From a Conceptual Model to a Knowledge Graph for Genomic Datasets

Data access at genomic repositories is problematic, as data is described by heterogeneous and hardly comparable metadata. We previously introduced a unified conceptual schema, collected metadata in a single repository and provided classical search methods upon them. We here propose a new paradigm to support semantic search of integrated genomic metadata, based on the Genomic Knowledge Graph, a semantic graph of genomic terms and concepts, which combines the original information provided by each source with curated terminological content from specialized ontologies. Commercial knowledge-assisted search is designed for transparently supporting keyword-based search without explaining inferences; in biology, inference understanding is instead critical. For this reason, we propose a graph-based visual search for data exploration; some expert users can navigate the semantic graph along the conceptual schema, enriched with simple forms of homonyms and term hierarchies, thus understanding the semantic reasoning behind query results

Trypanosoma brucei gambiense group 1 is distinguished by a unique amino acid substitution in the HpHb receptor implicated in human serum resistance

Trypanosoma brucei rhodesiense (Tbr) and T. b. gambiense (Tbg), causative agents of Human African Trypanosomiasis (sleeping sickness) in Africa, have evolved alternative mechanisms of resisting the activity of trypanosome lytic factors (TLFs), components of innate immunity in human serum that protect against infection by other African trypanosomes. In Tbr, lytic activity is suppressed by the Tbr-specific serum-resistance associated (SRA) protein. The mechanism in Tbg is less well understood but has been hypothesized to involve altered activity and expression of haptoglobin haemoglobin receptor (HpHbR). HpHbR has been shown to facilitate internalization of TLF-1 in T.b. brucei (Tbb), a member of the T. brucei species complex that is susceptible to human serum. By evaluating the genetic variability of HpHbR in a comprehensive geographical and taxonomic context, we show that a single substitution that replaces leucine with serine at position 210 is conserved in the most widespread form of Tbg (Tbg group 1) and not found in related taxa, which are either human serum susceptible (Tbb) or known to resist lysis via an alternative mechanism (Tbr and Tbg group 2). We hypothesize that this single substitution contributes to reduced uptake of TLF and thus may play a key role in conferring serum resistance to Tbg group 1. In contrast, similarity in HpHbR sequence among isolates of Tbg group 2 and Tbb/Tbr provides further evidence that human serum resistance in Tbg group 2 is likely independent of HpHbR functio

The accuracy of clinical staging of stage I-IIIa non-small cell lung cancer: An analysis based on individual participant data

BACKGROUND: Clinical staging of NSCLC helps determine prognosis and management of patients; few data exist on accuracy of clinical staging and the impact on treatment and survival of patients. We assessed whether participant or trial characteristics were associated with clinical staging accuracy as well as impact on survival. METHODS: We used individual participant data from RCTs, supplied for a meta-analysis of pre-operative chemotherapy (+/- radiotherapy) versus surgery alone (+/- radiotherapy) in NSCLC. We assessed agreement between clinical TNM (cTNM) stage at randomization and pathological TNM (pTNM) stage, for participants in the control group. RESULTS: Results are based on 698 patients who received surgery alone (+/- radiotherapy) with data for cTNM and pTNM stage. 46% of cases were cTNM stage I, 23% cTNM stage II and 31% cTNM stage IIIa. cTNM stage disagreed with pTNM stage in 48% of cases, with 34% clinically understaged and 14% clinically over-staged. Agreement was not associated with age (p=0.12), gender (p=0.62), histology (p=0.82), staging method (p=0.32) or year of randomisation (p=0.98). Poorer survival in understaged patients was explained by the underlying pTNM stage. Clinical staging failed to detect T4 disease in 10% of cases and misclassified nodal disease in 38%. CONCLUSIONS: This study demonstrates suboptimal agreement between clinical and pathological staging. Discrepancies between clinical and pathological T and N-staging could have led to different treatment decisions in 10% and 38% of cases respectively. There is therefore a need for further research into improving staging accuracy for patients with stage I-IIIa NSCLC

Bankrupting terrorism: the role of US anti-terrorism litigation in the prevention of terrorism and other hybrid threats: a legal assessment and outlook

