Limits...
Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management.

Roca J, Vargas C, Cano I, Selivanov V, Barreiro E, Maier D, Falciani F, Wagner P, Cascante M, Garcia-Aymerich J, Kalko S, De Mas I, Tegnér J, Escarrabill J, Agustí A, Gomez-Cabrero D, Synergy-COPD consorti - J Transl Med (2014)

Bottom Line: To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction.An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people).Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.

Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.

Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.

Show MeSH

Related in: MedlinePlus

Interaction networks using skeletal muscle expression profiling, plasma cytokines and physiological measurements. Uncoupling between bioenergetics, inflammation and skeletal muscle remodeling was observed in COPD patients as compared to healthy subjects [33]
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4255905&req=5

Figure 6: Interaction networks using skeletal muscle expression profiling, plasma cytokines and physiological measurements. Uncoupling between bioenergetics, inflammation and skeletal muscle remodeling was observed in COPD patients as compared to healthy subjects [33]

Mentions: Most importantly, the network medicine approach assessing associations among three major pathways, namely bioenergetics, inflammation and skeletal muscle remodeling showed clear differences between the probabilistic models obtained in healthy subjects and those seen in COPD patients indicating failure to coordinately activate these pivotal metabolic pathways in the patients (Figure 6). Moreover, a sub-analysis carried out with few muscle samples identified a potential role of epigenetic changes contributing to the phenomenon of abnormal regulation of key metabolic pathways seen in COPD patients.


Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management.

Roca J, Vargas C, Cano I, Selivanov V, Barreiro E, Maier D, Falciani F, Wagner P, Cascante M, Garcia-Aymerich J, Kalko S, De Mas I, Tegnér J, Escarrabill J, Agustí A, Gomez-Cabrero D, Synergy-COPD consorti - J Transl Med (2014)

Interaction networks using skeletal muscle expression profiling, plasma cytokines and physiological measurements. Uncoupling between bioenergetics, inflammation and skeletal muscle remodeling was observed in COPD patients as compared to healthy subjects [33]
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255905&req=5

Figure 6: Interaction networks using skeletal muscle expression profiling, plasma cytokines and physiological measurements. Uncoupling between bioenergetics, inflammation and skeletal muscle remodeling was observed in COPD patients as compared to healthy subjects [33]
Mentions: Most importantly, the network medicine approach assessing associations among three major pathways, namely bioenergetics, inflammation and skeletal muscle remodeling showed clear differences between the probabilistic models obtained in healthy subjects and those seen in COPD patients indicating failure to coordinately activate these pivotal metabolic pathways in the patients (Figure 6). Moreover, a sub-analysis carried out with few muscle samples identified a potential role of epigenetic changes contributing to the phenomenon of abnormal regulation of key metabolic pathways seen in COPD patients.

Bottom Line: To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction.An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people).Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.

Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.

Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.

Show MeSH
Related in: MedlinePlus