| 1. |
- Sieberts, SK, et al.
(författare)
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Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12460-
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.
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| 2. |
- Madar Johansson, Miralda, et al.
(författare)
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The binding mechanism of the virulence factor Streptococcus suis adhesin P subtype to globotetraosylceramide is associated with systemic disease
- 2020
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 295:42, s. 14305-14324
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus suis is part of the pig commensal microbiome but strains can also be pathogenic, causing pneumonia and meningitis in pigs as well as zoonotic meningitis. According to genomic analysis, S. suis is divided into asymptomatic carriage, respiratory and systemic strains with distinct genomic signatures. Because the strategies to target pathogenic S. suis are limited, new therapeutic approaches are needed. The virulence factor S. suis adhesin P (SadP) recognizes the galabiose Gal alpha 1-4Gal-oligosaccharide. Based on its oligosaccharide fine specificity, SadP can be divided into subtypes P-N and P-O. We show here that subtype P-N is distributed in the systemic strains causing meningitis, whereas type P-O is found in asymptomatic carriage and respiratory strains. Both types of SadP are shown to predominantly bind to pig lung globotriaosylceramide (Gb3). However, SadP adhesin from systemic subtype P-N strains also binds to globotetraosylceramide (Gb4). Mutagenesis studies of the galabiose-binding domain of type P-N SadP adhesin showed that the amino acid asparagine 285, which is replaced by an aspartate residue in type P-O SadP, was required for binding to Gb4 and, strikingly, was also required for interaction with the glycomimetic inhibitor phenylurea-galabiose. Molecular dynamics simulations provided insight into the role of Asn-285 for Gb4 and phenylurea-galabiose binding, suggesting additional hydrogen bonding to terminal GalNAc of Gb4 and the urea group. Thus, the Asn-285-mediated molecular mechanism of type P-N SadP binding to Gb4 could be used to selectively target S. suis in systemic disease without interfering with commensal strains, opening up new avenues for interventional strategies against this pathogen.
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| 3. |
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| 4. |
- Cui, Y., et al.
(författare)
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Simultaneous Predictive Gaussian Classifiers
- 2016
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Ingår i: Journal of Classification. - : Springer-Verlag New York. - 0176-4268 .- 1432-1343. ; , s. 1-30
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Tidskriftsartikel (refereegranskat)abstract
- Gaussian distribution has for several decades been ubiquitous in the theory and practice of statistical classification. Despite the early proposals motivating the use of predictive inference to design a classifier, this approach has gained relatively little attention apart from certain specific applications, such as speech recognition where its optimality has been widely acknowledged. Here we examine statistical properties of different inductive classification rules under a generic Gaussian model and demonstrate the optimality of considering simultaneous classification of multiple samples under an attractive loss function. It is shown that the simpler independent classification of samples leads asymptotically to the same optimal rule as the simultaneous classifier when the amount of training data increases, if the dimensionality of the feature space is bounded in an appropriate manner. Numerical investigations suggest that the simultaneous predictive classifier can lead to higher classification accuracy than the independent rule in the low-dimensional case, whereas the simultaneous approach suffers more from noise when the dimensionality increases.
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| 5. |
- Johansson, A., et al.
(författare)
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The Genetics of Sexuality and Aggression (GSA) Twin Samples in Finland
- 2013
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Ingår i: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 16:1, s. 150-156
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Tidskriftsartikel (refereegranskat)abstract
- The Genetics of Sexuality and Aggression (GSA) project was launched at the Abo Akademi University in Turku, Finland in 2005 and has so far undertaken two major population-based data collections involving twins and siblings of twins. To date, it consists of about 14,000 individuals (including 1,147 informative monozygotic twin pairs, 1,042 informative same-sex dizygotic twin pairs, 741 informative opposite-sex dizygotic twin pairs). Participants have been recruited through the Central Population Registry of Finland and were 18–49 years of age at the time of the data collections. Saliva samples for DNA genotyping (n = 4,278) and testosterone analyses (n = 1,168) were collected in 2006. The primary focus of the data collections has been on sexuality (both sexual functioning and sexual behavior) and aggressive behavior. This paper provides an overview of the data collections as well as an outline of the phenotypes and biological data assembled within the project. A detailed overview of publications can be found at the project's Web site: http://www.cebg.fi/.
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| 6. |
- Mageiros, Leonardos, et al.
(författare)
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Genome evolution and the emergence of pathogenicity in avian Escherichia coli
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Chickens are the most common birds on Earth and colibacillosis is among the most common diseases affecting them. This major threat to animal welfare and safe sustainable food production is difficult to combat because the etiological agent, avian pathogenic Escherichia coli (APEC), emerges from ubiquitous commensal gut bacteria, with no single virulence gene present in all disease-causing isolates. Here, we address the underlying evolutionary mechanisms of extraintestinal spread and systemic infection in poultry. Combining population scale comparative genomics and pangenome-wide association studies, we compare E. coli from commensal carriage and systemic infections. We identify phylogroup-specific and species-wide genetic elements that are enriched in APEC, including pathogenicity-associated variation in 143 genes that have diverse functions, including genes involved in metabolism, lipopolysaccharide synthesis, heat shock response, antimicrobial resistance and toxicity. We find that horizontal gene transfer spreads pathogenicity elements, allowing divergent clones to cause infection. Finally, a Random Forest model prediction of disease status (carriage vs. disease) identifies pathogenic strains in the emergent ST-117 poultry-associated lineage with 73% accuracy, demonstrating the potential for early identification of emergent APEC in healthy flocks.
