A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis.
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ABSTRACT:
SUBMITTER: Foulkes AC
PROVIDER: S-EPMC7239345 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
Publications
A Framework for Multi-Omic Prediction of Treatment Response to Biologic Therapy for Psoriasis.
Foulkes Amy C AC Watson David S DS Carr Daniel F DF Kenny John G JG Slidel Timothy T Parslew Richard R Pirmohamed Munir M Anders Simon S Reynolds Nick J NJ Griffiths Christopher E M CEM Warren Richard B RB Barnes Michael R MR
The Journal of investigative dermatology 20180717 1
Biologic therapies have shown high efficacy in psoriasis, but individual response varies and is poorly understood. To inform biomarker discovery in the Psoriasis Stratification to Optimise Relevant Therapy (i.e., PSORT) study, we evaluated a comprehensive array of omics platforms across three time points and multiple tissues in a pilot investigation of 10 patients with severe psoriasis, treated with the tumor necrosis factor (TNF) inhibitor, etanercept. We used RNA sequencing to analyze mRNA and ...[more]
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Project description:Background and objectives: Psoriasis is a chronic immune-mediated skin disease caused by several complex factors, both environmental and genetic, many of which are still not fully understood. Nowadays, several groups of biological drugs are being used for psoriasis treatment. Although these therapies are very effective, they show significant variability in efficacy among individuals. Therefore, there is a need for biomarkers to predict treatment outcomes in order to guide personalized therapeutic decisions. Pharmacogenetics is the study of variations in DNA sequences related to drug response. Materials and Methods: In this article, we review pharmacogenetics studies on the treatment of moderate-to-severe psoriasis focusing on anti-interleukin (IL) 12/23 (ustekinumab) and anti-IL17 drugs (secukinumab and ixekizumab), as well as recent studies concerning anti-TNF drugs. Results: Several polymorphisms have been studied over the years in reference to anti-TNF drugs; some of the most recent studies included the performance of a genome-wide association study (GWAS) and pharmacogenetics studies focused on the optimization of a treatment regimen. Various polymorphisms in different genes have been related to ustekinumab response; among them, the most commonly studied is the HLA-C*06:02 allele. Conclusions: Although not confirmed in some studies, most studies have shown that patients carrying this allele present a significantly higher response rate to ustekinumab. Some polymorphisms have been studied in patients treated with anti-IL17 drugs, mostly related to secukinumab; however, up to now, no association has been found between any of these polymorphisms and response. Nevertheless, further studies involving larger cohorts are needed in order to confirm these results before the implementation of this biomarker in clinical practice.
| S-EPMC7766592 | biostudies-literature
Project description:Aims/hypothesisThe identification of people who are at high risk of developing type 2 diabetes is a key part of population-level prevention strategies. Previous studies have evaluated the predictive utility of omics measurements, such as metabolites, proteins or polygenic scores, but have considered these separately. The improvement that combined omics biomarkers can provide over and above current clinical standard models is unclear. The aim of this study was to test the predictive performance of genome, proteome, metabolome and clinical biomarkers when added to established clinical prediction models for type 2 diabetes.MethodsWe developed sparse interpretable prediction models in a prospective, nested type 2 diabetes case-cohort study (N=1105, incident type 2 diabetes cases=375) with 10,792 person-years of follow-up, selecting from 5759 features across the genome, proteome, metabolome and clinical biomarkers using least absolute shrinkage and selection operator (LASSO) regression. We compared the predictive performance of omics-derived predictors with a clinical model including the variables from the Cambridge Diabetes Risk Score and HbA1c.ResultsAmong single omics prediction models that did not include clinical risk factors, the top ten proteins alone achieved the highest performance (concordance index [C index]=0.82 [95% CI 0.75, 0.88]), suggesting the proteome as the most informative single omic layer in the absence of clinical information. However, the largest improvement in prediction of type 2 diabetes incidence over and above the clinical model was achieved by the top ten features across several omic layers (C index=0.87 [95% CI 0.82, 0.92], Δ C index=0.05, p=0.045). This improvement by the top ten omic features was also evident in individuals with HbA1c <42 mmol/mol (6.0%), the threshold for prediabetes (C index=0.84 [95% CI 0.77, 0.90], Δ C index=0.07, p=0.03), the group in whom prediction would be most useful since they are not targeted for preventative interventions by current clinical guidelines. In this subgroup, the type 2 diabetes polygenic risk score was the major contributor to the improvement in prediction, and achieved a comparable improvement in performance when added onto the clinical model alone (C index=0.83 [95% CI 0.75, 0.90], Δ C index=0.06, p=0.002). However, compared with those with prediabetes, individuals at high polygenic risk in this group had only around half the absolute risk for type 2 diabetes over a 20 year period.Conclusions/interpretationOmic approaches provided marginal improvements in prediction of incident type 2 diabetes. However, while a polygenic risk score does improve prediction in people with an HbA1c in the normoglycaemic range, the group in whom prediction would be most useful, even individuals with a high polygenic burden in that subgroup had a low absolute type 2 diabetes risk. This suggests a limited feasibility of implementing targeted population-based genetic screening for preventative interventions.
