Hybrid eTFCE-GRF: Exact Cluster-Size Retrieval with Analytical p-Values for Voxel-Based Morphometry

Threshold-free cluster enhancement (TFCE) integrates cluster extent across thresholds to improve voxel-wise neuroimaging inference, but permutation testing makes it prohibitively slow for large datasets. Probabilistic TFCE (pTFCE) uses analytical Gaussian random field (GRF) p-values but discretises the threshold grid. Exact TFCE (eTFCE) eliminates discretisation via a union-find data structure but still requires permutations. We combine eTFCE's union-find for exact cluster-size retrieval with pTFCE's analytical GRF inference. The union-find builds the cluster hierarchy in one pass over sorted voxels and enables exact size queries at any threshold; GRF theory then converts these sizes to analytical p-values without permutations. Validation on synthetic phantoms (64^3, 80 subjects): FWER controlled at nominal level (0/200 null rejections, 95% CI [0.0%, 1.9%]); power matches baseline pTFCE (Dice >= 0.999); smoothness error below 1%; concordance r > 0.99. On UK Biobank (N=500) and IXI (N=563), significance maps form strict subsets of reference R pTFCE, which supports conservative error control. Implemented in pytfce (pip install pytfce): baseline completes whole-brain VBM in ~5s (75x faster than R pTFCE), hybrid in ~85s (4.6x faster) with exact cluster sizes; both >1000x faster than permutation TFCE.