@synsci/cli-darwin-x64-baseline 1.1.77 → 1.1.78

package/bin/skills/scvi-tools/references/models-specialized.md

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+# Specialized Modality Models
+
+This document covers models for specialized single-cell data modalities in scvi-tools.
+
+## MethylVI / MethylANVI (Methylation Analysis)
+
+**Purpose**: Analysis of single-cell bisulfite sequencing (scBS-seq) data for DNA methylation.
+
+**Key Features**:
+- Models methylation patterns at single-cell resolution
+- Handles sparsity in methylation data
+- Batch correction for methylation experiments
+- Label transfer (MethylANVI) for cell type annotation
+
+**When to Use**:
+- Analyzing scBS-seq or similar methylation data
+- Studying DNA methylation patterns across cell types
+- Integrating methylation data across batches
+- Cell type annotation based on methylation profiles
+
+**Data Requirements**:
+- Methylation count matrices (methylated vs. total reads per CpG site)
+- Format: Cells × CpG sites with methylation ratios or counts
+
+### MethylVI (Unsupervised)
+
+**Basic Usage**:
+```python
+import scvi
+
+# Setup methylation data
+scvi.model.METHYLVI.setup_anndata(
+    adata,
+    layer="methylation_counts",  # Methylation data
+    batch_key="batch"
+)
+
+model = scvi.model.METHYLVI(adata)
+model.train()
+
+# Get latent representation
+latent = model.get_latent_representation()
+
+# Get normalized methylation values
+normalized_meth = model.get_normalized_methylation()
+```
+
+### MethylANVI (Semi-supervised with cell types)
+
+**Basic Usage**:
+```python
+# Setup with cell type labels
+scvi.model.METHYLANVI.setup_anndata(
+    adata,
+    layer="methylation_counts",
+    batch_key="batch",
+    labels_key="cell_type",
+    unlabeled_category="Unknown"
+)
+
+model = scvi.model.METHYLANVI(adata)
+model.train()
+
+# Predict cell types
+predictions = model.predict()
+```
+
+**Key Parameters**:
+- `n_latent`: Latent dimensionality
+- `region_factors`: Model region-specific effects
+
+**Use Cases**:
+- Epigenetic heterogeneity analysis
+- Cell type identification via methylation
+- Integration with gene expression data (separate analysis)
+- Differential methylation analysis
+
+## CytoVI (Flow and Mass Cytometry)
+
+**Purpose**: Batch correction and integration of flow cytometry and mass cytometry (CyTOF) data.
+
+**Key Features**:
+- Handles antibody-based protein measurements
+- Corrects batch effects in cytometry data
+- Enables integration across experiments
+- Designed for high-dimensional protein panels
+
+**When to Use**:
+- Analyzing flow cytometry or CyTOF data
+- Integrating cytometry experiments across batches
+- Batch correction for protein panels
+- Cross-study cytometry integration
+
+**Data Requirements**:
+- Protein expression matrix (cells × proteins)
+- Flow cytometry or CyTOF measurements
+- Batch/experiment annotations
+
+**Basic Usage**:
+```python
+scvi.model.CYTOVI.setup_anndata(
+    adata,
+    protein_expression_obsm_key="protein_expression",
+    batch_key="batch"
+)
+
+model = scvi.model.CYTOVI(adata)
+model.train()
+
+# Get batch-corrected representation
+latent = model.get_latent_representation()
+
+# Get normalized protein values
+normalized = model.get_normalized_expression()
+```
+
+**Key Parameters**:
+- `n_latent`: Latent space dimensionality
+- `n_layers`: Network depth
+
+**Typical Workflow**:
+```python
+import scanpy as sc
+
+# 1. Load cytometry data
+adata = sc.read_h5ad("cytof_data.h5ad")
+
+# 2. Train CytoVI
+scvi.model.CYTOVI.setup_anndata(
+    adata,
+    protein_expression_obsm_key="protein",
+    batch_key="experiment"
+)
+model = scvi.model.CYTOVI(adata)
+model.train()
+
+# 3. Get batch-corrected values
+latent = model.get_latent_representation()
+adata.obsm["X_CytoVI"] = latent
+
+# 4. Downstream analysis
+sc.pp.neighbors(adata, use_rep="X_CytoVI")
+sc.tl.umap(adata)
+sc.tl.leiden(adata)
+
+# 5. Visualize batch correction
+sc.pl.umap(adata, color=["batch", "leiden"])
+```
+
+## SysVI (Systems-level Integration)
+
+**Purpose**: Batch effect correction with emphasis on preserving biological variation.
