DeepTraCDR/case_study/model.py

# model.py
import numpy as np
import torch
import torch.nn as nn
import torch.nn.functional as F
from torch.nn import MultiheadAttention, TransformerEncoder, TransformerEncoderLayer
from utils import torch_corr_x_y, cross_entropy_loss, prototypical_loss
from sklearn.metrics import roc_auc_score, average_precision_score


class ConstructAdjMatrix(nn.Module):
    """Module to construct normalized adjacency matrices for graph-based operations."""
    def __init__(self, original_adj_mat, device="cpu"):
        """
        Initialize the adjacency matrix constructor.

        Args:
            original_adj_mat (np.ndarray or torch.Tensor): Original adjacency matrix.
            device (str): Device to perform computations on (e.g., 'cpu' or 'cuda:0').
        """
        super().__init__()
        # Convert NumPy array to PyTorch tensor if necessary
        if isinstance(original_adj_mat, np.ndarray):
            original_adj_mat = torch.from_numpy(original_adj_mat).float()
        self.adj = original_adj_mat.to(device)
        self.device = device

    def forward(self):
        """
        Compute normalized adjacency matrices for cells and drugs.

        Returns:
            tuple: (agg_cell_lp, agg_drug_lp, self_cell_lp, self_drug_lp) normalized matrices.
        """
        with torch.no_grad():
            # Compute degree-normalized matrices
            d_x = torch.diag(torch.pow(torch.sum(self.adj, dim=1) + 1, -0.5))
            d_y = torch.diag(torch.pow(torch.sum(self.adj, dim=0) + 1, -0.5))
            agg_cell_lp = torch.mm(torch.mm(d_x, self.adj), d_y)
            agg_drug_lp = torch.mm(torch.mm(d_y, self.adj.T), d_x)
            self_cell_lp = torch.diag(torch.add(torch.pow(torch.sum(self.adj, dim=1) + 1, -1), 1))
            self_drug_lp = torch.diag(torch.add(torch.pow(torch.sum(self.adj, dim=0) + 1, -1), 1))

        return (
            agg_cell_lp.to(self.device),
            agg_drug_lp.to(self.device),
            self_cell_lp.to(self.device),
            self_drug_lp.to(self.device)
        )


class LoadFeature(nn.Module):
    """Module to load and preprocess cell and drug features."""
    def __init__(self, cell_exprs, drug_fingerprints, device="cpu"):
        """
        Initialize feature loading and preprocessing layers.

        Args:
            cell_exprs (np.ndarray): Cell expression data.
            drug_fingerprints (list): List of drug fingerprint arrays.
            device (str): Device to perform computations on.
        """
        super().__init__()
        self.device = device
        self.cell_exprs = torch.from_numpy(cell_exprs).float().to(device)
        self.drug_fingerprints = [torch.from_numpy(fp).float().to(device) for fp in drug_fingerprints]

        # Projection layers for drug fingerprints
        self.drug_proj = nn.ModuleList([
            nn.Sequential(
                nn.Linear(fp.shape[1], 512),
                nn.BatchNorm1d(512),
                nn.GELU(),
                nn.Dropout(0.3)
            ).to(device) for fp in drug_fingerprints
        ])

        # Transformer encoder for drug features
        self.transformer = TransformerEncoder(
            TransformerEncoderLayer(
                d_model=512,
                nhead=8,
                dim_feedforward=2048,
                batch_first=True
            ),
            num_layers=3
        ).to(device)

        # Normalization layers
        self.cell_norm = nn.LayerNorm(cell_exprs.shape[1]).to(device)
        self.drug_norm = nn.LayerNorm(512).to(device)

        # Encoder for cell features
        self.cell_encoder = nn.Sequential(
            nn.Linear(cell_exprs.shape[1], 1024),
            nn.BatchNorm1d(1024),
            nn.GELU(),
            nn.Dropout(0.3),
            nn.Linear(1024, 512)
        ).to(device)

    def forward(self):
        """
        Process cell and drug features through encoding and transformation.

