a) All rank sum tests now work for indels including multiallelic sites. For the latter cases, rank sum test is REF vs most common allele
b) Redid computation of HaplotypeScore for indels. It's now trivially easy to do because we are already computing likelihoods of each read vs haplotypes in GL computation so we reuse that if available. For multiallelic case, we score against N haplotypes where N is total called alleles.
Drawback is that all cases need information contained in likelihood table that stores likelihood for each pileup element, for each allele. If this table is not available we dont annotate, so we can only fully annotate indels right now when running UG but not when running VariantAnnotator alone.
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a) Genotype given alleles with indels
b) Genotyping and computing likelihoods of multi-allelic sites.
When GGA option is enabled, indels will be called on regular pileups, not on extended pileups (extended pileups will be removed shortly in a next iteration). As a result, likelihood computation is suboptimal since we can't see reads that start with an insertion right after a position, and hence quality of some insertions is removed and we could be missing a few marginal calls, but it makes everything else much simpler.
For multiallelic sites, we currently can't call them in discovery mode but we can genotype them and compute/report full PL's on them (annotation support comes in next commit). There are several suboptimal approximations made in exact model to compute this. Ideally, joint likelihood Pr(Data | AC1=i,AC2=j..) should be computed but this is hard. Instead, marginal likelihoods are computed Pr(Data | ACi=k) for all i,k, and QUAL is based on highest likelihood allele.
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- Verified that exact calculations do agree with R's dwilcox()
- Verified that exact calculations do not agree with R's wilcox.test
+ This is because R does a correction, and calculates CDFs rather than PDFs (e.g. sums over dwilcox() values)
- Can now specify MWU to calculate cumulative exact tests, rather than point probabilities
- Z-scores are now calculated properly for exact tests
+ Previously, z-values calculated by inverting normal CDF from U-statistic PDF
+ Now both inversions are done, with a smart heuristic (biased variance) to make the point-calculated Z-value more accurate
+ Additional tests
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continue to exist and live in playground (and thus outside of the normal release
/ git release branch).
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ReplicationValidationWalker: Just the skeleton of what will be the implementation of the replication/validation model.
dataProcessingV2: Committing an UNTESTED implementation of BWA alignment. I am running tests on it over the weekend.
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IndelRealignerIntegrationTest failures -- yes, it's the classic printf()
debugging technique. Will revert in a day or two once I get the data I need :)
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Fixed minor problem with WalkerTest for "" (for parameterization) md5s.
Added an explicit integrationtest for BAQ NONE
Now only creates the BAQ'd pileup, if the useBAQPileup parameter is provide in initializeAlternateAllele.
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on oneoffs. Thanks Guillermo! We'll polish the patch when you free up a bit.
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Also allows for the slightly more awesome name "MWUnitTest"
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z-value can not be NaN (and can't possibly be null)
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- Running a test when there are no observations of at least one of the sets now breaks the MWU contract
+ MWU returns Pair(Double.NaN,Double.NaN) in these instances to maintain the contract of never returning null
+ No more Double.Infinity values will appear
- RankSumTests now probe the return values for NaNs, and don't annotate if they appear
- For small sets where the probability is calculated recursively, the z-value is now the inversion of the error function
and not the approximate z-value
- UG and Annotator integration tests updated to reflect changes
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Right now, if you select a multi-sample VCF file down (or one with filters I see) down to a smaller set of samples, and the site isn't polymorphic in that subgroup, then the alt allele is lost. For example, when selecting down NA12878 from the OMNI, I previously received the following VCF:
1 82154 rs4477212 A . . PASS AC=0;AF=0.00;AN=2;CR=100.0;DP=0;GentrainScore=0.7826;HW=1.0 GT:GC 0/0:0.7205
1 534247 SNP1-524110 C . . PASS AC=0;AF=0.00;AN=2;CR=99.93414;DP=0;GentrainScore=0.7423;HW=1.0 GT:GC 0/0:0.6491
1 565286 SNP1-555149 C T . PASS AC=2;AF=1.00;AN=2;CR=98.8266;DP=0;GentrainScore=0.7029;HW=1.0 GT:GC 1/1:0.3471
1 569624 SNP1-559487 T C . PASS AC=2;AF=1.00;AN=2;CR=97.8022;DP=0;GentrainScore=0.8070;HW=1.0 GT:GC 1/1:0.3942
Where the first two records lost the ALT allele, because NA12878 is hom-ref at this site. My change results in a VCF that looks like:
1 82154 rs4477212 A G . PASS AC=0;AF=0.00;AN=2;CR=100.0;DP=0;GentrainScore=0.7826;HW=1.0 GT:GC 0/0:0.7205
1 534247 SNP1-524110 C T . PASS AC=0;AF=0.00;AN=2;CR=99.93414;DP=0;GentrainScore=0.7423;HW=1.0 GT:GC 0/0:0.6491
1 565286 SNP1-555149 C T . PASS AC=2;AF=1.00;AN=2;CR=98.8266;DP=0;GentrainScore=0.7029;HW=1.0 GT:GC 1/1:0.3471
1 569624 SNP1-559487 T C . PASS AC=2;AF=1.00;AN=2;CR=97.8022;DP=0;GentrainScore=0.8070;HW=1.0 GT:GC 1/1:0.3942
The genotype remains unchanged, but the ALT allele is now preserved. I think this is the correct behavior, as reducing samples down shouldn't change the character of the site, only the AC in the subpopulation. This is related to the tricky issue of isPolymorphic() vs. isVariant().
isVariant => is there an ALT allele?
isPolymorphic => is some sample non-ref in the samples?
In part this is complicated as the semantics of sites-only VCFs, where ALT = . is used to mean not-polymorphic. Unfortunately, I just don't think there's a consistent convention right now, but it might be worth at some point to adopt a single approach to handling this. Wiki docs updated.
Does anyone have critical infrastructure that depends on the previous convention? Let me know so we can coordinate the change.
There's a new function subContextFromGenotypes() that also takes a Set<Allele> to handle this type of behavior.
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GenomeLocs can officially have any start/stop values from -Inf - +Inf. Bounds w.r.t. the reference are enforced, optionally, by GenomeLocParser. General code cleanup throughout the subsystem.
All validation code for GLs is now centralized, and all I/O systems now validate their inputs. Because of this, the Picard interval processing code has been changed to examine whether an interval is valid, and only keep the valid intervals. Note that the scatter/gather test was changed, because the original hg18 chr20 interval files as actually malformed (all records for some reason where on chr20).
Many interval processing routines were moved to IntervalUtils, as this is their natural home.
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Refactored several Interval utilties from GenomeLocParser to IntervalUtils, as one might expect they go
Removed GenomeLoc.clone() method, as this was not correctly implemented, and actually unnecessary, as GenomeLocs are immutable. Several iterator classes have changed to remove their use of clone()
Removed misc. unnecessary imports
Disabled, temporarily, the validating pileup integration test, as it uses reads mapped to an different reference sequence for ecoli, and this now does not satisfy the contracts for GenomeLoc
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and its three or four nearest neighbors could be in memory at once. Tweaking
the iterators to ensure that previous AlignmentContexts don't have strong
references which means that the garbage collector can work effectively to
help us trundle through these regions.
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Also added more logging when extension generation fails.
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This step just changes storage of likelihoods so now we have, instead of an internal matrix, a class member which stores, as a hash table, a mapping from pileup element to an (allele, likelihood) pair. There's no functional change aside from internal data storage.
As a bonus, we get for free a 2-3x improvement in speed in calling because redundant likelihood computations are removed.
Next step will hook this up to, and redefine annotation engine interaction with UG for indel case.
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Added doc string for getNBoundRodTracks()
Intermediate commit for CalibrateGenotypeLikelihoods and GenotypeConcordanceTable, so I have a record of my work. Not ready for public consumption. Really looking forward to making local commits so I can track my progress without needing to push incomplete functionality up to the server.
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