Improving COPD Research

CIHR - INSTITUTE OF CIRCULATORY AND RESPIRATORY HEALTH AND NIH - NATIONAL HEART, LUNG, and BLOOD INSTITUTE joint US/Canada workshop

Leveraging Well-Phenotyped North American COPD Cohorts

Topics addressed during the discussions.

Early diagnosis of COPD.  The enablement of early COPD diagnosis could shift the management of the disease from palliation to prevention and disease modification.

Role of COPD Biomarkers, including CT imaging techniques, in COPD diagnosis and therapy. The identification of predictive biomarkers might permit the identification of patients at high risk of disease progression or of COPD sub-phenotypes that exhibit distinct responses to new and existing therapies. Approaches to develop panels of biomarkers that would better define COPD disease sub-phenotypes were discussed, including the advent of promising new biomarkers and platforms through epigenetic, proteomic, and transcriptomic approaches. The use of biomarkers to explore the influence of gender and co-morbid conditions on COPD was also discussed. The COPD Biomarker Qualification Consortium (CBQC), a collaboration between academic researchers, industry, and the FDA, was presented as an approach to identify promising diagnostic/prognostic biomarkers.  CT imaging was noted to be a powerful tool for identifying and describing a wide spectrum of COPD disease phenotypes. Participants discussed whether imaging for phenotyping was underutilized, particularly for patients with early COPD. The use of CT imaging to measure non-pulmonary structures, such as chest muscle mass, the gastro-intestinal system, aorta calcification, bone mineral density, and breathing mechanics, was also discussed. These non-pulmonary structures may also be used to examine longitudinal changes in some aspects of the disease.

COPD Cohorts in US and Canada and Identification of Potential Areas of Collaboration. Existing Canadian (CanCOLD and CLSA) and US (COPDGene, CCRN, LOTT, MESA Lung, and SPIROMICS) cohorts were discussed by the attendees. The group felt that it would be beneficial to form working groups, composed of representative investigators from each of these cohorts, to address the possibility of data harmonization and the challenges presented by that task. It was proposed that creation of an over-arching DCC or a data commons could serve as a mechanism for sharing of data and descriptive information, as well as providing a platform for data harmonization.

Scientific Questions and Areas of Potential Collaboration Identified.

Definition of COPD: Spirometry is used to define sub-sets of disease in different ways in different countries, and other diagnostic methods may be preferable to identify and classify patients. There was discussion as to whether it would be worthwhile to change the definition of COPD with the goal of improving diagnostic and care guidelines. Caution was urged, however, that if new criteria were identified for COPD sub-types they should be related to disease outcomes.

Methods of Sub-Phenotyping COPD Patients: Sub-phenotyping efforts would benefit from strong collaboration with industry as well as a clinical trials network. This might build from the Pulmonary Trials Consortium that NHLBI is currently building.

Determining COPD Progression: The ability to understand and predict COPD disease trajectories will require complex analyses of long-term longitudinal data from many COPD patients. This will only be possible with the participation and cooperation of multiple cohort studies.

Harmonization of CT Scans:  There is currently a group looking at the standardization of CT scanning. Potential challenges moving forward include major differences in technologies and the standardization of the equipment (e.g. GE CT scanners vs. Siemens CT scanners), as well as the standardization of data analysis.

Normative Age–Dependent Changes in Lung Function: Since little is known regarding age-related changes in pulmonary structure, it would be useful to explore cross-generational CT of the chest in a large healthy population. Two major factors to consider are radiation exposure resulting from CT imaging (especially relevant to longitudinal studies) and cost. CLSA was identified as a well-suited cohort that could potentially incorporate CT scans across the lifespan. Participants recommended that effort should be put towards securing funds to explore this possibility, as it would likely benefit the broader respiratory research community.

Examination of Rarer Patient Phenotypes: Currently, data on certain classes of COPD patients are not collected because those groups are excluded in cohort studies and drug trials. One example is represented by COPD patients who have never smoked. Because there is little data on these subjects, it is unknown whether their disease processes differ from those in smokers. Personalized approaches to treatment might be improved by understanding disease in uncommon as well as common COPD sub-classes.

Gene Expression Studies: Participants encouraged collaboration among investigators to analyze gene expression data from cohort studies. It was suggested that gene cluster profiles of COPD patients could potentially be examined to help interpret or predict drug therapeutic responses. If inducible biomarker phenotypes can be identified, these could potentially be used for selection of individuals for trials.

