Genetic Risk Predictor Might Boost Detection of Undiagnosed COPD

Considering a risk score generated from multiple genetic variants linked to chronic obstructive pulmonary disease (COPD) caught undiagnosed cases of the disease better than conventional risk factors and respiratory symptoms alone, a study showed.

Adding the COPD polygenic risk score (PRS) to the Lung Function Questionnaire clinical risk score significantly improved the area under the curve by 0.03 to 0.06, suggesting a 3 to 6 percentage point increase in accuracy in identifying spirometry-defined, moderate to severe COPD, as researchers led by Matthew Moll, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, reported in JAMA.

If a threshold of 10% risk of COPD was used to make spirometry referrals, the addition of the polygenic risk score correctly reclassified 13.8% of COPD cases in one of the cohorts analyzed for validation but didn’t improve reclassification in the other.

“The findings suggest that an individual’s genetic risk for COPD, as indicated by a PRS, has a potential added value to conventional case-finding approaches for identifying undiagnosed COPD and guiding referrals for confirmatory spirometry, particularly in community-based settings,” the group concluded.

While the U.S. Preventive Services Task Force recommends against spirometry to check everyone for COPD, some 5% of adults have undiagnosed COPD, based on Framingham Heart Study findings, and some 70% of COPD in the U.S. is undiagnosed.

“Underdiagnosis of COPD is a significant global problem,” commented Wassim W. Labaki, MD, of the University of Michigan in Ann Arbor, whose group previously reviewed risk assessment tools for COPD. “Timely diagnosis is essential to initiate appropriate medical therapy early in the disease course and to prioritize addressing modifiable contributing factors such as cigarette smoking, occupational hazards, and environmental exposures.”

Genetic testing, while not yet routine for any screening or case-finding in clinical practice, is appealing to help select individuals for spirometry testing, as it “only needs to be performed once, can aid in identifying risk for several diseases, and shows potential for complementing questionnaires for COPD case-finding,” Labaki noted.

And, Moll’s group noted, whole-genome genotyping can cost $35 or less per person. “A potentially practical approach would be to apply the PRS in the case finding of COPD among individuals who already have their genome genotyped for other reasons.”

Since the COPD PRS was developed based on the U.K. Biobank and SpiroMeta (also largely European) genome-wide association study data, Moll and colleagues analyzed its performance on two cohorts of U.S. patients.

Their study included participants age 35 years and older who reported no history of physician-diagnosed COPD from the community-based Framingham Heart Study (3,385 participants, median age 52.0, 45.9% male) and the COPD-enriched Genetic Epidemiology of COPD (COPDGene) study (4,095 participants, median age 56.8, 55.5% male). Among them, 160 (4.7%) in the Framingham study and 775 (18.9%) in COPDGene had spirometry-defined COPD.

For prediction, the researchers used the COPD PRS and a modified Lung Function Questionnaire, which was based on age, smoking history, and self-reported respiratory symptoms.

Adding the two together significantly improved the area under the curve from 0.78 to 0.84 (PP=0.04) in COPDGene non-Hispanic African American participants, and from 0.75 to 0.78 (P

“The COPD PRS captures only a small proportion of COPD heritability,” the researchers acknowledged, and the lower predictive ability in African Americans “reflects the well-known issue of low trans-ancestry portability of PRS, as the COPD PRS was developed based on genome-wide association studies using samples from individuals of European ancestry. The development of multiancestry PRS, along with advancements in PRS construction methods, may improve the predictive performance and the portability of the PRS in the future.”

Even more diverse cohorts need to be included in testing the COPD PRS, Labaki suggested.

The combined PRS and clinical risk score approach had higher sensitivity at lower risk thresholds and higher positive predictive value at higher risk thresholds, “highlighting the importance of considering the appropriate threshold for spirometry referrals in specific case-finding environments,” the researchers wrote.

Also, the combination didn’t add much among people with more extensive smoking history until relatively high spirometry testing thresholds, and it had comparable net benefit to just doing universal screening spirometry at relatively low risk thresholds.

“These findings suggest that the benefits of the PRS depend on the prevalence of undiagnosed COPD and the setting in which a spirometry testing threshold is deemed appropriate,” Moll and colleagues noted.

Labaki agreed, adding that availability of resources is also a factor in effectiveness of COPD case-finding strategies. “Ideally, data from clinical history, physiological measurements, chest imaging, and polygenic risk scores would be integrated to optimize COPD case-finding efforts.”

The researchers called for further research to evaluate the clinical use of COPD PRS in improving diagnosis and outcomes before it can be applied in practice.

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