A sensitive and specific assay to characterize plasma kallikrein activity in plasma from patients with hereditary angioedema
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Bibliographic record
Abstract
Introduction Plasma kallikrein (PKa) activity is increased in the plasma of patients with hereditary angioedema (HAE) and has been implicated in other kallikrein-kinin system (KKS)–mediated diseases. Exogenous substrates commonly used in PKa assays can be cleaved by multiple plasma proteases, which reduce assay specificity and sensitivity for PKa. We describe a sensitive and specific assay to detect PKa activity in plasma as a candidate biomarker for HAE. Methods PKa activity was measured in plasma samples from patients with HAE with decreased C1 inhibitor (C1INH) levels or activity who were not receiving prophylactic medications for HAE (HAE-C1INH; n = 25), from individuals with a presumptive diagnosis of HAE with normal C1INH (HAE-nC1INH; n = 3), and from age-matched controls without HAE ( n = 57). Samples were analyzed at baseline and after 6 h of cold incubation at 4 °C. Amidolytic activity was measured in the absence and presence of a PKa-specific inhibitor (KV999272). Specific PKa (sPKa) activity was quantified by the subtraction of amidolytic activity not inhibited by KV999272 from the total measured amidolytic activity. Results In control plasma, sPKa activity was 0.69 ± 0.07 nmol/min/mL at baseline and 0.88 ± 0.11 nmol/min/mL after 6 h of cold incubation (mean ± SEM, p = 0.0062); the 95th percentile of sPKa activity was 1.87 nmol/min/mL at baseline and 3.07 nmol/min/mL after cold incubation. In plasma from patients with HAE-C1INH, sPKa activity was 3.43 ± 0.64 nmol/min/mL at baseline and 24.53 ± 8.92 nmol/min/mL after 6 h of cold incubation ( p = 0.023). sPKa activity in HAE-C1INH plasma samples was above the 95th percentile for control plasma with assay sensitivity of 84% and specificity of 95%. The area under the receiver operating characteristic curve was 0.98 ( p < 0.0001). sPKa activity in all plasma samples from patients with HAE-nC1INH was above the 95th percentile for control plasma after 6 h of cold incubation. Conclusion We developed a specific PKa assay that can detect low levels of PKa activity in plasma and can differentiate patients with HAE-C1INH from controls without HAE with high sensitivity and specificity. Using this assay, we demonstrated that sPKa activity is elevated during the intercritical period in patients with HAE-C1INH and in those with HAE-nC1INH compared with controls when measured after 6 h of cold incubation. This sensitive and specific PKa assay could be useful to characterize PKa activity in plasma samples from patients with HAE and could potentially serve as a future candidate biomarker for HAE-nC1INH.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it