A North-American COPD Clinical Trials Network: There is a need for both the US and Canada to conduct clinical trials more rapidly, efficiently, and cost-effectively. The development of a North American COPD Clinical Trials Network (NA-COPD-CTN) could be a common goal, particularly for phase II clinical trials evaluating the benefit of biologicals. Resolving challenges associated with the parallel review process in both countries would be important. Biology-stratified clinical trials, and ways to identify these pathways in patients, should be considered, even if the biomarkers for stratification do not serve as a useful outcome measure.

Role of Bioinformatics, Systems Biology, Validation, & Clinical Assessment: Bioinformatics and systems biology approaches to COPD diagnosis and treatment can extend current research beyond GWAS studies.  Other roles for these approaches include a description of the relationship between RNA and protein expression levels and lung function. Such approaches will not only contribute new data, but also combine different layers of biological data to better elucidate the COPD molecular profile. Clustering data of strongly co-expressed genes may reduce the background noise of GWAS. Identification of clusters that may help predict the risk of exacerbation is also in progress.

Collaborative areas that could have high impact in COPD

Improving Diagnostics of COPD: Who really has the disease? - There is a need to move beyond simple pulmonary function testing to better diagnose COPD. A second diagnostic method, for example, CT imaging, could help better define the disease and contribute to a better understanding of disease progression. This improvement could also increase the number of individuals diagnosed with COPD in the US, possibly from 15 million to 25 million. In order to show that a ‘non-diagnosed’ group does have COPD, it will be necessary to demonstrate burden of disease, such as symptoms or a decreased quality of life. Identifying at-risk individuals is of greatest benefit when appropriate interventions that ease disease burden are also available.

Early Diagnosis of COPD: In addition to identifying therapies that will have an effect on the progression of the disease (e.g. when to optimally treat/prevent, etc.), there is a need to establish biomarkers that will pinpoint patients at risk of progressing faster than others.

Identification of Subtypes of COPD: Because the pathogenesis of one subtype of COPD may not specifically relate to that of another, therapy for one subtype may differ among subtypes.

Standardization of CT Scans and CT Determination of Normative Values for Age-Related Changes in the Lung: Characterization of lung structure by CT will likely require both inspiratory and expiratory data (for small airways assessment).

Validation Studies: One way that cohort studies can collaborate is to validate each other’s results. Such validation is frequently a requirement for publication, and is in line with the recent emphasis on study reproducibility.

Workshop Participants

Brigham and Women's Hospital, Boston
George R. Washko, MD, MMSc
Craig P. Hersh, MD
Qingling Duan, PhD

Columbia University, New York
R. Graham Barr, MD, DrPH

McGill University Montreal
Jean Bourbeau, MD, MSc, FRCP

McMaster University Hamilton, Ontario
Parminder Raina, BsC, PhD

National Jewish Health, Denver
Elizabeth A. Regan, MD, PhD

Temple University, Philadelphia
Gerard J. Criner, MD

University of British Columbia, Vancouver
James Hogg, MD, PhD
Harvey Coxson, PhD
Wan Lam, PhD
Raymond Ng, BSc, PhD, MMath
Maen Obeidat, BSPharm, PhD
Wan Tan, MD, FRCP

University of California, San Francisco
Prescott G. Woodruff, MD, MPH

University of Michigan, Ann Arbor
MeiLan Han, MD, MS

University of Nebraska Medical Center, Omaha
Stephen I. Rennard, MD

University of North Carolina, Chapel Hill
Wanda O`Neal, PhD, Ms,

University of Ottawa
Shawn Aaron, MD, FRCPC

University of Victoria BC
Christoph Borchers, BSc, MSc, PhD

Institute of Circulatory and Respiratory Health (ICRH, co-organizing)
Jean-Lucien Rouleau, MD, FRCPC
Pierre Boyle, PhD, MHA
Ilana Gombos, PhD
Lindsay Jacobi Cadete, MSc, BSc
Jennifer Ralph, BA
Caroline Wong, BA

National Heart, Lung, and Blood Institute (NHLBI, co-organizing)
James P. Kiley, PhD
Thomas L. Croxton, PhD, MD
Lisa A. Postow, PhD
Antonello Punturieri, MD, PhD