Whole blood transcriptomics identifies gene expression associated with peanut allergy in infants at high risk.
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ABSTRACT:
SUBMITTER: Devonshire AL
PROVIDER: S-EPMC9290487 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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Whole blood transcriptomics identifies gene expression associated with peanut allergy in infants at high risk.
Devonshire Ashley L AL Fan Hanli H Pujato Mario M Paranjpe Aditi A Gursel Demirkan D Schipma Matthew M Dunn Julia M JM Andorf Sandra S Pongracic Jacqueline A JA Kottyan Leah C LC Kumar Rajesh R
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20210915 10
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Project description:BackgroundThe prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy.MethodsWe randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was determined with the use of a skin-prick test--one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal measuring 1 to 4 mm in diameter. The primary outcome, which was assessed independently in each cohort, was the proportion of participants with peanut allergy at 60 months of age.ResultsAmong the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P=0.004). There was no significant between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy.ConclusionsThe early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00329784.).
| S-EPMC4416404 | biostudies-literature
Project description:BackgroundThe Learning Early About Peanut Allergy (LEAP) trial showed that early dietary introduction of peanut reduced the risk of developing peanut allergy by age 60 months in infants at high risk for peanut allergy. In this secondary analysis of LEAP data, we aimed to determine risk subgroups within these infants and estimate their respective intervention effects of early peanut introduction.MethodsLEAP raw data were retrieved from ITNTrialShare.org. Conditional random forest was applied to participants in the peanut avoidance arm to select statistically important features for the classification and regression tree (CART) analysis to group infants based on their risk of peanut allergy at 60 months of age. Intervention effects were estimated for each derived risk subgroup using data from both arms. Our main model was generated based on baseline data when the participants were 4-11 months old. Specific IgE measurements were truncated to account for the limit of detection commonly used by laboratories in clinical practice.ResultsThe model found infants with higher predicted probability of peanut allergy at 60 months of age had a similar relative risk reduction, but a greater absolute risk reduction in peanut allergy with early introduction of peanut, than those with lower probability. The intervention effects were significant across all risk subgroups. Participants with baseline peanut sIgE ≥0.22 kU/L (n = 78) had an absolute risk reduction of 40.4% (95% CI 27.3, 51.9) whereas participants with baseline peanut sIgE<0.22 kU/L and baseline Ara h 2 sIgE <0.10 kU/L (n = 226) had an absolute risk reduction of 6.5% (95% CI 2.6, 11.0). These findings were consistent in sensitivity analyses using alternative models.ConclusionIn this study, risk subgroups were determined among infants from the LEAP trial based on the probability of developing peanut allergy and the intervention effects of early peanut introduction were estimated. This may be relevant for further risk assessment and personalized clinical decision-making.
| S-EPMC10932885 | biostudies-literature
Project description:BackgroundSepsis is a highly heterogeneous syndrome, that has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.MethodsThe subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA-sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.ResultsPatients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells, and less diverse T-Cell receptor repertoires.ConclusionsTwo subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.Trial registrationThis is a secondary analysis of data generated as part of the observational CAF PINT ancillary of the HALF PINT study (NCT01565941). Registered 29 March 2012.
| S-EPMC10491329 | biostudies-literature
Project description:BackgroundSepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.MethodsThe subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.ResultsPatients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.ConclusionsTwo subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.
