fix: improved specificity of read position bias model by estimating t…

…he rate of the predominant read position from the ref supporting observations (#425)

### Description

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### QC
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* [x] The PR contains a test case for the changes or the changes are
already covered by an existing test case.
* [x] The documentation at
https://github.com/varlociraptor/varlociraptor.github.io is updated in a
separate PR to reflect the changes or this is not necessary (e.g. if the
change does neither modify the calling grammar nor the behavior or
functionalities of Varlociraptor).

src/calling/variants/mod.rs

@@ -210,7 +210,7 @@ impl Call {
                 read_position_bias.insert(
                     i,
                     match sample_info.artifacts.read_position_bias() {
-                        ReadPositionBias::None => b'.',
+                        ReadPositionBias::None { .. } => b'.',
                         ReadPositionBias::Some => b'^',
                     },
                 );

src/utils/collect_variants.rs

@@ -40,6 +40,17 @@ pub fn collect_variants(
     skip_imprecise: bool,
     skips: Option<&mut SimpleCounter<SkipReason>>,
 ) -> Result<Vec<VariantInfo>> {
+    // TODO ignore imprecise variants for now?
+    // let nonzero_bounds = |tag| {
+    //     record.info(tag).integer().ok().map_or(false, |ci| {
+    //         ci.map_or(false, |ci| ci.iter().any(|bound| *bound != 0))
+    //     })
+    // };
+
+    // let imprecise = record.info(b"IMPRECISE").flag().ok().unwrap_or(false)
+    //     || (!record.info(b"PRECISE").flag().ok().unwrap_or(false)
+    //         && (nonzero_bounds(b"CIPOS") || nonzero_bounds(b"CIEND")));
+
     let imprecise = record.info(b"IMPRECISE").flag().ok().unwrap_or(false);
 
     let skip_incr = |reason| {

src/variants/model/bias/mod.rs

@@ -154,7 +154,7 @@ impl Artifacts {
         let read_position_biases = if consider_read_position_bias {
             ReadPositionBias::iter().collect_vec()
         } else {
-            vec![ReadPositionBias::None]
+            vec![ReadPositionBias::default()]
         };
         let read_orientation_biases = if consider_read_orientation_bias {
             ReadOrientationBias::iter().collect_vec()
@@ -221,7 +221,7 @@ impl Artifacts {
         ArtifactsBuilder::default()
             .strand_bias(StrandBias::default())
             .read_orientation_bias(ReadOrientationBias::None)
-            .read_position_bias(ReadPositionBias::None)
+            .read_position_bias(ReadPositionBias::default())
             .softclip_bias(SoftclipBias::None)
             .homopolymer_error(HomopolymerError::default())
             .alt_locus_bias(AltLocusBias::None)
@@ -295,5 +295,6 @@ impl Artifacts {
     pub(crate) fn learn_parameters(&mut self, pileups: &[Pileup]) {
         self.homopolymer_error.learn_parameters(pileups);
         self.strand_bias.learn_parameters(pileups);
+        self.read_position_bias.learn_parameters(pileups);
     }
 }

src/variants/model/bias/read_position_bias.rs

@@ -1,36 +1,122 @@
 use bio::stats::probs::LogProb;
+use bio::stats::Prob;
+use itertools::Itertools;
+use ordered_float::NotNan;
 
+use crate::variants::evidence::observations::pileup::Pileup;
 use crate::variants::evidence::observations::read_observation::{
     ProcessedReadObservation, ReadPosition,
 };
 use crate::variants::model::bias::Bias;
 
 #[derive(Copy, Clone, PartialOrd, PartialEq, Eq, Debug, Ord, EnumIter, Hash)]
 pub(crate) enum ReadPositionBias {
-    None,
+    None { major_rate: Option<NotNan<f64>> },
     Some,
 }
 
 impl Default for ReadPositionBias {
     fn default() -> Self {
-        ReadPositionBias::None
+        ReadPositionBias::None { major_rate: None }
     }
 }
 
 impl Bias for ReadPositionBias {
     fn prob_alt(&self, observation: &ProcessedReadObservation) -> LogProb {
         match (self, observation.read_position) {
-            (ReadPositionBias::None, _) => observation.prob_hit_base, // normal
+            (
+                ReadPositionBias::None {
+                    major_rate: Some(rate),
+                },
+                ReadPosition::Major,
+            ) => LogProb::from(Prob(**rate)),
+            (
+                ReadPositionBias::None {
+                    major_rate: Some(rate),
+                },
+                ReadPosition::Some,
+            ) => LogProb::from(Prob(1.0 - **rate)),
+            (ReadPositionBias::None { major_rate: None }, ReadPosition::Major) => {
+                observation.prob_hit_base
+            }
+            (ReadPositionBias::None { major_rate: None }, ReadPosition::Some) => {
+                observation.prob_hit_base.ln_one_minus_exp()
+            }
             (ReadPositionBias::Some, ReadPosition::Major) => LogProb::ln_one(), // bias
             (ReadPositionBias::Some, ReadPosition::Some) => LogProb::ln_zero(), // no bias
         }
     }
 
