The Genetics of IBD: From Susceptibility to Drug Response and Patient Outcome

Inflammatory bowel disease (IBD) is a group of immune-mediated autoinflammatory disorders, primarily manifesting in the gastrointestinal tract. Affecting millions of people around the world, IBD has a severe impact on patients’ quality of life. Several pharmacologic treatments have been available since the 1950s. However, the majority of patients either do not respond to a given therapy or lose response to a previously effective treatment and thus require therapeutic escalation. In the first research chapter of my thesis, I describe the results of the Personalised Anti-TNF Therapy in Crohn’s disease study. Immunogenicity to anti-TNF therapy is a major cause of loss of response, hypersensitivity reactions, and discontinuation of treatment in patients. Currently, immunogenicity cannot be predicted prior to treatment. My analysis has identified a strong dominant association in the HLA region on chromosome 6 (HLA-DQA1*05, P=5.9e-13; HR=1.90; 95% CI, 1.60 to 2.25). Around 40% of individuals of European ancestry carry HLA-DQA1*05, and the data suggest that around 95% of these would develop immunogenicity within the first year of infliximab monotherapy treatment (a common anti-TNF treatment regime). In the second research chapter of my thesis, I describe a genome-wide association study of thiopurine-induced liver damage (TILI). Ultimately, the study was underpowered to detect any associations of moderate effect size and did not detect any associations of high effect size amongst the common genetic variants. Interestingly, I was not able to replicate the association in PTPN22, which was reported to be a risk factor for drug-induced liver damage by Cirulli et al. – suggesting that its effect might be heterogeneous depending on the therapy. Finally, the third research chapter describes the initial analysis of the IBD 15x dataset – a whole-genome sequencing association study of around 7,000 IBD patients paired with 12,000 matching controls. I provide an overview of the sample quality control procedures and describe some of the novel challenges that sequencing studies bring in comparison to standard GWAS (e.g., sample cross-contamination due to index mismatching). Finally, I also provide the results of the initial meta-analysis of the exome-sequencing dataset produced by the Broad Institute. The results demonstrate that rare coding genetic variants play a role in IBD pathogenesis.Wellcome Trus

HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease

Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

peer reviewe

Applying Image Recognition Methods for Classification of Galaxy Images

Problem solving in astronomy, using computer methods is a very topical issue nowadays. The topicality of object classification problem has been increasing during the last couple of years, especially because of the radio signal received from cosmos, the growth of the unclassified images from the telescope Hubble and the activity of such projects as Sloan Digital Sky Survey. Such projects as Sloan Digital Sky Survey provide enormous amounts of digital images from all the sides of the Universe. Today, the problem of galaxies classification is being solved using manual data classification, but it can be solved much more efficiently with the help of computer methods. Nowadays, there is a range of theories in astronomy, which could be proved or disapproved, provided that particular information, concerning the evolution of galaxies, is available. In order to obtain this information, astronomers investigate large groups of objects, belonging to the same class and existing at the different stages of development. Galaxies get born and die, but not in one day. These processes are very slow, and the current number of the starry sky images is enormous. Today, even quite large groups of volunteers cannot classify all the images of galaxies on the existing photographs. Therefore, astronomy needs the help of information technologies and computer methods, which are already applied successfully in other scientific fields, such as biology and engineering. Taking into account the capacity of computer’s memory and performance of modern computers, the problem of the analysis of huge amount of imagery data can be solved. THE OBJECT OF THE RESEARCH: computer methods of statistical astronomy. THE SUBJECT OF THE RESEARCH: Object recognition algorithms, aimed at galaxy classification. THE HYPOTHESIS OF THE RESEARCH: Computer system parameters can be adapted to enable automatic galaxy classification with the average accuracy, corresponding to the same or higher level of accuracy in comparison with the manual data processing. THE AIM OF THE RESEARCH: To broaden the application of computer systems, aimed at image recognition in bio-informatics, adapting them to the scientific tasks of astronomy. RESEARCH RESULTS: The ET-BOF method was selected for the experiment and adapted for the tasks of the research (method has been designed at The University of Liège in Belgium). The software configuration, training and testing was performed from November 2009 to April 2010. The best results of automatic recognition were achieved when using image segmentation with colour threshold and convolution matrix method and applying these methods for the etalon set of galactic images. The results were compared with the data from the international Galaxy Zoo open project. The experiment has proved that automatic classification of galaxies ensures the same or higher accuracy results in comparison with the manual classification. The experiment with the great set of data has proved that the automatic galaxy classification was performed with the accuracy of at least 90%. The existence of the 10% error in the automatic classification is not significant in the frame of the research. Fundamental astronomy is interested in information concerning types of galaxies in large clusters. The achieved level of accuracy is considered to be acceptable for creation of the Universe evolution models on a large scale. Thus, it is possible to say that the aim of the research has been achieved and the hypothesis has been proved

Approaches for Obtaining and Processing Snow Avalanche Acoustics Emission Data

Work overviews methods of acoustic signal acquisition and digital signal processing, applying them to task of geography and danger management. Previous researches indicate that snow slopes produce acoustic emission signals before the avalanche slides down. Sensors, preamplifier and recording-interface combinations are being tested for ability to record low-frequency acoustic impulses

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

0info:eu-repo/semantics/publishe

NetworKit: An interactive tool suite for high-performance network analysis,”

Abstract We introduce NetworKit, an open-source software package for high-performance analysis of large complex networks. Complex networks are equally attractive and challenging targets for data mining, and novel algorithmic solutions as well as parallelization are required to handle data sets containing billions of connections. Our goal for NetworKit is to package results of our algorithm engineering efforts and put them into the hands of domain experts. NetworKit is a hybrid combining the performance of kernels written in C++ with a convenient interactive interface written in Python. The package supports general multicore platforms and scales from notebooks to workstations to servers. In comparison with related software for network analysis, we propose NetworKit as the package which satisfies all of three important criteria: High performance (partly enabled by parallelism), interactive workflows and integration into an ecosystem of tested tools for data analysis and scientific computation. The current feature set includes standard network analytics kernels such as degree distribution, connected components, clustering coefficients, community detection, k-core decomposition, degree assortativity and centrality. Applying these to massive networks is enabled by efficient algorithms, parallelism or approximation. Furthermore, the package comes with a collection of graph generators and has basic support for visualization. With the current release, we present and open up the project to a community of both algorithm engineers and domain experts

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease.

BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies. METHODS: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease. RESULTS: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58). CONCLUSIONS: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn’s disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation