# NegBioDB Configuration
# Source of truth for thresholds, paths, and pipeline settings.

# === Inactivity Thresholds ===
inactivity_threshold_nm: 10000         # 10 uM in nM; compound inactive if IC50/Ki/Kd > this
positive_pchembl_min: 6.0             # pChEMBL >= 6 for positives (IC50 <= 1 uM)
borderline_exclusion:
  lower: 4.5                          # Exclude pChEMBL >= 4.5 from negative pool
  upper: 6.0                          # Matches positive_pchembl_min; effective gap: [4.5, 6.0)
davis_inactive_pkd_threshold: 5.0     # DAVIS: inactive if pKd <= 5 (NOT strictly < 5)
davis_active_pkd_threshold: 7.0       # DAVIS: active if pKd >= 7 (Kd <= 100 nM)

# === ChEMBL ETL Policy ===
# Core benchmark should remain conservative by default.
# Optional activity_comment route can be enabled for recall-focused expansion.
chembl_etl:
  include_activity_comment: false
  inactive_activity_comments:
    - "Not Active"
    - "Inactive"
    - "Not active"
    - "inactive"

# === ML Split Configuration ===
split_ratios:
  train: 0.7
  val: 0.1
  test: 0.2
random_seed: 42

# === Processing ===
pubchem_chunksize: 100000             # Rows per chunk for streaming PubChem processing

pubchem_etl:
  chunksize: 100000
  human_only: true

bindingdb_etl:
  chunksize: 100000
  inactive_threshold_nm: 10000
  human_only: true

# === Confidence Tier Ordering (gold = highest) ===
confidence_tiers:
  - gold
  - silver
  - bronze
  - copper

# === Paths (relative to project root) ===
paths:
  data_dir: data
  exports_dir: exports
  migrations_dir: migrations
  database: data/negbiodb.db

# === Download URLs ===
downloads:
  pubchem:
    # Legacy keys kept for backward compatibility
    url: "https://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/Extras/bioactivities.tsv.gz"
    dest: data/pubchem/bioactivities.tsv.gz
    min_size_bytes: 1000000000
    # Required files for full PubChem ETL
    bioassays_url: "https://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/Extras/bioassays.tsv.gz"
    bioassays_dest: data/pubchem/bioassays.tsv.gz
    bioassays_min_size_bytes: 10000000
    aid_uniprot_url: "https://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/Extras/Aid2GeneidAccessionUniProt.gz"
    aid_uniprot_dest: data/pubchem/Aid2GeneidAccessionUniProt.gz
    aid_uniprot_min_size_bytes: 1000000
    sid_cid_smiles_url: "https://ftp.ncbi.nlm.nih.gov/pubchem/Bioassay/Extras/Sid2CidSMILES.gz"
    sid_cid_smiles_dest: data/pubchem/Sid2CidSMILES.gz
    sid_cid_smiles_min_size_bytes: 1000000
    sid_lookup_db: data/pubchem/sid_lookup.sqlite
  chembl:
    dest_dir: data/chembl
  bindingdb:
    servlet_url: "https://www.bindingdb.org/rwd/bind/chemsearch/marvin/SDFdownload.jsp?download_file=/rwd/bind/downloads/BindingDB_All_202603_tsv.zip"
    file_url: "https://www.bindingdb.org/rwd/bind/downloads/BindingDB_All_202603_tsv.zip"
    dest_dir: data/bindingdb
    min_size_bytes: 500000000
  davis:
    base_url: "https://raw.githubusercontent.com/dingyan20/Davis-Dataset-for-DTA-Prediction/master"
    files:
      - drugs.csv
      - proteins.csv
      - drug_protein_affinity.csv
    dest_dir: data/davis
    min_rows: 25000

# ============================================================
# Clinical Trial Failure Domain
# ============================================================

ct_domain:
  # === Paths ===
  paths:
    database: data/negbiodb_ct.db
    migrations_dir: migrations_ct
    data_dir: data/ct

