Genetic signatures of responsiveness in idiopathic normal pressure Hydrocephalus: Insights from whole-exome and LASSO-based analysis
Why this work is in the frame
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Bibliographic record
Abstract
Background: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterised by the triad of gait disturbance, cognitive decline, and urinary incontinence, together with ventriculomegaly despite normal cerebrospinal fluid (CSF) pressure (1-3). Although traditionally considered non-genetic and multifactorial, emerging data suggest that rare pathogenic variants and cilia-related mechanisms may contribute to its pathogenesis and modulate responsiveness to CSF diversion (8-12). Methods: We performed whole-exome sequencing (WES) in 33 consecutive patients with clinically and radiologically confirmed iNPH who underwent a standardised 120-h lumbar drainage (LD) protocol. Responders were defined as those showing ≥20 % improvement in gait speed or ≥3-point increase in Montreal Cognitive Assessment (MoCA) score compared with baseline. Variants were filtered according to ACMG/AMP guidelines (19) and population allele frequency (minor allele frequency <1 %). Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression (20) with ten-fold cross-validation was applied to identify gene-level predictors of LD responsiveness. Results: After filtering, 110 genes with at least one pathogenic or likely pathogenic variant were retained for modelling. LASSO regression at the λ.1se threshold identified a five-gene panel-FANCD2, ATR, ORAI1, MUC1, and RP1L1-involved in DNA damage response, calcium signalling, epithelial barrier integrity, and ciliary architecture (21-28). The internally derived model achieved an accuracy of 81.8 %, sensitivity 68.8 %, specificity 94.1 %, and positive predictive value 91.7 % for prediction of LD response. Conclusions: Rare pathogenic variants in genes linked to genome stability, immune and calcium signalling, and ciliary structure may influence LD responsiveness in iNPH. The five-gene model represents a biologically plausible, hypothesis-generating tool for preoperative risk stratification. Validation in larger, multicentre cohorts, integration with shunt outcomes, and functional studies are required before any clinical implementation.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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