Xuekui Zhang

Publications (9)75.12 Total impact

• Source

  Available from: Gordon Robertson

  Article: Probabilistic inference for nucleosome positioning with MNase-based or sonicated short-read data.

  Xuekui Zhang, Gordon Robertson, Sangsoon Woo, Brad G Hoffman, Raphael Gottardo
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  ABSTRACT: We describe a model-based method, PING, for predicting nucleosome positions in MNase-Seq and MNase- or sonicated-ChIP-Seq data. PING compares favorably to NPS and TemplateFilter in scalability, accuracy and robustness to low read density. To demonstrate that PING predictions from widely available sonicated data can have sufficient spatial resolution to be to be useful for biological inference, we use Illumina H3K4me1 ChIP-seq data to detect changes in nucleosome positioning around transcription factor binding sites due to tamoxifen stimulation, to discriminate functional and non-functional transcription factor binding sites more effectively than with enrichment profiles, and to confirm that the pioneer transcription factor Foxa2 associates with the accessible major groove of nucleosomal DNA.
  PLoS ONE 01/2012; 7(2):e32095. · 4.09 Impact Factor
• Source

  Available from: Gordon Robertson

  Article: PICS: probabilistic inference for ChIP-seq.

  Xuekui Zhang, Gordon Robertson, Martin Krzywinski, Kaida Ning, Arnaud Droit, Steven Jones, Raphael Gottardo
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  ABSTRACT: ChIP-seq combines chromatin immunoprecipitation with massively parallel short-read sequencing. While it can profile genome-wide in vivo transcription factor-DNA association with higher sensitivity, specificity, and spatial resolution than ChIP-chip, it poses new challenges for statistical analysis that derive from the complexity of the biological systems characterized and from variability and biases in its sequence data. We propose a method called PICS (Probabilistic Inference for ChIP-seq) for identifying regions bound by transcription factors from aligned reads. PICS identifies binding event locations by modeling local concentrations of directional reads, and uses DNA fragment length prior information to discriminate closely adjacent binding events via a Bayesian hierarchical t-mixture model. It uses precalculated, whole-genome read mappability profiles and a truncated t-distribution to adjust binding event models for reads that are missing due to local genome repetitiveness. It estimates uncertainties in model parameters that can be used to define confidence regions on binding event locations and to filter estimates. Finally, PICS calculates a per-event enrichment score relative to a control sample, and can use a control sample to estimate a false discovery rate. Using published GABP and FOXA1 data from human cell lines, we show that PICS' predicted binding sites were more consistent with computationally predicted binding motifs than the alternative methods MACS, QuEST, CisGenome, and USeq. We then use a simulation study to confirm that PICS compares favorably to these methods and is robust to model misspecification.
  Biometrics 03/2011; 67(1):151-63. · 1.83 Impact Factor
• Source

  Available from: Gordon Robertson

  Article: An integrated pipeline for the genome-wide analysis of transcription factor binding sites from ChIP-Seq.

  Eloi Mercier, Arnaud Droit, Leping Li, Gordon Robertson, Xuekui Zhang, Raphael Gottardo
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  ABSTRACT: ChIP-Seq has become the standard method for genome-wide profiling DNA association of transcription factors. To simplify analyzing and interpreting ChIP-Seq data, which typically involves using multiple applications, we describe an integrated, open source, R-based analysis pipeline. The pipeline addresses data input, peak detection, sequence and motif analysis, visualization, and data export, and can readily be extended via other R and Bioconductor packages. Using a standard multicore computer, it can be used with datasets consisting of tens of thousands of enriched regions. We demonstrate its effectiveness on published human ChIP-Seq datasets for FOXA1, ER, CTCF and STAT1, where it detected co-occurring motifs that were consistent with the literature but not detected by other methods. Our pipeline provides the first complete set of Bioconductor tools for sequence and motif analysis of ChIP-Seq and ChIP-chip data.
  PLoS ONE 01/2011; 6(2):e16432. · 4.09 Impact Factor
• Article: Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease.

  Don D Sin, Bruce E Miller, Annelyse Duvoix, S F Paul Man, Xuekui Zhang, Edwin K Silverman, John E Connett, Nicholas A Anthonisen, Robert A Wise, Donald Tashkin, Bartolome R Celli, Lisa D Edwards, Nicholas Locantore, William Macnee, Ruth Tal-Singer, David A Lomas
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  ABSTRACT: There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum. To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality. Methods: PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study. Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort. Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.
  American Journal of Respiratory and Critical Care Medicine 01/2011; 183(9):1187-92. · 11.08 Impact Factor
• Article: Budesonide and the risk of pneumonia: a meta-analysis of individual patient data.

