Multimodal Neuroimaging‐Guided Stratification in Amyotrophic Lateral Sclerosis Reveals Three Disease Subtypes: A Multi‐Cohort Analysis
Bibliographic record
Abstract
Amyotrophic lateral sclerosis (ALS) is a multisystem disease with marked pathophysiological and clinical heterogeneity, making individual and objective characterization of the degree of disease progression and disease-related subtrajectories challenging. Here, we use in vivo multimodal neuroimaging data and computational models to generate personalized indices of ALS progression and subtrajectory. We used structural and diffusion weighted imaging of 691 participants (58% ALS) from two independent ALS data sets (North American and Utrecht cohorts) to extract regional values of grey matter (DM) density and white matter (WM) microstructural integrity. Contrastive trajectory inference (cTI) allowed us to identify and separate latent, multivariate patterns in neuroimaging features highlighting ALS-associated pathological processes, which were used to generate subject-specific indices of disease progression and subtrajectory. Disease subtrajectories were based on distinct patterns of alterations in neuroimaging data considering subjects at different disease progression levels. The neuroimaging-based, personalized index of disease progression is indicative of clinical symptom severity (North American: p < 0.01 and Utrecht: p < 0.01) and displays alignment with the King's College staging system (p = 0.001 and p = 0.002). Three ALS subtrajectories were identified that displayed distinct alterations in the motor, limbic system, and widespread cortical and subcortical changes that also differed in clinical symptom manifestation. Our analysis has shown that neuroimaging data encodes subject-specific, disease-related patterns that can be leveraged to obtain an in vivo proxy of disease progression and putative disease subtype.
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How this classification was reachedexpand
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".