Global terrorist networks are dependent on receiving financial support from a variety of sources, including individuals, charities and corporations. Also known as terrorist financing, the potential of terrorism finance to resemble a global threat has been recognised and also its closeness to other international crimes such as money laundering and organized crime. As a result, possible responses have to constitute co-ordinated, multi-lateral and multi faceted actions under the umbrella of a wide range of international stakeholders such as the United Nations Security Council and the Financial Action Task Force. Combating terrorism requires a ‘holistic’ approach which allows for a mix of possible responses. Besides “kinetic” security operations (such as targeted killings) and the adoption of criminal prosecution measures another possible response could be the use of US styled transnational civil litigation by victims of terrorism against both, terrorist groups and their sponsors. Corporations, both profit and non profit, such as banks and other legal entities, as well as individuals, are often complicit in international terrorism in a role of aiders and abettors by providing financial assistance to the perpetrators (cf. UN Al-Qaida Sanctions List: The List established and maintained by the 1267 Committee with respect to individuals, groups, undertakings and other entities associated with Al-Qaida). Such collusion in acts of terrorism gains additional importance against the background of so called “Hybrid Threats”, NATO’s new concept of identifying and countering new threats arising from multi-level threat scenarios. This article discusses the potential impact of US terrorism lawsuits for the global fight against terrorism

Viral population estimation using pyrosequencing

The diversity of virus populations within single infected hosts presents a major difficulty for the natural immune response as well as for vaccine design and antiviral drug therapy. Recently developed pyrophosphate based sequencing technologies (pyrosequencing) can be used for quantifying this diversity by ultra-deep sequencing of virus samples. We present computational methods for the analysis of such sequence data and apply these techniques to pyrosequencing data obtained from HIV populations within patients harboring drug resistant virus strains. Our main result is the estimation of the population structure of the sample from the pyrosequencing reads. This inference is based on a statistical approach to error correction, followed by a combinatorial algorithm for constructing a minimal set of haplotypes that explain the data. Using this set of explaining haplotypes, we apply a statistical model to infer the frequencies of the haplotypes in the population via an EM algorithm. We demonstrate that pyrosequencing reads allow for effective population reconstruction by extensive simulations and by comparison to 165 sequences obtained directly from clonal sequencing of four independent, diverse HIV populations. Thus, pyrosequencing can be used for cost-effective estimation of the structure of virus populations, promising new insights into viral evolutionary dynamics and disease control strategies.Comment: 23 pages, 13 figure

Genomic Tools for Evolution and Conservation in the Chimpanzee: Pan troglodytes ellioti Is a Genetically Distinct Population

In spite of its evolutionary significance and conservation importance, the population structure of the common chimpanzee, Pan troglodytes, is still poorly understood. An issue of particular controversy is whether the proposed fourth subspecies of chimpanzee, Pan troglodytes ellioti, from parts of Nigeria and Cameroon, is genetically distinct. Although modern high-throughput SNP genotyping has had a major impact on our understanding of human population structure and demographic history, its application to ecological, demographic, or conservation questions in non-human species has been extremely limited. Here we apply these tools to chimpanzee population structure, using ∼700 autosomal SNPs derived from chimpanzee genomic data and a further ∼100 SNPs from targeted re-sequencing. We demonstrate conclusively the existence of P. t. ellioti as a genetically distinct subgroup. We show that there is clear differentiation between the verus, troglodytes, and ellioti populations at the SNP and haplotype level, on a scale that is greater than that separating continental human populations. Further, we show that only a small set of SNPs (10–20) is needed to successfully assign individuals to these populations. Tellingly, use of only mitochondrial DNA variation to classify individuals is erroneous in 4 of 54 cases, reinforcing the dangers of basing demographic inference on a single locus and implying that the demographic history of the species is more complicated than that suggested analyses based solely on mtDNA. In this study we demonstrate the feasibility of developing economical and robust tests of individual chimpanzee origin as well as in-depth studies of population structure. These findings have important implications for conservation strategies and our understanding of the evolution of chimpanzees. They also act as a proof-of-principle for the use of cheap high-throughput genomic methods for ecological questions