Defining SOD1 ALS natural history to guide therapeutic clinical trial design
Why this work is in the frame
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Bibliographic record
Abstract
<h3>Importance</h3> Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by <i>SOD1</i> mutations (ALS<sup>SOD1</sup>) will provide key information for optimising clinical trials in this patient population. <h3>Objective</h3> To establish an updated natural history of ALS<sup>SOD1</sup>. <h3>Design, setting and participants</h3> Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed <i>SOD1</i> mutations, cared for after the year 2000. <h3>Main outcomes and measures</h3> Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1<sup>A4V</sup>), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1<sup>non-A4V</sup>) for analysis. <h3>Results</h3> Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1<sup>A4V</sup> and SOD1<sup>non-A4V</sup> (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1<sup>A4V</sup>. SOD1<sup>A4V</sup> survival probability (median survival 1.2 years) was significantly decreased compared with SOD1<sup>non-A4V</sup> (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1<sup>A4V</sup> compared with SOD1<sup>non-A4V</sup> participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1<sup>A4V</sup> compared with SOD1<sup>non-A4V</sup> (p=0.02). <h3>Conclusions and relevance</h3> SOD1<sup>A4V</sup> is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS<sup>SOD1</sup> patient population.
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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 | 0.008 | 0.006 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.001 | 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 it