Project description:Background: Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance. Methods: In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate. Results: In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. Conclusions: The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.

Project description:Background: Multiple sclerosis (MS) is a complex disorder thought to result from an interaction between environmental and genetic predisposing factors which have not yet been characterised, although it is known to be associated with the HLA region on 6p21.32. Recently, a picture of chronic cerebrospinal venous insufficiency (CCSVI), consequent to stenosing venous malformation of the main extra-cranial outflow routes (VM), has been described in patients affected with MS, introducing an additional phenotype with possible pathogenic significance. Methods: In order to explore the presence of copy number variations (CNVs) within the HLA locus, a custom CGH array was designed to cover 7 Mb of the HLA locus region (6,899,999bp; chr6:29,900,001-36,800,000). Genomic DNA of the 15 patients with CCSVI/VM and MS was hybridised in duplicate. Results: In total, 322 CNVs, of which 225 were extragenic and 97 intragenic, were identified in 15 patients. 234 known polymorphic CNVs were detected, the majority of these being situated in non-coding or extragenic regions. The overall number of CNVs (both extra- and intragenic) showed a robust and significant correlation with the number of stenosing VMs (Spearman: r=0.6590, p=0.0104; linear regression analysis r=0.6577, p=0.0106). The region we analysed contains 211 known genes. By using pathway analysis focused on angiogenesis and venous development, MS, and immunity, we tentatively highlight several genes as possible susceptibility factor candidates involved in this peculiar phenotype. Conclusions: The CNVs contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease. 8 female and 7 male MS patients

Project description:BackgroundCaries Impacts and Experiences Questionnaire for Children (CARIES-QC) is a child-centred caries-specific quality of life measure. This study aimed to select, and validate with children, a classification system for a paediatric condition-specific preference-based measure, based on CARIES-QC.MethodsFirst, a provisional classification system for a preference-based measure based on CARIES-QC was identified using Rasch analysis, psychometric testing, involvement of children and parents, and the developer of CARIES-QC. Second, qualitative, semi-structured 'think aloud' validation interviews were undertaken with a purposive sample of children with dental caries. The interviewer aimed to identify whether items were considered important and easily understood, whether any were overlapping and if any excluded items should be reintroduced. Interview recordings were transcribed verbatim and thematic analysis conducted.ResultsRasch analysis identified poor item spread for the items 'cross' and 'school'. Items relating to eating were correlated and the better performing items were considered for selection. Children expressed some confusion regarding the items 'school' and 'food stuck'. Parent representatives thought that impacts surrounding toothbrushing ('brushing') were encompassed by the item 'hurt'. Five items were selected from CARIES-QC for inclusion in the provisional classification system; 'hurt', 'annoy', 'carefully', 'kept awake' and 'cried'. Validation interviews were conducted with 20 children aged 5-16 years old. Participants thought the questionnaire was straightforward and covered a range of impacts. Children thought an item about certain foods being 'hard to eat' was more relevant than one about having to eat more carefully because of their teeth and so the 'carefully' item was replaced with 'hard to eat'.ConclusionFollowing child-centred modification, the preliminary five-item classification system is considered valid and suitable for use in a valuation survey. The innovative child-centred methods used to both identify and validate the classification system can be applied in the development of other preference-based measures.

Dataset Information

Development of a Bilingual MS-Specific Health Classification System: The Preference-Based Multiple Sclerosis Index.

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Methods

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Publications

Development of a Bilingual MS-Specific Health Classification System: The Preference-Based Multiple Sclerosis Index.

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