O35: A genotype-first approach among adults at risk for treatable monogenic disorders reveals underdiagnosis and incomplete penetrance
Why this work is in the frame
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Bibliographic record
Abstract
Introduction: Fabry disease is an X-linked disease associated with the GLA gene.The cornerstone of therapy in Fabry disease has been to improve enzyme levels by exogenous enzyme replacement therapy (ERT) or chaperone to increase endogenous enzyme activity.These medications have to be taken in repeated doses for life.The goal of lentiviral gene therapy is to provide a lifelong increase in endogenous enzyme levels by a single therapeutic application.Methods: A phase 1 clinical trial using a single dose of lentivirus-transduced CD34+ autologous hematopoietic stem cells with engineered GLA (LV-GLA) was conducted in Canada (FACTS NCT #02800070) and we report results from the 5-year end-of study analysis.All participants were males with the classical phenotype and undetectable enzyme levels at baseline.Results: At 5 years, all 5 patients had increased leukocyte and plasma enzyme levels and detectable vector copy number of the transgene.Based on the initial response, all patients were eligible to stop their standard ERT and 3 patients stopped ERT.The slope, change in eGFR, was +0.09, -0.38, -0.59, -1.80 and -5.20 ml/min/1.73m2/ year, respectively with the last 2 patients having a slope similar to pre-LV-GLA values.The slope for 24-hour protein excretion was -0.058, -0.402, -0.11, +0.003 and + 0.006 grams/24 hour, respectively.Evaluation of cardiac measures such as left ventricular mass index, and the degree of
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| 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