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- Aad, G., et al.
(författare)
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- 2013
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Ingår i: The European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6052. ; 73:3
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Tidskriftsartikel (refereegranskat)
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- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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- Ferrari, Raffaele, et al.
(författare)
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Frontotemporal dementia and its subtypes: a genome-wide association study.
- 2014
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Ingår i: Lancet Neurology. - 1474-4465. ; 13:7, s. 686-699
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
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- Alcorn, Sara R, et al.
(författare)
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Practice patterns of photon and proton pediatric image guided radiation treatment : results from an International Pediatric Research consortium
- 2014
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Ingår i: Practical radiation oncology. - : Elsevier BV. - 1879-8500. ; 4:5, s. 336-341
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Image guided radiation therapy (IGRT) has become common practice for both photon and proton radiation therapy, but there is little consensus regarding its application in the pediatric population. We evaluated clinical patterns of pediatric IGRT practice through an international pediatrics consortium comprised of institutions using either photon or proton radiation therapy.METHODS AND MATERIALS: Seven international institutions with dedicated pediatric expertise completed a 53-item survey evaluating patterns of IGRT use in definitive radiation therapy for patients ≤21 years old. Two institutions use proton therapy for children and all others use IG photon therapy. Descriptive statistics including frequencies of IGRT use and means and standard deviations for planning target volume (PTV) margins by institution and treatment site were calculated.RESULTS: Approximately 750 pediatric patients were treated annually across the 7 institutions. IGRT was used in tumors of the central nervous system (98%), abdomen or pelvis (73%), head and neck (100%), lung (83%), and liver (69%). Photon institutions used kV cone beam computed tomography and kV- and MV-based planar imaging for IGRT, and all proton institutions used kV-based planar imaging; 57% of photon institutions used a specialized pediatric protocol for IGRT that delivers lower dose than standard adult protocols. Immobilization techniques varied by treatment site and institution. IGRT was utilized daily in 45% and weekly in 35% of cases. The PTV margin with use of IGRT ranged from 2 cm to 1 cm across treatment sites and institution.CONCLUSIONS: Use of IGRT in children was prevalent at all consortium institutions. There was treatment site-specific variability in IGRT use and technique across institutions, although practices varied less at proton facilities. Despite use of IGRT, there was no consensus of optimum PTV margin by treatment site. Given the desire to restrict any additional radiation exposure in children to instances where the exposure is associated with measureable benefit, prospective studies are warranted to optimize IGRT protocols by modality and treatment site.
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- van de Ven, Johannes P. H., et al.
(författare)
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A functional variant in the CFI gene confers a high risk of age-related macular degeneration
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:7, s. 813-813
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Tidskriftsartikel (refereegranskat)abstract
- Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants(1-5). Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 x 10(-6); odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.
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| 10. |
- Woll, Petter S, et al.
(författare)
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Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.
- 2014
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 25:6, s. 794-808
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
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