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| 7. |
- Schaufler, Katharina, et al.
(författare)
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Genomic and Functional Analysis of Emerging Virulent and Multidrug-Resistant Escherichia coli Lineage Sequence Type 648
- 2019
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Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 63:6
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenic extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli lineage ST648 is increasingly reported from multiple origins. Our study of a large and global ST648 collection from various hosts (87 whole-genome sequences) combining core and accessory genomics with functional analyses and in vivo experiments suggests that ST648 is a nascent and generalist lineage, lacking clear phylogeographic and host association signals. By including large numbers of ST131 (n = 107) and ST10 (n = 96) strains for comparative genomics and phenotypic analysis, we demonstrate that the combination of multidrug resistance and high-level virulence are the hallmarks of ST648, similar to international high-risk clonal lineage ST131. Specifically, our in silico, in vitro, and in vivo results demonstrate that ST648 is well equipped with biofilm-associated features, while ST131 shows sophisticated signatures indicative of adaption to urinary tract infection, potentially conveying individual ecological niche adaptation. In addition, we used a recently developed NFDS (negative frequency-dependent selection) population model suggesting that ST648 will increase significantly in frequency as a cause of bacteremia within the next few years. Also, ESBL plasmids impacting biofilm formation aided in shaping and maintaining ST648 strains to successfully emerge worldwide across different ecologies. Our study contributes to understanding what factors drive the evolution and spread of emerging international high-risk clonal lineages.
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| 8. |
- Skwark, Marcin J., et al.
(författare)
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Interacting networks of resistance, virulence and core machinery genes identified by genome-wide epistasis analysis
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in the scale and diversity of population genomic datasets for bacteria now provide the potential for genome-wide patterns of co-evolution to be studied at the resolution of individual bases. Here we describe a new statistical method, genomeDCA, which uses recent advances in computational structural biology to identify the polymorphic loci under the strongest co-evolutionary pressures. We apply genomeDCA to two large population data sets representing the major human pathogens Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A Streptococcus). For pneumococcus we identified 5,199 putative epistatic interactions between 1,936 sites. Over three-quarters of the links were between sites within the pbp2x, pbp1a and pbp2b genes, the sequences of which are critical in determining non-susceptibility to beta-lactam antibiotics. A network-based analysis found these genes were also coupled to that encoding dihydrofolate reductase, changes to which underlie trimethoprim resistance. Distinct from these antibiotic resistance genes, a large network component of 384 protein coding sequences encompassed many genes critical in basic cellular functions, while another distinct component included genes associated with virulence. The group A Streptococcus (GAS) data set population represents a clonal population with relatively little genetic variation and a high level of linkage disequilibrium across the genome. Despite this, we were able to pinpoint two RNA pseudouridine synthases, which were each strongly linked to a separate set of loci across the chromosome, representing biologically plausible targets of co-selection. The population genomic analysis method applied here identifies statistically significantly co-evolving locus pairs, potentially arising from fitness selection interdependence reflecting underlying protein- protein interactions, or genes whose product activities contribute to the same phenotype. This discovery approach greatly enhances the future potential of epistasis analysis for systems biology, and can complement genome-wide association studies as a means of formulating hypotheses for targeted experimental work.
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| 9. |
- Jern, Patrick, et al.
(författare)
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Are single nucleotide polymorphisms in the oxytocin and vasopressin 1A/1B receptor genes likely candidates for variation in ejaculatory function?
- 2012
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Ingår i: Bju International. - 1464-4096. ; 110:11C
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES To investigate associations between single nucleotide polymorphisms (SNPs) linked to the oxytocin, To investigate these associations in a large, population-based sample. PATIENTS AND METHODS In all, 1517 male twins and non-twin brothers of twins aged 18-45 years (mean = 26.43; SD = 4.87) A Bayesian linear mixed-effects model, which appropriately controls for between subjects dependence, We corrected for multiple testing using a linkage disequilibrium correlation measure. RESULTS We found a heterozygote effect on one SNP in the oxytocin receptor gene (rs75775), so that individuals Several SNPs in the arginine vasopressin receptor genes had rare or very rare genotypes. This study CONCLUSIONS Our results regarding the oxytocin receptor polymorphisms support previous studies that indicate a Oxytocin receptor genes are, for example, unlikely suitable targets for pharmacogenetic intervention Rare variants in arginine vasopressin receptor genes may have significant effects on premature
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| 10. |
- Johansson, A, et al.
