# Main figure caption book v09.80

## Figure captions

### Figure 1

Figure file: `figures/Figure_1_evidence_governance_v09_80.pdf` (matched PNG/SVG/TIFF also provided in the v09.80 packet).

**Figure 1. Evidence objects preserve context, unit structure and claim boundaries.**  
**a,** A research question identity, an evidence-state record and a claim contract are represented as separable objects. Transformations may change representation but cannot silently change evidence origin, context match, biological or inferential unit, lifecycle state or outcome state. **b,** DMD, FSHD, DM1 and SMA share the evidence-contract schema while retaining disease-specific biological anchors; no pooled cross-disease therapeutic score is released. **c,** Lifecycle states make prospective work auditable without converting local locks or pending DOI deposition into completed outcomes. **d,** The DMD evidence ladder stops before direct disease-context candidate validation: 21 of 21 candidates have source-context responses and 21 of 21 have pathway-cascade objects, but 0 of 21 have direct DMD candidate responses and 0 of 21 are functionally validated. **Guardrail.** This figure defines the evidence-governance object and DMD claim ceiling; it does not establish therapeutic efficacy, safety, clinical utility or candidate validation.

### Figure 2

Figure file: `figures/Figure_2_dmd_axes_v09_80.pdf` (matched PNG/SVG/TIFF also provided in the v09.80 packet).

**Figure 2. Measured DMD axes define references, not candidate outcomes.**  
**a,** The unselected 23,324-gene engineered-versus-patient DMD comparison is the primary denominator and is shown without differential-expression selection. **b,** The selected significant-gene intersection shows higher apparent directional agreement and is displayed separately as a conditioning-sensitive contrast. **c,** DMD-locus correction alignment varies across dup2, dup2-9 and dup8-9 backgrounds. **d,** Significant-gene reversal is genotype dependent; 171 genes reverse in at least two backgrounds and only eight reverse in all three. These measured DMD axes are reference evidence, not candidate-level DMD perturbation outcomes.

### Figure 3

Figure file: `figures/Figure_3_candidate_assignment_audit_matrix_v09_80.pdf` (matched PNG/SVG/TIFF also provided in the v09.80 packet).

**Figure 3. Candidate provenance and source-bound assignment audit define a bounded pilot stratum without DMD validation.**  
**a,** The DMD candidate lineage starts at the first checksum-addressed recoverable checkpoint: a historical 58-candidate source queue is reported, but the original source TSV and full replay manifest are unavailable, so the retained 21-row vector is treated as an inherited hypothesis set rather than a new genome-wide discovery result.  
**b,** Coverage and endpoint evidence remain distinct: 21 of 21 candidates have source-context responses and pass the HepG2 coverage floor; 9 of 21 are covered by an independent healthy-myoblast fusion screen, 0 of 9 are fusion-defect hits, and 12 of 21 are not measured in that endpoint.  
**c,** Five dependent local audit rules summarize current assignment. Seven of 21 candidates pass repeated-resampling stability, 16 of 21 pass bulk skeletal-muscle expression feasibility, 14 of 21 pass cross-context dependency caution, 11 of 21 pass DMD-source projection, and 12 of 21 pass target-engagement margin. The repeated-resampling and target-engagement-margin counts are taken from the locked v08.5 rule-freeze table, whereas the muscle-expression, dependency-caution and DMD-source-projection counts are taken from the current candidate network summary; these are dependent audit filters, not independent validation streams. ADAM10, CALR and MPHOSPH6 pass all five and form the current 3-of-21 pilot stratum; the remaining 18 receive reason-coded abstentions.  
**d,** Direct-seed, no-propagation and RWR graph models are numerically distinct but converge on the same current pilot set.  
**Guardrail.** This figure shows provenance recovery, source-context adequacy and conditional assignment robustness. It does not show candidate responses measured in DMD muscle, therapeutic efficacy, safety, clinical utility or functional validation.

### Figure 4

Figure file: `figures/Figure_4_boundary_holdout_v09_80.pdf` (matched PNG/SVG/TIFF also provided in the v09.80 packet).

**Figure 4. A sealed Replogle holdout exposes a cell-state boundary for source-to-target perturbation transfer.**  
**A,** Frozen primary comparisons for the locked diagonal shrinkage model in Replogle K562 essential perturbations transferred to Replogle RPE1 essential perturbations. Points show paired median comparator-minus-diagonal angular-risk differences; bars show bootstrap 95% confidence intervals. The shaded region marks the prespecified pass direction. Both comparisons fail. **B,** Median angular risk across reference models. Lower values are better; labels report median risk and the number of perturbations for which each model was best. **C,** Perturbation-level paired risk differences show that diagonal shrinkage was broadly worse than target-context and scalar-calibrated comparators. Points mark medians and thick bars mark interquartile ranges. **D,** Post-hoc Reactome module-family enrichment for gene-level diagonal excess error relative to scalar calibration. Points show Cliff's δ; size indicates scored genes; color indicates -log10 BH q; black outlines indicate Holm-significant families. **E,** Median angular risk recomputed after restricting perturbation vectors to module genes. **F,** Leading mitotic/chromosome module genes ranked by diagonal excess error relative to scalar calibration. **Guardrail.** Panels D-F are explanatory mechanism anatomy after the sealed primary failure; they are not a replacement primary endpoint.

### Figure 5

Figure file: `figures/Figure_5_disease_module_matrix_v09_80.pdf` (matched PNG/SVG/TIFF also provided in the v09.80 packet).

**Figure 5. Disease modules preserve negative and residual evidence instead of collapsing routes into a shared score.**  
**a,** FSHD, DM1, SMA muscle and SMA neuronal routes are represented with the same evidence-preservation grammar: measured axis, retained negative or residual result, claim ceiling and next experiment. FSHD separates patient-state and DUX4-induction evidence; DM1 separates global-expression non-reversal from splice-event convergence; SMA separates weak global ASO reversal from residual muscle programs and neuronal KIF5A response. **b,** FSHD target-high nuclei remain a sample-dependent state-localization signal and do not constitute donor replication. **c,** DM1 retains negligible global expression alignment between repeat excision and patient disease while preserving event-level splice convergence as the interpretable endpoint. **d,** SMA preserves weak global ASO reversal, residual OXPHOS/denervation/fibrosis muscle programs and KIF5A decreases after SMN loss as separate measured questions. **Guardrail.** The modules share a claim-governed evidence contract, not a pooled therapeutic score. Negative and residual results define next experiments and do not establish therapeutic efficacy, safety, clinical utility or validated targets.

### Figure 6

Figure file: `figures/Figure_6_single_cell_extensions_v09_80.pdf` (matched PNG/SVG/TIFF also provided in the v09.80 packet).

**Figure 6. Single-cell extensions refine localization without raising the claim ceiling.**  
**a,** GSE303359 and GSE290980 analysis plans were frozen locally before complete-matrix access but lack public timestamped registration. **b,** FSHD genotype-by-injury module intervals cross zero, including the prespecified DUX4-target module. **c,** SMA marker-state composition is shown after eight technical libraries collapse to four biological lines. **d,** SMA gene and module effects retain pairwise ranges rather than calibrated small-n claims. Both analyses remain directional at two lines per genotype and promote zero targets.