Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma.

Multiple myeloma is characterized by genomic alterations frequently involving gains and losses of chromosomes. Single nucleotide polymorphism (SNP)-based mapping arrays allow the identification of copy number changes at the sub-megabase level and the identification of loss of heterozygosity (LOH) due to monosomy and uniparental disomy (UPD). We have found that SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well, making the technique robust as a tool to investigate myeloma genomics. The most frequently identified alterations are located at 1p, 1q, 6q, 8p, 13, and 16q. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. We have identified that UPD is prevalent in myeloma and occurs through a number of mechanisms including mitotic nondisjunction and mitotic recombination. For the first time in myeloma, integration of mapping and expression data has allowed us to reduce the complexity of standard gene expression data and identify candidate genes important in both the transition from normal to monoclonal gammopathy of unknown significance (MGUS) to myeloma and in different subgroups within myeloma. We have documented these genes, providing a focus for further studies to identify and characterize those that are key in the pathogenesis of myeloma.

A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma

Purpose: Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup.Experimental Design: Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 55) and without (n = 24) a t(4;14) by using global gene expression analysis.Results: Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation.Conclusions: t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.

Towards a knowledge-based approach for effective decision-making in railway safety

Purpose – This paper aims to contribute towards understanding how safety knowledge can be elicited from railway experts for the purposes of supporting effective decision-making. Design/methodology/approach – A consortium of safety experts from across the British railway industry is formed. Collaborative modelling of the knowledge domain is used as an approach to the elicitation of safety knowledge from experts. From this, a series of knowledge models is derived to inform decision-making. This is achieved by using Bayesian networks as a knowledge modelling scheme, underpinning a Safety Prognosis tool to serve meaningful prognostics information and visualise such information to predict safety violations. Findings – Collaborative modelling of safety-critical knowledge is a valid approach to knowledge elicitation and its sharing across the railway industry. This approach overcomes some of the key limitations of existing approaches to knowledge elicitation. Such models become an effective tool for prediction of safety cases by using railway data. This is demonstrated using passenger–train interaction safety data. Practical implications – This study contributes to practice in two main directions: by documenting an effective approach to knowledge elicitation and knowledge sharing, while also helping the transport industry to understand safety. Social implications – By supporting the railway industry in their efforts to understand safety, this research has the potential to benefit railway passengers, staff and communities in general, which is a priority for the transport sector. Originality/value – This research applies a knowledge elicitation approach to understanding safety based on collaborative modelling, which is a novel approach in the context of transport.