# Mosaic Detection

The default mode of the small variant caller has been optimized to detect germline variants with typical AFs of 0%, 50% or 100%. Non-cancer post-zygotic mosaic variants have typical allele frequencies (AFs) lower than 50% and therefore more challenging to find with the default small variant caller. To improve sensitivity of low AF calls, a new machine learning (ML) model trained using read and context evidence from low AF calls is used. This allows the model to identify variants down to approximately 5% AF on 35x WGS and 3% AF on 300x WGS. The mosaic ML model is applied to all calls that are rejected by the germline model and variants detected with the mosaic detection are identified by a `MOSAIC` flag in the VCF INFO field.

![](/files/PtaUHvSGTYSdTGX7M1SO)

When the mosaic detection is enabled, the hard filter `QUAL` threshold for both SNPs and INDELs is lowered to `0.4` in this mode to allow low AF calls to be set as `PASS` in the FILTER field. `MOSAIC` tagged variants with `QUAL` smaller than `3` are filtered with the `MosaicHardQUAL` filter.

We provide an optional `MosaicLowAF` filtering option to filter `MOSAIC` tagged variants with `AF` smaller than the `AF` threshold. The threshold for this filter can be set with the `--vc-mosaic-af-filter-threshold` option.

Furthermore, the output of `MOSAIC` tagged calls can be restricted using an optional target BED provided with the `--vc-mosaic-target-bed` option.

## Command line options

* `--vc-enable-mosaic-detection`

  Set to true to enable mosaic detection with mosaic AF filter threshold set to `0.0`. Set to false to disable mosaic detection. The default is true with mosaic AF filter threshold set to `0.2`.
* `--vc-mosaic-af-filter-threshold`

  Set the allele frequency threshold for the application of the `MosaicLowAF` filter to mosaic calls. All `MOSAIC` tagged variants with `AF` smaller than the `AF` threshold are filtered with the `MosaicLowAF` filter. The default mosaic `AF` filter threshold is set to `0.2` when the germline variant caller is enabled. The AF default threshold is set to `0.0` when the mosaic detection mode is enabled with `--vc-enable-mosaic-detection=true`.
* `--vc-mosaic-qual-filter-threshold`

  Set the `QUAL` threshold for the application of the `MosaicHardQUAL` filter to mosaic calls. All `MOSAIC` tagged variants with `QUAL` smaller than the threshold `QUAL` are filtered with the `MosaicHardQUAL` filter. The default mosaic `QUAL` filter threshold is set to `3.0`.
* `--vc-mosaic-target-bed`

  Optional target BED file to restrict the output of `MOSAIC` tagged variant calls only in the specified regions.

## Comparison with DRAGEN 4.2 High Sensitivity Mode

Small variant calling features comparison between default germline small variant caller and mosaic detection mode in DRAGEN 4.2 and DRAGEN 4.3

| Tag        | Name                                    | Command line options                                                | QUAL threshold | MAPQ0 | Mosaic Detection | Mosaic AF filter threshold |
| ---------- | --------------------------------------- | ------------------------------------------------------------------- | -------------- | ----- | ---------------- | -------------------------- |
| 4.2        | DRAGEN 4.2 default Small Variant Caller | --enable-variant-caller=true                                        | 3              | No    | No               | N/A                        |
| 4.2 HSM    | DRAGEN 4.2 High Sensitivity Mode        | --enable-variant-caller=true --vc-enable-high-sensitivity-mode=true | 0.4            | Yes   | Yes (Alpha)      | N/A                        |
| 4.3        | DRAGEN 4.3 default Small Variant Caller | --enable-variant-caller=true                                        | 3              | Yes   | Yes (Full)       | 20%                        |
| 4.3 Mosaic | DRAGEN 4.3 Mosaic Detection Mode        | --enable-variant-caller=true --vc-enable-mosaic-detection=true      | 0.4            | Yes   | Yes (Full)       | 0%                         |


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