  Don D Sin, Donald Tashkin, Xuekui Zhang, Finn Radner, Ulf Sjöbring, Anders Thorén, Peter M A Calverley, Stephen I Rennard
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  ABSTRACT: Concern is continuing about increased risk of pneumonia in patients with chronic obstructive pulmonary disease (COPD) who use inhaled corticosteroids. We aimed to establish the effects of inhaled budesonide on the risk of pneumonia in such patients. We pooled patient data from seven large clinical trials of inhaled budesonide (320-1280 mug/day), with or without formoterol, versus control regimen (placebo or formoterol alone) in patients with stable COPD and at least 6 months of follow-up. The primary analysis compared treatment groups for the risk of pneumonia as an adverse event or serious adverse event during the trial or within 15 days of the trial end. Cox proportional hazards regression was used to analyse the data on an intention-to-treat basis. Data were adjusted for patients' age, sex, smoking status, body-mass index, and postbronchodilator percent of predicted forced expiratory volume in 1 s (FEV(1)). We analysed data from 7042 patients, of whom 3801 were on inhaled budesonide and 3241 were on control treatment, with 5212 patient-years of exposure to treatment. We recorded no significant difference between treatment groups for the occurrence of pneumonia as an adverse event (3% [n=122 patients] vs 3% [n=103]; adjusted hazard ratio 1.05, 95% CI 0.81-1.37) or a serious adverse event (1% [n=53] vs 2% [n=50]; 0.92, 0.62-1.35), or for time to pneumonia as an adverse event (log-rank test 0.94) or a serious adverse event (0.61). Increasing age and decreasing percent of predicted FEV(1) were the only two variables that were significantly associated with occurrence of pneumonia as an adverse event or a serious adverse event. Budesonide treatment for 12 months does not increase the risk of pneumonia in patients with COPD during that time and therefore is safe for clinical use in such patients. Michael Smith Foundation for Health Research.
  The Lancet 09/2009; 374(9691):712-9. · 38.28 Impact Factor
• Article: Associations of IL6 polymorphisms with lung function decline and COPD.

  J-Q He, M G Foreman, K Shumansky, X Zhang, L Akhabir, D D Sin, S F P Man, D L DeMeo, A A Litonjua, E K Silverman, J E Connett, N R Anthonisen, R A Wise, P D Paré, A J Sandford
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  ABSTRACT: Interleukin-6 (IL6) is a pleiotropic pro-inflammatory and immunomodulatory cytokine which probably plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). There is a functional single nucleotide polymorphism (SNP), -174G/C, in the promoter region of IL6. It was hypothesised that IL6 SNPs influence susceptibility for impaired lung function and COPD in smokers. Seven and five SNPs in IL6 were genotyped in two nested case-control samples derived from the Lung Health Study (LHS) based on phenotypes of rate of decline of forced expiratory volume in 1 s (FEV(1)) over 5 years and baseline FEV(1) at the beginning of the LHS. Serum IL6 concentrations were measured for all subjects. A partially overlapping panel of nine IL6 SNPs was genotyped in 389 cases of COPD from the National Emphysema Treatment Trial (NETT) and 420 controls from the Normative Aging Study (NAS). In the LHS, three IL6 SNPs were associated with decline in FEV(1) (0.023< or =p< or =0.041 in additive models). Among them, the IL6_-174C allele was associated with a rapid decline in lung function. The association was more significant in a genotype-based analysis (p = 0.006). In the NETT-NAS study, IL6_-174G/C and four other IL6 SNPs, all of which are in linkage disequilibrium with IL6_-174G/C, were associated with susceptibility to COPD (0.01< or =p< or =0.04 in additive genetic models). The results suggest that the IL6_-174G/C SNP is associated with a rapid decline in FEV(1) and susceptibility to COPD in smokers.
  Thorax 05/2009; 64(8):698-704. · 6.84 Impact Factor
• Article: The effects of inhaled and oral corticosteroids on serum inflammatory biomarkers in COPD: an exploratory study.

