Also, fixes to large-scale validation script: lower -minIndelFrac threshold or else we'll kill most indels since default 0.25 is too high for pools, fix also VE stratifications and add one VE run where eval=1KG, comp=pool data and AC stratification based on 1KG annotation
The old BaseRecalibrator walker is and never will be thread-safe, since it's a
LocusWalker that uses read attributes to track state.
ONLY the newer DelocalizedBaseRecalibrator is believed likely to be thread-safe
at this point. It is safe to run the DelocalizedBaseRecalibrator with -nct > 1
for testing purposes, but wait for further testing to be done before using it
for production purposes in multithreaded mode.
The ReadGroupCovariate class was not thread-safe. This led to horrible race conditions
in multithreaded runs of the BQSR where (for example) the same read group could get
inserted into the reverse lookup table twice with different IDs.
Should fix the intermittent crash reported in GSA-492.
-With this change, BQSR performance scales properly by thread rather
than gaining nothing from additional threads.
-Benefits are seen when using either -nt (HierarchicalMicroScheduler) or -nct
(NanoScheduler)
-Removes high-level locks in the recalibration engines and NestedIntegerArray
in favor of maximally-granular locks on and around manipulation of the leaf
nodes of the NestedIntegerArray.
-NestedIntegerArray now creates all interior nodes upfront rather than on
the fly to avoid the need for locking during tree traversals. This uses
more memory in the initial part of BQSR runs, but the BQSR would eventually
converge to use this memory anyway over the course of a typical run.
IMPORTANT NOTE: This does not mean it's safe to run the old BaseRecalibrator
walker with multiple threads. The BaseRecalibrator walker is and will never be
thread-safe, as it's a LocusWalker that uses read attributes to track
state information. ONLY the newer DelocalizedBaseRecalibrator can be made
thread-safe (and will hopefully be made so in my subsequent commits). This
commit addresses performance, not correctness.
-- Resolves issue GSA-515 / Nanoscheduler GSA-605 / Seems that -nct may deadlock as not reproducible
-- It seems that it's not an input error problem (or at least cannot be provoked with unit tests)
-- I'll keep an eye on this later
Bringing in the following relevant changes:
* Fixes the indel realigner N-Way out null pointer exception DEV-10
* Optimizations to ReduceReads that bring the run time to 1/3rd.
Conflicts:
protected/java/src/org/broadinstitute/sting/gatk/walkers/compression/reducereads/SlidingWindow.java
DEV-10 #resolve #time 2m
-- Included logic to only add priors for alleles with sufficient evidence to be called polymorphic. If no alleles are poly make sure to add priors of first allele
-- There's been no report of problems with the nano scheduled version of TraverseLoci and TraverseReads, so I'm removing the old versions since they are no longer needed
-- Removing unnecessary intermediate base classes
-- GSA-515 / Nanoscheduler GSA-549 / https://jira.broadinstitute.org/browse/GSA-549
-- Updated StandardCallerArgumentCollection to remove MaxAltAllelesForIndels. Previous argument is deprecated with meaningful doc message for people to use maxAltAlleles
-- All constructores, factory methods, and test builders and their users updated to provide just a single argument
-- Updating MD5s for integration tests that change due to genotyping more alleles
-- Adding more alleles to genotyping results in slight changes in the QUAL value for multi-allelic loci where one or more alleles aren't polymorphic. That's simply due to the way that alternative hypotheses contribute as reference evidence against each true allele. The effect can be large (new qual = old qual / 2 in one case here).
-- If we want more precision in our estimates we could decide (Eric, should we discuss?) to actually separately do a discovery phase in the genotyping, eliminate all variants not considered polymorphic, and then do a final round of calling to get the exact QUAL value for only those that are segregating. This would have the value of having the QUAL stay constant as more alleles are genotyped, at the cost of some code complexity increase and runtime. Might be worth it through
-- This is no longer a core GATK activity, and the tests need to run for so long (2 min each) that it's just too painful to run them. Should be re-eabled if we come to care about this capability again, or if we can run these tests all in parallel in the future.
