Cluster analysis in phenotyping a Portuguese population
a Pneumology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
b Centre of Pneumology, Faculty of Medicine, University of Coimbra, Portugal
c Center for Research and Development in Mathematics and Applications, Department of Mathematics, University of Aveiro, Aveiro, Portugal
d Immunoallergology Unit, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
e University Hospital Arnaud de Villeneuve, Montpellier, France
f Inserm, CESP Centre for Research in Epidemiology and Population Health, U1018, Respiratory and Environmental Epidemiology Team, Villejuif, France
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Loureiro, P. Sa-Couto, A. Todo-Bom, J. Bousquet" "autores" => array:4 [ 0 => array:4 [ "Iniciales" => "C.C." "apellidos" => "Loureiro" "email" => array:1 [ 0 => "cchloureiro@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor1" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 1 => array:3 [ "Iniciales" => "P." "apellidos" => "Sa-Couto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 2 => array:3 [ "Iniciales" => "A." 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Identification of each corresponding endotype requires the definition of their clinical characteristics, biomarkers, lung physiology, genetic aspects, disease history and therapeutic response.<a href="#bib23" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">4</span></a> According to Wenzel, the first step to better understand asthma is to define phenotypes by cluster analysis.<a href="#bib24" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a></p><p class="elsevierStylePara">The objective of this observational study was to cluster an asthmatic Portuguese population, treated in secondary medical care, combining clinical, inflammatory, lung function and severity parameters.</p><a name="sec0010" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Methods</span><a name="sec0015" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Study design</span><p class="elsevierStylePara">Consecutive patients with asthma were recruited from the outpatient clinic, using written informative material. They were included if aged between 18 and 79 years and excluded in the presence of any of the following: cystic fibrosis, interstitial lung disease, auto-immune disease, neoplastic disease, untreated cardiac failure.</p><p class="elsevierStylePara">Asthma was defined on the basis of a relevant symptom history, plus one or more of the following: history of airway reversibility to salbutamol according to GINA guidelines,<a href="#bib25" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">6</span></a> positive test for airway hyperresponsiveness using methacholine.<a href="#bib26" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">7</span></a></p><p class="elsevierStylePara">Asthma control was measured under optimized treatment, with validated asthma questionnaires (asthma control test (ACT), control asthma and allergic rhinitis test (CARAT), asthma life quality (ALQ), and severity of asthma score (SOA)).</p><p class="elsevierStylePara">Severe exacerbations were defined as events requiring urgent action to prevent a serious outcome and at least one of the following: use of systemic corticosteroids or an increase from a stable maintenance dose, for at least 3 days, and/or hospitalization or emergency room visit due to asthma requiring systemic corticosteroid treatment.<a href="#bib27" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">8</span></a></p><p class="elsevierStylePara">The risk of future adverse events was evaluated considering loss of control, number of exacerbations in the previous year, number of systemic corticosteroids in the previous year, accelerated decline in lung function, and side-effects of treatment. A low basal FEV<span class="elsevierStyleInf">1</span> (% predicted value) and low reversibility were also taken into account.</p><p class="elsevierStylePara">Lung function was assessed with spirometry and plethysmography according to ATS criteria;<a href="#bib28" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleSup">, </span><a href="#bib29" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">10</span></a> skin prick tests (SPT) were performed using standardized allergens and/or specific serum IgE, FeNO measurement was done using a CLD 88 SP (EcoMedics<span class="elsevierStyleSup">®</span>) analyzer before any forced expiratory manoeuvers<a href="#bib30" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">11</span></a> and sputum induction and collection was performed using hypertonic saline 4.5% if stable asthma, delivered via an ultrasonic nebulizer.<a href="#bib31" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">12</span></a> Induced sputum was collected by a trained nurse, stored on ice and processed within two hours after expectoration. Sputum processing and immunophenotypical analysis of sputum cells was performed according to laboratory procedures.</p><p class="elsevierStylePara">If the need to exclude other diagnoses occurred, specific procedures were scheduled (Table E1).</p><a name="sec0020" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Data processing</span><p class="elsevierStylePara">Variables were selected according to previous studies<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a><span class="elsevierStyleSup">, </span><a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> and included demographic data; comorbidities; evaluation of disease control, quality of life and risk assessment; lung function and blood biomarkers (<a href="#t0005" class="elsevierStyleCrossRefs">Table 1</a>). Patients with missing data were excluded. Summary statistics were reported as mean and standard deviation values for continuous variables and as percentages and counts for categorical variables. Geometric mean was reported for total serum IgE.</p><p class="elsevierStylePara">Table 1. Variables selected for cluster analysis (continuous, binary and composed).</p><a name="t0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td>Number</td><td>Variable name</td><td>Type of data</td><td>Key</td></tr><tr align="left"><td colspan="4"><span class="elsevierStyleItalic">Demographic and comorbidities – Questionnaire data</span></td></tr><tr align="left"><td>1</td><td>Gender</td><td>Binary</td><td>0 – Female/1 – Male</td></tr><tr align="left"><td>2</td><td>Age</td><td>Continuous</td><td> </td></tr><tr align="left"><td>3</td><td>BMI</td><td>Continuous</td><td> </td></tr><tr align="left"><td>4</td><td>Onset under 12 y</td><td>Binary</td><td>0 – Yes/1 – No</td></tr><tr align="left"><td>5</td><td>Years of disease</td><td>Continuous</td><td> </td></tr><tr align="left"><td>6</td><td>Comorbidities</td><td>Composite: atopy; rhinitis; polyposis; sinusitis; any smoke exposure; pneumonia history; NSAID's HS; GERD; α1-AT deficit; Bronchiectasic; COPD; Other obstructive disease; <span class="elsevierStyleItalic">Aspergillus</span> (IgEpos)</td><td>Presence: 1 Absence: 0<br></br>Minimum: 0<br></br>Maximum: 13</td></tr><tr align="left"><td colspan="4"> </td></tr><tr align="left"><td colspan="4"><span class="elsevierStyleItalic">Control and severity of disease, risk of adverse events, and quality of life</span></td></tr><tr align="left"><td>7</td><td>Control of disease and patient at risk</td><td>Composite: hospitalization (in previous year); Severe exacerbation (in previousyear); Disease control; % patients at risk; OCS</td><td>Presence: 1 Absence: 