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A28-04 Measuring the Polygenic Risk of Thrombosis May Accelerate the Detection of Chronic Thromboembolic Pulmonary Hypertension Among Other Forms of Pulmonary Hypertension
Accurate classification of a patient with pulmonary hypertension (PH) into one of five groups is fundamental for appropriate disease management strategies. The time from disease onset to correct diagnosis is unacceptably long in many cases. Chronic thromboembolic pulmonary hypertension (CTEPH) develops as a consequence of venous thromboemboli, resulting in a more pronounced hereditary predisposition to thrombosis in these patients compared with other PH patients. We investigated the potential for incorporating polygenic risk data into the diagnostic algorithm for PH evaluation.
The study enrolled 423 patients of European ancestry with PH (124 with CTEPH, 299 with pulmonary arterial hypertension). Mean age was 54.4 ± 16.73 years; 104 (24.6%) were male and 319 (75.4%) were female. Functional class distribution was as follows: WHO FC I in 10 (2.4%) patients, FC II in 95 (22.5%), FC III in 292 (69.0%), and FC IV in 26 (6.1%). Raynaud syndrome was present in 45 (10.6%) patients. All patients underwent whole genome sequencing. We utilized polygenic risk scores (PRSs) for venous thromboembolism: “Venous thromboembolism PGS004854” and “I26 (Pulmonary embolism) PGS004460,” both validated in European populations, as well as “Phlebitis and thrombophlebitis PGS002056,” validated across multiple populations. PRSs were calculated by weighted summation of risk alleles. A predictive model for CTEPH diagnosis was constructed using the chi-squared automatic interaction detection (CHAID) decision tree method with an automatically determined number of classification levels. Model classification quality was assessed by the ratio of correctly to incorrectly classified patients.
The “Venous thromboembolism PGS004854” PRS demonstrated the greatest predictive value when incorporated into the decision tree model. The first-order node was age at symptom onset (≤28.0 years, 28-71 years, and >71 years), the second-order node was the PRS score (≤0.70476 and >0.70476), and third-order nodes were presence of Raynaud syndrome and sex. Area under the curve (AUC) in receiver operating characteristic (ROC) analysis was 0.809 ± 0.022, 95% confidence interval (CI) [0.766; 0.852], p < 0.001. Application of this algorithm enables definitive exclusion of CTEPH in 278 (93.0% [92.1-93.9%]) p = 0.005 patients with other forms of pulmonary hypertension and definitive confirmation in 58 (46.8%[42.4-51.2%]), p = 0.048 patients with CTEPH. Negative predictive value was 81,3% [79.1-83.5%] p = 0.020. A study limitation is the absence of an independent validation cohort.
Thus, we confirmed the diagnostic utility of the “Venous thromboembolism PGS004854” PRS and demonstrated the potential for accelerating CTEPH detection when this score is incorporated into the diagnostic algorithm.