opencode-knowledge-work 0.0.0-stage → 0.1.1

package/content/bio-research/skills/bio-research-single-cell-rna-qc/LICENSE.txt

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package/content/bio-research/skills/bio-research-single-cell-rna-qc/SKILL.md

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+---
+name: single-cell-rna-qc
+description: Performs quality control on single-cell RNA-seq data (.h5ad or .h5 files) using scverse best practices with MAD-based filtering and comprehensive visualizations. Use when users request QC analysis, filtering low-quality cells, assessing data quality, or following scverse/scanpy best practices for single-cell analysis.
+---
+
+# Single-Cell RNA-seq Quality Control
+
+Automated QC workflow for single-cell RNA-seq data following scverse best practices.
+
+## When to Use This Skill
+
+Use when users:
+- Request quality control or QC on single-cell RNA-seq data
+- Want to filter low-quality cells or assess data quality
+- Need QC visualizations or metrics
+- Ask to follow scverse/scanpy best practices
+- Request MAD-based filtering or outlier detection
+
+**Supported input formats:**
+- `.h5ad` files (AnnData format from scanpy/Python workflows)
+- `.h5` files (10X Genomics Cell Ranger output)
+
+**Default recommendation**: Use Approach 1 (complete pipeline) unless the user has specific custom requirements or explicitly requests non-standard filtering logic.
+
+## Approach 1: Complete QC Pipeline (Recommended for Standard Workflows)
+
+For standard QC following scverse best practices, use the convenience script `scripts/qc_analysis.py`:
+
+```bash
+python3 scripts/qc_analysis.py input.h5ad
+# or for 10X Genomics .h5 files:
+python3 scripts/qc_analysis.py raw_feature_bc_matrix.h5
+```
+
+The script automatically detects the file format and loads it appropriately.
+
+**When to use this approach:**
+- Standard QC workflow with adjustable thresholds (all cells filtered the same way)
+- Batch processing multiple datasets
+- Quick exploratory analysis
+- User wants the "just works" solution
+
+**Requirements:** anndata, scanpy, scipy, matplotlib, seaborn, numpy
+
+**Parameters:**
+
+Customize filtering thresholds and gene patterns using command-line parameters:
+- `--output-dir` - Output directory
+- `--mad-counts`, `--mad-genes`, `--mad-mt` - MAD thresholds for counts/genes/MT%
+- `--mt-threshold` - Hard mitochondrial % cutoff
+- `--min-cells` - Gene filtering threshold
+- `--mt-pattern`, `--ribo-pattern`, `--hb-pattern` - Gene name patterns for different species
+
+Use `--help` to see current default values.
+
+**Outputs:**
+
+All files are saved to `<input_basename>_qc_results/` directory by default (or to the directory specified by `--output-dir`):
+- `qc_metrics_before_filtering.png` - Pre-filtering visualizations
+- `qc_filtering_thresholds.png` - MAD-based threshold overlays
+- `qc_metrics_after_filtering.png` - Post-filtering quality metrics
+- `<input_basename>_filtered.h5ad` - Clean, filtered dataset ready for downstream analysis
+- `<input_basename>_with_qc.h5ad` - Original data with QC annotations preserved
+
+If copying outputs for user access, copy individual files (not the entire directory) so users can preview them directly.