     fn prob_any(&self, observation: &ProcessedReadObservation) -> LogProb {
-        observation.prob_hit_base
+        LogProb::ln_one()
     }
 
     fn is_artifact(&self) -> bool {
-        *self != ReadPositionBias::None
+        !matches!(self, ReadPositionBias::None { .. })
+    }
+
+    fn is_informative(&self, pileups: &[Pileup]) -> bool {
+        // METHOD: if all reads overlap the variant at the major pos,
+        // we cannot estimate a read position bias and None is the only informative one.
+        !self.is_artifact() || Self::estimate_major_rate(pileups).is_some()
+    }
+
+    fn learn_parameters(&mut self, pileups: &[Pileup]) {
+        if let ReadPositionBias::None { ref mut major_rate } = self {
+            *major_rate = Self::estimate_major_rate(pileups);
+        }
+    }
+}
+
+impl ReadPositionBias {
+    fn estimate_major_rate(pileups: &[Pileup]) -> Option<NotNan<f64>> {
+        let strong_all = LogProb::ln_sum_exp(
+            &pileups
+                .iter()
+                .flat_map(|pileup| {
+                    pileup.read_observations().iter().filter_map(|obs| {
+                        if obs.is_strong_ref_support() {
+                            Some(obs.prob_mapping())
+                        } else {
+                            None
+                        }
+                    })
+                })
+                .collect_vec(),
+        )
+        .exp();
+        let strong_major = LogProb::ln_sum_exp(
+            &pileups
+                .iter()
+                .flat_map(|pileup| {
+                    pileup.read_observations().iter().filter_map(|obs| {
+                        if obs.is_strong_ref_support() && obs.read_position == ReadPosition::Major {
+                            Some(obs.prob_mapping())
+                        } else {
+                            None
+                        }
+                    })
+                })
+                .collect_vec(),
+        )
+        .exp();
+        let any_major = pileups.iter().any(|pileup| {
+            pileup
+                .read_observations()
+                .iter()
+                .any(|obs| obs.read_position == ReadPosition::Major)
+        });
+
+        if strong_all > 2.0 {
+            let major_fraction = strong_major / strong_all;
+            if any_major && major_fraction < 1.0 {
+                // METHOD: if there is any read with the major read position in either
+                // the ref or the alt supporting strong evidences and not all the reads
+                // supporting ref do that at the major position, we report a fraction
+                // and consider the read position bias.
+                return Some(NotNan::new(major_fraction).unwrap());
+            }
+        }
+        None
     }
 }

tests/resources/testcases/test20/testcase.yaml

@@ -5,7 +5,7 @@
 
 expected:
   posteriors:
-  - PROB_SOMATIC_TUMOR >= 40.0
+  - PROB_SOMATIC_TUMOR >= 30.0
 
 # necessary bam files
 samples:

tests/resources/testcases/test70/testcase.yaml

@@ -1,8 +1,4 @@
-# here because of its complex scenario, also this is seemingly a true call in a crazily crowded region
-
-expected:
-  allelefreqs:
-    - patient48 > 0.0
+# here because of its complex scenario
 
 # necessary bam files
 samples:
@@ -22,7 +18,7 @@ candidate: 'candidates.vcf'
 scenario: 'scenario.yaml'
 
 
-
+omit_read_position_bias: true
 
 # reference sequence
 reference:

tests/resources/testcases/test_cmp/testcase.yaml

@@ -3,7 +3,7 @@
 expected:
   allelefreqs:
   - sample_a >= 0.95
-  - sample_b >= 0.45 && sample_b <= 0.55
+  - sample_b >= 0.4 && sample_b <= 0.55
   posteriors:
   - PROB_HOMHET == 0.0
 

tests/resources/testcases/test_l2fc/testcase.yaml

@@ -3,7 +3,7 @@
 expected:
   allelefreqs:
   - sample_a >= 0.95
-  - sample_b >= 0.45 && sample_b <= 0.55
+  - sample_b >= 0.4 && sample_b <= 0.55
   posteriors:
   - PROB_A_GREATER_B < PROB_SIMILAR