33 research outputs found
Reconstruction of metabolic networks from high-throughput metabolite profiling data: in silico analysis of red blood cell metabolism
We investigate the ability of algorithms developed for reverse engineering of
transcriptional regulatory networks to reconstruct metabolic networks from
high-throughput metabolite profiling data. For this, we generate synthetic
metabolic profiles for benchmarking purposes based on a well-established model
for red blood cell metabolism. A variety of data sets is generated, accounting
for different properties of real metabolic networks, such as experimental
noise, metabolite correlations, and temporal dynamics. These data sets are made
available online. We apply ARACNE, a mainstream transcriptional networks
reverse engineering algorithm, to these data sets and observe performance
comparable to that obtained in the transcriptional domain, for which the
algorithm was originally designed.Comment: 14 pages, 3 figures. Presented at the DIMACS Workshop on Dialogue on
Reverse Engineering Assessment and Methods (DREAM), Sep 200
From Violation to Reconstruction: The Process of Self-Renewal Associated with Chronic Fatigue Syndrome
Chronic Fatigue Syndrome (CFS) is a contested condition that generates scepticism and occupies a marginalised position within medical and social contexts. The thesis examines the illness experiences, and specifically the experiences of self, for people affected with CFS. Using qualitative inquiry, a substantive theory related to the process of self-renewal and adaptation associated with CFS is explicated. The theory encompasses the trajectory of CFS from onset to chronicity, and in exceptional instances, recovery. Illness narratives were derived from in-depth, semi-structured interviews of 19 adults, including 16 people affected with, and 3 people recovered from, CFS. Data was coded and analysed using a grounded theory approach. Analysis generated two parallel narratives that defined the illness experience of CFS: the narrative of the illness biographies and the narrative of self, specifically the struggling and diminished self seeking renewal. The illness biographies encompassed the stories of symptoms and their explanations, the encounters that ensued and their contentious milieu. The narrative of self was the primary narrative. It articulated the negative consequences to self and personhood associated with CFS, named the Violation of Self, and the consequent efforts of participants to decrease the struggle and violation by use of the Guardian Response and the Reconstructing Response. The Guardian Response provided protection and self-reclamation. The Reconstructing Response fostered self-renewal and meaning. The two narratives were bridged by the threats of CFS. That is, the illness biographies were accompanied by threats of disruption related to chronic illness, and by threats of invalidation that arose from CFS as a contested condition. In turn, these threats provided the catalyst to the violation and responses as described in the narrative of self. Under different conditions the relative strengths of violation, guardianship or reconstruction fluctuated, and it was these fluctuations that presented the participants with the ongoing struggle of CFS
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men
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Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium
Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,771) and generalized our findings in 9 additional studies (HISLA Stage 2, n=10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification
Reducing the Computational Complexity of Information Theoretic Approaches for Reconstructing Gene Regulatory Networks
Information theoretic approaches are increasingly being used for reconstructing regulatory networks from microarray data. These approaches start by computing the pairwise mutual information (MI) between all gene pairs. The resulting MI matrix is then manipulated to identify regulatory relationships. A barrier to these approaches is the time-consuming step of computing the MI matrix. We present a method to reduce this computation time. We apply spectral analysis to re-order the genes, so that genes that share regulatory relationships are more likely to be placed close to each other. Then, using a “sliding window” approach with appropriate window size and step size, we compute the MI for the genes within the sliding window, and the remainder is assumed to be zero. Using both simulated data and microarray data, we demonstrate that our method does not incur performance loss in regions of high-precision and low-recall, while the computational time is significantly lowered. The proposed method can be used with any method that relies on the mutual information to reconstruct networks
Modelling non-homogeneous dynamic Bayesian networks with piece-wise linear regression models
In statistical genomics and systems biology non-homogeneous dynamic Bayesian networks (NH-DBNs) have become an important tool for learning regulatory networks and signalling pathways from post-genomic data, such as gene expression time series. This chapter gives an overview of various state-of-the-art NH-DBN models with a variety of features. All NH-DBNs, presented here, have in common that they are Bayesian models that combine linear regression with multiple changepoint processes. The NH-DBN models can be used for learning the network structures of time-varying regulatory processes from data, where the regulatory interactions are subject to temporal change. We conclude this chapter with an illustration of the methodology on two applications, related to morphogenesis in Drosophila and synthetic biology in yeast