+
+### Workflow Steps
+
+The script performs the following steps:
+
+1. **Calculate QC metrics** - Count depth, gene detection, mitochondrial/ribosomal/hemoglobin content
+2. **Apply MAD-based filtering** - Permissive outlier detection using MAD thresholds for counts/genes/MT%
+3. **Filter genes** - Remove genes detected in few cells
+4. **Generate visualizations** - Comprehensive before/after plots with threshold overlays
+
+## Approach 2: Modular Building Blocks (For Custom Workflows)
+
+For custom analysis workflows or non-standard requirements, use the modular utility functions from `scripts/qc_core.py` and `scripts/qc_plotting.py`:
+
+```python
+# Run from scripts/ directory, or add scripts/ to sys.path if needed
+import anndata as ad
+from qc_core import calculate_qc_metrics, detect_outliers_mad, filter_cells
+from qc_plotting import plot_qc_distributions  # Only if visualization needed
+
+adata = ad.read_h5ad('input.h5ad')
+calculate_qc_metrics(adata, inplace=True)
+# ... custom analysis logic here
+```
+
+**When to use this approach:**
+- Different workflow needed (skip steps, change order, apply different thresholds to subsets)
+- Conditional logic (e.g., filter neurons differently than other cells)
+- Partial execution (only metrics/visualization, no filtering)
+- Integration with other analysis steps in a larger pipeline
+- Custom filtering criteria beyond what command-line params support
+
+**Available utility functions:**
+
+From `qc_core.py` (core QC operations):
+- `calculate_qc_metrics(adata, mt_pattern, ribo_pattern, hb_pattern, inplace=True)` - Calculate QC metrics and annotate adata
+- `detect_outliers_mad(adata, metric, n_mads, verbose=True)` - MAD-based outlier detection, returns boolean mask
+- `apply_hard_threshold(adata, metric, threshold, operator='>', verbose=True)` - Apply hard cutoffs, returns boolean mask
+- `filter_cells(adata, mask, inplace=False)` - Apply boolean mask to filter cells
+- `filter_genes(adata, min_cells=20, min_counts=None, inplace=True)` - Filter genes by detection
+- `print_qc_summary(adata, label='')` - Print summary statistics
+
+From `qc_plotting.py` (visualization):
+- `plot_qc_distributions(adata, output_path, title)` - Generate comprehensive QC plots
+- `plot_filtering_thresholds(adata, outlier_masks, thresholds, output_path)` - Visualize filtering thresholds
+- `plot_qc_after_filtering(adata, output_path)` - Generate post-filtering plots
+
+**Example custom workflows:**
+
+**Example 1: Only calculate metrics and visualize, don't filter yet**
+```python
+adata = ad.read_h5ad('input.h5ad')
+calculate_qc_metrics(adata, inplace=True)
+plot_qc_distributions(adata, 'qc_before.png', title='Initial QC')
+print_qc_summary(adata, label='Before filtering')
+```
+
+**Example 2: Apply only MT% filtering, keep other metrics permissive**
+```python
+adata = ad.read_h5ad('input.h5ad')
+calculate_qc_metrics(adata, inplace=True)
+
+# Only filter high MT% cells
+high_mt = apply_hard_threshold(adata, 'pct_counts_mt', 10, operator='>')
+adata_filtered = filter_cells(adata, ~high_mt)
+adata_filtered.write('filtered.h5ad')
+```
+
+**Example 3: Different thresholds for different subsets**
+```python
+adata = ad.read_h5ad('input.h5ad')
+calculate_qc_metrics(adata, inplace=True)
+
+# Apply type-specific QC (assumes cell_type metadata exists)
+neurons = adata.obs['cell_type'] == 'neuron'
+other_cells = ~neurons
+
+# Neurons tolerate higher MT%, other cells use stricter threshold
+neuron_qc = apply_hard_threshold(adata[neurons], 'pct_counts_mt', 15, operator='>')
+other_qc = apply_hard_threshold(adata[other_cells], 'pct_counts_mt', 8, operator='>')
+```
+
+## Best Practices
+
+1. **Be permissive with filtering** - Default thresholds intentionally retain most cells to avoid losing rare populations
+2. **Inspect visualizations** - Always review before/after plots to ensure filtering makes biological sense
+3. **Consider dataset-specific factors** - Some tissues naturally have higher mitochondrial content (e.g., neurons, cardiomyocytes)
+4. **Check gene annotations** - Mitochondrial gene prefixes vary by species (mt- for mouse, MT- for human)
+5. **Iterate if needed** - QC parameters may need adjustment based on the specific experiment or tissue type
+
+## Reference Materials
+
+For detailed QC methodology, parameter rationale, and troubleshooting guidance, see `references/scverse_qc_guidelines.md`. This reference provides:
+- Detailed explanations of each QC metric and why it matters
+- Rationale for MAD-based thresholds and why they're better than fixed cutoffs
+- Guidelines for interpreting QC visualizations (histograms, violin plots, scatter plots)
+- Species-specific considerations for gene annotations
+- When and how to adjust filtering parameters
+- Advanced QC considerations (ambient RNA correction, doublet detection)
+
+Load this reference when users need deeper understanding of the methodology or when troubleshooting QC issues.