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Project description:BACKGROUND:Network meta-analyses (NMAs) of psoriasis treatments, undertaken as part of the NICE Single Technology Appraisal (STA) process, have included heterogeneous studies. When there is inconsistency or heterogeneity across the different comparisons or trials within the network of studies, the results of the NMA may not be valid. We explored the impact of including studies with heterogeneous patient characteristics on the results of NMAs of psoriasis treatments. METHODS:All NMAs undertaken for psoriasis STAs were identified and the included studies tabulated, including patient characteristics that may influence relative treatment effects. In addition to the original network of all studies using licensed treatment doses, a range of smaller, less heterogeneous networks were mapped: 'no previous biologic use' (<?25% patients had prior biologic therapy exposure), 'Psoriasis Area and Severity Index score ??25', 'weight ??90 kg' and 'white ethnicity' (??90% patients were white). RESULTS:Sixty-nine studies were included in our synthesis (34,924 participants). A random effects model with a log-normal prior distribution was chosen for each of the subgroup NMAs. Heterogeneity was reduced for the four smaller networks. There were no significant differences in the relative treatment effect (PASI 75 response) for each treatment across the five NMAs, with all credible intervals overlapping, although there were noticeable differences. Treatment rankings based on the median relative risks were also generally consistent across the networks. However, the NMA that included only studies in which <?25% patients had prior biologic therapy exposure had slightly different treatment rankings; the anti-TNF therapies certolizumab pegol and infliximab ranked higher in this network than any other network, although credible intervals were large. CONCLUSIONS:This work has highlighted potential differences in treatment response for biologic-naïve patients. When conducting NMAs in any area, heterogeneity in patient characteristics of included trials should be carefully assessed and effect modification related to certain patient characteristics investigated through clinically relevant subgroup analyses.
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Project description:AIMS:The use of biologic therapy has increased over the past decade well beyond primary autoimmune diseases. Indeed, a recent trial using an anti-IL-1beta antibody reduced second myocardial infarction (MI) in those who have had MI. Psoriasis is a chronic inflammatory disease often treated with biologics when severe, is associated with increased risk of MI, in part driven by high-risk coronary plaque phenotypes by coronary computed tomography angiography (CCTA). We hypothesized that we would observe a reduction in inflammatory-driven phenotypes of coronary plaque, including non-calcified coronary plaque burden and lipid-rich necrotic core in those treated with biologic therapy after one-year compared with non-biologic therapy. METHODS AND RESULTS:In a prospective, observational study, 290 participants were recruited from 1 January 2013 through 31 October 2018 with 215 completing one-year follow-up. Of the 238, 121 consecutive participants who were biologic treatment naïve at baseline were included. A blinded reader (blinded to patient demographics, visit and treatment) quantified total coronary plaque burden and plaque subcomponents (calcified and non-calcified) in the three main coronary vessels >2 mm using dedicated software (QAngio, Medis, Netherlands). Psoriasis patients were middle-aged [mean (standard deviation) age, 50.5 (12.1) years], mostly male (n = 70, 58%) with low cardiovascular risk by Framingham score [median (interquartile range, IQR), 3 (1-6)] and had moderate to severe skin disease at baseline [median (IQR) Psoriasis Area Severity Index, PASI, 8.6 (5.3-14.0)]. Biologic therapy was associated with a 6% reduction in non-calcified plaque burden (P = 0.005) reduction in necrotic core (P = 0.03), with no effect on fibrous burden (P = 0.71). Decrease in non-calcified plaque burden in the biologic treated group was significant compared with slow plaque progression in non-biologic treated (Δ, -0.07 mm2 vs. 0.06 mm2; P = 0.02) and associated with biologic treatment beyond adjustment for traditional cardiovascular risk factors (β = 0.20, P = 0.02). CONCLUSION:In this observational study, we demonstrate that biologic therapy in severe psoriasis was associated with favourable modulation of coronary plaque indices by CCTA. These findings highlight the importance of systemic inflammation in coronary artery disease and support the conduct of larger, randomized trials.