0<br></br>Minimum: 0<br></br>Maximum: 5</td></tr><tr align="left"><td colspan="4"> </td></tr><tr align="left"><td colspan="4"><span class="elsevierStyleItalic">Demographic and comorbidities – Questionnaire data</span></td></tr><tr align="left"><td>8</td><td>Medication used</td><td>Composite: Imunotherapy; ICS dose; LABA; Tiotropium; Montelukast; Omalizumab; Aminophylline; nasal CS</td><td>Presence: 1 Absence: 0<br></br>Minimum: 0<br></br>Maximum: 8</td></tr><tr align="left"><td>9</td><td>No. of allergies</td><td>Composite: Mites; Pollens; Fungus; Cockroach; Cat</td><td>Presence: 1 Absence: 0<br></br>Minimum: 0<br></br>Maximum: 5</td></tr><tr align="left"><td>10</td><td>Risk of adverse events</td><td>Composite: hospitalizations >0 (previous year); OCS≥2 (previous year); FEV<span class="elsevierStyleInf">1</span><80%; ΔFEV<span class="elsevierStyleInf">1</span> after BD<200 ml; adverse effects (1 = yes)</td><td>Minimum: 0<br></br>Maximum: 5</td></tr><tr align="left"><td>11</td><td>SOA</td><td>Continuous</td><td> </td></tr><tr align="left"><td>12</td><td>ACT</td><td>Continuous</td><td> </td></tr><tr align="left"><td>13</td><td>CARAT (Rhinitis)</td><td>Continuous</td><td> </td></tr><tr align="left"><td>14</td><td>CARAT (Asthma)</td><td>Continuous</td><td> </td></tr><tr align="left"><td>15</td><td>ALQ</td><td>Continuous</td><td> </td></tr><tr align="left"><td colspan="4"> </td></tr><tr align="left"><td colspan="4"><span class="elsevierStyleItalic">Lung function</span></td></tr><tr align="left"><td>16</td><td>Bronchial lability</td><td>Composite: fixed obstruction; bronchial reversibility; fixed obstruction despite BD response</td><td>Presence: 1 Absence: 0<br></br>Minimum: 0<br></br>Maximum: 3</td></tr><tr align="left"><td>17</td><td>Basal FEV<span class="elsevierStyleInf">1</span> (%predicted)</td><td>Continuous</td><td> </td></tr><tr align="left"><td>18</td><td>Basal FEV<span class="elsevierStyleInf">1</span>/CVF (%predicted)</td><td>Continuous</td><td> </td></tr><tr align="left"><td>19</td><td>Basal FEV<span class="elsevierStyleInf">25%–75%</span> (%predicted)</td><td>Continuous</td><td> </td></tr><tr align="left"><td>20</td><td>Basal RV (%predicted)</td><td>Continuous</td><td> </td></tr><tr align="left"><td colspan="4"> </td></tr><tr align="left"><td colspan="4"><span class="elsevierStyleItalic">Biomarkers</span></td></tr><tr align="left"><td>21</td><td>Blood eosinophils (%):</td><td>Continuous</td><td>Log scale</td></tr><tr align="left"><td>22</td><td>Seric IgE (mmol/L):</td><td>Continuous</td><td>Log scale</td></tr></table><p class="elsevierStylePara">ACT: asthma control test; ALQ: asthma life quality; CARAT: Control of Allergic Rhinitis and Asthma Test; CS: corticosteroids;; ICS: inhaled corticosteroids; LABA: long-acting b-agonists; SOA: severity asthma score; OCS: oral corticosteroids.<br></br></p><p class="elsevierStylePara">Clinically redundant variables (or with correlation values above 0.9 in module) were reduced. Binary questionnaire data and data with a spectrum of responses were transformed into “composite variables” (<a href="#t0005" class="elsevierStyleCrossRefs">Table 1</a>) to capture multiple questions in a ranked ordinal scale.<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">, </span><a href="#bib32" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">13</span></a><span class="elsevierStyleSup">, </span><a href="#bib33" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">14</span></a></p><p class="elsevierStylePara">A cluster analysis of 22 variables (<a href="#t0005" class="elsevierStyleCrossRefs">Table 1</a>) was applied to identify groups of patients with the same characteristics. Ward's minimum-variance hierarchical clustering method was performed using an agglomerative approach, and the linkage measure was the squared Euclidean distance with standardization in <span class="elsevierStyleItalic">z</span> scores, according to Moore et al.<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> By visual inspection of dendrogram, no single member, small clusters or observations with large distances from all other observations were observed. Therefore, no formal method for outliers’ detection was used. Analysis of variance (ANOVA or Kruskal–Wallis) or contingency table tests (Person chi-square or Fisher) were used to compare differences between clusters. All statistical analyses were performed using SPSS<span class="elsevierStyleSup">®</span> Software, version 20.0 (SPSS, Inc., Chicago, IL), and <span class="elsevierStyleItalic">p</span>-values under 0.05 were considered significant.</p><a name="sec0025" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Results</span><p class="elsevierStylePara">Of the 72 patients enrolled, 57 had completed data for the considered variables (79.2% of total sample).</p><p class="elsevierStylePara">The optimum number of clusters was estimated by visual inspection of the dendrogram (<a href="#f0005" class="elsevierStyleCrossRefs">Figure 1</a>) and by representation of the difference between consecutive clusters (Fig. E1). A second cluster method was used (two-step cluster approach) to ensure that Ward's cluster solutions were not bias due to small sample size or by the measurement level of the considerable variables. For both clustering methods, the five cluster solution was the one that, from a clinical perspective, best explained the results.</p><a name="f0005" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v21n06-90445967fig1.jpg" alt="Dendrogram obtained using Ward's method."></img></p><p class="elsevierStylePara">Figure 1. Dendrogram obtained using Ward's method.</p><p class="elsevierStylePara">Elements were then distributed in five clusters. From variables that showed significance in distribution the following stand out: gender, age, BMI, number of exacerbations in previous year, disease severity, disease control, scores in ACT, CARAT, ALQ, SOA, ICS dose, fixed obstruction, basal FEV<span class="elsevierStyleInf">1</span>, blood eosinophils (<a href="#t0010" class="elsevierStyleCrossRefs">Table 2</a>).</p><p class="elsevierStylePara">Table 2. Main characteristics obtained for total sample and each of five clusters.</p><a name="t0010" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"></p><table><tr align="left"><td>Variables<br></br>Qualitative (<span class="elsevierStyleItalic">n</span>, %)<br></br>Quantitative (<span class="elsevierStyleItalic">M</span> ± SD)</td><td>Total (<span class="elsevierStyleItalic">n</span> = 57)</td><td>C1 (<span class="elsevierStyleItalic">n</span> = 6)</td><td>C2 (<span class="elsevierStyleItalic">n</span> = 15)</td><td>C3 (<span class="elsevierStyleItalic">n</span> = 10)</td><td>C4 (<span class="elsevierStyleItalic">n</span> = 19)</td><td>C5 (<span class="elsevierStyleItalic">n</span> = 7)</td><td>Statistical analysis</td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Gender</span></td></tr><tr align="left"><td>Female</td><td>42 (73.7)</td><td>2 (4.8)</td><td>12 (28.6)</td><td>10 (23.8)</td><td>18 (42.9)</td><td>0 (0.0)</td><td>Fisher = 29.5</td></tr><tr align="left"><td>Male</td><td>15 (26.3)</td><td>4 (26.7)</td><td>3 (20.0)</td><td>0 (20.0)</td><td>1 (6.7)</td><td>7 (46.7)</td><td><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td><span class="elsevierStyleItalic">Age (years)</span></td><td>45.6 ± 18.0</td><td>23.0 ± 6.8</td><td>53.7 ± 15.9</td><td>25.9 ± 8.4</td><td>49.9 ± 11.9</td><td>64.3 ± 8.3</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 19.0<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td><span