""" SBDenoiser — Anisotropic Schrödinger Bridge denoiser. Training: Joint velocity + score matching with anisotropic bridge paths. v_θ target = x_T - x₀ (PF-ODE velocity, same as scDFM). s_θ target = -(x_t - μ_t) / var_t (conditional score). Minibatch anisotropic OT per step. Inference: Euler-Maruyama SDE using drift = v_θ + (σ²/2)·s_θ. Or PF-ODE ablation: drift = v_θ. """ import math import torch import torch.nn as nn import torchdiffeq from ._scdfm_imports import make_lognorm_poisson_noise from .model.model import SBModel from .ot_anisotropic import AnisotropicOTSampler def pairwise_sq_dists(X, Y): return torch.cdist(X, Y, p=2) ** 2 @torch.no_grad() def median_sigmas(X, scales=(0.5, 1.0, 2.0, 4.0)): D2 = pairwise_sq_dists(X, X) tri = D2[~torch.eye(D2.size(0), dtype=bool, device=D2.device)] m = torch.median(tri).clamp_min(1e-12) s2 = torch.tensor(scales, device=X.device) * m return [float(s.item()) for s in torch.sqrt(s2)] def mmd2_unbiased_multi_sigma(X, Y, sigmas): m, n = X.size(0), Y.size(0) Dxx = pairwise_sq_dists(X, X) Dyy = pairwise_sq_dists(Y, Y) Dxy = pairwise_sq_dists(X, Y) vals = [] for sigma in sigmas: beta = 1.0 / (2.0 * (sigma ** 2) + 1e-12) Kxx = torch.exp(-beta * Dxx) Kyy = torch.exp(-beta * Dyy) Kxy = torch.exp(-beta * Dxy) term_xx = (Kxx.sum() - Kxx.diag().sum()) / (m * (m - 1) + 1e-12) term_yy = (Kyy.sum() - Kyy.diag().sum()) / (n * (n - 1) + 1e-12) term_xy = Kxy.mean() vals.append(term_xx + term_yy - 2.0 * term_xy) return torch.stack(vals).mean() class SBDenoiser(nn.Module): """ Anisotropic Schrödinger Bridge Denoiser. σ_g simultaneously controls: 1. OT coupling cost (Mahalanobis weights) 2. Bridge noise level (conditional bridge variance) 3. SDE diffusion strength (Euler-Maruyama noise) """ def __init__( self, model: SBModel, noise_type: str = "Gaussian", use_mmd_loss: bool = True, gamma: float = 0.5, poisson_alpha: float = 0.8, poisson_target_sum: float = 1e4, # Score training score_weight: float = 0.1, score_t_clip: float = 0.02, use_score: bool = True, # σ_g regularization sigma_base: float = 0.5, sigma_sparse_weight: float = 0.01, sigma_volume_weight: float = 0.01, # OT coupling ot_method: str = "sinkhorn", ot_reg: float = 0.05, ot_use_sigma: bool = True, sigma_min: float = 0.01, # Time sampling t_sample_mode: str = "logit_normal", t_mean: float = 0.0, t_std: float = 1.0, # SDE inference sde_steps: int = 50, use_sde_inference: bool = True, # Source-Anchored Bridge source_anchored: bool = False, ): super().__init__() self.model = model self.noise_type = noise_type self.use_mmd_loss = use_mmd_loss self.gamma = gamma self.poisson_alpha = poisson_alpha self.poisson_target_sum = poisson_target_sum self.score_weight = score_weight self.score_t_clip = score_t_clip self.use_score = use_score self.sigma_base = sigma_base self.sigma_sparse_weight = sigma_sparse_weight self.sigma_volume_weight = sigma_volume_weight self.ot_use_sigma = ot_use_sigma self.t_sample_mode = t_sample_mode self.t_mean = t_mean self.t_std = t_std self.sde_steps = sde_steps self.use_sde_inference = use_sde_inference self.source_anchored = source_anchored self.ot_sampler = AnisotropicOTSampler( method=ot_method, reg=ot_reg, sigma_min=sigma_min, ) def _make_noise(self, source: torch.Tensor) -> torch.Tensor: if self.noise_type == "Gaussian": return torch.randn_like(source) elif self.noise_type == "Poisson": return make_lognorm_poisson_noise( target_log=source, alpha=self.poisson_alpha, per_cell_L=self.poisson_target_sum, ) else: raise ValueError(f"Unknown noise_type: {self.noise_type}") def _sample_t(self, n: int, device: torch.device) -> torch.Tensor: if self.t_sample_mode == "logit_normal": t = torch.sigmoid(torch.randn(n, device=device) * self.t_std + self.t_mean) else: t = torch.rand(n, device=device) return t.clamp(self.score_t_clip, 1.0 - self.score_t_clip) def train_step( self, source: torch.Tensor, # (B, G) control expression target: torch.Tensor, # (B, G) perturbed expression perturbation_id: torch.Tensor, # (B, n_pert) gene_input: torch.Tensor, # (B, G) vocab-encoded gene IDs ) -> dict: """ Single training step with anisotropic bridge + minibatch OT. """ B = source.shape[0] device = source.device # 1. Sample time t = self._sample_t(B, device) # (B,) t_col = t.unsqueeze(-1) # (B, 1) # 2. Get σ_g from sigma_net (independent of backbone) # Need gene_emb and pert_emb — compute