        Returns:
            tuple: (cell_encoded, drug_feat) encoded cell and drug features.
        """
        # Normalize and encode cell features
        cell_feat = self.cell_norm(self.cell_exprs)
        cell_encoded = self.cell_encoder(cell_feat)

        # Project and transform drug fingerprints
        projected = [proj(fp) for proj, fp in zip(self.drug_proj, self.drug_fingerprints)]
        stacked = torch.stack(projected, dim=1)
        drug_feat = self.transformer(stacked)
        drug_feat = self.drug_norm(drug_feat.mean(dim=1))

        return cell_encoded, drug_feat


class GEncoder(nn.Module):
    """Graph encoder module for processing cell and drug embeddings."""
    def __init__(self, agg_c_lp, agg_d_lp, self_c_lp, self_d_lp, device="cpu"):
        """
        Initialize the graph encoder.

        Args:
            agg_c_lp (torch.Tensor): Aggregated cell Laplacian matrix.
            agg_d_lp (torch.Tensor): Aggregated drug Laplacian matrix.
            self_c_lp (torch.Tensor): Self-loop cell Laplacian matrix.
            self_d_lp (torch.Tensor): Self-loop drug Laplacian matrix.
            device (str): Device to perform computations on.
        """
        super().__init__()
        self.agg_c_lp = agg_c_lp
        self.agg_d_lp = agg_d_lp
        self.self_c_lp = self_c_lp
        self.self_d_lp = self_d_lp
        self.device = device

        # Cell feature encoder
        self.cell_encoder = nn.Sequential(
            nn.Linear(512, 1024),
            nn.BatchNorm1d(1024),
            nn.GELU(),
            nn.Dropout(0.3),
            nn.Linear(1024, 512)
        ).to(device)

        # Drug feature encoder
        self.drug_encoder = nn.Sequential(
            nn.Linear(512, 1024),
            nn.BatchNorm1d(1024),
            nn.GELU(),
            nn.Dropout(0.3),
            nn.Linear(1024, 512)
        ).to(device)

        # Attention mechanism
        self.attention = MultiheadAttention(embed_dim=512, num_heads=8, batch_first=True).to(device)
        self.residual = nn.Linear(512, 512).to(device)
        self.fc = nn.Sequential(
            nn.Linear(1024, 512),
            nn.BatchNorm1d(512),
            nn.GELU(),
            nn.Dropout(0.2)
        ).to(device)

    def forward(self, cell_f, drug_f):
        """
        Encode cell and drug features using graph-based aggregation and attention.

        Args:
            cell_f (torch.Tensor): Cell features.
            drug_f (torch.Tensor): Drug features.

        Returns:
            tuple: (cell_emb, drug_emb) encoded embeddings.
        """
        # Aggregate features using Laplacian matrices
        cell_agg = torch.mm(self.agg_c_lp, drug_f) + torch.mm(self.self_c_lp, cell_f)
        drug_agg = torch.mm(self.agg_d_lp, cell_f) + torch.mm(self.self_d_lp, drug_f)

        # Encode aggregated features
        cell_fc = self.cell_encoder(cell_agg)
        drug_fc = self.drug_encoder(drug_agg)

        # Apply attention mechanism
        attn_output, _ = self.attention(
            query=cell_fc.unsqueeze(0),
            key=drug_fc.unsqueeze(0),
            value=drug_fc.unsqueeze(0)
        )
        attn_output = attn_output.squeeze(0)
        cell_emb = cell_fc + self.residual(attn_output)

        # Apply final activation
        cell_emb = F.gelu(cell_emb)
        drug_emb = F.gelu(drug_fc)

        return cell_emb, drug_emb


class GDecoder(nn.Module):
    """Decoder module to predict interaction scores from embeddings."""
    def __init__(self, emb_dim, gamma):
        """
        Initialize the decoder.

        Args:
            emb_dim (int): Embedding dimension.
            gamma (float): Scaling factor for output scores.
        """
        super().__init__()
        self.gamma = gamma
        self.decoder = nn.Sequential(
            nn.Linear(2 * emb_dim, 1024),
            nn.BatchNorm1d(1024),
            nn.GELU(),
            nn.Dropout(0.2),
            nn.Linear(1024, 1)
        )
        self.corr_weight = nn.Parameter(torch.tensor(0.5))

    def forward(self, cell_emb, drug_emb):
        """
        Decode embeddings to predict interaction scores.