| S-EPMC10709863 | biostudies-literature
Project description:BACKGROUND:Prognostication of peanut allergy (PNA) is relevant for early interventions. We aimed to determine baseline parameters associated with the development of PNA in 3- to 15-month-olds with likely egg and/or milk allergy, and/or moderate to severe atopic dermatitis (AD) and a positive egg/milk skin prick test (SPT), but no known PNA. METHODS:The primary endpoint was PNA [confirmed/convincing diagnosis or last classified as serologic PNA (<2 years, ≥5 kUA/L, otherwise ≥14 kUA/L, peanut IgE)] among 511 participants (median follow-up, 7.3 years). Associations were explored with univariate logistic regression; factors with P < 0.15 were analyzed by stepwise multiple logistic regression, using data stratified by PNA status and randomly assigned to development and validation datasets. RESULTS:205/511 (40.1%) had PNA. Univariate factors associated with PNA (P < 0.01) included increased AD severity, larger egg and peanut SPT, greater egg, milk, peanut, Ara h1-h3 IgE, higher peanut IgG and IgG4, and increased pregnancy peanut consumption. P-values were between 0.01 and 0.05 for younger age, non-white race, lack of breastfeeding, and increased lactation peanut consumption. Using a development dataset, the multivariate model identified younger age at enrollment, greater peanut and Ara h2 IgE, and lack of breastfeeding as prognosticators. The final model predicted 79% in the development and 75% in the validation dataset (AUC = 0.83 for both). Models using stricter or less strict PNA criteria both found Ara h2 as predictive. CONCLUSIONS:Key factors associated with PNA in this high-risk population included lack of breastfeeding, age, and greater Ara h2 and peanut-specific IgE, which can be used to prognosticate outcomes.
| S-EPMC6817376 | biostudies-literature
Project description:ImportanceRandomized clinical trials showed that earlier peanut introduction can prevent peanut allergy in select high-risk populations. This led to changes in infant feeding guidelines in 2016 to recommend early peanut introduction for all infants to reduce the risk of peanut allergy.ObjectiveTo measure the change in population prevalence of peanut allergy in infants after the introduction of these new guidelines and evaluate the association between early peanut introduction and peanut allergy.DesignTwo population-based cross-sectional samples of infants aged 12 months were recruited 10 years apart using the same sampling frame and methods to allow comparison of changes over time. Infants were recruited from immunization centers around Melbourne, Australia. Infants attending their 12-month immunization visit were eligible to participate (eligible age range, 11-15 months), regardless of history of peanut exposure or allergy history.ExposuresQuestionnaires collected data on demographics, food allergy risk factors, peanut introduction, and reactions.Main outcome and measuresAll infants underwent skin prick tests to peanut and those with positive results underwent oral food challenges. Prevalence estimates were standardized to account for changes in population demographics over time.ResultsThis study included 7209 infants (1933 in 2018-2019 and 5276 in 2007-2011). Of the participants in the older vs more recent cohort, 51.8% vs 50.8% were male; median (IQR) ages were 12.5 (12.2-13.0) months vs 12.4 (12.2-12.9) months. There was an increase in infants of East Asian ancestry over time (16.5% in 2018-2019 vs 10.5% in 2007-2011), which is a food allergy risk factor. After standardizing for infant ancestry and other demographics changes, peanut allergy prevalence was 2.6% (95% CI, 1.8%-3.4%) in 2018-2019, compared with 3.1% in 2007-2011 (difference, -0.5% [95% CI, -1.4% to 0.4%]; P = .26). Earlier age of peanut introduction was significantly associated with a lower risk of peanut allergy among infants of Australian ancestry in 2018-2019 (age 12 months compared with age 6 months or younger: adjusted odds ratio, 0.08 [05% CI, 0.02-0.36]; age 12 months compared with 7 to less than 10 months: adjusted odds ratio, 0.09 [95% CI, 0.02-0.53]), but not significant among infants of East Asian ancestry (P for interaction = .002).Conclusions and relevanceIn cross-sectional analyses, introduction of a guideline recommending early peanut introduction in Australia was not associated with a statistically significant lower or higher prevalence of peanut allergy across the population.
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Project description: Not available
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Project description:Peanut allergy is an IgE-mediated, persisting immune disorder that is of major concern worldwide. Currently, no routine immunotherapy is available to treat this often severe and sometimes fatal food allergy. Traditional subcutaneous allergen immunotherapy with crude peanut extracts has proven not feasible due to the high risk of severe systemic side effects. The allergen-specific approaches under preclinical and clinical investigation comprise subcutaneous, oral, sublingual and epicutaneous immunotherapy with whole-peanut extracts as well as applications of hypoallergenic peanut allergens or T cell epitope peptides. Allergen-nonspecific approaches include monoclonal anti-IgE antibodies, TCM herbal formulations and Toll-like receptor 9-based immunotherapy. The potential of genetically engineered plants with reduced allergen levels is being explored as well as the beneficial influence of lactic acid bacteria and soybean isoflavones on peanut allergen-induced symptoms. Although the underlying mechanisms still need to be elucidated, several of these strategies hold great promise. It can be estimated that individual strategies or a combination thereof will result in a successful immunotherapy regime for peanut-allergic individuals within the next decade.
