train/SB/SA7/src/denoiser.py

"""
SACFMDenoiser — Source-Anchored Conditional Flow Matching.

Training: x_0 = source + sigma_aug * eps (noisy source, not pure noise).
          Standard affine path: x_t = (1-t)*x_0 + t*target.
          Velocity target: dx_t = target - x_0.
          Gene-weighted MSE loss.

Inference: ODE from clean source (no noise, no SDE).
"""

import torch
import torch.nn as nn
import torchdiffeq

from ._scdfm_imports import AffineProbPath, CondOTScheduler


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 SACFMDenoiser(nn.Module):
    """
    Source-Anchored Conditional Flow Matching Denoiser.

    Key differences from scDFM baseline:
    - x_0 = source + sigma_aug * eps (not pure noise)
    - Gene-weighted velocity loss
    - Inference starts from clean source

    Key differences from SB:
    - No SigmaNet (sigma_aug is fixed, data-driven)
    - No ScoreDecoder
    - No SDE inference
    - No bridge formulation (standard affine path)
    """

    def __init__(
        self,
        model: nn.Module,
        sigma_aug: torch.Tensor,       # (G,) per-gene augmentation noise
        gene_weight: torch.Tensor,      # (G,) per-gene loss weight
        noise_type: str = "Gaussian",
        use_mmd_loss: bool = True,
        gamma: float = 0.5,
    ):
        super().__init__()
        self.model = model
        self.noise_type = noise_type
        self.use_mmd_loss = use_mmd_loss
        self.gamma = gamma

        # Fixed per-gene tensors (not learned)
        self.register_buffer("sigma_aug", sigma_aug)
        self.register_buffer("gene_weight", gene_weight)

        # Standard affine flow matching path (same as scDFM)
        self.flow_path = AffineProbPath(scheduler=CondOTScheduler())

    def train_step(
        self,
        source: torch.Tensor,          # (B, G_sub) control expression
        target: torch.Tensor,          # (B, G_sub) perturbed expression
        perturbation_id: torch.Tensor, # (B, n_pert)
        gene_input: torch.Tensor,      # (B, G_sub) vocab-encoded gene IDs
        input_gene_ids: torch.Tensor,  # (G_sub,) indices into full gene set
    ) -> dict:
        B = source.shape[0]
        device = source.device

        # 1. Sample time (uniform, clamped away from boundaries)
        t = torch.rand(B, device=device).clamp(1e-5, 1 - 1e-5)

        # 2. Look up per-gene sigma and weight for current gene subset
        sigma_sub = self.sigma_aug[input_gene_ids]      # (G_sub,)
        weight_sub = self.gene_weight[input_gene_ids]    # (G_sub,)

        # 3. Source-anchored x_0 with data-driven augmentation noise
        eps = torch.randn_like(source)
        x_0 = source + sigma_sub.unsqueeze(0) * eps     # (B, G_sub)

        # 4. Standard affine flow matching (reuses scDFM AffineProbPath)
        #    x_t = (1-t)*x_0 + t*target
        #    dx_t = target - x_0 = (target - source) - sigma * eps
        path_sample = self.flow_path.sample(t=t, x_0=x_0, x_1=target)

        # 5. Model forward (scDFM convention: cell_1=x_t, cell_2=source)
        pred_v = self.model(
            gene_input, path_sample.x_t, path_sample.t, source,
            perturbation_id, gene_input, mode="predict_y",
        )

        # 6. Gene-weighted velocity loss
        loss_v = (weight_sub.unsqueeze(0) * (pred_v - path_sample.dx_t) ** 2).mean()

        # 7. MMD loss (optional, same as scDFM baseline)
        loss_mmd = torch.tensor(0.0, device=device)
        if self.use_mmd_loss:
            t_col = t.unsqueeze(-1)
            x1_hat = path_sample.x_t + pred_v * (1 - t_col)
            sigmas_mmd = median_sigmas(target, scales=(0.5, 1.0, 2.0, 4.0))
            loss_mmd = mmd2_unbiased_multi_sigma(x1_hat, target, sigmas_mmd)

        loss = loss_v + self.gamma * loss_mmd

        return {
            "loss": loss,
            "loss_v": loss_v.detach(),
            "loss_mmd": loss_mmd.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 = 20,
        method: str = "rk4",
    ) -> torch.Tensor:
        """Generate perturbed expression via PF-ODE starting from clean source."""
        B, G = source.shape
        device = source.device

        if gene_ids.dim() == 1:
            gene_ids = gene_ids.unsqueeze(0).expand(B, -1)

        # Start from clean source (no augmentation noise at inference)
        x_0 = source.clone()

        def ode_func(t_scalar, x):
            t_batch = torch.full((B,), t_scalar.item(), device=device)
            pred_v = self.model(
                gene_ids, x, t_batch, source,
                perturbation_id, gene_ids, mode="predict_y",
            )
            return pred_v

        t_span = torch.linspace(0, 1, steps, device=device)
        trajectory = torchdiffeq.odeint(
            ode_func, x_0, t_span,
            method=method, atol=1e-4, rtol=1e-4,
        )
        return torch.clamp(trajectory[-1], min=0)