  S F Paul Man, Xuekui Zhang, Rupert Vessey, Terry Walker, Kwan Lee, Dan Park, Don D Sin
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  ABSTRACT: Several studies suggest that inhaled and oral corticosteroids repress systemic inflammation in chronic obstructive pulmonary disease (COPD). However, the cytokines that may respond to these medications are unclear. We used data from 41 patients with a history of stable moderate COPD (average age 64 years) who were randomised to inhaled fluticasone (500 microg twice daily from a Diskus inhaler), oral prednisone (30 mg daily) or placebo for 2 weeks. Using a multiplexed array system, different serum cytokines that have been implicated in COPD pathogenesis were measured. We found that compared with placebo, inhaled fluticasone significantly reduced levels of soluble tumour necrosis factor receptor-2 (sTNF-R2) by 24% (95% CI, 7-38%; p = 0.01), monocyte chemoattractant protein-1 by 20% (95% CI, 5-32%; p = 0.01), interferon gamma inducible CXCL10 (IP-10) by 43% (95% CI, 3-66%; p = 0.04), and soluble L-selectin levels by 15% (95% CI, 1-28%; p = 0.04). Compared with placebo, oral prednisone reduced levels of sTNF-R2 by 26% (95% CI, 15-36%; p < 0.001), L-selectin by 22% (95% CI, 8-34%; p = 0.004), intercellular adhesion molecule-1 by 31% (95% CI, 9-48%; p = 0.01), pulmonary and activation-regulated chemokine (PARC) by 18% (95% CI, 2-32%; p = 0.03) and IP-10 by 40% (95% CI, 0-64%; p = 0.05). sTNF-R2, L-selectin and IP-10 were significantly reduced by both oral and inhaled corticosteroids. The other cytokines were not significantly repressed by either oral or inhaled corticosteroids. In summary, inhaled and oral corticosteroids significantly repressed a selected number of systemic cytokines in patients with stable, moderate COPD; most of the steroid-responsive cytokines appear to be chemoattractants.
  Therapeutic Advances in Respiratory Disease 04/2009; 3(2):73-80.
• Article: Particulate matter exposure induces persistent lung inflammation and endothelial dysfunction.

  Eiji Tamagawa, Ni Bai, Kiyoshi Morimoto, Claire Gray, Tammy Mui, Kazuhiro Yatera, Xuekui Zhang, Li Xing, Yuexin Li, Ismail Laher, Don D Sin, S F Paul Man, Stephan F van Eeden
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  ABSTRACT: Epidemiologic and animal studies have shown that exposure to particulate matter air pollution (PM) is a risk factor for the development of atherosclerosis. Whether PM-induced lung and systemic inflammation is involved in this process is not clear. We hypothesized that PM exposure causes lung and systemic inflammation, which in turn leads to vascular endothelial dysfunction, a key step in the initiation and progression of atherosclerosis. New Zealand White rabbits were exposed for 5 days (acute, total dose 8 mg) and 4 wk (chronic, total dose 16 mg) to either PM smaller than 10 mum (PM(10)) or saline intratracheally. Lung inflammation was quantified by morphometry; systemic inflammation was assessed by white blood cell and platelet counts and serum interleukin (IL)-6, nitric oxide, and endothelin levels. Endothelial dysfunction was assessed by vascular response to acetylcholine (ACh) and sodium nitroprusside (SNP). PM(10) exposure increased lung macrophages (P<0.02), macrophages containing particles (P<0.001), and activated macrophages (P<0.006). PM(10) increased serum IL-6 levels in the first 2 wk of exposure (P<0.05) but not in weeks 3 or 4. PM(10) exposure reduced ACh-related relaxation of the carotid artery with both acute and chronic exposure, with no effect on SNP-induced vasodilatation. Serum IL-6 levels correlated with macrophages containing particles (P=0.043) and ACh-induced vasodilatation (P=0.014 at week 1, P=0.021 at week 2). Exposure to PM(10) caused lung and systemic inflammation that were both associated with vascular endothelial dysfunction. This suggests that PM-induced lung and systemic inflammatory responses contribute to the adverse vascular events associated with exposure to air pollution.
  AJP Lung Cellular and Molecular Physiology 07/2008; 295(1):L79-85. · 3.66 Impact Factor
• Article: A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo.

  Joan B Soriano, Don D Sin, Xuekui Zhang, Pat G Camp, Julie A Anderson, Nick R Anthonisen, A Sonia Buist, P Sherwood Burge, Peter M Calverley, John E Connett, Stefan Petersson, Dirkje S Postma, Wojciech Szafranski, Jørgen Vestbo
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  ABSTRACT: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1). The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking. There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers. We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials.
  Chest 03/2007; 131(3):682-9. · 5.25 Impact Factor