-- The old way of overloading constructors and calling super didn't work (might have been a consequence of merge). This is the right way to do the copy constructor with the call to super()
-- Potentially a very fast implementation (it's very clean) but restricted to the biallelic case
-- A starting point for future bi-allelic only optimized (logless) or generalized (bi-allelic general ploidy) implementations
-- Added systematic unit tests covering this implementation, and comparing it to others
-- Uncovered a nasty normalization bug in StateTracker that was capping our likelihoods at 0, even after summing up multiple likelihoods, which is just not safe to do and was causing us to lose likelihood in some cases
-- Removed the restriction that a likelihood be <= 0 in StateTracker, and the protection for these cases in GeneralPloidyExactAFCalc which just wasn't right
-- Changed UG / HC to use this one via the StandardCallerArgumentCollection
-- Update the AFCalcFactory.Calculation to have a getDefault() value instead of having a duplicate entry in the enums
-- GeneralPloidyExactAFCalc turns -Infinity values into -Double.MAX_VALUE, so our calculations pass unit tests
-- Bugfix for GeneralPloidyGenotypeLikelihoodsCalculationModel, return a null VC when the only allele we get from our final alleles to use method is the reference base
-- Fix calculation of reference posteriors when P(AF == 0) = 0.0 and P(AF == 0) = X for some meaningful value of X. Added unit test to ensure this behavior is correct
-- Fix horrible sorting bug in IndependentAllelesDiploidExactAFCalc that applied the theta^N priors in the wrong order. Add contract to ensure this doesn't ever happen again
-- Bugfix in GLBasedSampleSelector, where VCs without any polymorphic alleles were being sent to the exact model
--
-- These two classes were really the same, and now they are actually the same!
-- Cleanuped the interfaces, removed duplicate data
-- Added lots of contracts, some of which found numerical issues with GeneralPloidyExactAFCalc (which have been patched over but not fixed)
-- Moved goodProbability and goodProbabilityVector utilities to MathUtils. Very useful for contracts!
Changed ReflectionUtils.getGenericTypes' order of looking for @ClassType since the primitive generic wasn't completely erased, only changed to Object which is incorrect.
More fixes to @Arguments labeled as java.io.File via incorrect @Input annotation.
Put in a default undocumented implementation of @Argument doc() to match the one added to @Input.
The CompressionStash is now responsible for keeping track of all intervals that must be kept uncompressed by all samples. In general this is a list generated by a tumor sample that will enforce all normal samples to abide.
- Updated ReduceReads integration tests
- Sliding Window is now using the CompressionStash (single sample).
DEV-104 #resolve #time 3m
-- Ensures that the posteriors remain within reasonable ranges. Fixed bug where normalization of posteriors = {-1e30, 0.0} => {-100000, 0.0} which isn't good. Now tests ensure that the normalization process preserves log10 precision where possible
-- Updated MathUtils to make this possible
-- Remove capability to truncate genotype likelihoods -- this wasn't used and isn't really useful after all
-- Added lots of contracts and docs, still more to come.
-- Created a default makeMaxLikelihoods function in ReferenceDiploidExactAFCalc and DiploidExactAFCalc so that multiple subclasses don't just do the default thing
-- Generalized reference bi-allelic model in IndependentAllelesDiploidExactAFCalc so that in principle any bi-allelic reference model can be used.
-- Fixed minor numerical stability issue in AFCalcResult
-- posterior of joint A/B/C is 1 - (1 - P(D | AF_b == 0)) x (1 - P(D | AF_c == 0)), for any number of alleles, obviously. Now computes the joint posterior like this, and then back-calculates likelihoods that generate these posteriors given the priors. It's not pretty but it's the best thing to do
-- Superceded by IndependentAFCalc
-- Added support to read in an ExactModelLog in AFCalcPerformanceTest and run the independent alleles model on it.
-- A few misc. bug fixes discovered during running the performance test
Added targets to build.xml to effectively 'mvn install' packaged GATK/Queue from ant.
TODO: Versions during 'mvn install' are hardcoded at 0.0.1 until a better versioning scheme that works with maven dependencies has been identified.
Modified the SAMFileWriterArgumentTypeDescriptor to accept output bam files that are null if they're not required (in the @Output annotation).
This change enables the nWayOut parameter for the IndeRealigner and ReduceReads to operate optionally while maintaining the original single way out.
[#DEV-10 transition:31 resolution:1]
-- Before this branch, the EXACT calculation implementation was largely based on historical choices in the UnifiedGenotyper. The code was badly organized, there were no unit tests, and the Diploid EXACT calculation was super slow O(n.samples ^ n.alt.alleles)
-- Reorganized code into a single class AFCalc superclass that carries out the calculation and an AFCalcResult object that contains only the information we should expose to code users, and is well-validated.
