SP023CLASSIFICATION OF MALE FABRY PATIENTS: VALIDATION OF GROUP CONSENSUS BY SURVIVOR ANALYSIS FOR MAJOR CLINICAL EVENTS
Bibliographic record
Abstract
INTRODUCTION AND AIMS: Fabry disease is an X-linked lysosomal storage disorder with marked allelic and phenotypic heterogeneity. The “fabry-database.org” database reports phenotype classifications of numerous GLA mutations, most of which occur in one or few families. Stratification by patients’ genotypes and phenotype is needed for current and future clinical studies. METHODS: A multi-specialty Fabry genotype-phenotype working group (WG) classified phenotypes of adult males with GLA mutations reported to the Fabry Registry (NCT00196742; sponsor: Sanofi Genzyme) for ≥ 4 patients that remained unclassified in the “fabry-database.org” database. Using an iterative process, the WG agreed on criteria to classify phenotypes: expert clinical judgment, published literature, and clinical evidence of mutation severity. The Kaplan-Meier severe clinical event-free survival curve method was used to validate the final classification consensus (event: composite of renal, cardiac, cerebrovascular events, and death). RESULTS: 43 previously unclassified GLA mutations (300 adult male Fabry patients, average 7 males/mutation) qualified for inclusion. Preliminary consensus (classic, nonclassic, uncertain, or polymorphism) was achieved based on individual expert assessments. A 2-point scoring system (characteristic Fabry symptoms: angiokeratoma, cornea verticillata; Fabry Registry data) was used for initial process validation. Final consensus was achieved for 42/43 mutations based on preliminary phenotype consensus, the updated “fabry-database.org” report, and the 2-point Registry scoring scale. Final classifications included: classic, 30 mutations (192 males); nonclassic, 11 (100 males); uncertain, 1 (4 males); benign polymorphism, 1 (4 males). Comparison of event-free survival for male patients enrolled in the Fabry Registry based on available “fabry-database.org” classic/nonclassic classifications to survival after inclusion of the WG consensus re-classification of 42 unknown “fabry-database.org” classifications in the analysis showed similar separation of the curves for patients within the mutation categories (p-values <0.01; median time-to-event in classic vs. nonclassic patients 46.8 and 64.6 years and 46.7 and 63.4 years, respectively). CONCLUSIONS: This validated approach toward classification of phenotypes may aid in analyzing Fabry Registry clinical outcome data from cohorts of male patients with classic and nonclassic Fabry mutations in the future.Funding: Sanofi Genzyme.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.036 | 0.045 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.006 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.001 | 0.001 |
| 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".