class="elsevierStyleItalic">BMI (kg/m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">)</span></td><td>27.8 ± 6.0</td><td>21.2 ± 1.8</td><td>28.1 ± 4.7</td><td>26.9 ± 7.0</td><td>30.3 ± 6.8</td><td>27.3 ± 1.4</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 3.2<br></br><span class="elsevierStyleItalic">p</span> = 0.020</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Years of disease (years)</span></td><td>24.0 ± 14.0</td><td>12.8 ± 8.7</td><td>31.8 ± 18.5</td><td>14.3 ± 7.4</td><td>24.4 ± 13.0</td><td>29.7 ± 13.8</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 3.8<br></br><span class="elsevierStyleItalic">p</span> = 0.009</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Disease onset under age 12 Y</span></td></tr><tr align="left"><td>No</td><td>27 (47.4)</td><td>2 (7.4)</td><td>6 (22.2)</td><td>1 (3.7)</td><td>11 (40.7)</td><td>7 (25.9)</td><td>Fisher = 15.4</td></tr><tr align="left"><td>Yes</td><td>30 (52.6)</td><td>4 (13.3)</td><td>9 (30.0)</td><td>9 (30.0)</td><td>8 (26.7)</td><td>0 (0.0)</td><td><span class="elsevierStyleItalic">p</span> = 0.003</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">IgE sensitization</span></td></tr><tr align="left"><td>No</td><td>18 (31.6)</td><td>0 (0.0)</td><td>5 (27.8)</td><td>2 (11.1)</td><td>9 (50.0)</td><td>2 (11.1)</td><td>Fisher = 5.3</td></tr><tr align="left"><td>Yes</td><td>39 (68.4)</td><td>6 (15.4)</td><td>10 (25.6)</td><td>8 (20.5)</td><td>10 (25.6)</td><td>5 (12.8)</td><td><span class="elsevierStyleItalic">p</span> = 0.255</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Any smoke exposure</span></td></tr><tr align="left"><td>No</td><td>36 (63.2)</td><td>4 (11.1)</td><td>10 (27.8)</td><td>7 (19.4)</td><td>13 (36.1)</td><td>2 (5.6)</td><td>Fisher = 3.9</td></tr><tr align="left"><td>Yes</td><td>21 (36.8)</td><td>2 (9.5)</td><td>5 (23.8)</td><td>3 (14.3)</td><td>6 (28.6)</td><td>5 (23.8)</td><td><span class="elsevierStyleItalic">p</span> = 0.432</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Pneumonia history</span></td></tr><tr align="left"><td>No</td><td>36 (63.2)</td><td>5 (13.9)</td><td>10 (27.8)</td><td>6 (16.7)</td><td>11 (30.6)</td><td>4 (11.1)</td><td>Fisher = 1.6</td></tr><tr align="left"><td>Yes</td><td>21 (36.8)</td><td>1 (4.8)</td><td>5 (23.8)</td><td>4 (19.0)</td><td>8 (38.1)</td><td>3 (14.3)</td><td><span class="elsevierStyleItalic">p</span> = 0.857</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Rhinitis</span></td></tr><tr align="left"><td>No</td><td>10 (17.5)</td><td>0 (0.0)</td><td>5 (10.0)</td><td>1 (10.0)</td><td>4 (40.0)</td><td>0 (0.0)</td><td>Fisher = 4.6</td></tr><tr align="left"><td>Yes</td><td>47 (82.5)</td><td>6 (12.8)</td><td>10 (21.3)</td><td>9 (19.1)</td><td>15 (31.9)</td><td>7 (14.9)</td><td><span class="elsevierStyleItalic">p</span> = 0.282</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td><span class="elsevierStyleItalic">Anxiety</span> (<span class="elsevierStyleItalic">yes)</span></td><td>13 (22.8)</td><td>2 (15.4)</td><td>5 (38.5)</td><td>1 (7.7)</td><td>5 (38.5)</td><td>0 (0.0)</td><td>Fisher = 4.3<br></br><span class="elsevierStyleItalic">p</span> = 0.361</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Depression</span> (<span class="elsevierStyleItalic">yes)</span></td><td>6 (10.5)</td><td>0 (0.0)</td><td>3 (50.0)</td><td>0 (0.0)</td><td>3 (50.0)</td><td>0 (0.0)</td><td>Fisher = 3.4<br></br><span class="elsevierStyleItalic">p</span> = 0.482</td></tr><tr align="left"><td><span class="elsevierStyleItalic">No. of comorbidities</span></td><td>3.7 ± 1.8</td><td>3.5 ± 1.0</td><td>3.6 ± 1.4</td><td>3.6 ± 1.4</td><td>3.3 ± 1.4</td><td>5.6 ± 3.0</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 2.6<br></br><span class="elsevierStyleItalic">p</span> = 0.046</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Disease control</span></td></tr><tr align="left"><td>Yes</td><td>10 (17.5)</td><td>4 (40.0)</td><td>5 (50.0)</td><td>1 (10.0)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>Fisher = 15.7</td></tr><tr align="left"><td>No</td><td>47 (82.5)</td><td>2 (4.3)</td><td>10 (21.3)</td><td>9 (19.1)</td><td>19 (40.4)</td><td>7 (14.9)</td><td><span class="elsevierStyleItalic">p</span> = 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td><span class="elsevierStyleItalic">Asthma control test</span> (<span class="elsevierStyleItalic">ACT)</span></td><td>19.4 (4.35)</td><td>23.5 ± 1.4</td><td>21.8 ± 2.1</td><td>19.6 ± 4.0</td><td>17.7 ± 3.2</td><td>14.8 ± 6.7</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 7.6<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td><span class="elsevierStyleItalic">CARAT</span> (<span class="elsevierStyleItalic">Rhinitis)</span></td><td>6.7 (3.3)</td><td>6.2 ± 1.8</td><td>9.3 ± 2.4</td><td>5.5 ± 2.1</td><td>6.0 ± 3.7</td><td>5.6 ± 4.0</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 3.7<br></br><span class="elsevierStyleItalic">p</span> = 0.010</td></tr><tr align="left"><td><span class="elsevierStyleItalic">CARAT</span> (<span class="elsevierStyleItalic">Asthma)</span></td><td>11.7 (4.5)</td><td>15.7 ± 2.5</td><td>15.5 ± 3.4</td><td>11.1 ± 3.4</td><td>8.7 ± 3.1</td><td>9.4 ± 5.0</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 9.5<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Asthma life quality</span> (<span class="elsevierStyleItalic">ALQ)</span></td><td>11.7 ± 3.8</td><td>7.7 ± 3.3</td><td>9.6 ± 2.9</td><td>11.7 ± 3.5</td><td>14.2 ± 2.7</td><td>12.9 ± 4.0</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 7.5<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td><span class="elsevierStyleItalic">Severe asthma score</span> (<span class="elsevierStyleItalic">SOA)</span></td><td>10.3 ± 3.9</td><td>4.8 ± 2.5</td><td>8.7 ± 2.7</td><td>10.3 ± 4.0</td><td>11.6 ± 2.5</td><td>15.0 ± 2.8</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 9.4<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Therapeutics</span> (<span class="elsevierStyleItalic">GINA)</span></td></tr><tr align="left"><td>Until step3</td><td>3 (5.3)</td><td>0 (0.0)</td><td>2 (66.6)</td><td>1 (33.3)</td><td>0 (0.0)</td><td>0 (0.0)</td><td> </td></tr><tr align="left"><td>Step3</td><td>14 (24.6)</td><td>5 (35.7)</td><td>1 (7.1)</td><td>4 (28.6)</td><td>4 (28.6)</td><td>0 (0.0)</td><td>Fisher = 22.1</td></tr><tr align="left"><td>Step4</td><td>37 (64.9)</td><td>1 (2.7)</td><td>12 (32.4)</td><td>5 (13.5)</td><td>14 (37.8)</td><td>5 (13.5)</td><td><span class="elsevierStyleItalic">p</span> = 0.003</td></tr><tr align="left"><td>Step5</td><td>3 (5.3)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>1 (33.3)</td><td>2 (66.7)</td><td> </td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">High-dose ICS</span></td></tr><tr align="left"><td>No</td><td>35 (61.4)</td><td>6 (17.1)</td><td>13 (37.1)</td><td>7 (20.0)</td><td>9 (25.7)</td><td>0 (0.0)</td><td>Fisher = 20.6</td></tr><tr align="left"><td>Yes</td><td>22 (38.6)</td><td>0 (0.0)</td><td>2 (9.1)</td><td>3 (13.6)</td><td>10 (45.5)</td><td>7 (31.8)</td><td><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">OCS (last year)</span></td></tr><tr align="left"><td>0</td><td>26 (45.6)</td><td>5 (19.2)</td><td>11 (42.3)</td><td>4 (15.4)</td><td>6 (23.1)</td><td>0 (0.0)</td><td>Fisher = 20.9</td></tr><tr align="left"><td>1</td><td>18 (31.6)</td><td>1 (5.6)</td><td>3 (16.7)</td><td>5 (27.8)</td><td>7 (38.9)</td><td>2 (11.1)</td><td><span class="elsevierStyleItalic">p</span> = 0.013</td></tr><tr align="left"><td>2</td><td>6 (10.5)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>0 (0.0)</td><td>4 (66.7)</td><td>2 (33.3)</td><td> </td></tr><tr align="left"><td>≥3</td><td>7 (12.3)</td><td>0 (0.0)</td><td>1 (14.3)</td><td>1 (14.3)</td><td>2 (28.6)</td><td>3 (42.9)</td><td> </td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Severe exacerbation (previous year)</span></td></tr><tr align="left"><td>No</td><td>27 (47.4)</td><td>5 (18.5)</td><td>11 (40.7)</td><td>2 (7.4)</td><td>8 (29.6)</td><td>1 (3.7)</td><td>Fisher = 12.9</td></tr><tr align="left"><td>Yes</td><td>30 (52.6)</td><td>1 (3.3)</td><td>4 (13.3)</td><td>8 (26.7)</td><td>11 (36.7)</td><td>6 (20.0)</td><td><span class="elsevierStyleItalic">p</span> = 0.009</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">FEV1 (%)</span></td></tr><tr align="left"><td>Baseline</td><td>92.6 ± 26.4</td><td>114.0 ± 27.2</td><td>88.0 ± 24.0</td><td>114.7 ± 13.8</td><td>87.5 ± 24.3</td><td>66.1 ± 16.2</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 6.7<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">FEV1/CVF (%)</span></td></tr><tr align="left"><td>Baseline</td><td>76.7 ± 17.2</td><td>96.3 ± 5.7</td><td>71.1 ± 7.9</td><td>93.7 ± 15.4</td><td>73.4 ± 15.3</td><td>56.3 ± 6.6</td><td><span class="elsevierStyleItalic">F</span>(2,52) = 14.9<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">Fixed obstruction</span></td></tr><tr align="left"><td>No</td><td>39 (68.4)</td><td>6 (15.4)</td><td>10 (25.6)</td><td>10 (25.6)</td><td>13 (33.3)</td><td>0 (0.0)</td><td>Fisher = 21.4</td></tr><tr align="left"><td>Yes</td><td>18 (31.6)</td><td>0 (0.0)</td><td>5 (27.8)</td><td>0 (0.0)</td><td>6 (33.3)</td><td>7 (38.9)</td><td><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">WHO</span></td></tr><tr align="left"><td>Non-severe</td><td>24 (42.1)</td><td>6 (25.0)</td><td>7 (29.2)</td><td>6 (25.0)</td><td>5 (20.8)</td><td>0 (0.0)</td><td>Fisher = 16.8</td></tr><tr align="left"><td>Severe</td><td>33 (57.9)</td><td>0 (0.0)</td><td>8 (24.2)</td><td>4 (12.1)</td><td>14 (42.4)</td><td>7 (21.2)</td><td><span class="elsevierStyleItalic">p</span> = 0.001</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td colspan="8"><span class="elsevierStyleItalic">FeNO (ppb):</span></td></tr><tr align="left"><td><35</td><td>20 (60.6)</td><td>2 (10.0)</td><td>4 (20.0)</td><td>5 (25.0)</td><td>8 (40.0)</td><td>1 (5.0)</td><td>Fisher = 4.8</td></tr><tr align="left"><td>≥35</td><td>13 (39.9)</td><td>3 (23.1)</td><td>3 (23.1)</td><td>2 (15.4)</td><td>2 (15.4)</td><td>3 (23.1)</td><td><span class="elsevierStyleItalic">p</span> = 0.320</td></tr><tr align="left"><td colspan="8"> </td></tr><tr align="left"><td><span class="elsevierStyleItalic">Serum IgE (log (mmol/L))</span></td><td>2.2 ± 0.6</td><td>2.7 ± 0.2</td><td>2.3 ± 0.7</td><td>2.1 ± 0.7</td><td>1.9 ± 0.4</td><td>2.5 ± 0.4</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 3.2<br></br><span class="elsevierStyleItalic">p</span> = 0.019</td></tr><tr align="left"><td>Blood eosinophils (%):</td><td>3.3 ± 3.3</td><td>3.3 ± 1.6</td><td>1.5 ± 1.3</td><td>1.8 ± 1.7</td><td>3.9 ± 1.7</td><td>7.7 ± 6.8</td><td><span class="elsevierStyleItalic">F</span>(4,52) = 7.0<br></br><span class="elsevierStyleItalic">p</span> < 0.001</td></tr><tr align="left"><td>Sputum eosinophils (%)</td><td>24.0 ± 26.6</td><td>44.5 ± 48.8 (<span class="elsevierStyleItalic">n</span> = 2)</td><td>21.3 ± 25.6 (<span class="elsevierStyleItalic">n</span> = 7)</td><td>5.8 ± 6.3 (<span class="elsevierStyleItalic">n</span> = 4)</td><td>24.3 ± 30.3 (<span class="elsevierStyleItalic">n</span> = 11)</td><td>32.0 ± 21.4 (<span class="elsevierStyleItalic">n</span> = 6)</td><td>n.a.</td></tr><tr align="left"><td>Sputum neutrophils (%)</td><td>50.8 ± 30.8</td><td>38.0 ± 53.7 (<span class="elsevierStyleItalic">n</span> = 2)</td><td>59.4 ± 31.8 (<span class="elsevierStyleItalic">n</span> = 7)</td><td>36.3 ± 32.1 (<span class="elsevierStyleItalic">n</span> = 4)</td><td>50.6 ± 32.1 (<span class="elsevierStyleItalic">n</span> = 11)</td><td>55.2 ± 25.7 (<span class="elsevierStyleItalic">n</span> = 6)</td><td>n.a.</td></tr></table><p class="elsevierStylePara"><span class="elsevierStyleSup">*</span><span class="elsevierStyleItalic">p</span> value from analysis of variance or Chi-square analysis between five clusters.<br></br>High-dose ICS: dose equivalent to over 750 μg fluticasone propionate daily.<br></br>Definition of abbreviations: BMI: body mass index; CARAT: control of allergic rhinitis and asthma test; CS: corticosteroids; FeNO: fractional concentration of nitric oxide in exhaled air; ICS: inhaled corticosteroids; LABA: long-acting b-agonists; NSAID HS: nonsteroidal anti-inflammatory drugs hypersensitivity; OCS: oral corticosteroids.<br></br></p><p class="elsevierStylePara">Sample characteristics obtained for total sample and each of five clusters are depicted in <a href="#t0010" class="elsevierStyleCrossRefs">Table 2</a>.</p><a name="sec0030" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Cluster description</span><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">1</span> (<span class="elsevierStyleItalic">n</span> = 6), <span class="elsevierStyleBold">early onset mild allergic asthma, with eosinophilic inflammation</span>: it was the youngest and the least severe group, with a male prevalence. Subjects showed the lowest grade of obesity, the best lung function and disease control and the lowest health care recurrence, despite elevated FeNO values.</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">2</span> (<span class="elsevierStyleItalic">n</span> = 15), <span class="elsevierStyleBold">moderate allergic asthma, long evolution, female prevalence, mixed inflammation</span>: although the older age and the high BMI, questionnaires showed good disease control, low impact of disease (both in life quality and lung function) and low severity.</p><p class="elsevierStylePara">Regarding biomarkers, there was no blood eosinophilia and sputum neutrophil percentage was the highest of all groups.</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">3</span> (<span class="elsevierStyleItalic">n</span> = 10), <span class="elsevierStyleBold">allergic brittle asthma, young females, early onset, no evidence of inflammation</span>: mostly with disease onset before the age of 12, atopy was present in 80% of them. Mean BMI was lower, compared to C2. Lung function was normal in all evaluated parameters and disease was more frequently classified as non-severe. We found a good score in the ACT questionnaire, with normal lung function and no evidence of eosinophilic inflammation, despite high hospitalizations and severe exacerbation rates, suggesting a brittle phenotype.<a href="#bib34" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">15</span></a></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster 4</span></span> (<span class="elsevierStyleItalic">n</span> = 19), <span class="elsevierStyleBold">severe asthma in obese females, late onset, mixed inflammation, highly symptomatic:</span> this was the most prevalent and obese group, with a marked female prevalence, the majority having disease onset after the age of 12. Atopy was less frequent, compared with other groups, and depression-anxiety had more protagonists. None of these subjects showed disease control, reporting the worst quality of life of all groups.</p><p class="elsevierStylePara">Despite the high grade of symptoms and therapeutics, with frequent use of OCS and emergency care, lung function was not very impaired. There was a low grade of Th2 inflammation as we found a low percentage of blood eosinophils, with FeNO values frequently inferior to 35 ppb.