"""Main pipeline: embedding-based prompt selection for Stack generation. Supports two modes: --shared-only : Run shared steps only (download ckpt, extract query_ctrl & prompt_ctrl, compute their embeddings). --perturbation X: Run per-perturbation steps (extract prompt_pert, bridge prediction, pert embeddings, custom generation). Execution order for per-perturbation (3 model loads): Step 0' : Extract prompt_pert from source AnnData Load 1 : bc_large_aligned.ckpt → bridge prediction → release Load 2 : bc_large.ckpt → pert embeddings → release Load 3 : bc_large_aligned.ckpt → custom generation → release """ from __future__ import annotations import argparse import gc import logging import sys from pathlib import Path _THIS_DIR = Path(__file__).resolve().parent if str(_THIS_DIR.parent) not in sys.path: sys.path.insert(0, str(_THIS_DIR.parent)) import anndata as ad import numpy as np import torch from scipy.sparse import csr_matrix, issparse from stack.model_loading import load_model_from_checkpoint from prompt_selection import config as cfg from prompt_selection.custom_generation import custom_generation_loop logging.basicConfig( level=logging.INFO, format="%(asctime)s [%(name)s] %(levelname)s: %(message)s", ) LOGGER = logging.getLogger("prompt_selection.pipeline") # --------------------------------------------------------------------------- # Helpers # --------------------------------------------------------------------------- def _release_model(model): """Delete model and free GPU memory.""" del model gc.collect() if torch.cuda.is_available(): torch.cuda.empty_cache() def _filter_adata(adata: ad.AnnData, filters: dict) -> ad.AnnData: """Subset AnnData by column-value filters.""" mask = np.ones(adata.n_obs, dtype=bool) for col, val in filters.items(): mask &= (adata.obs[col] == val).values return adata[mask].copy() # --------------------------------------------------------------------------- # Shared steps # --------------------------------------------------------------------------- def step0_download_checkpoint(): """Download bc_large.ckpt from HuggingFace if not present.""" if cfg.EMBED_CKPT.exists(): LOGGER.info("Embedding checkpoint already exists: %s", cfg.EMBED_CKPT) return LOGGER.info("Downloading %s from HuggingFace...", cfg.HF_EMBED_REPO) from huggingface_hub import snapshot_download snapshot_download( repo_id=cfg.HF_EMBED_REPO, local_dir=str(cfg.EMBED_MODEL_DIR), allow_patterns=["bc_large.ckpt"], ) if not cfg.EMBED_CKPT.exists(): import glob matches = glob.glob(str(cfg.EMBED_MODEL_DIR / "**" / "bc_large.ckpt"), recursive=True) if matches: Path(matches[0]).rename(cfg.EMBED_CKPT) assert cfg.EMBED_CKPT.exists(), f"Failed to download {cfg.EMBED_CKPT}" LOGGER.info("Downloaded embedding checkpoint to %s", cfg.EMBED_CKPT) def step0_extract_shared_subsets(): """Extract query_ctrl and prompt_ctrl (shared across all perturbations).""" cfg.RESULTS_DIR.mkdir(parents=True, exist_ok=True) query_path = cfg.RESULTS_DIR / cfg.QUERY_CTRL_H5AD ctrl_path = cfg.RESULTS_DIR / cfg.PROMPT_CTRL_H5AD if query_path.exists() and ctrl_path.exists(): LOGGER.info("Shared cell subsets already extracted, skipping.") return LOGGER.info("Loading source AnnData: %s", cfg.SOURCE_ADATA) adata = ad.read_h5ad(str(cfg.SOURCE_ADATA)) if