Prospective prediction of germ line mutations in patients with pheochromocytomas and paragangliomas according to biochemical profiles
Bibliographic record
Abstract
Background: Over 30% of pheochromocytomas and paragangliomas (PPGLs) are hereditary, and at least 16 tumor susceptibility genes have been identified to date. Measurements of plasma O-methylated metabolites may be useful predictive markers of underlying germ line mutations among PPGLs patients, but this has not been validated in any prospective study. Methods: Underlying mutations were predicted according to plasma concentrations of O-methylated metabolites measured by liquid chromatography tandem mass spectrometry in 159 patients with PPGLs at 6 European centers. Predictions were compared with results of mutation testing. Results: Patients included 68 with tumors characterized by epinephrine production, among whom 65 were predicted for RET , NF1 or TMEM 127 mutations, 2 for MAX , and 1 for VHL / SDH or MAX mutations. For 91 patients, disease was without tumoral epinephrine production, among whom 1 was predicted for MAX and 87 for VHL or SDHx gene mutations. The latter included 29 patients with elevated methoxytyramine (MTY) in who SDHx mutations only were predicted. Among all patients, there were 53 determined to have underlying mutations of tumor susceptibility genes (13 SDHB , 1 SDHC , 16 SDHD , 8 VHL , 5 NF1 and 10 RET ). Among these 53 patients, the pattern of biochemical results correctly predicted the underlying mutations in all but in one case. Fourteen patients were correctly identified to have RET or NF1 mutations according to elevations in plasma metanephrine (MN) levels, whereas 1 patient with a RET mutation was incorrectly predicted for either a VHL , SDHx or MAX mutation according to an elevation in both MN and normetanephrine. All 38 patients with VHL/SDHx mutations were correctly identified according to lack of elevation in plasma MN, including 17 patients who were correctly identified for SDHx mutations based on elevated plasma MTY levels. Conclusions: This prospective study establishes that among patients with mutations of tumor susceptibility genes, plasma catecholamine O-methylated metabolites can predict the nature of the underlying mutations with 98% accuracy.
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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 | 0.002 |
| 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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".