        Args:
            cell_emb (torch.Tensor): Cell embeddings.
            drug_emb (torch.Tensor): Drug embeddings.

        Returns:
            torch.Tensor: Predicted interaction scores.
        """
        # Expand embeddings for pairwise combinations
        cell_exp = cell_emb.unsqueeze(1).repeat(1, drug_emb.size(0), 1)
        drug_exp = drug_emb.unsqueeze(0).repeat(cell_emb.size(0), 1, 1)
        combined = torch.cat([cell_exp, drug_exp], dim=-1)

        # Decode combined embeddings
        scores = self.decoder(combined.view(-1, 2 * cell_emb.size(1))).view(cell_emb.size(0), drug_emb.size(0))
        corr = torch_corr_x_y(cell_emb, drug_emb)

        # Combine scores with correlation and apply sigmoid
        return torch.sigmoid(self.gamma * (self.corr_weight * scores + (1 - self.corr_weight) * corr))


class DeepTraCDR(nn.Module):
    """DeepTraCDR model for cell-drug interaction prediction."""
    def __init__(self, adj_mat, cell_exprs, drug_finger, layer_size, gamma, device="cpu"):
        """
        Initialize the DeepTraCDR model.

        Args:
            adj_mat (np.ndarray or torch.Tensor): Adjacency matrix.
            cell_exprs (np.ndarray): Cell expression data.
            drug_finger (list): Drug fingerprints.
            layer_size (list): Layer sizes for the model.
            gamma (float): Scaling factor for decoder.
            device (str): Device to perform computations on.
        """
        super().__init__()
        self.device = device
        if isinstance(adj_mat, np.ndarray):
            adj_mat = torch.from_numpy(adj_mat).float()
        self.adj_mat = adj_mat.to(device)

        # Initialize submodules
        self.construct_adj = ConstructAdjMatrix(self.adj_mat, device=device)
        self.load_feat = LoadFeature(cell_exprs, drug_finger, device=device)

        # Compute fixed adjacency matrices
        agg_c, agg_d, self_c, self_d = self.construct_adj()

        self.encoder = GEncoder(agg_c, agg_d, self_c, self_d, device=device).to(device)
        self.decoder = GDecoder(512, gamma).to(device)  # Fixed emb_dim to 512

    def forward(self):
        """
        Forward pass through the DeepTraCDR model.

        Returns:
            tuple: (predicted_scores, cell_emb, drug_emb) predicted scores and embeddings.
        """
        cell_f, drug_f = self.load_feat()
        cell_emb, drug_emb = self.encoder(cell_f, drug_f)
        return self.decoder(cell_emb, drug_emb), cell_emb, drug_emb

    def get_cell_embeddings(self):
        """
        Retrieve cell embeddings from the model.

        Returns:
            torch.Tensor: Cell embeddings.
        """
        cell_f, drug_f = self.load_feat()
        cell_emb, _ = self.encoder(cell_f, drug_f)
        return cell_emb


class Optimizer:
    """Optimizer class for training the DeepTraCDR model with early stopping."""
    def __init__(self, model, train_data, test_data, test_mask, train_mask, adj_matrix, evaluate_fun,
                 lr=0.001, wd=1e-05, epochs=200, test_freq=20, patience=50, device="cpu"):
        """
        Initialize the optimizer.

