Genetic signatures of responsiveness in idiopathic normal pressure Hydrocephalus: Insights from whole-exome and LASSO-based analysis
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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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".