  # === Downloads ===
  downloads:
    aact:
      # AACT pipe-delimited snapshot; URL changes monthly — update as needed
      # Get latest from: https://aact.ctti-clinicaltrials.org/pipe_files
      dest_dir: data/ct/aact
      required_disk_gb: 6.0
      # 13 of 46 AACT tables needed for v1
      tables:
        - studies
        - interventions
        - conditions
        - outcomes
        - outcome_analyses
        - outcome_measurements
        - designs
        - sponsors
        - calculated_values
        - browse_interventions
        - browse_conditions
        - drop_withdrawals
        - documents
    opentargets:
      url: "https://huggingface.co/api/datasets/opentargets/clinical_trial_reason_to_stop/parquet/default/train/0000.parquet"
      dest: data/ct/opentargets/stop_reasons.parquet
    cto:
      url: "https://huggingface.co/api/datasets/chufangao/CTO/parquet/human_labels/test/0.parquet"
      dest: data/ct/cto/cto_outcomes.parquet
    shi_du:
      # Figshare: Shi & Du 2024, doi:10.6084/m9.figshare.c.6860254.v1
      efficacy_url: "https://ndownloader.figshare.com/files/42520528"
      efficacy_dest: data/ct/shi_du/efficacy_df.csv
      safety_url: "https://ndownloader.figshare.com/files/42520534"
      safety_dest: data/ct/shi_du/safety_df.csv

  # === Failure Classification ===
  failure_category_precedence:
    - safety
    - efficacy
    - pharmacokinetic
    - enrollment
    - strategic
    - regulatory
    - design
    - other

  # === Drug Name Resolution ===
  drug_resolution:
    fuzzy_threshold: 0.90
    pubchem_rate_limit_per_sec: 5
    pubchem_cache: data/ct/pubchem_name_cache.json
    overrides_file: data/ct/drug_name_overrides.csv

  # === NLP Classifier ===
  classifier:
    max_features: 10000
    ngram_range: [1, 2]
    cv_folds: 5

# ============================================================
# Protein-Protein Interaction Negative Domain
# ============================================================

ppi_domain:
  # === Paths ===
  paths:
    database: data/negbiodb_ppi.db
    migrations_dir: migrations_ppi
    data_dir: data/ppi

  # === Downloads ===
  downloads:
    huri:
      hi_union_url: "https://www.interactome-atlas.org/data/HI-union.tsv"
      # hi_iii_url removed — HI-III-20.tsv returns 404 as of 2026-03
      idmapping_url: "https://ftp.uniprot.org/pub/databases/uniprot/current_release/knowledgebase/idmapping/by_organism/HUMAN_9606_idmapping.dat.gz"
      dest_dir: data/ppi/huri
    intact:
      url: "https://ftp.ebi.ac.uk/pub/databases/intact/current/psimitab/intact_negative.txt"
      dest: data/ppi/intact/intact_negative.txt
      min_size_bytes: 1000000
    humap:
      base_url: "https://humap3.proteincomplexes.org/static/downloads/humap3"
      neg_train: ComplexPortal_reduced_20230309.neg_train_ppis.txt
      neg_test: ComplexPortal_reduced_20230309.neg_test_ppis.txt
      pos_train: ComplexPortal_reduced_20230309.train_ppis.txt
      pos_test: ComplexPortal_reduced_20230309.test_ppis.txt
      dest_dir: data/ppi/humap
    string:
      links_url: "https://stringdb-downloads.org/download/protein.links.v12.0/9606.protein.links.v12.0.txt.gz"
      mapping_url: "https://stringdb-downloads.org/download/mapping_files/uniprot/human.uniprot_2_string.2018.tsv.gz"
      dest_dir: data/ppi/string
    biogrid:
      url: "https://downloads.thebiogrid.org/Download/BioGRID/Latest-Release/BIOGRID-ALL-LATEST.tab3.zip"
      dest_dir: data/ppi/biogrid

  # === Evidence Type Priority (best first) ===
  evidence_type_priority:
    - experimental_non_interaction
    - literature_reported
    - ml_predicted_negative
    - low_score_negative
    - compartment_separated

  # === STRING ETL Settings ===
  string_etl:
    min_protein_degree: 5
    max_negative_pairs: 500000

  # === Benchmark Split ===
  split_ratios: {train: 0.7, val: 0.1, test: 0.2}
  random_seed: 42