+
+## Next Steps After QC
+
+Typical downstream analysis steps:
+- Ambient RNA correction (SoupX, CellBender)
+- Doublet detection (scDblFinder)
+- Normalization (log-normalize, scran)
+- Feature selection and dimensionality reduction
+- Clustering and cell type annotation

package/content/bio-research/skills/bio-research-single-cell-rna-qc/references/scverse_qc_guidelines.md

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+# scverse Quality Control Guidelines
+
+This document provides detailed information about quality control best practices for single-cell RNA-seq data, following the scverse ecosystem recommendations.
+
+## Quality Control Metrics
+
+### Count Depth (Total Counts)
+- **What it measures**: Total number of UMI/reads per cell
+- **Why it matters**: Low count cells may be empty droplets, debris, or poorly captured cells
+- **Typical range**: 500-50,000 counts per cell (varies by protocol)
+- **Red flags**: Bimodal distributions may indicate mixing of high and low-quality cells
+
+### Gene Detection (Genes per Cell)
+- **What it measures**: Number of genes with at least 1 count
+- **Why it matters**: Strongly correlates with count depth; low values indicate poor capture
+- **Typical range**: 200-5,000 genes per cell
+- **Red flags**: Very low values (<200) suggest technical failures
+
+### Mitochondrial Content
+- **What it measures**: Percentage of counts from mitochondrial genes
+- **Why it matters**: High MT% indicates cell stress, apoptosis, or lysed cells
+- **Typical range**: <5% for most tissues, up to 10-15% for metabolically active cells
+- **Species-specific patterns**:
+  - Mouse: Genes start with 'mt-' (e.g., mt-Nd1, mt-Co1)
+  - Human: Genes start with 'MT-' (e.g., MT-ND1, MT-CO1)
+- **Context matters**: Some cell types (cardiomyocytes, neurons) naturally have higher MT content
+
+### Ribosomal Content
+- **What it measures**: Percentage of counts from ribosomal protein genes
+- **Why it matters**: Can indicate cell state or contamination
+- **Patterns**: Genes start with 'Rpl'/'RPL' (large subunit) or 'Rps'/'RPS' (small subunit)
+- **Note**: High ribosomal content isn't always bad - metabolically active cells have more ribosomes
+
+### Hemoglobin Content
+- **What it measures**: Percentage of counts from hemoglobin genes
+- **Why it matters**: Indicates blood contamination in non-blood tissues
+- **Patterns**: Genes matching '^Hb[^(p)]' or '^HB[^(P)]' (excludes Hbp1/HBP1)
+- **When to use**: Particularly important for tissue samples (brain, liver, etc.)
+
+## MAD-Based Filtering Rationale
+
+### Why MAD Instead of Fixed Thresholds?
+
+Fixed thresholds (e.g., "remove cells with <500 genes") fail because:
+- Different protocols yield different ranges
+- Different tissues have different characteristics
+- Different species have different gene counts
+- Fixed thresholds are arbitrary and not data-driven
+
+MAD (Median Absolute Deviation) is robust to outliers and adapts to your dataset:
+```
+MAD = median(|X - median(X)|)
+Outlier bounds = median ± n_MADs × MAD
+```
+
+### Recommended MAD Thresholds
+
+Following scverse best practices (deliberately permissive):
+
+**5 MADs for count depth (log-transformed)**
+- Very permissive to retain rare cell populations
+- Catches extreme outliers (empty droplets, debris)
+- Log transformation handles the typical right-skewed distribution
+
+**5 MADs for gene counts (log-transformed)**
+- Parallels count depth filtering
+- Most informative when combined with count filtering
+- Log transformation normalizes the distribution
+
+**3 MADs for mitochondrial percentage**
+- More stringent because high MT% strongly indicates dying cells
+- Uses raw percentages (not log-transformed)
+- Combined with hard threshold for extra stringency
+
+**Hard threshold: 8% mitochondrial content**
+- Additional filter beyond MAD-based detection
+- Conservative cutoff that works across most tissues
+- Adjust higher (10-15%) for metabolically active cell types
+
+### Why Be Permissive?
