A divisive Shuffling Approach (VIStA) for gene expression analysis to identify subtypes in Chronic Obstructive Pulmonary Disease

An important step toward understanding the biological mechanisms underlying a complex disease is a refined understanding of its clinical heterogeneity. Relating clinical and molecular differences may allow us to define more specific subtypes of patients that respond differently to therapeutic interventions. Results We developed a novel unbiased method called diVIsive Shuffling Approach (VIStA) that identifies subgroups of patients by maximizing the difference in their gene expression patterns. We tested our algorithm on 140 subjects with Chronic Obstructive Pulmonary Disease (COPD) and found four distinct, biologically and clinically meaningful combinations of clinical characteristics that are associated with large gene expression differences. The dominant characteristic in these combinations was the severity of airflow limitation. Other frequently identified measures included emphysema, fibrinogen levels, phlegm, BMI and age. A pathway analysis of the differentially expressed genes in the identified subtypes suggests that VIStA is capable of capturing specific molecular signatures within in each group. Conclusions The introduced methodology allowed us to identify combinations of clinical characteristics that correspond to clear gene expression differences. The resulting subtypes for COPD contribute to a better understanding of its heterogeneity

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD

BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. METHODS: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). RESULTS: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. CONCLUSIONS: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations

Random Sidon Sequences

A subsetAof the set [n]={1,2,...,n}, A=k, is said to form aSidon(orBh) sequence,h≥2, if each of the sumsa1+a2+...+ah,a1≤a 2≤...≤ah;ai∈A, are distinct. We investigate threshold phenomena for the Sidon property, showing that ifAnis a random subset of [n], then the probability thatAnis aBhsequence tends to unity asn→∞ ifkn=An≪n1/2h, and thatP(Anis Sidon)→0 provided thatkn≫n1/2h. The main tool employed is the Janson exponential inequality. The validity of the Sidon propertyatthe threshold is studied as well. We prove, using the Stein-Chen method of Poisson approximation, thatP(Anis Sidon) →exp{-λ} (n→∞) ifkn~Lambda;·n1/2h(Λ∈R+), whereλis a constant that depends in a well-specified way onΛ. Multivariate generalizations are presented

Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort

Exacerbations of COPD requiring hospital admission have important clinical and societal implications. We sought to investigate the incidence, recurrence, risk factors, and mortality of patients with COPD exacerbations requiring hospital admission compared with those without hospital admission during 3-year follow-up. Patients with COPD (N = 2,138) were identified from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) observational cohort. An analysis of time to first event of hospital admission was performed using Kaplan-Meier curves and Cox proportional hazard regression adjusting for possible confounders. Of the 2,138 patients, 670 (31%) reported a total of 1,452 COPD exacerbations requiring hospital admission during the study period; 313 patients (15%) reported multiple events. A prior history of exacerbation of COPD requiring hospital admission was the factor associated with the highest risk of a new hospitalization for exacerbation (hazard ratio, 2.71; 95% CI, 2.24-3.29; P < .001). Other risk factors included more severe airflow limitation, poorer health status, older age, radiologic evidence of emphysema, and higher WBC count. Having been hospitalized for exacerbation significantly increased the risk of mortality (P < .001). Exacerbations of COPD requiring hospital admission occur across all stages of airflow limitation and are a significant prognostic factor of reduced survival across all COPD stages. Patients with COPD at a high risk for hospitalization can be identified by their past history for similar events, and other factors, including the severity of airflow limitation, poor health status, age, presence of emphysema, and leukocytosis. ClinicalTrials.gov; No.: NCT00292552; URL: www.clinicaltrials.gov

Susceptibility to exacerbation in chronic obstructive pulmonary disease

Background Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. Methods We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End points (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both)or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Results Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient"s recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Conclusions Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials .gov number, NCT00292552.