Biology subjects

Ng, B.

Publications and source records attributed to Ng, B..

5 recordsLinked to original sources

bioRxiv2018

The costs of misdiagnosed asthma in a longitudinal study of the general population

ObjectivesA current diagnosis of asthma cannot be objectively confirmed in many patients with physician-diagnosed asthma. Estimates of resource use in overdiagnosed cases of asthma are necessary to measure the burden of overdiagnosis and evaluate strategies to reduce this burden. We assessed the difference in asthma-related healthcare resource use between patients with a confirmed asthma diagnosis and those with asthma ruled out.\n\nDesignPopulation-based prospective cohort study.\n\nSettingParticipants were recruited through random-digit dialling of both landlines and mobile phones in BC, Canada.\n\nParticipantsWe included 345 individuals [≥]12 years of age with a self-reported physician diagnosis of asthma which was confirmed by a bronchodilator reversibility or methacholine challenge test at the end of the 12-month follow-up.\n\nPrimary and secondary outcome measuresSelf-reported annual asthma-related direct healthcare costs (2017 Canadian dollars), outpatient physician visits, and medication use from the Canadian healthcare system perspective.\n\nResultsAsthma was ruled out in 86 (24.9%) participants. Average annual asthma-related direct healthcare costs for participants with confirmed asthma were $497.9 (SD $677.9), and $307.7 (SD $424.1) for participants with asthma ruled out. In the adjusted analyses, a confirmed diagnosis was associated with higher direct healthcare costs (Relative Ratio [RR]=1.60, 95%CI 1.14-2.22), increased rate of specialist visits (RR=2.41, 95%CI 1.05-5.40) and reliever medication use (RR=1.62, 95%CI 1.09-2.35), but not primary care physician visits (p=0.10) or controller medication use (p=0.11).\n\nConclusionsA quarter of individuals with a physician diagnosis of asthma did not have asthma after objective re-evaluation. These participants still consumed a significant amount of asthma-related healthcare resources. The population-level economic burden of asthma overdiagnosis could be substantial.\n\nStrengths and limitations of this studyO_LIParticipants were recruited through random sampling of the general population in the province of British Columbia.\nC_LIO_LIAsthma diagnosis was confirmed or ruled out using sequential guideline-recommended objective airway tests.\nC_LIO_LIHealthcare resource use was self-reported, potential recall bias may have led to reduced accuracy.\nC_LIO_LIThe study was unable to evaluate the indirect costs of overdiagnosis or the cost-savings from correcting the diagnosis.\nC_LIO_LIThe generalizability of the results may be limited by regional differences in medical costs and practices.\nC_LI

epidemiology↗

bioRxiv2018

DNA Methylation Network Estimation with Sparse Latent Gaussian Graphical Model

Inferring molecular interaction networks from genomics data is important for advancing our understanding of biological processes. Whereas considerable research effort has been placed on inferring such networks from gene expression data, network estimation from DNA methylation data has received very little attention due to the substantially higher dimensionality and complications with result interpretation for non-genic regions. To combat these challenges, we propose here an approach based on sparse latent Gaussian graphical model (SLGGM). The core idea is to perform network estimation on q latent variables as opposed to d CpG sites, with q<<d. To impose a correspondence between the latent variables and genes, we use the distance between CpG sites and transcription starting sites of the genes to generate a prior on the CpG sites latent class membership. We evaluate this approach on synthetic data, and show on real data that the gene network estimated from DNA methylation data significantly explains gene expression patterns in unseen datasets.

genomics↗

bioRxiv2018

IL-11 is a therapeutic target in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) remains a progressive disease despite best medical management. We previously identified IL-11 as a critical factor for cardiovascular fibrosis and examine here its role in pulmonary fibrosis. IL-11 is consistently upregulated in IPF genomic datasets, which we confirmed by histology. Pulmonary fibroblasts stimulated with IL-11 transform into invasive myofibroblasts whereas fibroblasts from Il11ra deleted mice did not respond to pro-fibrotic stimuli. In the mouse, injection of recombinant Il-11 or fibroblast-specific expression of Il-11 caused pulmonary fibrosis. We then generated a neutralising IL-11 binding antibody that blocks lung fibroblast activation across species. In a mouse model of IPF, anti-IL-11 therapy attenuated lung fibrosis and specifically blocked Erk activation. These data prioritise IL-11 as an accessible drug target in IPF.\n\nOne Sentence SummaryNon-canonical IL-11 signalling is a central hallmark of idiopathic pulmonary fibrosis and represents a novel target for antibody therapies.

molecular biology↗

bioRxiv2017

Integrative analyses of splicing in the aging brain: role in susceptibility to Alzheimer’s Disease

We use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLFPC) of 450 subjects from two prospective cohort studies of aging. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimers Disease (AD). We also generate a catalog of splicing quantitative trait loci (sQTL) effects in the human cortex: splicing of 3,198 genes is influenced by genetic variation. sQTLs are enriched among those variants influencing DNA methylation and histone acetylation. In assessing known AD loci, we report that altered splicing is the mechanism for the effects of the PICALM, CLU, and PTK2B susceptibility alleles. Further, we leverage our sQTL catalog to identify genes whose aberrant splicing is associated with AD and mediated by genetics. This transcriptome-wide association study identified 21 genes with significant associations, many of which are found in AD GWAS loci, but 8 are in novel AD loci, including FUS, which is a known amyotrophic lateral sclerosis (ALS) gene. This highlights an intriguing shared genetic architecture that is further elaborated by the convergence of old and new AD genes in autophagy-lysosomal-related pathways already implicated in AD and other neurodegenerative diseases. Overall, this study of the aging brains transcriptome provides evidence that dysregulation of mRNA splicing is a feature of AD and is, in some genetically-driven cases, causal.

genomics↗

bioRxiv2017

Brain xQTL Map: Integrating The Genetic Architecture Of The Human Brain Transcriptome And Epigenome

We perform quantitative trait locus (xQTL) analyses on a multi-omic dataset, comprising RNA sequence, DNA methylation, and histone acetylation ChIP sequence data from the dorsolateral prefrontal cortex of 411 older adult individuals. We identify SNPs that are significantly associated with gene expression, DNA methylation, and histone modification levels. Many SNPs influence more than one type of molecular feature, and epigenetic features are shown to mediate eQTLs in a number of (9%) such loci. We illustrate the utility of our new resource, xQTL Serve, in prioritizing the cell type most affected by an xQTL and in enhancing genome wide association studies (GWAS) as we report 18 additional CNS disease susceptibility loci after re-analyzing published studies.

bioinformatics↗