-- Implement a new model for the multi-allelic exact calculation that sweeps for each alt allele B all likelihoods into a bi-allelic model XB where X is all alleles != B, and calls these all separately using the reference bi-allelic model. It produces identical quals for the bi-allelic case but slightly different results for multi-allelics due to a genuine model difference in that this Independent model doesn't penalize fully all genotype configurations as occurs in the Reference multi-allelic implementation. However, it seems after much debate that the reference model is doing the wrong thing, so in fact the Independent model seems correct. This code isn't the default implementation yet, simply because I want to do some cleanup and discuss with the methods group before enabling.
-- Constrained search model implemented, but will be deleted in a subsequent code cleanup
-- Massive (40K) suite of unit tests the exact models, which are passing for the reference and the independent alleles exact model.
-- Restored -- but isn't 100% hooked up -- the original clean bi-allelic model for Ryan to pass his optimized logless version on.
-- The only way to create these AFCalc objects is through an AFCalcFactory, which again validates its arguments. The AFCalcFactory.Calculation enum exposes calculations to the UG / HC as the AFModel.
-- Separated AFCalc from UG, into its own package that could in principle be pushed into utils now
-- Created a simple main[] function to run performance tests of the EXACT model.
-- Updating integration tests, confirming that results for the original EXACT model are as expected given our new more rigorous application of likelihoods, priors, and posteriors
-- Fix basic logic bug in AFCalcResult.isPolymorphic and UnifiedGenotypeEngine, where isNonRef really meant isRef. Not ideal. Finally caught by some tests, but good god it almost made it into the code
-- Now takes the Math.abs of the phred-scaled confidence so that we don't see -0.0
-- Massive new suite of unit tests to ensure that bi-allelic and tri-allele events are called properly with all models, and that the IndependentAllelesDiploidExactAFCalc calls events with up to 4 alt alleles correctly. ID'd some of the bugs below
-- Fix sort order bug in IndependentAllelesDiploidExactAFCalc caught by new unit tests
-- Fix bug in GeneralPloidyExactAFCalc where the AFCalcResult has meaningless values in the likelihoods when no there we no informative GLs.
-- UnifiedGenotyperEngine uses only the alleles used in genotyping, not the original alleles, when considering which alleles to include in output
-- AFCalcFactory has a more informative info message when looking for and selecting an exact model to use in genotyping
-- New capabilities in IndependentAllelesDiploidExactAFCalc to actually apply correct theta^n.alt.allele prior.
-- Tests that theta^n.alt.alleles is being applied correctly
-- Bugfix: keep in logspace when computing posterior probability in toAFCalcResult in AFCalcResultTracker.java
-- Bugfix: use only the alleles used in genotyping when assessing if an allele is polymorphic in a sample in UnifiedGenotyperEngine
-- AFCalcFactory is the only way to make AFCalcs now. There's a nice ordered enum there describing the models and their ploidy and max alt allele restrictions. The factory makes it easy to create them, and to find models that work for you given your ploidy and max alt alleles.
-- AFCalc no longer has UAC constructor -- only AFCalcFactory does. Code cleanup throughout
-- Enabling more unit tests, all of which almost pass now (except for IndependentAllelesDiploidExactAFCalc which will be fixed next)
-- It's now possible to run the UG / HC with any of the exact models currently in the system.
-- Code cleanup throughout the system, reorganizing the unit tests in particular
-- Continuing to get IndependentAllelesDiploidExactAFCalc working correctly. A long way towards the right answer now, but still not there
-- Restored (but not tested) OriginalDiploidExactAFCalc, the clean diploid O(N) version for Ryan
-- MathUtils.normalizeFromLog10 no longer returns -Infinity when kept in log space, enforces the min log10 value there
-- New convenience method in VariantContext that looks up the allele index in the alleles
-- AFCalcResult now sports a isPolymorphic and getLog10PosteriorAFGt0ForAllele functions that allow you to ask individually whether specific alleles we've tried to genotype are polymorphic given some confidence threshold
-- Lots of contracts for AFCalcResult
-- Slowly killing off AFCalcResultsTracker
-- Fix for the way UG checks for alt alleles being polymorphic, which is now properly conditioned on the alt allele
-- Change in behavior for normalizeFromLog10 in MathUtils: now sets the log10 for 0 values to -10000, instead of -Infinity, since this is really better to ensure that we don't have -Infinity values traveling around the system
-- ExactAFCalculationModelUnitTest now checks for meaningful pNonRef values for each allele, uncovering a bug in the GeneralPloidy (not fixed, related to Eric's summation issue from long ago that was reverted) in that we get different results for diploid and general-ploidy == 2 models for multi-allelics.
