Abstract 4366728: Proteomics analysis identifies sub-phenotypes amongst clinically similar patients with Idiopathic Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background: Patients with idiopathic pulmonary arterial hypertension (IPAH), a progressive pulmonary vasculopathy, may be clinically similar, yet have different responses to therapy and outcomes. Understanding proteomic profiles that distinguish amongst clinically similar patients could improve disease classification to better target treatment. Research Question: Can proteomic profiling identify molecular sub-phenotypes amongst otherwise clinically similar patients with IPAH? Methods: A cross-sectional, prevalent cohort of patients with IPAH (N=120, 60 survivors/60 non-survivors) was selected from the PAH Biobank to have similar clinical, genetic hemodynamic and risk profiles. Plasma protein levels of 11,000 proteins (SomaScan 11K Platform) were assayed. The top 10% of proteins with highest variance were used for spectral clustering. Survival by cluster was evaluated by Kaplan-Meier analysis and Cox proportional hazards model, adjusted for enrollment age and sex. Clinical differences between clusters were assessed with Chi-squared, Kruskal-Wallis and Fisher’s exact tests. Pathway analysis identified major proteomic pathways differentiating each cluster. Results: Spectral clustering identified 3 clusters, with 36%, 45% and 68% events over 5-years in clusters 1, 2 and 3 respectively (Figure 1, p=0.0025). The adjusted hazard ratio for death was 1.40 and 2.78 in clusters 2, 3 comparing to cluster 1. Subjects in cluster 3 were older than cluster 1 and 2. Medications, six-minute walk test and hemodynamics were similar across clusters and most subjects were intermediate risk (ERS criteria) and low or average risk (REVEAL 2.0)(Table 1).Differentially expressed proteins showed enrichment of Vascular Endothelial Growth Factor (VEGF) signaling (p=9.30E-04) between clusters 1 and 2, the Wnt signaling between clusters 1 and 3 (p=0.0014), and Neurotrophin signaling (p=4.82E-09) and VEGF signaling (p=5.93E-09) between clusters 2 and 3. Conclusions: This study identified differential expression of 3 pathways across clusters of similar IPAH patients with differences in outcomes not predicted by clinical risk assessment. All three of these pathways, Wnt, VEGF and Neurotrophin, have been implicated in pulmonary vascular and right ventricular dysfunction and may identify patients at higher risk or at different stages of the IPAH disease process. Understanding the proteome may identify molecular phenotypes of IPAH associated with outcomes but missed by clinical classification.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".