Polygenic Risk Score Added to Conventional Case Finding to Identify Undiagnosed Chronic Obstructive Pulmonary Disease

Abstract

Importance: Chronic obstructive pulmonary disease (COPD) is often undiagnosed. Although genetic risk plays a significant role in COPD susceptibility, its utility in guiding spirometry testing and identifying undiagnosed cases is unclear.

Objective: To determine whether a COPD polygenic risk score (PRS) enhances the identification of undiagnosed COPD beyond a case-finding questionnaire (eg, the Lung Function Questionnaire) using conventional risk factors and respiratory symptoms.

Design, setting, and participants: This cross-sectional analysis of participants 35 years or older who reported no history of physician-diagnosed COPD was conducted using data from 2 observational studies: the community-based Framingham Heart Study (FHS) and the COPD-enriched Genetic Epidemiology of COPD (COPDGene) study.

Exposures: Modified Lung Function Questionnaire (mLFQ) scores and COPD PRS.

Main outcomes and measures: The primary outcome was spirometry-defined moderate to severe COPD (forced expiratory volume in the first second of expiration/forced vital capacity [FEV1/FVC] <0.7 and FEV1 [percent predicted] <80%). The performance of logistic models was assessed using the PRS, mLFQ score, and PRS plus mLFQ score for predicting spirometry-defined COPD.

Results: Among 3385 FHS participants (median age, 52.0 years; 45.9% male) and 4095 COPDGene participants (median age, 56.8 years; 55.5% male) who reported no history of COPD, 160 (4.7%) FHS and 775 (18.9%) COPDGene participants had spirometry-defined COPD. Adding the PRS to the mLFQ score significantly improved the area under the curve from 0.78 to 0.84 (P < .001) in FHS, 0.69 to 0.72 (P = .04) in COPDGene non-Hispanic African American, and 0.75 to 0.78 (P < .001) in COPDGene non-Hispanic White participants. At a risk threshold for spirometry referral of 10%, the addition of the PRS to the mLFQ score correctly reclassified 13.8% (95% CI, 6.6%-21.0%) of COPD cases in FHS, but not in COPDGene.

Conclusions and relevance: A COPD PRS enhances the identification of undiagnosed COPD beyond a conventional case-finding approach in the general population. Further research is needed to assess its impact on COPD diagnosis and outcomes.

Figure 1.. Study Flow of the Analytic Samples From the Framingham Heart Study and COPDGene Study

^aThe mLFQ score was calculated based on study participants’ data that best matched the questions from the Lung Function Questionnaire, a COPD case-finding questionnaire using age, smoking history, and respiratory symptoms to estimate an individual’s clinical risk for COPD. Further details of the calculation of the mLFQ score can be found in the eMethods in Supplement 1. ^bGOLD 1 COPD is defined as forced expiratory volume in the first second/forced vital capacity (FEV₁/FVC) <0.7 and FEV₁ (percent predicted) ≥80%. ^cPRISm is defined as FEV₁/FVC ≥0.7 and FEV₁ (percent predicted) <80%. COPD indicates chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mLFQ, modified Lung Function Questionnaire; PRISm, preserved ratio impaired spirometry.

Figure 2.. Receiver Operating Characteristic Curve and Area Under the Curve for the PRS, mLFQ Score, and Combined PRS and mLFQ Score in Predicting Moderate to Severe COPD

Moderate to severe COPD is defined as forced expiratory volume in the first second/forced vital capacity (FEV₁/FVC) <0.7 and FEV₁ (percent predicted) <80%. The mLFQ score was calculated using study participants’ data that best matched the questions from the Lung Function Questionnaire, a COPD case-finding questionnaire using age, smoking history, and respiratory symptoms to estimate an individual’s clinical risk for COPD. AUC indicates area under the receiver operating characteristic curve; COPD, chronic obstructive pulmonary disease; COPDGene, Genetic Epidemiology of Chronic Obstructive Pulmonary Disease study; mLFQ, modified Lung Function questionnaire; PRS, polygenic risk score.

Figure 3.. Net Reclassification Comparing the Combined PRS and mLFQ Score vs the mLFQ Score Alone for Predicting Moderate to Severe COPD Using a Risk Threshold ≥10%

Moderate to severe COPD is defined as forced expiratory volume in the first second/forced vital capacity (FEV₁/FVC) <0.7 and FEV₁ (percent predicted) <80%. The modified Lung Function questionnaire (mLFQ) score was calculated using study participants’ data that best matched the questions from the Lung Function Questionnaire, a chronic obstructive pulmonary disease (COPD) case finding questionnaire using age, smoking history, and respiratory symptoms to estimate an individual’s clinical risk for COPD. A model classifies an individual as a case if the predicted risk is higher than or equal to the risk threshold. The net reclassification index (NRI) quantifies how well a model (in this case, the combined polygenic risk score [PRS] and mLFQ score) reclassifies individuals into correct risk categories compared with an older model (mLFQ score alone). The NRI for cases is calculated as the proportion of cases correctly reclassified into a higher risk category by the new model minus the proportion of cases incorrectly reclassified into a lower risk category. Similarly, the NRI for noncases is calculated as the percentage of noncases correctly reclassified into a lower risk category by the new model minus the percentage of noncases incorrectly reclassified into a higher risk category. The net reclassification comparing the combined PRS and mLFQ score vs the mLFQ score alone, using risk thresholds of ≥5% and ≥20%, is provided in eFigures 1 and 2 in Supplement 1, respectively. COPDGene indicates Genetic Epidemiology of COPD Study.