11 research outputs found
Surfing waves of data in San Diego: Sophisticated analyses provide a broad view of human genetic diversity
A report on the 64th annual American Society of Human Genetics meeting held in San Diego, USA, 18-22 October, 2014
Characterizing the Initial Phase of Epidemic Growth on some Empirical Networks
A key parameter in models for the spread of infectious diseases is the basic
reproduction number , which is the expected number of secondary cases a
typical infected primary case infects during its infectious period in a large
mostly susceptible population. In order for this quantity to be meaningful, the
initial expected growth of the number of infectious individuals in the
large-population limit should be exponential.
We investigate to what extent this assumption is valid by performing repeated
simulations of epidemics on selected empirical networks, viewing each epidemic
as a random process in discrete time. The initial phase of each epidemic is
analyzed by fitting the number of infected people at each time step to a
generalised growth model, allowing for estimating the shape of the growth. For
reference, similar investigations are done on some elementary graphs such as
integer lattices in different dimensions and configuration model graphs, for
which the early epidemic behaviour is known.
We find that for the empirical networks tested in this paper, exponential
growth characterizes the early stages of the epidemic, except when the network
is restricted by a strong low-dimensional spacial constraint, such as is the
case for the two-dimensional square lattice. However, on finite integer
lattices of sufficiently high dimension, the early development of epidemics
shows exponential growth.Comment: To be included in the conference proceedings for SPAS 2017
(International Conference on Stochastic Processes and Algebraic Structures),
October 4-6, 201
Genotyping, sequencing and analysis of 140,000 adults from Mexico City
The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of CoyoacĂĄn and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142âmillion genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent
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
Baseline expression of immune gene modules in blood is associated with primary response to anti-TNF therapy in Crohn's disease patients
BACKGROUND AND AIMS: Anti-TNF therapy is widely used for treatment of inflammatory bowel disease, yet many patients are primary non-responders, failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders and primary non-responders to anti-TNF monoclonal antibodies (infliximab and adalimumab); and to predict response status from blood gene expression and clinical data. METHODS: The Personalised Anti-TNF Therapy in Crohn's Disease (PANTS) study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF naive Crohn's disease patients (ClinicalTrials.gov identifier: NCT03088449). Blood gene expression in 324 unique patients was measured by RNA-seq at baseline (week 0), and at weeks 14, 30, and 54 after treatment initiation (total sample size = 814). RESULTS: After adjusting for clinical covariates and estimated blood cell composition, baseline expression of major histocompatibility complex, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders versus non-responders. Expression changes from baseline to week 14 were generally of consistent direction but greater magnitude (i.e. amplified) in responders, however interferon-related genes were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at week 30 and week 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor. CONCLUSIONS: Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these baseline expression differences did not predict response with sufficient sensitivity for clinical use.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
Whole blood DNA methylation changes are associated with anti-TNF drug concentration in patients with Crohn's disease
BACKGROUND AND AIMS: Anti-TNF treatment failure in patients with inflammatory bowel disease (IBD) is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14. METHODS: DNA methylation from 1,104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease (PANTS) study were assessed using the Illumina EPIC Beadchip (v1.0) at baseline, weeks 14, 30 and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 and if they were assessed at subsequent time points, were not in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 94), with patients who responded at week 14 and when assessed at subsequent time points, were in remission at week 30 or 54 (infliximab n = 99, adalimumab n = 93). RESULTS: Overall, between baseline and week 14, we observed 4,999 differentially methylated probes (DMPs) annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses.Epigenome-wide association (EWAS) analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at week 14. Of these, 125 DMPs demonstrated shared associations with other common traits (proportion of shared CpGs compared to DMPs) including body mass index (23.2%), followed by CRP (11.5%), smoking (7.4%), alcohol consumption per day (7.1%) and IBD type (6.8%). EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients (Spearman's rho = -0.94, p < 0.001). CONCLUSION: Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy.Published version, accepted version (12 month embargo), submitted versionThe article is available via Open Access. Click on the 'Additional link' above to access the full-text
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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-naĂŻve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer â„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 à 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 à 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