        Args:
            model (nn.Module): DeepTraCDR model to optimize.
            train_data (torch.Tensor): Training data.
            test_data (torch.Tensor): Test data.
            test_mask (torch.Tensor): Test mask.
            train_mask (torch.Tensor): Training mask.
            adj_matrix (torch.Tensor): Adjacency matrix.
            evaluate_fun (callable): Evaluation function.
            lr (float): Learning rate.
            wd (float): Weight decay.
            epochs (int): Number of training epochs.
            test_freq (int): Frequency of evaluation.
            patience (int): Patience for early stopping.
            device (str): Device to perform computations on.
        """
        self.model = model.to(device)
        self.train_data = train_data.float().to(device)
        self.test_data = test_data.float().to(device)
        self.train_mask = train_mask.to(device)
        self.test_mask_bool = test_mask.to(device).bool()
        self.adj_matrix = adj_matrix.to(device)
        self.evaluate_fun = evaluate_fun
        self.optimizer = torch.optim.Adam(self.model.parameters(), lr=lr, weight_decay=wd)
        self.epochs = epochs
        self.test_freq = test_freq
        self.patience = patience
        self.best_auc = 0.0
        self.best_auprc = 0.0
        self.best_weights = None
        self.counter = 0
        self.device = device
        self.best_epoch_auc = None
        self.best_epoch_auprc = None

    def train(self):
        """
        Train the model with early stopping and evaluate performance.

        Returns:
            tuple: (true_data, final_pred_masked, best_auc, best_auprc) evaluation results.
        """
        true_data = torch.masked_select(self.test_data, self.test_mask_bool).cpu().numpy()

        for epoch in range(self.epochs):
            self.model.train()
            # Forward pass and compute loss
            pred_train, cell_emb, drug_emb = self.model()
            ce_loss = cross_entropy_loss(self.train_data, pred_train, self.train_mask)
            proto_loss = prototypical_loss(cell_emb, drug_emb, self.adj_matrix)
            total_loss = 0.7 * ce_loss + 0.3 * proto_loss

            # Backpropagation
            self.optimizer.zero_grad()
            total_loss.backward()
            self.optimizer.step()

            self.model.eval()
            with torch.no_grad():
                # Evaluate training performance
                train_pred, _, _ = self.model()
                train_pred_masked = torch.masked_select(train_pred, self.train_mask).cpu().numpy()
                train_true_data = torch.masked_select(self.train_data, self.train_mask).cpu().numpy()
                try:
                    train_auc = roc_auc_score(train_true_data, train_pred_masked)
                    train_auprc = average_precision_score(train_true_data, train_pred_masked)
                except ValueError:
                    train_auc, train_auprc = 0.0, 0.0

                # Evaluate test performance
                pred_eval, _, _ = self.model()
                pred_masked = torch.masked_select(pred_eval, self.test_mask_bool).cpu().numpy()
                try:
                    auc = roc_auc_score(true_data, pred_masked)
                    auprc = average_precision_score(true_data, pred_masked)
                except ValueError:
                    auc, auprc = 0.0, 0.0

            # Update best metrics and weights
            if auc > self.best_auc:
                self.best_auc = auc
                self.best_auprc = auprc
                self.best_weights = self.model.state_dict().copy()
                self.counter = 0
                self.best_epoch_auc = auc
                self.best_epoch_auprc = auprc
            else:
                self.counter += 1

            # Log progress
            if epoch % self.test_freq == 0 or epoch == self.epochs - 1:
                print(f"Epoch {epoch}: Loss={total_loss.item():.4f}, Train AUC={train_auc:.4f}, "
                      f"Train AUPRC={train_auprc:.4f}, Test AUC={auc:.4f}, Test AUPRC={auprc:.4f}")

            # Check early stopping
            if self.counter >= self.patience:
                print(f"\nEarly stopping triggered at epoch {epoch}!")
                print(f"No improvement in AUC for {self.patience} consecutive epochs.")
                break

        # Restore best weights
        if self.best_weights is not None:
            self.model.load_state_dict(self.best_weights)

        # Final evaluation
        self.model.eval()
        with torch.no_grad():
            final_pred, _, _ = self.model()
            final_pred_masked = torch.masked_select(final_pred, self.test_mask_bool).cpu().numpy()
            best_auc = roc_auc_score(true_data, final_pred_masked)
            best_auprc = average_precision_score(true_data, final_pred_masked)

        # Log final results
        print("\nBest Metrics After Training (on Test Data):")
        print(f"AUC: {self.best_auc:.4f}")
        print(f"AUPRC: {self.best_auprc:.4f}")

        return true_data, final_pred_masked, self.best_auc, self.best_auprc