-- All of the code now uses the AFCalc object, not the not package protected AFCalcResultTracker. Nearly all unit tests pass (expect for a contract failing one that will be dealt with in subsequent commit), due to -Infinity values from normalizeLog10.
-- Changed the way that UnifiedGenotyper decides if the best model is non-ref. Previously looked at the MAP AC, but the MAP AC values are no longer provided by AFCalcResult. This is on purpose, because the MAP isn't a meaningful quantity for the exact model (i.e., everything is going to go to MLE AC in some upcoming commit). If you want to understand why come talk to me. Now uses the isPolymorphic function and the EMIT confidence, so that if pNonRef > EMIT then the site is poly, otherwise it's mono.
-- Renamed old class AFCalcResultTracker. This object is now allocated by the AFCalc itself, since it is heavy-weight and was badly optimized in the UG with a thread-local variable. Now, since there's already a AFCalc thread-local there, we get that optimization for free.
-- Removed the interface to provide the AFCalcResultTracker to getlog10PNonRef.
-- Wrote new, clean but unused AFCalcResult object that will soon replace the tracker as the external interface to the AFCalc model results, leaving the tracker as an internal tracker structure. This will allow me to (1) finally test things exhaustively, as the contracts on this class are clear (2) finalize the IndependentAllelesDiploidExactAFCalc class as it can work with a meaningfully defined result across each object
-- This model separates each of N alt alleles, combines the genotype likelihoods into the X/X, X/N_i, and N_i/N_i biallelic case, and runs the exact model on each independently to handle the multi-allelic case. This is very fast, scaling at O(n.alt.alleles x n.samples)
-- Many outstanding TODOs in order to truly pass unit tests
-- Added proper unit tests for the pNonRef calculation, which all of the models pass
-- Now contained in a package called afcalc
-- Extracted standard alone classes from private static classes in ExactAF
-- Most fields are now private, with accessors
-- Overall cleaner organization now
-- Now there's no duplication between exact old and constrained models. The behavior is controlled by an overloaded abstract function
-- No more static function to access the linear exact model -- you have to create the surrounding class. Updated code in the system
-- Everything passes unit tests
-- walks over the genotypes in VC, and computes for each alt allele the maximum AC we need to consider in that alt allele dimension. Does the calculation based on the PLs in each genotype g, choosing to update the max AC for the alt alleles corresponding to that PL. Only takes the first lowest PL, if there are multiple genotype configurations with the same PL value. It takes values in the order of the alt alleles.
Validation of GenomeLocs in the FilePointer class was extremely inefficient
when the GenomeLocs were added one at a time rather than all at once.
Appears to mostly fix GSA-604
-- Right now the state of the AFCaclulationResult can be corrupt (ie, log10 likelihoods can be -Infinity). Forced me to disable reasonable contracts. Needs to be thought through
-- exactCallsLog should be optional
-- Update UG integration tests as the calculation of the normalized posteriors is done in a marginally different way so the output is rounded slightly differently.
-- UnifiedGenotyperEngine no longer keeps a thread local double[2] array for the normalized posteriors array. This is way heavy-weight compared to just making the array each time.
-- Added getNormalizedPosteriorOfAFGTZero and getNormalizedPosteriorOfAFzero to AFResult object. That's the place it should really live
-- Add tests for priors, uncovering bugs in the contracts of the tri-allelic priors w.r.t. the AC of the MAP. Added TODOs
-- AFResult now tracks the number of evaluations (turns through the model calculation) so we can now compute the scaling of exact model itself as a function of n samples
-- Added unittests for priors (flat and human)
-- Discovered nasty general ploidy bug (enabled with Guillermo_FIXME)
-- Added combinatorial unit tests for both Diploid and General (in diploid-case) for 2 and 3 alleles in all combinations of sample types (i.e., AA, AB, BB and equiv. for tri-allelic). More assert statements to ensure quality of the result.