+
+The default thresholds intentionally err on the side of keeping cells because:
+1. **Rare populations**: Stringent filtering may remove rare but viable cell types
+2. **Biological variation**: Some healthy cells naturally have extreme values
+3. **Reversibility**: Easier to filter more later than to recover lost cells
+4. **Downstream robustness**: Modern normalization methods handle moderate quality variation
+
+## Interpreting QC Visualizations
+
+### Histograms
+- **Bimodal distributions**: May indicate mixing of cell types or quality issues
+- **Long tails**: Common for count depth; MAD filtering handles this
+- **Sharp cutoffs**: May indicate prior filtering or technical artifacts
+
+### Violin Plots
+- Shows distribution shape and density
+- Median (line) and mean (diamond) should be similar for symmetric distributions
+- Wide distributions suggest high heterogeneity
+
+### Scatter Plots
+
+**Counts vs Genes (colored by MT%)**
+- Should show strong positive correlation (R² > 0.8 typical)
+- Points deviating from trend may be outliers
+- High MT% cells often cluster at low counts/genes
+
+**Counts vs MT%**
+- Negative correlation expected (dying cells have fewer counts)
+- Vertical stratification may indicate batch effects
+- Cells with high counts + high MT% are suspicious
+
+**Genes vs MT%**
+- Similar to counts vs MT%, but often weaker correlation
+- Useful for identifying cells with gene detection issues
+
+## Gene Filtering
+
+After filtering cells, remove genes detected in fewer than 20 cells:
+- **Why 20?**: Balances noise reduction with information retention
+- **Benefits**: Reduces dataset size, speeds up computation, removes noisy genes
+- **Trade-offs**: May lose very rare markers; adjust to 10 if studying rare populations
+
+## Species-Specific Considerations
+
+### Mouse (Mus musculus)
+- Mitochondrial genes: mt-* (lowercase)
+- Ribosomal genes: Rpl*, Rps* (capitalized first letter)
+- Hemoglobin genes: Hb* (but not Hbp1)
+
+### Human (Homo sapiens)
+- Mitochondrial genes: MT-* (uppercase)
+- Ribosomal genes: RPL*, RPS* (all uppercase)
+- Hemoglobin genes: HB* (but not HBP1)
+
+### Other Species
+Adjust gene name patterns in the script to match your organism's gene nomenclature. Consult Ensembl or your reference annotation for correct prefixes.
+
+## When to Adjust Parameters
+
+Consider adjusting filtering thresholds when:
+
+**More stringent (lower MADs)**
+- High ambient RNA contamination suspected
+- Many low-quality cells observed in visualizations
+- Downstream analysis shows quality-driven clustering
+
+**More permissive (higher MADs)**
+- Studying rare cell populations
+- Dataset has high technical quality
+- Cell types naturally have extreme values (e.g., neurons with high MT%)
+
+**Tissue-specific adjustments**
+- Brain/neurons: May need higher MT% threshold (10-15%)
+- Blood: Can be more stringent with MT% (5-8%)
+- Tumor samples: Often need more permissive thresholds due to biological variation
+
+## Advanced QC Considerations
+
+### Not Included in This Workflow
+
+**Ambient RNA correction**
+- Tool: SoupX, CellBender, DecontX
+- When: High background RNA in droplet-based data
+- Effect: Removes contamination from lysed cells
+
+**Doublet detection**
+- Tool: scDblFinder, scrublet, DoubletFinder
+- When: Always recommended for droplet-based data
+- Effect: Identifies and removes multiplets (2+ cells in one droplet)
+
+**Cell cycle scoring**
+- Tool: scanpy's score_genes_cell_cycle
+- When: Cell cycle effects confound biological signal
+- Effect: Allows regressing out or accounting for cell cycle phase
+
+**Batch correction**
+- Tool: Harmony, scVI, ComBat
+- When: Integrating data from multiple batches/experiments
+- Effect: Removes technical batch effects while preserving biology
+
+## References
+
+- scverse Best Practices: https://www.sc-best-practices.org/preprocessing_visualization/quality_control.html
+- Luecken & Theis (2019): Current best practices in single-cell RNA-seq analysis
+- Osorio & Cai (2021): Systematic determination of the mitochondrial proportion in human and mouse genomes
+- Germain et al. (2020): Doublet identification in single-cell sequencing data using scDblFinder