Analysis has appeared as a useful tool to 
identify subgroups of Ergocalciferol biological activity patients with airway diseases [7,8,9,10], including subgroups of patients with COPD [11,12].In the present study, we performed a cluster analysis using multiple variables (including lung function, imaging, and comorbidities) obtained in a large cohort of COPD subjects recruited in stable condition. The clinical relevance of these clusters of subjects was validated using survival data obtained during longitudinal follow-up. Our aim was to examine whether clusters of COPD patients identified with an unsupervised approach differed in mortality.Methods PatientsClinical, functional and imaging data obtained in COPD patients [1] at inclusion in the study (cross-sectional data) were analyzed using unsupervised analysis. Validation of the clinical relevance of these clusters of patients was achieved using survival data obtained during prospective follow-up. To ensure sufficient patient heterogeneity, subjects recruited in two separate cohorts were studied. The first cohort was composed of 506 subjectsCOPD Phenotypes at High Risk of Mortalityrecruited at the LEUVEN university hospital COPD outpatient clinic. The second cohort was composed of 378 subjects recruited in the neighbourhood of LEUVEN as part of the Dutch-Belgian randomized lung cancer screening (NELSON study) [13]. Inclusion criteria in this latter cohort were a smoking history 15 pack-years and age .50 years, and only 154 patients had a diagnosis of COPD (according to a post-bronchodilator FEV1/ FVC,0.70) [1]. Further, eleven patients were excluded from the cohort LEUVEN 10236-47-2 web clinic cohort due to a FEV1/FVC ratio 0.70. Thus, our COPD population was composed of 649 subjects (495 from the LEUVEN clinic and 154 from the NELSON study). The COPD subjects included in this cluster analysis were required to have complete information for 7 selected continuous variables (see below), leading to the exclusion of 122 COPD subjects (121 from the LEUVEN clinic) due to missing data. The final study population included in the cluster analysis contained 527 COPD (LEUVEN clinic n = 374; NELSON subjects, n = 153) [13]. A flow chart describing patient selection is provided in Figure 1. A description of characteristics of COPD patients recruited in the LEUVEN clinic and in the NELSON study and a description of the excluded COPD subjects is provided in Table S2. All studies were approved by the Ethics Committee at the University Hospitals of Leuven (Leuven, Belgium) and all participants provided written informed consent.Data CollectionData were obtained at the time of inclusion in the studies. Demographic characteristics, post-bronchodilator pulmonary function assessment, CT scan of the chest, and questionnaires on dyspnoea (mMRC) and quality of life (CCQ) [14] were collected. In patients recruited at the LEUVEN clinic, data on 
comorbidities were 15755315 obtained from medical records at the time of inclusion. Comorbidities of subjects enrolled via the NELSON study were obtained by detailed interview and review of concomitant medications at the time of inclusion. In case of doubt, general practitioners were contacted for double checking. Data on the following COPD-related comorbidities were collected: ischemic heart disease, stroke, peripheral arterial disease, diabetes, osteoporosis, skeletal muscle weakness (quadriceps force ,80 predicted) and anaemia (haemoglobin ,11 g/dl on last venous blood sample). Patients recruited in the NELSON study had no data.Analysis has appeared as a useful tool to identify subgroups of patients with airway diseases [7,8,9,10], including subgroups of patients with COPD [11,12].In the present study, we performed a cluster analysis using multiple variables (including lung function, imaging, and comorbidities) obtained in a large cohort of COPD subjects recruited in stable condition. The clinical relevance of these clusters of subjects was validated using survival data obtained during longitudinal follow-up. Our aim was to examine whether clusters of COPD patients identified with an unsupervised approach differed in mortality.Methods PatientsClinical, functional and imaging data obtained in COPD patients [1] at inclusion in the study (cross-sectional data) were analyzed using unsupervised analysis. Validation of the clinical relevance of these clusters of patients was achieved using survival data obtained during prospective follow-up. To ensure sufficient patient heterogeneity, subjects recruited in two separate cohorts were studied. The first cohort was composed of 506 subjectsCOPD Phenotypes at High Risk of Mortalityrecruited at the LEUVEN university hospital COPD outpatient clinic. The second cohort was composed of 378 subjects recruited in the neighbourhood of LEUVEN as part of the Dutch-Belgian randomized lung cancer screening (NELSON study) [13]. Inclusion criteria in this latter cohort were a smoking history 15 pack-years and age .50 years, and only 154 patients had a diagnosis of COPD (according to a post-bronchodilator FEV1/ FVC,0.70) [1]. Further, eleven patients were excluded from the cohort LEUVEN clinic cohort due to a FEV1/FVC ratio 0.70. Thus, our COPD population was composed of 649 subjects (495 from the LEUVEN clinic and 154 from the NELSON study). The COPD subjects included in this cluster analysis were required to have complete information for 7 selected continuous variables (see below), leading to the exclusion of 122 COPD subjects (121 from the LEUVEN clinic) due to missing data. The final study population included in the cluster analysis contained 527 COPD (LEUVEN clinic n = 374; NELSON subjects, n = 153) [13]. A flow chart describing patient selection is provided in Figure 1. A description of characteristics of COPD patients recruited in the LEUVEN clinic and in the NELSON study and a description of the excluded COPD subjects is provided in Table S2. All studies were approved by the Ethics Committee at the University Hospitals of Leuven (Leuven, Belgium) and all participants provided written informed consent.Data CollectionData were obtained at the time of inclusion in the studies. Demographic characteristics, post-bronchodilator pulmonary function assessment, CT scan of the chest, and questionnaires on dyspnoea (mMRC) and quality of life (CCQ) [14] were collected. In patients recruited at the LEUVEN clinic, data on comorbidities were 15755315 obtained from medical records at the time of inclusion. Comorbidities of subjects enrolled via the NELSON study were obtained by detailed interview and review of concomitant medications at the time of inclusion. In case of doubt, general practitioners were contacted for double checking. Data on the following COPD-related comorbidities were collected: ischemic heart disease, stroke, peripheral arterial disease, diabetes, osteoporosis, skeletal muscle weakness (quadriceps force ,80 predicted) and anaemia (haemoglobin ,11 g/dl on last venous blood sample). Patients recruited in the NELSON study had no data.