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Heterogeneity's ruses: the neglected role of between-individual variability in longitudinal studies of COPD exacerbations.

ABSTRACT: Studying the causal and temporal association between past and future exacerbations in COPD is an active area of research. Standard survival analysis techniques often used in such studies typically produce results that pertain to the overall population, whereas the greatest interest is in the study of associations within individuals. A factor that can lead to profound discrepancies between population-level and individual-level survival patterns is the between-individual heterogeneity in the rate of exacerbations. We briefly review two studies that, while reporting valid results for the overall population, drew conclusions at the individual level that could not be supported by the observations. We caution on the distinction between population and individual-level associations in survival analysis, and recommend accounting for heterogeneity in future studies.

SUBMITTER: Sadatsafavi M

PROVIDER: S-EPMC4215271 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Heterogeneity's ruses: the neglected role of between-individual variability in longitudinal studies of COPD exacerbations.

Sadatsafavi Mohsen M FitzGerald J Mark JM

Thorax 20140218 11

Studying the causal and temporal association between past and future exacerbations in COPD is an active area of research. Standard survival analysis techniques often used in such studies typically produce results that pertain to the overall population, whereas the greatest interest is in the study of associations within individuals. A factor that can lead to profound discrepancies between population-level and individual-level survival patterns is the between-individual heterogeneity in the rate ...[more]

PMID: 24550058

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Project description:BackgroundChronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by frequent exacerbation phenotypes independent of disease stage. Increasing evidence shows that the microbiota plays a role in disease progression and severity, but long-term and international multicenter assessment of the variations in viral and bacterial communities as drivers of exacerbations are lacking.MethodsTwo-hundred severe COPD patients from Europe and North America were followed longitudinally for 3 years. We performed nucleic acid detection for 20 respiratory viruses and 16S ribosomal RNA gene sequencing to evaluate the bacterial microbiota in 1179 sputum samples collected at stable, acute exacerbation and follow-up visits.ResultsSimilar viral and bacterial taxa were found in patients from the USA compared to Bulgaria and Czech Republic but their microbiome diversity was significantly different (P < 0.001) and did not impact exacerbation rates. Virus infection was strongly associated with exacerbation events (P < 5E-20). Human rhinovirus (13.1%), coronavirus (5.1%) and influenza virus (3.6%) constitute the top viral pathogens in triggering exacerbation. Moraxella and Haemophilus were 5-fold and 1.6-fold more likely to be the dominating microbiota during an exacerbation event. Presence of Proteobacteria such as Pseudomonas or Staphylococcus amongst others, were associated with exacerbation events (OR > 0.17; P < 0.02) but more strongly associated with exacerbation frequency (OR > 0.39; P < 4E-10), as confirmed by longitudinal variations and biotyping of the bacterial microbiota, and suggesting a role of the microbiota in sensitizing the lung.ConclusionsThis study highlights bacterial taxa in lung sensitization and viral triggers in COPD exacerbations. It provides a global overview of the diverse targets for drug development and explores new microbiome analysis methods to guide future patient management applications.

Project description:Background:The morning is the most troublesome time of day for patients with chronic obstructive pulmonary disease (COPD). However, the association of morning symptoms and COPD exacerbations in longitudinal follow-up has not been studied. In this study, we mainly aimed to investigate the relationship between morning symptoms and exacerbations over a one-year follow-up period. And the secondary aim was an investigation of the association between morning symptoms and baseline clinical features. Patients and Methods:Ninety-two patients with stable COPD provided the baseline information. Morning symptoms were assessed with the Chinese version of Chronic Obstructive Pulmonary Disease Morning Symptom Diary (Ch-COPD-MSD); the median morning symptoms score was used as a cut-off to separate the study cohort in two groups. Modified Medical Research Council (mMRC), COPD assessment test (CAT), and Clinical COPD Questionnaire (CCQ) were used and exacerbation history of the previous year was recorded. Seventy-eight patients (84.8%) completed the longitudinal follow-up of exacerbations. Results:The median morning symptoms score was 30 in stable COPD patients. Morning symptoms severity was different between COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups (p<0.001). Patients with high morning symptoms (score > 30) had higher scores of mMRC, CAT, and CCQ (p< 0.05). CAT score was an independent risk factor of morning symptoms. During follow-up, 41% of patients experienced ?1 exacerbation. The frequency of severe exacerbations was higher in patients with high morning symptoms compared to patients with low morning symptoms (p<0.005). The Ch-COPD-MSD score could predict future severe exacerbations; the area under the ROC curve was 0.751 (95% CI: 0.633-0.868, p=0.002). Conclusion:Worse health status and more dyspnea symptom were associated with increased severity of morning symptoms. Morning symptoms were most strongly related to future severe exacerbations and could predict future exacerbations in patients with COPD.

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Heterogeneity's ruses: the neglected role of between-individual variability in longitudinal studies of COPD exacerbations.

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Heterogeneity's ruses: the neglected role of between-individual variability in longitudinal studies of COPD exacerbations.

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