not query_path.exists(): query = _filter_adata(adata, cfg.QUERY_FILTER) LOGGER.info("query_ctrl: %d cells", query.n_obs) query.write_h5ad(query_path) del query if not ctrl_path.exists(): ctrl = _filter_adata(adata, cfg.PROMPT_CTRL_FILTER) LOGGER.info("prompt_ctrl: %d cells", ctrl.n_obs) ctrl.write_h5ad(ctrl_path) del ctrl del adata gc.collect() def step_extract_shared_embeddings(): """Extract embeddings for query_ctrl and prompt_ctrl (shared).""" emb_files = [ (cfg.QUERY_EMB_NPY, cfg.QUERY_CTRL_H5AD), (cfg.PROMPT_CTRL_EMB_NPY, cfg.PROMPT_CTRL_H5AD), ] all_exist = all((cfg.RESULTS_DIR / npy).exists() for npy, _ in emb_files) if all_exist: LOGGER.info("Shared embeddings already exist, skipping.") return LOGGER.info("=== Loading bc_large.ckpt for shared embedding extraction ===") device = torch.device("cuda" if torch.cuda.is_available() else "cpu") model = load_model_from_checkpoint(str(cfg.EMBED_CKPT), device=device) for npy_name, h5ad_name in emb_files: npy_path = cfg.RESULTS_DIR / npy_name if npy_path.exists(): LOGGER.info(" %s already exists, skipping.", npy_name) continue h5ad_path = str(cfg.RESULTS_DIR / h5ad_name) LOGGER.info(" Extracting embeddings: %s -> %s", h5ad_name, npy_name) embeddings, _ = model.get_latent_representation( adata_path=h5ad_path, genelist_path=str(cfg.GENELIST_PATH), batch_size=cfg.BATCH_SIZE, num_workers=cfg.NUM_WORKERS, show_progress=True, ) np.save(npy_path, embeddings) LOGGER.info(" Saved: %s, shape=%s", npy_path, embeddings.shape) _release_model(model) def run_shared_steps(): """Run all shared steps (checkpoint download, subset extraction, embeddings).""" LOGGER.info("=" * 60) LOGGER.info("Running shared steps") LOGGER.info("=" * 60) step0_download_checkpoint() step0_extract_shared_subsets() step_extract_shared_embeddings() LOGGER.info("Shared steps complete.") # --------------------------------------------------------------------------- # Per-perturbation steps # --------------------------------------------------------------------------- def step_extract_prompt_pert(pcfg: cfg.PertConfig): """Extract prompt_pert (T cells + drug X) for a specific perturbation.""" pcfg.results_dir.mkdir(parents=True, exist_ok=True) pert_path = pcfg.results_dir / cfg.PROMPT_PERT_H5AD if pert_path.exists(): LOGGER.info("prompt_pert already exists for %s, skipping.", pcfg.perturbation_name) return True LOGGER.info("Loading source AnnData: %s", cfg.SOURCE_ADATA) adata = ad.read_h5ad(str(cfg.SOURCE_ADATA)) pert = _filter_adata(adata, pcfg.prompt_pert_filter) LOGGER.info("prompt_pert (%s): %d cells", pcfg.perturbation_name, pert.n_obs) if pert.n_obs == 0: LOGGER.warning("No T cells found for perturbation '%s'. Skipping.", pcfg.perturbation_name) (pcfg.results_dir / "SKIPPED_no_tcells.txt").touch() del adata, pert gc.collect() return False pert.write_h5ad(pert_path) del adata, pert gc.collect() return True def step_bridge_prediction(pcfg: cfg.PertConfig): """Generate predicted perturbation for control T cells using aligned model.""" pred_path = pcfg.results_dir / cfg.PREDICTED_PERT_H5AD if pred_path.exists(): LOGGER.info("Predicted perturbation already exists for %s, skipping.", pcfg.perturbation_name) return LOGGER.info("=== Load 1: bc_large_aligned.ckpt for bridge prediction (%s) ===", pcfg.perturbation_name) device = torch.device("cuda" if torch.cuda.is_available() else "cpu") model = load_model_from_checkpoint( str(cfg.ALIGNED_CKPT), model_class="ICL_FinetunedModel", device=device, ) prompt_pert_path = str(pcfg.results_dir / cfg.PROMPT_PERT_H5AD) prompt_ctrl_path = str(cfg.RESULTS_DIR / cfg.PROMPT_CTRL_H5AD) LOGGER.info("Running bridge prediction: prompt_pert → prompt_ctrl") result = model.get_incontext_generation( base_adata_or_path=prompt_pert_path, test_adata_or_path=prompt_ctrl_path, genelist_path=str(cfg.GENELIST_PATH), mode="mdm", num_steps=cfg.NUM_STEPS, prompt_ratio=cfg.PROMPT_RATIO, context_ratio=cfg.CONTEXT_RATIO, context_ratio_min=cfg.CONTEXT_RATIO_MIN, batch_size=cfg.BATCH_SIZE, num_workers=cfg.NUM_WORKERS, ) pred_X, _ = result _release_model(model) ctrl_adata = ad.read_h5ad(prompt_ctrl_path) if issparse(pred_X): pred_X_dense = pred_X.toarray() else: pred_X_dense = np.asarray(pred_X) pred_adata = ad.AnnData( X=csr_matrix(pred_X_dense.astype(np.float32)), obs=ctrl_adata.obs.copy(), var=ctrl_adata.var.copy(), ) pred_adata.obs["sm_name"] = pcfg.perturbation_name pred_adata.write_h5ad(pred_path) LOGGER.info("Saved predicted perturbation: %s (%d cells)", pred_path, pred_adata.n_obs) del ctrl_adata, pred_adata, pred_X, pred_X_dense gc.collect() def step_extract_pert_embeddings(pcfg: cfg.PertConfig): """Extract embeddings for prompt_pert and predicted_pert.""" emb_files = [ (cfg.PROMPT_PERT_EMB_NPY, cfg.PROMPT_PERT_H5AD), (cfg.PREDICTED_PERT_EMB_NPY, cfg.PREDICTED_PERT_H5AD), ] all_exist = all((pcfg.results_dir / npy).exists() for npy, _ in emb_files) if all_exist: LOGGER.info("Pert embeddings already exist for %s, skipping.", pcfg.perturbation_name) return LOGGER.info("=== Load 2: bc_large.ckpt for pert embedding extraction (%s) ===", pcfg.perturbation_name) device = torch.device("cuda" if torch.cuda.is_available() else "cpu") model = load_model_from_checkpoint(str(cfg.EMBED_CKPT), device=device) for npy_name, h5ad_name in emb_files: npy_path = pcfg.results_dir / npy_name if npy_path.exists(): LOGGER.info(" %s already exists, skipping.", npy_name) continue h5ad_path = str(pcfg.results_dir / h5ad_name) LOGGER.info(" Extracting embeddings: %s -> %s", h5ad_name, npy_name) embeddings, _ = model.get_latent_representation( adata_path=h5ad_path, genelist_path=str(cfg.GENELIST_PATH), batch_size=cfg.BATCH_SIZE, num_workers=cfg.NUM_WORKERS, show_progress=True, ) np.save(npy_path, embeddings) LOGGER.info(" Saved: %s, shape=%s", npy_path, embeddings.shape) _release_model(model) def step_custom_generation(pcfg: cfg.PertConfig): """Run MDM generation with per-step embedding-based prompt selection.""" final_path = pcfg.results_dir / pcfg.final_result_h5ad if final_path.exists(): LOGGER.info("Final result already exists for %s, skipping.", pcfg.perturbation_name) return LOGGER.info("=== Load 3: bc_large_aligned.ckpt for custom generation (%s) ===", pcfg.perturbation_name) device = torch.device("cuda" if torch.cuda.is_available() else "cpu") model = load_model_from_checkpoint( str(cfg.ALIGNED_CKPT), model_class="ICL_FinetunedModel", device=device, ) # Load data query_adata = ad.read_h5ad(str(cfg.RESULTS_DIR / cfg.QUERY_CTRL_H5AD)) prompt_pert_adata = ad.read_h5ad(str(pcfg.results_dir / cfg.PROMPT_PERT_H5AD)) # Load precomputed embeddings (shared + per-pert) query_emb = np.load(cfg.RESULTS_DIR / cfg.QUERY_EMB_NPY) prompt_ctrl_emb = np.load(cfg.RESULTS_DIR / cfg.PROMPT_CTRL_EMB_NPY) predicted_pert_emb = np.load(pcfg.results_dir / cfg.PREDICTED_PERT_EMB_NPY) prompt_pert_emb = np.load(pcfg.results_dir / cfg.PROMPT_PERT_EMB_NPY) LOGGER.info("Embeddings loaded: query=%s, ctrl=%s, pred_pert=%s, pert=%s", query_emb.shape, prompt_ctrl_emb.shape, predicted_pert_emb.shape, prompt_pert_emb.shape) result, final_logit = custom_generation_loop( model=model, query_adata=query_adata, prompt_pert_adata=prompt_pert_adata, genelist_path=str(cfg.GENELIST_PATH), query_embeddings=query_emb, prompt_ctrl_embeddings=prompt_ctrl_emb, predicted_pert_embeddings=predicted_pert_emb, prompt_pert_embeddings=prompt_pert_emb, num_steps=cfg.NUM_STEPS, prompt_ratio=cfg.PROMPT_RATIO, context_ratio=cfg.CONTEXT_RATIO, context_ratio_min=cfg.CONTEXT_RATIO_MIN, top_k1=cfg.TOP_K1, batch_size=cfg.BATCH_SIZE, num_workers=cfg.NUM_WORKERS, ) _release_model(model) query_ctrl_clean = ad.read_h5ad(str(cfg.RESULTS_DIR / cfg.QUERY_CTRL_H5AD)) result_adata = ad.AnnData( X=result, obs=query_ctrl_clean.obs.copy(), var=query_ctrl_clean.var.copy(), ) result_adata.obs["sm_name"] = pcfg.perturbation_name result_adata.obs["control"] = False result_adata.obs["gen_logit"] = np.asarray(final_logit) result_adata.write_h5ad(final_path) LOGGER.info("Saved final result: %s (%d cells)", final_path, result_adata.n_obs) def run_perturbation(pert_name: str): """Run all per-perturbation steps for a given drug.""" pcfg = cfg.get_pert_config(pert_name) LOGGER.info("=" * 60) LOGGER.info("Running perturbation: %s", pert_name) LOGGER.info("=" * 60) # Verify shared files exist for shared_file in [cfg.QUERY_CTRL_H5AD, cfg.PROMPT_CTRL_H5AD, cfg.QUERY_EMB_NPY, cfg.PROMPT_CTRL_EMB_NPY]: if not (cfg.RESULTS_DIR / shared_file).exists(): raise FileNotFoundError( f"Shared file {shared_file} not found. Run --shared-only first." ) # Extract prompt_pert has_data = step_extract_prompt_pert(pcfg) if not has_data: LOGGER.warning("Skipping %s (no T cell data).", pert_name) return # Bridge prediction step_bridge_prediction(pcfg) # Pert embeddings step_extract_pert_embeddings(pcfg) # Custom generation step_custom_generation(pcfg) LOGGER.info("=" * 60) LOGGER.info("Perturbation %s complete!", pert_name) LOGGER.info("Final result: %s", pcfg.results_dir / pcfg.final_result_h5ad) LOGGER.info("=" * 60) # --------------------------------------------------------------------------- # Main # --------------------------------------------------------------------------- def main(): parser = argparse.ArgumentParser( description="Prompt Selection Pipeline for Stack generation." ) parser.add_argument( "--perturbation", type=str, default=None, help="Perturbation name (e.g., Dabrafenib). Required unless --shared-only.", ) parser.add_argument( "--shared-only", action="store_true", help="Only run shared steps (extract query_ctrl, prompt_ctrl, their embeddings).", ) args = parser.parse_args() if args.shared_only: run_shared_steps() elif args.perturbation: run_perturbation(args.perturbation) else: parser.error("Either --perturbation or --shared-only is required.") if __name__ == "__main__": main()