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Background Epigenetic alterations may provide valuable insights into gene–environment interactions in the pathogenesis of inflammatory bowel disease [IBD]. Methods Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 Crohn's disease [CD], 161 ulcerative colitis [UC], 28 IBD unclassified [IBD-U)] with covariates of age, sex and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using the Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Results A total of 137 differentially methylated positions [DMPs] were identified in IBD, including VMP1/MIR21 [ p  = 9.11 × 10−15] and RPS6KA2 [6.43 × 10−13], with consistency seen across Scandinavia and the UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 [ p  = 1.53 × 10−15]. Age acceleration is seen in IBD [coefficient 0.94, p  < 2.2 × 10−16]. Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r = −0.32, p = 3.64 × 10−7 vs non-IBD r = −0.14, p  = 0.77]. Multi-omic integration of the methylome, genome and transcriptome also implicated specific pathways that associate with immune activation, response and regulation at disease inception. At follow-up, a signature of three DMPs [ TAP1 , TESPA1 , RPTOR ] were associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 [CI: 2.14–12.56], logrank p  = 9.70 × 10−4). Conclusion These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease. [ABSTRACT FROM AUTHOR]

Aim To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease [IBD]. Methods We analysed whole-blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn's disease [CD; n = 156], ulcerative colitis [UC; n = 167], and controls [ n = 267]), exploring differential expression [DESeq2], co-expression networks [WGCNA], and transcription factor involvement [EPEE, ChEA, DoRothEA]. Findings were validated by analysis of an independent replication cohort [99 CD, 100 UC, 95 controls]. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Results Disease-specific transcriptomes were defined in IBD [8697 transcripts], CD [7152], and UC [8521], with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10-118), MCEMP1 [LFC = 2.45, p = 7.37 × 10-109], and S100A12 [LFC = 2.31, p = 2.15 × 10-93]. Significantly over-represented pathways included IL-1 [ p = 1.58 × 10-11], IL-4, and IL-13 [ p = 8.96 × 10-9]. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 [PU.1], CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A / CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval [CI] 5.3–102.0). Conclusions Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications. [ABSTRACT FROM AUTHOR]

Background Success in personalized medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay [PEA] to identify diagnostic and prognostic biomarkers in inflammatory bowel disease [IBD]. Methods We conducted a prospective case-control study in an inception cohort of 552 patients [328 IBD, 224 non-IBD], profiling proteins recruited across six centres. Treatment escalation was characterized by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross-validation was used to examine the performance of diagnostic and prognostic proteins. Results A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls, including matrix metallopeptidase-12 [MMP-12; Holm-adjusted p  = 4.1 × 10–23] and oncostatin-M [OSM; p  = 3.7 × 10–16]. Nine of these proteins are associated with cis -germline variation [59 independent single nucleotide polymorphisms]. Fifteen proteins, all members of tumour necrosis factor-independent pathways including interleukin-1 (IL-1) and OSM, predicted escalation, over a median follow-up of 518 [interquartile range 224–756] days. Nested cross-validation of the entire data set allowed characterization of five-protein models [96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7 and IL8], which define a high-risk subgroup in IBD [hazard ratio 3.90, confidence interval: 2.43–6.26], or allowed distinct two- and three-protein models for ulcerative colitis and Crohn's disease respectively. Conclusion We have characterized a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings. [ABSTRACT FROM AUTHOR]

Background MicroRNAs [miRNAs] are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in inflammatory bowel disease [IBD] pathogenesis. Here we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD. Methods In a two-stage prospective multi-centre case control study, next generation sequencing was performed on a discovery cohort of immunomagnetically separated leukocytes from 32 patients (nine Crohn's disease [CD], 14 ulcerative colitis [UC], eight healthy controls) and differentially expressed signals were validated in whole blood in 294 patients [97 UC, 98 CD, 98 non-IBD, 1 IBDU] using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards. Results In stage 1, each leukocyte subset [CD4+ and CD8+ T-cells and CD14+ monocytes] was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p [ p  = 0.01], miR-3615 [ p  = 0.02] and miR-4792 [ p  = 0.01]. In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (hazard ratio [HR] 1.98, interquartile range [IQR]: 1.20–3.27; logrank p  = 1.80 × 10–3), in particular CD [HR 2.81; IQR: 1.11–3.53, p  = 6.50 × 10–4]. Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if two or more criteria were met and 90% for UC if three or more criteria are met. Interpretation We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated. [ABSTRACT FROM AUTHOR]