</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">5</span> (<span class="elsevierStyleItalic">n</span> = 7), <span class="elsevierStyleBold">severe asthma with chronic airflow obstruction, late onset, long evolution, eosinophilic inflammation:</span> subjects were all male, with age of disease onset above 12 years old, and presented a mean BMI of over 25 kg/m<span class="elsevierStyleSup">2</span>. The mean age was the highest, with long disease evolution and more comorbidities (in particular IgE sensitization, smoke exposure and NSAID's HS). The ACT and CARAT scores were low, and ALQ and SOA were high, with frequent severe exacerbations, hospitalizations and use of OCS. Most of them showed CT scan abnormalities, air trapping being the most prevalent. Lung function evaluation showed the worst FEV<span class="elsevierStyleInf">1</span> out of all groups, with fixed obstruction in all patients (two with COPD overlap). The blood eosinophils count was the highest noted and FeNO was frequently over 35 ppb. Sputum analysis showed a mixed inflammation.</p><a name="sec0035" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Discussion</span><p class="elsevierStylePara">According to Moore et al.,<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> the algorithm approach using 5 clusters is sufficient for the classification of disease severity. We have here confirmed many results of Moore et al. but found other parameters of interest such as age, weight, disease control or severity, quality of life and blood eosinophilia. In other studies,<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">, </span><a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a> some of these characteristics were used in the cluster analysis, suggesting our data relevance.</p><a name="sec0040" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Cluster discussion</span><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">1</span> (<span class="elsevierStyleBold">early onset mild allergic asthma, eosinophilic inflammation</span>) overlapped with the less severe groups from other large-scale studies: C1 from Haldar et al.,<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> C1 from Moore et al.<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> and C1 from Wu et al.<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a></p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">2</span> (<span class="elsevierStyleBold">moderate allergic asthma, long evolution, female prevalence, mixed inflammation</span>), appears to overlap with some of the characteristics from C5 in Moore et al.<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> (female prevalence, older age, high BMI). However there is differentiation in other variables (questionnaires showed good disease control, low impact of disease and low grade of severity).</p><p class="elsevierStylePara">Once asthmatic phenotypes are not static, with intrinsic and extrinsic factors acting as modifiers, it appears that C2 may be an evolution of mild allergic asthma, probably due to weight gain. This could modify the immunocellular response of early-onset allergic asthma into a mixed phenotype obesity related.</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">3</span> (<span class="elsevierStyleBold">allergic brittle asthma, young females, early onset, no evidence of inflammation)</span> shared some of the characteristics with C3 from Haldar et al.<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> (early onset asthma, symptom predominance) and with C1 from Moore et al.<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> (mild allergic asthma). Despite the good score in the ACT questionnaire, a discordant score in CARAT (rhinitis) was noticed, showing a possible correlation to aeroallergen exacerbation triggers, responsible for the exacerbation rates, as described in the literature. The mean age of this group, as well as the female prevalence, may suggest some correlation of exacerbations to hormonal changes.</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster 4</span></span> (<span class="elsevierStyleBold">severe asthma in obese females, late onset, mixed inflammation, highly symptomatic)</span> overlapped with C2 from Haldar et al.<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> and C3 from Moore et al.<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> (non-Th2 asthma-obesity related). The discordance between the high-intensity treatment, low disease control and relatively preserved lung function suggests a relation to factors, such as mechanics and psychogenics, and to concurrent comorbidities (like GERD or sedentary lifestyle). Another factor that might explain insensitivity to CS and better response to obesity-targeted treatment, already described in this phenotype,<a href="#bib35" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">16</span></a> is the noticed low grade of Th2 inflammation. This gains importance as it points to a pathobiologic disease mechanism different from the Th2-eosinophilic phenotype.</p><p class="elsevierStylePara"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Cluster</span></span><span class="elsevierStyleBold">5</span> (<span class="elsevierStyleBold">severe asthma with chronic airflow obstruction, late onset, long evolution, eosinophilic inflammation)</span> presented the highest severity grade, corresponding to C5 of Moore et al.<a href="#bib20" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">1</span></a> (severe patients with fixed obstruction) and C4 of Haldar et al.<a href="#bib21" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">2</span></a> (asthma with predominant inflammation). Coincident with cluster results of a more recent study<a href="#bib22" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">3</span></a> we verified blood eosinophilia and high FeNO values, most having eosinophilic or mixed sputum phenotype, with high blood eosinophils count, according to current data regarding severe patients.</p><p class="elsevierStylePara">This cluster also shares many of the characteristics found by the TENOR study<a href="#bib36" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">17</span></a> for patients with asthma and chronic airway obstruction, being older, with frequent history of smoke exposure and many years of disease evolution, showing eosinophilic inflammation. Consistently, it is known that one of the mechanisms for persistent inflammation in asthmatics despite CS treatment is the reduction of HDAC2.<a href="#bib37" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">18</span></a> Other pathobiologic mechanisms may be involved in this group as it had the highest prevalence of NSAID's HS.</p><p class="elsevierStylePara">According to Wenzel's questions regarding phenotype distinction<a href="#bib24" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">5</span></a> (age of disease onset, eosinophilic inflammation and allergy), C4 and C5 (more severe groups) had disease onset after 12 years of age, and C3 and C2 before that age. C1 and C5 (less severe and most severe groups) showed an eosinophilic inflammation, and allergy was present in all groups.