(författare)
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Alcohol and aggressive behavior in men-moderating effects of oxytocin receptor gene (OXTR) polymorphisms.
- 2012
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Ingår i: Genes, brain, and behavior. - 1601-183X. ; 11:2, s. 214-221
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Tidskriftsartikel (refereegranskat)abstract
- We explored if the disposition to react with aggression while alcohol intoxicated was moderated by polymorphic variants of the oxytocin receptor gene (OXTR). Twelve OXTR polymorphisms were genotyped in 116 Finnish men [aged 18-30, M = 22.7, standard deviation (SD) = 2.4] who were randomly assigned to an alcohol condition in which they received an alcohol dose of 0.7 g pure ethanol/kg body weight or a placebo condition. Aggressive behavior was measured using a laboratory paradigm in which it was operationalized as the level of aversive noise administered to a fictive opponent. No main effects of the polymorphisms on aggressive behavior were found after controlling for multiple testing. The interactive effects between alcohol and two of the OXTR polymorphisms (rs4564970 and rs1488467) on aggressive behavior were nominally significant and remained significant for the rs4564970 when controlled for multiple tests. To the best of our knowledge, this is the first experimental study suggesting interactive effects of specific genetic variants and alcohol on aggressive behavior in humans.
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| 11. |
- Koslicki, David, et al.
(författare)
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ARK : Aggregation of Reads by K-Means for Estimation of Bacterial Community Composition
- 2015
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 10:10
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Tidskriftsartikel (refereegranskat)abstract
- Motivation Estimation of bacterial community composition from high-throughput sequenced 16S rRNA gene amplicons is a key task in microbial ecology. Since the sequence data from each sample typically consist of a large number of reads and are adversely impacted by different levels of biological and technical noise, accurate analysis of such large datasets is challenging. Results There has been a recent surge of interest in using compressed sensing inspired and convex-optimization based methods to solve the estimation problem for bacterial community composition. These methods typically rely on summarizing the sequence data by frequencies of low-order k-mers and matching this information statistically with a taxonomically structured database. Here we show that the accuracy of the resulting community composition estimates can be substantially improved by aggregating the reads from a sample with an unsupervised machine learning approach prior to the estimation phase. The aggregation of reads is a pre-processing approach where we use a standard K-means clustering algorithm that partitions a large set of reads into subsets with reasonable computational cost to provide several vectors of first order statistics instead of only single statistical summarization in terms of k-mer frequencies. The output of the clustering is then processed further to obtain the final estimate for each sample. The resulting method is called Aggregation of Reads by K-means (ARK), and it is based on a statistical argument via mixture density formulation. ARK is found to improve the fidelity and robustness of several recently introduced methods, with only a modest increase in computational complexity. Availability An open source, platform-independent implementation of the method in the Julia programming language is freely available at https://github.com/dkoslicki/ARK. A Matlab implementation is available at http://www.ee.kth.se/ctsoftware.
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| 12. |
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| 13. |
- Simola, U., et al.
(författare)
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Machine learning accelerated likelihood-free event reconstruction in dark matter direct detection
- 2019
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Reconstructing the position of an interaction for any dual-phase time projection chamber (TPC) with the best precision is key to directly detecting Dark Matter. Using the likelihood-free framework, a newalgorithm to reconstruct the 2-D (x; y) position and the size of the charge signal (e) of an interaction is presented. The algorithm uses the secondary scintillation light distribution (S2) obtained by simulating events using a waveform generator. To deal with the computational effort required by the likelihood-free approach, we employ the Bayesian Optimization for LikelihoodFree Inference (BOLFI) algorithm. Together with BOLFI, prior distributions for the parameters of interest (x; y; e) and highly informative discrepancy measures to performthe analyses are introduced. We evaluate the quality of the proposed algorithm by a comparison against the currently existing alternative methods using a large-scale simulation study. BOLFI provides a natural probabilistic uncertainty measure for the reconstruction and it improved the accuracy of the reconstruction over the next best algorithm by up to 15% when focusing on events at large radii (R > 30 cm, the outer 37% of the detector). In addition, BOLFI provides the smallest uncertainties among all the tested methods.
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| 14. |
- von Mentzer, Astrid, 1983, et al.
(författare)
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Identification of enterotoxigenic Escherichia coli (ETEC) clades with long-term global distribution
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:12, s. 1321-1326
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Tidskriftsartikel (refereegranskat)abstract
- Enterotoxigenic Escherichia coil (ETEC), a major cause of infectious diarrhea, produce heat-stable and/or heat-labile enterotoxins and at least 25 different colonization factors that target the intestinal mucosa. The genes encoding the enterotoxins and most of the colonization factors are located on plasmids found across diverse E. coli serogroups. Whole-genome sequencing of a representative collection of ETEC isolated between 1980 and 2011 identified globally distributed lineages characterized by distinct colonization factor and enterotoxin profiles. Contrary to current notions, these relatively recently emerged lineages might harbor chromosome and plasmid combinations that optimize fitness and transmissibility. These data have implications for understanding, tracking and possibly preventing ETEC disease.
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