Continuous Ant-based Topology Search (CANTS) is a previously introduced novel nature-inspired neural architecture search (NAS) algorithm that is based on ant colony optimization (ACO). CANTS utilizes a continuous search space to indirectly-encode a neural architecture search space. Synthetic ant agents explore CANTS' continuous search space based on the density and distribution of pheromones, strongly inspired by how ants move in the real world. This continuous search space allows CANTS to automate the design of artificial neural networks (ANNs) of any size, removing a key limitation inherent to many current NAS algorithms that must operate within structures of a size that is predetermined by the user. This work expands CANTS by adding a fourth dimension to its search space representing potential neural synaptic weights. Adding this extra dimension allows CANTS agents to optimize both the architecture as well as the weights of an ANN without applying backpropagation (BP), which leads to a significant reduction in the time consumed in the optimization process: at least an average of 96% less time consumption with very competitive optimization performance, if not better. The experiments of this study – using real-world data – demonstrate that the BP-Free CANTS algorithm exhibits highly competitive performance compared to both CANTS and ANTS while requiring significantly less operation time. [Display omitted] • Metaheuristic algorithm that indirectly-encodes neural space to continuous 4D space. • Highly time-efficient swarm-intelligence-based, backpropagation-free NeuroEvolution. • Vast unbounded continuous search space can help in avoiding local-minima traps. • CANTS is nature inspired and can be scaled up. • The asynchronous design of CANTS significantly accelerates the optimization process. [ABSTRACT FROM AUTHOR]

Abstract: Biometric-based access control systems (BACSs) are vulnerable to replay attacks. Replay attacks occur when a biometric template is intercepted and maliciously used to gain unauthorized access to a system. In this paper, we introduce a Genetic and Evolutionary Biometric Security (GEBS) application which uses a Genetic and Evolutionary Computation to develop disposable Feature Extractors (FEs) in an effort to mitigate replay attacks. We describe how a previously developed system known as GEFE (Genetic and Evolutionary Feature Extraction) can be used to evolve unique and disposable FEs for users of BACS. Furthermore, we propose two access control protocols based on the use of disposable FEs and/or their resulting templates (also referred to as feature vectors (FVs)). In our proposed protocols, FEs/FVs are used to authenticate the identity of individuals and are then discarded. Our results show that this GEBS application can be successfully used to mitigate biometric replay attacks. [Copyright &y& Elsevier]

Biometric-based access control systems (BACSs) are vulnerable to replay attacks. Replay attacks occur when a biometric template is intercepted and maliciously used to gain unauthorized access to a system. In this paper, we introduce a Genetic and Evolutionary Biometric Security (GEBS) application which uses a Genetic and Evolutionary Computation to develop disposable Feature Extractors (FEs) in an effort to mitigate replay attacks. We describe how a previously developed system known as GEFE (Genetic and Evolutionary Feature Extraction) can be used to evolve unique and disposable FEs for users of BACS. Furthermore, we propose two access control protocols based on the use of disposable FEs and/or their resulting templates (also referred to as feature vectors (FVs)). In our proposed protocols, FEs/FVs are used to authenticate the identity of individuals and are then discarded. Our results show that this GEBS application can be successfully used to mitigate biometric replay attacks. [ABSTRACT FROM AUTHOR]

Abstract: Background: The presence of Mycobacterium avium subspecies paratuberculosis (MAP) has previously been inferred in the genesis of Crohn''s disease (CD), and a higher incidence of MAP PCR positivity has been demonstrated in the gut and peripheral blood of CD patients than in healthy individuals. The objective of this prospective study was to assess the potential etiological role of MAP in the pathogenesis of CD. Methods: The presence of mycobacteria was assessed in bowel biopsies from newly diagnosed, treatment naïve Norwegian patients with IBD, including CD and ulcerative colitis (UC), as compared to a hospital-based cohort of CD and UC patients. Biopsies were collected from the small and large bowel in 354 individuals with suspected IBD. Detection of mycobacteria was performed by long-term cultivation in combination with direct detection by MAP IS900-specific PCR. Results: Among the specimens included from the patients with early IBD, samples from only two of the patients with CD (2.7%) and two of the non-IBD controls (1.5%) exhibited a positive growth signal. None of the CD patients and only one of the non-IBD controls was MAP PCR positive. Only the single PCR positive non-IBD control was also mycobacterial culture positive with Mycobacterium avium subsp. hominissuis. In the referral patients with long-term IBD, the prevalence of growth signal and MAP PCR positivity was higher (52 and 9%, respectively). Conclusions: These findings demonstrate the paucity of MAP in the gut of treatment naïve CD patients. This study does not provide evidence for a role of MAP in early IBD. [Copyright &y& Elsevier]

Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P <.05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors. [Display omitted] To characterize the preclinical inflammation in ulcerative colitis, we explored systemic inflammatory markers in a population-based cohort of healthy individuals. A 6-protein signature could separate individuals who later developed disease. [ABSTRACT FROM AUTHOR]