| S-EPMC6432047 | biostudies-literature
Project description:As biologic therapies become first line treatments for many inflammatory disorders, it becomes increasingly important for the practicing physician to be familiar with how these drugs function at the molecular level. This information is useful in making therapeutic decisions and helping patients understand their treatment options. It is critical to patient safety and clinical response that the molecular differences between these drugs inform prescribing practices. To this end, we present and analyze the available structural biology information about the biologics used in the treatment of psoriasis including inhibitors of tumor necrosis factor alpha (TNF?), interleukin-17 (IL-17), and interleukin-23 (IL-23). We describe and analyze the molecular surface character of known binding epitopes for medications in these classes, showing that significant differences exist in epitope location, hydrophobicity, and charge. Some of these differences can be correlated with clinical data, but our analysis ultimately points to the need for more structural information to allow for a better understanding of the structure-function relationship of biologic therapies.
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Project description:Identification of cancer driver mutations is critical for advancing cancer research and personalized medicine. Due to inter-tumor genetic heterogeneity, many driver mutations occur at low frequencies, which make it challenging to distinguish them from passenger mutations. Here, we show that a novel Bayesian hierarchical modeling approach, named rDriver can achieve enhanced prediction accuracy by identifying mutations that not only have high functional impact scores but also are associated with systemic variation in gene expression levels. In examining 3,080 tumor samples from 8 cancer types in The Cancer Genome Atlas, rDriver predicted 1,389 driver mutations. Compared with existing tools, rDriver identified more low frequency mutations associated with lineage specific functional properties, timing of occurrence and patient survival. Evaluation of rDriver predictions using engineered cell-line models resulted in a positive predictive value of 0.94 in PIK3CA genes. Our study highlights the importance of integrating multi-omic data in predicting cancer driver mutations and provides a statistically rigorous solution for cancer target discovery and development.
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Project description:BackgroundGenomic prediction (GP) based on single nucleotide polymorphisms (SNP) has become a broadly used tool to increase the gain of selection in plant breeding. However, using predictors that are biologically closer to the phenotypes such as transcriptome and metabolome may increase the prediction ability in GP. The objectives of this study were to (i) assess the prediction ability for three yield-related phenotypic traits using different omic datasets as single predictors compared to a SNP array, where these omic datasets included different types of sequence variants (full-SV, deleterious-dSV, and tolerant-tSV), different types of transcriptome (expression presence/absence variation-ePAV, gene expression-GE, and transcript expression-TE) sampled from two tissues, leaf and seedling, and metabolites (M); (ii) investigate the improvement in prediction ability when combining multiple omic datasets information to predict phenotypic variation in barley breeding programs; (iii) explore the predictive performance when using SV, GE, and ePAV from simulated 3'end mRNA sequencing of different lengths as predictors.ResultsThe prediction ability from genomic best linear unbiased prediction (GBLUP) for the three traits using dSV information was higher than when using tSV, all SV information, or the SNP array. Any predictors from the transcriptome (GE, TE, as well as ePAV) and metabolome provided higher prediction abilities compared to the SNP array and SV on average across the three traits. In addition, some (di)-similarity existed between different omic datasets, and therefore provided complementary biological perspectives to phenotypic variation. Optimal combining the information of dSV, TE, ePAV, as well as metabolites into GP models could improve the prediction ability over that of the single predictors alone.ConclusionsThe use of integrated omic datasets in GP model is highly recommended. Furthermore, we evaluated a cost-effective approach generating 3'end mRNA sequencing with transcriptome data extracted from seedling without losing prediction ability in comparison to the full-length mRNA sequencing, paving the path for the use of such prediction methods in commercial breeding programs.