| S-EPMC5548240 | biostudies-other
Project description:ImportanceEarly peanut introduction reduces the risk of developing peanut allergy, especially in high-risk infants. Current US recommendations endorse screening but are not cost-effective relative to other international strategies.ObjectiveTo identify scenarios in which current early peanut introduction guidelines would be cost-effective.Design, setting, and participantsThis simulation/cohort economic evaluation used microsimulations and cohort analyses in a Markov model to evaluate the cost-effectiveness of early peanut introduction with and without peanut skin prick test (SPT) screening in high-risk infants during an 80-year horizon from a societal perspective. Data were analyzed from April to May 2019.ExposuresHigh-risk infants with early-onset eczema and/or egg allergy underwent early peanut introduction with and without peanut SPT screening (100 000 infants per treatment strategy) using a dichotomous 8-mm SPT cutoff value (stipulated in the current US guideline).Main outcomes and measuresCost, quality-adjusted life-years (QALYs), net monetary benefit, peanut allergic reactions, severe allergic reactions, and deaths due to peanut allergy.ResultsIn the simulated cohort of 200 000 infants and using the base case during the model horizon, a no-screening approach had lower mean (SD) costs ($13 449 [$38 163] vs $15 279 [$38 995]) and higher mean (SD) gain in QALYs (29.25 [3.28] vs 29.23 [3.30]) vs screening but resulted in more allergic reactions (mean [SD], 1.07 [3.15] vs 1.01 [3.02]), severe allergic reactions (mean [SD], 0.53 [1.66] vs 0.52 [1.62]), and anaphylaxis involving cardiorespiratory compromise (mean [SD], 0.50 [1.59] vs 0.49 [1.47]) per individual. In deterministic SPT sensitivity analyses at base-case sensitivity and specificity rates, screening could be cost-effective at a high disutility rate (the negative effect of a food allergic reaction) (76-148 days of life traded) for an at-home vs in-clinic reaction in combination with high baseline peanut allergy prevalence among infants at high risk for peanut allergy and not yet exposed to peanuts. If an equivalent rate and disutility of accidental and index anaphylaxis was assumed and the 8-mm SPT cutoff had 0.85 sensitivity and 0.98 specificity, screening was cost-effective at a peanut allergy prevalence of 36%.Conclusions and relevanceThe results of this study suggest that the current screening approach to early peanut introduction could be cost-effective at a particular health utility for an in-clinic reaction, SPT sensitivity and specificity, and high baseline peanut allergy prevalence among high-risk infants. However, such conditions are unlikely to be plausible to realistically achieve. Further research is needed to define the health state utility associated with reaction location.
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Project description:Biological systems are immensely complex, organized into a multi-scale hierarchy of functional units based on tightly regulated interactions between distinct molecules, cells, organs, and organisms. While experimental methods enable transcriptome-wide measurements across millions of cells, popular bioinformatic tools do not support systems-level analysis. Here we present hdWGCNA, a comprehensive framework for analyzing co-expression networks in high-dimensional transcriptomics data such as single-cell and spatial RNA sequencing (RNA-seq). hdWGCNA provides functions for network inference, gene module identification, gene enrichment analysis, statistical tests, and data visualization. Beyond conventional single-cell RNA-seq, hdWGCNA is capable of performing isoform-level network analysis using long-read single-cell data. We showcase hdWGCNA using data from autism spectrum disorder and Alzheimer's disease brain samples, identifying disease-relevant co-expression network modules. hdWGCNA is directly compatible with Seurat, a widely used R package for single-cell and spatial transcriptomics analysis, and we demonstrate the scalability of hdWGCNA by analyzing a dataset containing nearly 1 million cells.
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