</p><p class="elsevierStylePara">We can then match our clusters to Wenzel endotypes:<a href="#bib38" class="elsevierStyleCrossRefs"><span class="elsevierStyleSup">19</span></a> C1 is clearly associated with Th2 response; C4 with non-Th2 response; C2 and C5 with a mixed response with Th2 prevalence. Possible exogenous factors could be related with the mixed response in C5 (such as smoke exposure) and in C2 (weight could have modified the original endotype of these females) (<a href="#f0010" class="elsevierStyleCrossRefs">Figure 2</a>).</p><a name="f0010" class="elsevierStyleCrossRefs"></a><p class="elsevierStylePara"><img src="320v21n06-90445967fig2.jpg" alt="Adaptation of obtained clusters to Wenzel endotypes."></img></p><p class="elsevierStylePara">Figure 2. Adaptation of obtained clusters to Wenzel endotypes.</p><a name="sec0045" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Limitations and strengths</span><p class="elsevierStylePara">Cluster analysis requires a large number of patients and this study may give the impression of being underpowered. However, both methods used to assess cluster analysis (Ward method and two-step method) empirically validate our cluster results.</p><p class="elsevierStylePara">Another limitation is the applicability of our results to all clinical scenarios: our approach, applied to patients treated in a secondary health care unit, may not apply in primary health care.</p><a name="sec0050" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conclusions</span><p class="elsevierStylePara">The results of this cluster analysis are consistent with those from other larger-scale studies. C1, early-onset mild allergic asthma, was recognized in previous Moore, Haldar and Wu clusters; C2 and C3, female clusters with symptom predominant early-onset disease in Haldar and Wu clusters; C4, a female obese cluster less allergic with late onset disease, in Moore clusters; C5, a late-onset eosinophilic cluster associated with nasal polyposis and mixed inflammatory cellular phenotype, in Moore, Haldar and Wu clusters.</p><p class="elsevierStylePara">Variables such as age at disease onset, obesity, lung function, FeNO (as Th2 biomarker) and severity were important for cluster characterization and distinction.</p><a name="sec0055" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Authors’ contribution statements</span><p class="elsevierStylePara">CCL contributed to the study design, collected clinical data, contributed to the interpretation and global integration of the results, and wrote the manuscript draft; PSC performed the cluster analysis and statistical data analysis, and contributed to the interpretation of the results; ATB contributed to the study design and manuscript revision; JB contributed to the discussion on severe asthma and the writing of the paper.</p><a name="sec0060" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Ethical disclosures</span><a name="sec0065" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Protection of human and animal subjects</span><p class="elsevierStylePara">The authors declare that no experiments were performed on humans or animals for this study.</p><a name="sec0070" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Confidentiality of data</span><p class="elsevierStylePara">The authors declare that no patient data appear in this article.</p><a name="sec0075" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Right to privacy and informed consent</span><p class="elsevierStylePara">The authors declare that no patient data appear in this article.</p><a name="sec0080" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Conflict of interest</span><p class="elsevierStylePara">The authors stated that there are no conflicts of interest regarding the publication of this article.</p><p class="elsevierStylePara">Acknowledgements</p><p class="elsevierStylePara">PSC's work was supported by Portuguese funds through the CIDMA – Center for Research and Development in Mathematics and Applications, and the FCT within the project UID/MAT/04106/2013.</p><p class="elsevierStylePara">We thank Anna Bedbrook for writing assistance.</p><a name="sec0085" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Appendix A. Supplementary data</span><p class="elsevierStylePara">Supplementary material associated with this article can be found in the online version available at doi:10.1016/j.rppnen.2015.07.006.</p><a name="sec0090" class="elsevierStyleCrossRefs"></a><span class="elsevierStyleSectionTitle">Appendix A. Supplementary data</span><p class="elsevierStylePara">The following are the supplementary data to this article:</p><p class="elsevierStylePara"><elsevierMultimedia href="320v21n06-90445967mmc1.pdf"></elsevierMultimedia></p><p class="elsevierStylePara"><elsevierMultimedia href="320v21n06-90445967mmc2.docx"></elsevierMultimedia></p><p class="elsevierStylePara">Received 28 May 2015 <br></br>Accepted 17 July 2015 </p><p class="elsevierStylePara">Corresponding author. cchloureiro@gmail.com</p>" "pdfFichero" => "320v21n06a90445967pdf001.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec640962" "palabras" => array:3 [ 0 => "Asthma" 1 => "Phenotypes" 2 => "Cluster analysis" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => "<span class="elsevierStyleSectionTitle">Background</span><br/><p class="elsevierStylePara">Unbiased cluster analysis using clinical parameters has identified asthma phenotypes. Adding inflammatory biomarkers to this analysis provided a better insight into the disease mechanisms. This approach has not yet been applied to asthmatic Portuguese patients.</p><span class="elsevierStyleSectionTitle">Aim</span><br/><p class="elsevierStylePara">To identify phenotypes of asthma using cluster analysis in a Portuguese asthmatic population treated in secondary medical care.</p><span class="elsevierStyleSectionTitle">Methods</span><br/><p class="elsevierStylePara">Consecutive patients with asthma were recruited from the outpatient clinic. Patients were optimally treated according to GINA guidelines and enrolled in the study. Procedures were performed according to a standard evaluation of asthma. Phenotypes were identified by cluster analysis using Ward's clustering method.</p><span class="elsevierStyleSectionTitle">Results</span><br/><p class="elsevierStylePara">Of the 72 patients enrolled, 57 had full data and were included for cluster analysis. Distribution was set in 5 clusters described as follows: cluster (C) 1, early onset mild allergic asthma; C2, moderate allergic asthma, with long evolution, female prevalence and mixed inflammation; C3, allergic brittle asthma in young females with early disease onset and no evidence of inflammation; C4, severe asthma in obese females with late disease onset, highly symptomatic despite low Th2 inflammation; C5, severe asthma with chronic airflow obstruction, late disease onset and eosinophilic inflammation.</p><span class="elsevierStyleSectionTitle">Conclusions</span><br/><p class="elsevierStylePara">In our study population, the identified clusters were mainly coincident with other larger-scale cluster analysis. Variables such as age at disease onset, obesity, lung function, FeNO (Th2 biomarker) and disease severity were important for cluster distinction.</p>" ] ] "multimedia" => array:6 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445967fig1.jpg" "Alto" => 2752 "Ancho" => 1559 "Tamanyo" => 450291 ] ] "descripcion" => array:1 [ "en" => "Dendrogram obtained using Ward's method." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "320v21n06-90445967fig2.jpg" "Alto" => 1386 "Ancho" => 1588 "Tamanyo" => 329814 ] ] "descripcion" => array:1 [ "en" => "Adaptation of obtained clusters to Wenzel endotypes." ] ] 2 => array:6 [ "identificador" => "fig3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "Dendrogram obtained using Ward's method." ] ] 3 => array:6 [ "identificador" => "fig4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "descripcion" => array:1 [ "en" => "Adaptation of obtained clusters to Wenzel endotypes." ] ] 4 => array:6 [ "identificador" => "mmc1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "320v21n06-90445967mmc1.pdf" "ficheroTamanyo" => 195195 ] ] 5 => array:5 [ "identificador" => "mmc2" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:19 [ 0 => array:3 [ "identificador" => "bib20" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010; 181:315-23." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Moore W" 1 => "Meyers D" 2 => "Wenzel S" 3 => "Teague W" 4 => "Li H" 5 => "Li X" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.200906-0896OC" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2010" "volumen" => "181" "paginaInicial" => "315" "paginaFinal" => "323" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19892860" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib21" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Cluster Analysis and Clinical Asthma Phenotypes. Am J Respir Crit Care Med. 2008; 178:218-24." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Cluster Analysis and Clinical Asthma Phenotypes." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Haldar P" 1 => "Pavord I" 2 => "Shaw D" 3 => "Berry M" 4 => "Thomas M" 5 => "Brightling C" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.200711-1754OC" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2008" "volumen" => "178" "paginaInicial" => "218" "paginaFinal" => "224" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18480428" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib22" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data. J Allergy Clin Immunol. 2014; 133:1280-8." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Unsupervised phenotyping of Severe Asthma Research Program participants using expanded lung data." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Wu W" 1 => "Bleecker E" 2 => "Moore W" 3 => "Busse W" 4 => "Castro M." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2013.11.042" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol. " "fecha" => "2014" "volumen" => "133" "paginaInicial" => "1280" "paginaFinal" => "1288" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24589344" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib23" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011; 127:355-60." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Lotvall J" 1 => "Akdis C" 2 => "Bacharier L" 3 => "Bjermer L" 4 => "Casale T" 5 => "Custovic A" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2010.11.037" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol. " "fecha" => "2011" "volumen" => "127" "paginaInicial" => "355" "paginaFinal" => "360" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21281866" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib24" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Complex phenotypes in asthma: current definitions. Pulm Pharmacol Ther. 2013; 26:710-5." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Complex phenotypes in asthma: current definitions." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Wenzel SE." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.pupt.2013.07.003" "Revista" => array:6 [ "tituloSerie" => "Pulm Pharmacol Ther. " "fecha" => "2013" "volumen" => "26" "paginaInicial" => "710" "paginaFinal" => "715" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23880027" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib25" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org/ [accessed 02.02.14]." "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org/ [accessed 02.02.14]." "idioma" => "en" ] ] "host" => array:1 [ 0 => array:1 [ "WWW" => array:1 [ "link" => "From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org/ [accessed 02.02.14]." ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib26" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report of the Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993; 16:53-83." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Airway responsiveness: standardized challenge testing with pharmacological, physical and sensitizing stimuli in adults. Report of the Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Sterk PJ" 1 => "Fabbri LM" 2 => "Quanjer PH" 3 => "Cockcroft DW" 4 => "O’Byrne PM" 5 => "Anderson SD" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur Respir J Suppl. " "fecha" => "1993" "volumen" => "16" "paginaInicial" => "53" "paginaFinal" => "83" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8499055" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib27" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009; 59-99." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations standardizing endpoints for clinical asthma trials and clinical practice." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Reddel HK" 1 => "Taylor DR" 2 => "Bateman ED" 3 => "Boulet LP" 4 => "Boushey HA" 5 => "Busse WW" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/ajrccm.149.1.8111598" "Revista" => array:5 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "2009" "paginaInicial" => "59" "paginaFinal" => "99" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8111598" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib28" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Standardisation of spirometry. Eur Respir J. 2005; 26:319-38." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Standardisation of spirometry." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Miller MR" 1 => "Hankinson J" 2 => "Brusasco V" 3 => "Burgos F" 4 => "Casaburi R" 5 => "Coates A" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.05.00034805" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2005" "volumen" => "26" "paginaInicial" => "319" "paginaFinal" => "338" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16055882" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib29" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Standardisation of the measurement of lung volumes. Eur Respir J. 2005; 26:511-22." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Standardisation of the measurement of lung volumes." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Wanger J" 1 => "Clausen JL" 2 => "Coates A" 3 => "Pedersen OF" 4 => "Brusasco V" 5 => "Burgos F" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.05.00035005" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2005" "volumen" => "26" "paginaInicial" => "511" "paginaFinal" => "522" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16135736" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib30" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999. Am J Respir Crit Care Med. 1999; 160:2104-17." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Recommendations for standardized procedures for the on-line and off-line measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide in adults and children-1999." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "American Thoracic Society." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/ajrccm.160.6.ats8-99" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med. " "fecha" => "1999" "volumen" => "160" "paginaInicial" => "2104" "paginaFinal" => "2117" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10588636" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib31" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Methods of sputum processing for cell counts, immunocytochemistry and in situ hybridisation. Eur Respir J. 2002; 20:19s-23s." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Methods of sputum processing for cell counts, immunocytochemistry and in situ hybridisation." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Efthimiadis A" 1 => "Spanevello A" 2 => "Hamid Q" 3 => "Kelly MM" 4 => "Linden M" 5 => "Louis R" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2002" "volumen" => "20" "paginaInicial" => "19s" "paginaFinal" => "23s" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib32" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A clustering technique for summarising multivariate data. Behav Sci. 1967; 12:153-5." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A clustering technique for summarising multivariate data." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "Ball GH" 1 => "Hall DJ." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Behav Sci. " "fecha" => "1967" "volumen" => "12" "paginaInicial" => "153" "paginaFinal" => "155" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6030099" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib33" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "A robust and scalable clustering algorithm for mixed type attributes in large database environment. Proceedings of the 7th ACM SIGKDD international conference in knowledge discovery and data mining. San Francisco, CA: Association for Computing Machinery; 2001. 263-8." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "A robust and scalable clustering algorithm for mixed type attributes in large database environment." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Chiu T" 1 => "Fang D" 2 => "Chen J" 3 => "Wang Y" 4 => "Jeris C." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "titulo" => "A robust and scalable clustering algorithm for mixed type attributes in large database environment." "paginaInicial" => "263" "paginaFinal" => "268" ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib34" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Brittle asthma. Thorax. 1998; 53:315-21." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Brittle asthma." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Ayres J" 1 => "Miles J" 2 => "Barnes PJ." ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Thorax. " "fecha" => "1998" "volumen" => "53" "paginaInicial" => "315" "paginaFinal" => "321" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9741378" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib35" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Asthma and obesity. Clin Exp Allergy. 2013; 43:8-21." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Asthma and obesity." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Boulet LP." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1365-2222.2012.04040.x" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Allergy. " "fecha" => "2013" "volumen" => "43" "paginaInicial" => "8" "paginaFinal" => "21" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23278876" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib36" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004; 92:32-9." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "Dolan CM" 1 => "Fraher KE" 2 => "Bleecker ER" 3 => "Borish L" 4 => "Chipps B" 5 => "Hayden ML" 6 => "et-al." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1081-1206(10)61707-3" "Revista" => array:6 [ "tituloSerie" => "Ann Allergy Asthma Immunol. " "fecha" => "2004" "volumen" => "92" "paginaInicial" => "32" "paginaFinal" => "39" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14756462" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib37" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. 2005; 25:552-63." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Histone acetylation and deacetylation: importance in inflammatory lung diseases." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "Barnes PJ" 1 => "Adcock IM" 2 => "Ito K." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.05.00117504" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J. " "fecha" => "2005" "volumen" => "25" "paginaInicial" => "552" "paginaFinal" => "563" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15738302" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib38" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012; 18:716-25." "contribucion" => array:1 [ 0 => array:3 [ "titulo" => "Asthma phenotypes: the evolution from clinical to molecular approaches." "idioma" => "en" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Wenzel SE." ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nm.2678" "Revista" => array:6 [ "tituloSerie" => "Nat Med. " "fecha" => "2012" "volumen" => "18" "paginaInicial" => "716" "paginaFinal" => "725" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22561835" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/08732159/0000002100000006/v0_201604141141/X087321591545967X/v0_201604141141/en/main.assets" "Apartado" => array:4 [ "identificador" => "18133" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Artigos originais" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/08732159/0000002100000006/v0_201604141141/X087321591545967X/v0_201604141141/en/320v21n06a90445967pdf001.pdf?idApp=UINPBA00004E&text.app=https://journalpulmonology.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X087321591545967X?idApp=UINPBA00004E" ]
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| 2020 October | 62 | 12 | 74 |
| 2020 September | 60 | 25 | 85 |
| 2020 August | 84 | 24 | 108 |
| 2020 July | 102 | 19 | 121 |
| 2020 June | 84 | 20 | 104 |
| 2020 May | 81 | 25 | 106 |
| 2020 April | 104 | 10 | 114 |
| 2020 March | 89 | 12 | 101 |
| 2020 February | 110 | 41 | 151 |
| 2020 January | 124 | 11 | 135 |
| 2019 December | 66 | 18 | 84 |
| 2019 November | 56 | 21 | 77 |
| 2019 October | 72 | 18 | 90 |
| 2019 September | 54 | 25 | 79 |
| 2019 August | 172 | 17 | 189 |
| 2019 July | 182 | 15 | 197 |
| 2019 June | 185 | 16 | 201 |
| 2019 May | 250 | 16 | 266 |
| 2019 April | 167 | 24 | 191 |
| 2019 March | 243 | 18 | 261 |
| 2019 February | 230 | 5 | 235 |
| 2019 January | 200 | 29 | 229 |
| 2018 December | 82 | 4 | 86 |
| 2018 November | 21 | 5 | 26 |
| 2018 October | 27 | 10 | 37 |
| 2018 September | 17 | 6 | 23 |
| 2018 August | 41 | 25 | 66 |
| 2018 July | 35 | 17 | 52 |
| 2018 June | 32 | 15 | 47 |
| 2018 May | 44 | 22 | 66 |
| 2018 April | 60 | 14 | 74 |
| 2018 March | 106 | 24 | 130 |
| 2018 February | 66 | 6 | 72 |
| 2018 January | 86 | 14 | 100 |
| 2017 December | 154 | 25 | 179 |
| 2017 November | 35 | 19 | 54 |
| 2017 October | 24 | 15 | 39 |
| 2017 September | 22 | 20 | 42 |
| 2017 August | 22 | 20 | 42 |
| 2017 July | 20 | 12 | 32 |
| 2017 June | 17 | 14 | 31 |
| 2017 May | 25 | 20 | 45 |
| 2017 April | 13 | 6 | 19 |
| 2017 March | 10 | 5 | 15 |
| 2017 February | 5 | 8 | 13 |
| 2017 January | 12 | 7 | 19 |
| 2016 December | 20 | 21 | 41 |
| 2016 November | 20 | 17 | 37 |
| 2016 October | 31 | 12 | 43 |
| 2016 September | 15 | 20 | 35 |
| 2016 August | 23 | 18 | 41 |
| 2016 July | 28 | 56 | 84 |
| 2016 June | 4 | 64 | 68 |
| 2016 May | 5 | 10 | 15 |
| 2016 April | 19 | 26 | 45 |
| 2016 March | 26 | 26 | 52 |
| 2016 February | 41 | 38 | 79 |
| 2016 January | 86 | 52 | 138 |
| 2015 December | 111 | 71 | 182 |
Show all