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Project description:The progression of tumorigenesis starts with a few mutational and structural driver events in the cell. Various cohort-based computational tools exist to identify driver genes but require multiple samples to identify less frequently mutated driver genes. Many studies use different methods to identify driver mutations/genes from mutations that have no impact on tumor progression; however, a small fraction of patients show no mutational events in any known driver genes. Current unsupervised methods map somatic and expression data onto a network to identify personalized driver genes based on changes in expression. Our method is the first machine learning model to classify genes as tumor suppressor gene (TSG), oncogene (OG), or neutral, thus assigning the functional impact of the gene in the patient. In this study, we develop a multi-omic approach, PIVOT (Personalized Identification of driVer OGs and TSGs), to train on experimentally or computationally validated mutational and structural driver events. Given the lack of any gold standards for the identification of personalized driver genes, we label the data using four strategies and, based on classification metrics, show gene-based labeling strategies perform best. We build different models using SNV, RNA, and multi-omic features to be used based on the data available. Our models trained on multi-omic data improved predictions compared with mutation and expression data, achieving an accuracy ≥0.99 for BRCA, LUAD, and COAD datasets. We show network and expression-based features contribute the most to PIVOT. Our predictions on BRCA, COAD, and LUAD cancer types reveal commonly altered genes such as TP53 and PIK3CA, which are predicted drivers for multiple cancer types. Along with known driver genes, our models also identify new driver genes such as PRKCA, SOX9, and PSMD4. Our multi-omic model labels both CNV and mutations with a more considerable contribution by CNV alterations. While predicting labels for genes mutated in multiple samples, we also label rare driver events occurring in as few as one sample. We also identify genes with dual roles within the same cancer type. Overall, PIVOT labels personalized driver genes as TSGs and OGs and also identified rare driver genes.
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Project description:OBJECTIVE: Antibiotic (AB) usage strongly affects microbial intestinal metabolism and thereby impacts human health. Understanding this process and the underlying mechanisms remains a major research goal. Accordingly, we conducted the first comparative omic investigation of gut microbial communities in faecal samples taken at multiple time points from an individual subjected to ?-lactam therapy. METHODS: The total (16S rDNA) and active (16S rRNA) microbiota, metagenome, metatranscriptome (mRNAs), metametabolome (high-performance liquid chromatography coupled to electrospray ionisation and quadrupole time-of-flight mass spectrometry) and metaproteome (ultra high performing liquid chromatography coupled to an Orbitrap MS(2) instrument [UPLC-LTQ Orbitrap-MS/MS]) of a patient undergoing AB therapy for 14 days were evaluated. RESULTS: Apparently oscillatory population dynamics were observed, with an early reduction in Gram-negative organisms (day 6) and an overall collapse in diversity and possible further colonisation by 'presumptive' naturally resistant bacteria (day 11), followed by the re-growth of Gram-positive species (day 14). During this process, the maximum imbalance in the active microbial fraction occurred later (day 14) than the greatest change in the total microbial fraction, which reached a minimum biodiversity and richness on day 11; additionally, major metabolic changes occurred at day 6. Gut bacteria respond to ABs early by activating systems to avoid the antimicrobial effects of the drugs, while 'presumptively' attenuating their overall energetic metabolic status and the capacity to transport and metabolise bile acid, cholesterol, hormones and vitamins; host-microbial interactions significantly improved after treatment cessation. CONCLUSIONS: This proof-of-concept study provides an extensive description of gut microbiota responses to follow-up ?-lactam therapy. The results demonstrate that ABs targeting specific pathogenic infections and diseases may alter gut microbial ecology and interactions with host metabolism at a much higher level than previously assumed.
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