them via the model's encoder with torch.no_grad(): gene_emb = self.model.encoder(gene_input) # (B, G, d) pert_emb = self.model.get_perturbation_emb( perturbation_id, cell_1=source) # (B, d) # σ_g with gradient (for regularization loss) sigma_g = self.model.sigma_net(pert_emb, t, gene_emb) # (B, G) sigma_g_det = sigma_g.detach() # for bridge sampling # 3. Create x_0 and do minibatch anisotropic OT if self.source_anchored: x_0 = source # bridge from control else: x_0 = self._make_noise(source) # bridge from noise if self.ot_use_sigma: sigma_for_ot = sigma_g_det.mean(0) # (G,) batch mean x_0, target_matched = self.ot_sampler.sample_plan_fix_x0( x_0, target, sigma_for_ot) else: x_0, target_matched = self.ot_sampler.sample_plan_fix_x0( x_0, target, sigma_g=None) # 4. Anisotropic conditional bridge sampling mu_t = (1 - t_col) * x_0 + t_col * target_matched # (B, G) var_t = (sigma_g_det ** 2 * (t_col * (1 - t_col))).clamp(min=1e-8) std_t = torch.sqrt(var_t) # (B, G) eps = torch.randn_like(x_0) x_t = mu_t + std_t * eps # (B, G) # 5. Targets v_target = target_matched - x_0 # source-anchored: Δ s_target = -eps / (std_t + 1e-8) # conditional score # 6. Full model forward pred_v, pred_s, sigma_g_pred = self.model( gene_input, source, x_t, t, perturbation_id) # 7. Velocity loss loss_v = ((pred_v - v_target) ** 2).mean() # 8. Score loss (var_t-weighted DSM — equivalent to ε-prediction) # var_t weighting cancels the 1/var_t in s_target, giving bounded loss ~O(1) loss_s = torch.tensor(0.0, device=device) if self.use_score and pred_s is not None: loss_s = (var_t * (pred_s - s_target) ** 2).mean() # 9. σ_g regularization # Volume penalty anchors geometric mean at σ_base (global scale). # L1 sparse penalty removed — it killed per-gene anisotropy by # pulling every σ_g to σ_base. Sigmoid [σ_min, σ_max] prevents # collapse/explosion; volume penalty alone is sufficient. loss_sparse = (sigma_g_pred - self.sigma_base).abs().mean() # monitor only loss_volume = (sigma_g_pred.log().mean() - math.log(self.sigma_base)) ** 2 # 10. MMD loss (optional) loss_mmd = torch.tensor(0.0, device=device) if self.use_mmd_loss: x1_hat = x_t + pred_v * (1 - t_col) sigmas_mmd = median_sigmas(target_matched, scales=(0.5, 1.0, 2.0, 4.0)) loss_mmd = mmd2_unbiased_multi_sigma(x1_hat, target_matched, sigmas_mmd) # 11. Total loss # loss_sparse excluded — kept in return dict for monitoring loss = ( loss_v + self.score_weight * loss_s + self.sigma_volume_weight * loss_volume + self.gamma * loss_mmd ) return { "loss": loss, "loss_v": loss_v.detach(), "loss_s": loss_s.detach(), "loss_mmd": loss_mmd.detach(), "loss_sparse": loss_sparse.detach(), "loss_volume": loss_volume.detach(), "sigma_mean": sigma_g_pred.mean().detach(), "sigma_std": sigma_g_pred.std().detach(), } @torch.no_grad() def generate( self, source: torch.Tensor, # (B, G) perturbation_id: torch.Tensor, # (B, n_pert) gene_ids: torch.Tensor, # (B, G) or (G,) steps: int = None, method: str = "sde", ) -> torch.Tensor: """ Generate perturbed expression via SDE or PF-ODE. SDE: dX = [v_θ + (σ²/2)·s_θ] dt + σ·dB (Euler-Maruyama) PF-ODE: dx/dt = v_θ (torchdiffeq RK4) """ B, G = source.shape device = source.device steps = steps or self.sde_steps if gene_ids.dim() == 1: gene_ids = gene_ids.unsqueeze(0).expand(B, -1) if self.source_anchored: x_0 = source.clone() # start from control else: x_0 = self._make_noise(source) # start from noise use_sde = self.use_sde_inference and (method != "ode") if use_sde: # SDE: Euler-Maruyama (no high-order SDE solver available) x_t = x_0 dt = 1.0 / steps for i in range(steps): t_val = i * dt t = torch.full((B,), t_val, device=device) pred_v, pred_s, sigma_g = self.model( gene_ids, source, x_t, t, perturbation_id) if pred_s is not None: drift = pred_v + 0.5 * sigma_g ** 2 * pred_s diffusion_noise = sigma_g * math.sqrt(dt) * torch.randn_like(x_t) x_t = x_t + drift * dt + diffusion_noise else: x_t = x_t + pred_v * dt else: # PF-ODE: torchdiffeq RK4 (matches scDFM inference) def ode_func(t_scalar, x): t_batch = torch.full((B,), t_scalar.item(), device=device) pred_v, _, _ = self.model( gene_ids, source, x, t_batch, perturbation_id) return pred_v t_span = torch.linspace(0, 1, steps, device=device) trajectory = torchdiffeq.odeint( ode_func, x_0, t_span, method="rk4", atol=1e-4, rtol=1e-4, ) x_t = trajectory[-1] return torch.clamp(x_t, min=0)