-- Added docs (DOCUMENT YOUR CODE!) to AlleleFrequencyCalculationResult, with proper input error handling and contracts. Made mutation functions all protected
-- No longer need to call reset on your AlleleFrequencyCalculationResult -- it'd done for you in the calculation function. reset is a protected method now, so it's all cleaner and nicer this way
-- TODO still -- need to add edge-case tests for non-informative samples (0,0,0), for the impact of priors, and I need to add some way to test the result of the pNonRef
-- Added a true base class that only does truly common tasks (like manage call logging)
-- This base class provides the only public method (getLog10PNonRef) and calls into a protected compute function that's abstract
-- Split ExactAF into superclass ExactAF with common data structures and two subclasses: DiploidExact and GeneralPloidyExact
-- Added an abstract reduceScope function that manages the simplification of the input VariantContext in the case where there are too many alleles or other constraints require us to only attempt a smaller computation
-- All unit tests pass
-- This allows us to log all of the information about the exact model call (alleles, priors, PLs, result, and runtime) to a file for later debugging / optimization
1) GATKArgumentCollection has a command to turn off randomization if setting the seed isn't enough. Right now it's only hooked into RankSumTest.
2) RankSumTest now can be passed a boolean telling it whether to use a dithering or non-randomizing comparator. Unit tested.
3) VariantsToBinaryPed can now output in both individual-major and SNP-major mode. Integration test.
4) Updates to PlinkBed-handling python scripts and utilities.
5) Tool for calculating (LD-corrected) GRMs put under version control. This is analysis for T2D, but I don't want to lose it should something happen to my computer.
Sometimes the GATK engine creates a single monolithic FilePointer representing all regions
in all BAM files. In such cases, the monolithic FilePointer is the only FilePointer emitted
by the BAMScheduler, and it's safe to allow it to contain regions and intervals from multiple
contigs.
This fixes support for reading unindexed BAM files (since an unindexed BAM is one case
in which the engine creates a monolithic FilePointer).
Nasty, nasty bug -- if we were extremely unlucky with shard boundaries, we might
end up with a shard containing only unmapped mates of mapped reads. In this case,
ReadShard.getReadsSpan() would not behave correctly, since the shard as a whole would
be marked "mapped" (since it refers to mapped intervals) yet consist only of unmapped
mates of mapped reads located within those intervals.
1) ValidateVariants removed in favor of direct validation VariantContexts. Integration test added to test broken contexts.
2) Enabling indel and SV output. Still bi-allelic sites only. Integration tests added for these cases.
3) Found a bug where GQ recalculation (if a genotype has PLs but no GQ) would only happen for flipped encoding. Fixed. Integration test added.
Merge all FilePointers for each contig into a single, merged, optimized FilePointer
representing all regions to visit in all BAM files for a given contig.
This helps us in several ways:
-It allows us to create a single, persistent set of iterators for each contig,
finally and definitively eliminating all Shard/FilePointer boundary issues for
the new experimental ReadWalker downsampling
-We no longer need to track low-level file positions in the sharding system (which
was no longer possible anyway given the new experimental downsampling system)
-We no longer revisit BAM file chunks that we've visited in the past -- all BAM
file access is purely sequential
-We no longer need to constantly recreate our full chain of read iterators
There are also potential dangers:
-We hold more BAM index data in memory at once. Given that we merge and optimize
the index data during the merge, and only hold one contig's worth of data at a
time, this does not appear to be a major issue. TODO: confirm this!
-With a huge number of samples and intervals, the FilePointer merge operation
might become expensive. With the latest implementation, this does not
appear to be an issue even with a huge number of intervals (for one sample, at least),
but if it turns out to be a problem for > 1 sample there are things we can do.
Still TODO: unit tests for the new FilePointer.union() method
-- Fixes monster bug in the way that traversal engines interacted with the NanoScheduler via the output tracker.
-- ThreadLocalOutputTracker is now a ThreadBasedOutputTracker that associates via a map from a master thread -> the storage map. Lookups occur by walking through threads in the same thread group, not just the thread itself (TBD -- should have a map from ThreadGroup instead)
-- Removed unnecessary debug statement in GenomeLocParser
-- nt and nct officially work together now
Guillermo del Angel
Eric Banks
Ami Levy Moonshine
David Roazen
Mark DePristo
Mauricio Carneiro
Khalid Shakir
Ryan Poplin
Joel Thibault
Christopher Hartl
Yossi Farjoun