Offline BioMart mode only skips ID lookup, not per-variant sequence fetches

[jonasscheid]

Description of the bug

The --biomart_dump_path parameter (added in #316) is documented as enabling offline BioMart usage, but it only partially works offline. The dump file provides transcript→protein ID mappings, which skips the initial get_protein_ids_from_transcripts() call (epaa.py L1135-1137).

However, the main performance bottleneck — the per-variant loop at L607-611 — still uses the live martsadapter to call generator.generate_transcripts_from_variants() for every variant. This function fetches actual transcript/protein sequences from Ensembl BioMart to compute mutated peptides, and it runs once per variant (O(N) network calls).

This means:

• "Offline" mode still requires internet access for the sequence lookup step
• CI tests using VCF input take 4-6 hours due to per-variant BioMart queries, even with the dump file
• Tests are non-deterministic — when BioMart is flaky, some variants produce no peptides, leading to snapshot mismatches

Relevant code

# L1135-1137: This is the ONLY part skipped by --biomart_dump (ID mapping)
if args.biomart_dump:
    transcriptProteinTable = get_protein_ids_from_transcripts_offline(transcripts, args.biomart_dump)

# L607-611: This still hits BioMart live for every variant (sequence fetches)
for v in variants:
    try:
        transcripts.extend(generator.generate_transcripts_from_variants([v], martsadapter, ID_SYSTEM_USED, db=ensembl_dataset))
    except Exception:
        logger.warning(f"Could not generate transcripts for variant {v}. Skipping.")

Upstream epytope issues

Fixing this properly likely requires changes in the epytope library to support offline/cached sequence lookups in generate_transcripts_from_variants. Relevant upstream issues:

• Consider migrating MartsAdapter from BioMart to Ensembl REST API KohlbacherLab/epytope#103
• Add PyEnsemblAdapter as offline alternative to MartsAdapter KohlbacherLab/epytope#106

Impact

• test_offline config advertises offline support but the pipeline still requires live BioMart access
• All VCF-based CI tests (8 out of 12) are slow and flaky due to this dependency
• Users in air-gapped environments cannot actually run the pipeline offline with VCF input

System information

• Observed on current dev branch (dc0107e)
• Affects all VCF-based test profiles