Dataset Information

Cluster analysis of obesity and asthma phenotypes.

ABSTRACT: Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype.In a cohort of clinical trial participants (n?=?250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCR?) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F?=?57.1, p<0.0001 and F?=?44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCR?, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasoneObesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.

SUBMITTER: Sutherland ER

PROVIDER: S-EPMC3350517 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Cluster analysis of obesity and asthma phenotypes.

Sutherland E Rand ER Goleva Elena E King Tonya S TS Lehman Erik E Stevens Allen D AD Jackson Leisa P LP Stream Amanda R AR Fahy John V JV Leung Donald Y M DY

PloS one 20120511 5

<h4>Background</h4>Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables t ...[more]

PMID: 22606276

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Project description:BackgroundAsthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED.MethodsFuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13.ResultsFour phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort.ConclusionsFocusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies.Trial registrationNCT01274507 (ADEPT), registered October 28, 2010 and NCT01982162 (U-BIOPRED), registered October 30, 2013.

Project description:ObjectiveTo investigate the possible subgroups of patients with Cluster Headache (CH) by using K-means cluster analysis.MethodsA total of 209 individuals (mean (SD) age: 39.8 (11.3) years), diagnosed with CH by headache experts, participated in this cross-sectional multi-center study. All patients completed a semi-structured survey either face to face, preferably, or through phone interviews with a physician. The survey was composed of questions that addressed sociodemographic characteristics as well as detailed clinical features and treatment experiences.ResultsCluster analysis revealed two subgroups. Cluster one patients (n = 81) had younger age at diagnosis (31.04 (9.68) vs. 35.05 (11.02) years; p = 0.009), a higher number of autonomic symptoms (3.28 (1.16) vs. 1.99(0.95); p < 0.001), and showed a better response to triptans (50.00% vs. 28.00; p < 0.001) during attacks, compared with the cluster two subgroup (n = 122). Cluster two patients had higher rates of current smoking (76.0 vs. 33.0%; p=0.002), higher rates of smoking at diagnosis (78.0 vs. 32.0%; p=0.006), higher rates of parental smoking/tobacco exposure during childhood (72.0 vs. 33.0%; p = 0.010), longer duration of attacks with (44.21 (34.44) min. vs. 34.51 (24.97) min; p=0.005) and without (97.50 (63.58) min. vs. (83.95 (49.07) min; p = 0.035) treatment and higher rates of emergency department visits in the last year (81.0 vs. 26.0%; p< 0.001).ConclusionsCluster one and cluster two patients had different phenotypic features, possibly indicating different underlying genetic mechanisms. The cluster 1 phenotype may suggest a genetic or biology-based etiology, whereas the cluster two phenotype may be related to epigenetic mechanisms. Toxic exposure to cigarettes, either personally or secondarily, seems to be an important factor in the cluster two subgroup, inducing drug resistance and longer attacks. We need more studies to elaborate the causal relationship and the missing links of neurobiological pathways of cigarette smoking regarding the identified distinct phenotypic classes of patients with CH.

Project description:Background Clustering key clinical characteristics of participants in the Severe Asthma Research Program (SARP), a large, multicenter prospective observational study of patients with asthma and healthy controls, has led to the identification of novel asthma phenotypes. Purpose To determine whether quantitative CT (qCT) could help distinguish between clinical asthma phenotypes. Materials and Methods A retrospective cross-sectional analysis was conducted with the use of qCT images (maximal bronchodilation at total lung capacity [TLC], or inspiration, and functional residual capacity [FRC], or expiration) from the cluster phenotypes of SARP participants (cluster 1: minimal disease; cluster 2: mild, reversible; cluster 3: obese asthma; cluster 4: severe, reversible; cluster 5: severe, irreversible) enrolled between September 2001 and December 2015. Airway morphometry was performed along standard paths (RB1, RB4, RB10, LB1, and LB10). Corresponding voxels from TLC and FRC images were mapped with use of deformable image registration to characterize disease probability maps (DPMs) of functional small airway disease (fSAD), voxel-level volume changes (Jacobian), and isotropy (anisotropic deformation index [ADI]). The association between cluster assignment and qCT measures was evaluated using linear mixed models. Results A total of 455 participants were evaluated with cluster assignments and CT (mean age ± SD, 42.1 years ± 14.7; 270 women). Airway morphometry had limited ability to help discern between clusters. DPM fSAD was highest in cluster 5 (cluster 1 in SARP III: 19.0% ± 20.6; cluster 2: 18.9% ± 13.3; cluster 3: 24.9% ± 13.1; cluster 4: 24.1% ± 8.4; cluster 5: 38.8% ± 14.4; P < .001). Lower whole-lung Jacobian and ADI values were associated with greater cluster severity. Compared to cluster 1, cluster 5 lung expansion was 31% smaller (Jacobian in SARP III cohort: 2.31 ± 0.6 vs 1.61 ± 0.3, respectively, P < .001) and 34% more isotropic (ADI in SARP III cohort: 0.40 ± 0.1 vs 0.61 ± 0.2, P < .001). Within-lung Jacobian and ADI SDs decreased as severity worsened (Jacobian SD in SARP III cohort: 0.90 ± 0.4 for cluster 1; 0.79 ± 0.3 for cluster 2; 0.62 ± 0.2 for cluster 3; 0.63 ± 0.2 for cluster 4; and 0.41 ± 0.2 for cluster 5; P < .001). Conclusion Quantitative CT assessments of the degree and intraindividual regional variability of lung expansion distinguished between well-established clinical phenotypes among participants with asthma from the Severe Asthma Research Program study. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.

Dataset Information

Cluster analysis of obesity and asthma phenotypes.

Publications

Cluster analysis of obesity and asthma phenotypes.

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