+
+**Key Features**:
+- Specialized batch integration approach
+- Preserves biological signals while removing technical effects
+- Designed for large-scale integration studies
+
+**When to Use**:
+- Large-scale multi-batch integration
+- Need to preserve subtle biological variation
+- Systems-level analysis across many studies
+
+**Basic Usage**:
+```python
+scvi.model.SYSVI.setup_anndata(
+    adata,
+    layer="counts",
+    batch_key="batch"
+)
+
+model = scvi.model.SYSVI(adata)
+model.train()
+
+latent = model.get_latent_representation()
+```
+
+## Decipher (Trajectory Inference)
+
+**Purpose**: Trajectory inference and pseudotime analysis for single-cell data.
+
+**Key Features**:
+- Learns cellular trajectories and differentiation paths
+- Pseudotime estimation
+- Accounts for uncertainty in trajectory structure
+- Compatible with scVI embeddings
+
+**When to Use**:
+- Studying cellular differentiation
+- Time-course or developmental datasets
+- Understanding cell state transitions
+- Identifying branching points in development
+
+**Basic Usage**:
+```python
+# Typically used after scVI for embeddings
+scvi_model = scvi.model.SCVI(adata)
+scvi_model.train()
+
+# Decipher for trajectory
+scvi.model.DECIPHER.setup_anndata(adata)
+decipher_model = scvi.model.DECIPHER(adata, scvi_model)
+decipher_model.train()
+
+# Get pseudotime
+pseudotime = decipher_model.get_pseudotime()
+adata.obs["pseudotime"] = pseudotime
+```
+
+**Visualization**:
+```python
+import scanpy as sc
+
+# Plot pseudotime on UMAP
+sc.pl.umap(adata, color="pseudotime", cmap="viridis")
+
+# Gene expression along pseudotime
+sc.pl.scatter(adata, x="pseudotime", y="gene_of_interest")
+```
+
+## peRegLM (Peak Regulatory Linear Model)
+
+**Purpose**: Linking chromatin accessibility to gene expression for regulatory analysis.
+
+**Key Features**:
+- Links ATAC-seq peaks to gene expression
+- Identifies regulatory relationships
+- Works with paired multiome data
+
+**When to Use**:
+- Multiome data (RNA + ATAC from same cells)
+- Understanding gene regulation
+- Linking peaks to target genes
+- Regulatory network construction
+
+**Basic Usage**:
+```python
+# Requires paired RNA + ATAC data
+scvi.model.PEREGLM.setup_anndata(
+    multiome_adata,
+    rna_layer="counts",
+    atac_layer="atac_counts"
+)
+
+model = scvi.model.PEREGLM(multiome_adata)
+model.train()
+
+# Get peak-gene links
+peak_gene_links = model.get_regulatory_links()
+```
+
+## Model-Specific Best Practices
+
+### MethylVI/MethylANVI
+1. **Sparsity**: Methylation data is inherently sparse; model accounts for this
+2. **CpG selection**: Filter CpGs with very low coverage
+3. **Biological interpretation**: Consider genomic context (promoters, enhancers)
+4. **Integration**: For multi-omics, analyze separately then integrate results
+
+### CytoVI
+1. **Protein QC**: Remove low-quality or uninformative proteins
+2. **Compensation**: Ensure proper spectral compensation before analysis
+3. **Batch design**: Include biological and technical replicates
+4. **Controls**: Use control samples to validate batch correction
+
+### SysVI
+1. **Sample size**: Designed for large-scale integration
+2. **Batch definition**: Carefully define batch structure
+3. **Biological validation**: Verify biological signals preserved
+
+### Decipher
+1. **Start point**: Define trajectory start cells if known
+2. **Branching**: Specify expected number of branches
