets all IUPAC nucleotide symbols, allows searches with elements specified by long sequences (such as SNPs), accepts ranges in the expected PCR size input field, requires substantially less memory for analysis of large sequences and corrects a number of minor flaws causing misreporting of hits in exceptional cases. Thus, me-PCR provides increased annotation capabilities for complex genomes to non-expert laboratories.
    Bioinformatics 04/2004; 20(4):588-90. · 5.32 Impact Factor
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    ABSTRACT: GeneTaggerCRF is an application for tagging gene names and references in text. It is based on the MALLET natural language processing package and uses a machine learning technique called conditional random fields. It is the first installment of a set of information extraction tools called BioSFIER (Biology Software For Information Extraction and Retrieval). We tested GeneTaggerCRF's performance by 10- fold cross validation on 190 MEDLINE abstracts pertaining to Neuroblastoma cancer genetics. Performance was 0.93 precision and 0.60 recall. Availability: The software is available at
    01/2004;
  • R. Scott Winters
    Endeavour 06/2003; 27(2):45–46. · 0.17 Impact Factor
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    ABSTRACT: The study narrows the candidate gene search for SCCD to the UBIAD1 gene and provides supporting evidence that the presence of UBIAD1 mutations are the cause of SCCD. Of the eight mutations found in the study, the 637 A>G mutation found in the protein product N102S, may be a mutation hot spot. This mutation is also located in a highly conserved region among species and in a structurally important domain.
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    ABSTRACT: MTag is an application for identifying and extracting clinical descriptions of malignancy presented in text. The application uses the machine learning technique Conditional Random Fields and incorporates domain-specific features. MTag was tested with 1,010 training and 432 evaluation documents pertaining to cancer genomics. Our experiments resulted in 0.85 precision, 0.82 recall, and 0.83 F-measure on the evaluation set.

Publication Stats

117 Citations
102 Downloads
758 Views
120.01 Total Impact Points

Institutions

  • 2003–2008
    • The Children's Hospital of Philadelphia
      • Division of Oncology
      Philadelphia, Pennsylvania, United States
  • 2006
    • University of Pennsylvania
      • Department of Computer and Information Science
      Philadelphia, PA, United States