+3. **Validation**: Use known markers to validate pseudotime
+4. **Integration**: Works well with scVI embeddings
+
+## Integration with Other Models
+
+Many specialized models work well in combination:
+
+**Methylation + Expression**:
+```python
+# Analyze separately, then integrate
+methylvi_model = scvi.model.METHYLVI(meth_adata)
+scvi_model = scvi.model.SCVI(rna_adata)
+
+# Integrate results at analysis level
+# E.g., correlate methylation and expression patterns
+```
+
+**Cytometry + CITE-seq**:
+```python
+# CytoVI for flow/CyTOF
+cyto_model = scvi.model.CYTOVI(cyto_adata)
+
+# totalVI for CITE-seq
+cite_model = scvi.model.TOTALVI(cite_adata)
+
+# Compare protein measurements across platforms
+```
+
+**ATAC + RNA (Multiome)**:
+```python
+# MultiVI for joint analysis
+multivi_model = scvi.model.MULTIVI(multiome_adata)
+
+# peRegLM for regulatory links
+pereglm_model = scvi.model.PEREGLM(multiome_adata)
+```
+
+## Choosing Specialized Models
+
+### Decision Tree
+
+1. **What data modality?**
+   - Methylation → MethylVI/MethylANVI
+   - Flow/CyTOF → CytoVI
+   - Trajectory → Decipher
+   - Multi-batch integration → SysVI
+   - Regulatory links → peRegLM
+
+2. **Do you have labels?**
+   - Yes → MethylANVI (methylation)
+   - No → MethylVI (methylation)
+
+3. **What's your main goal?**
+   - Batch correction → CytoVI, SysVI
+   - Trajectory/pseudotime → Decipher
+   - Peak-gene links → peRegLM
+   - Methylation patterns → MethylVI/ANVI
+
+## Example: Complete Methylation Analysis
+
+```python
+import scvi
+import scanpy as sc
+
+# 1. Load methylation data
+meth_adata = sc.read_h5ad("methylation_data.h5ad")
+
+# 2. QC: filter low-coverage CpG sites
+sc.pp.filter_genes(meth_adata, min_cells=10)
+
+# 3. Setup MethylVI
+scvi.model.METHYLVI.setup_anndata(
+    meth_adata,
+    layer="methylation",
+    batch_key="batch"
+)
+
+# 4. Train model
+model = scvi.model.METHYLVI(meth_adata, n_latent=15)
+model.train(max_epochs=400)
+
+# 5. Get latent representation
+latent = model.get_latent_representation()
+meth_adata.obsm["X_MethylVI"] = latent
+
+# 6. Clustering
+sc.pp.neighbors(meth_adata, use_rep="X_MethylVI")
+sc.tl.umap(meth_adata)
+sc.tl.leiden(meth_adata)
+
+# 7. Differential methylation
+dm_results = model.differential_methylation(
+    groupby="leiden",
+    group1="0",
+    group2="1"
+)
+
+# 8. Save
+model.save("methylvi_model")
+meth_adata.write("methylation_analyzed.h5ad")
+```
+
+## External Tools Integration
+
+Some specialized models are available as external packages:
+
+**SOLO** (doublet detection):
+```python
+from scvi.external import SOLO
+
+solo = SOLO.from_scvi_model(scvi_model)
+solo.train()
+doublets = solo.predict()
+```
+
+**scArches** (reference mapping):
+```python
+from scvi.external import SCARCHES
+
+# For transfer learning and query-to-reference mapping
+```
+
+These external tools extend scvi-tools functionality for specific use cases.
+
+## Summary Table
+
+| Model | Data Type | Primary Use | Supervised? |
+|-------|-----------|-------------|-------------|
+| MethylVI | Methylation | Unsupervised analysis | No |
+| MethylANVI | Methylation | Cell type annotation | Semi |
+| CytoVI | Cytometry | Batch correction | No |
+| SysVI | scRNA-seq | Large-scale integration | No |
+| Decipher | scRNA-seq | Trajectory inference | No |
+| peRegLM | Multiome | Peak-gene links | No |
+| SOLO | scRNA-seq | Doublet detection | Semi |