From 2fa45a342e1c884e557cf822c19fb99b009dcb7e Mon Sep 17 00:00:00 2001 From: Dave Larson Date: Fri, 19 Jan 2018 11:35:01 -0600 Subject: [PATCH 1/6] Change parameters for duplication genotyping model This relaxes the allele balance expectation for duplications. For a simple tandem duplication, we expect to see 1/5 of the reads supporting the duplication in the heterozygous state and 1/3 supporting the duplication in the homozygous state. Additional copies of the duplicon will alter this ratio, but this is not handled by the previous or current model. --- svtyper/statistics.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/svtyper/statistics.py b/svtyper/statistics.py index f542e34..0f0ddec 100644 --- a/svtyper/statistics.py +++ b/svtyper/statistics.py @@ -23,7 +23,7 @@ def log_choose(n, k): def bayes_gt(ref, alt, is_dup): # probability of seeing an alt read with true genotype of of hom_ref, het, hom_alt respectively if is_dup: # specialized logic to handle non-destructive events such as duplications - p_alt = [1e-2, 1/3.0, 0.5] + p_alt = [1e-2, 1/5.0, 1/3.0] else: p_alt = [1e-3, 0.5, 0.9] From 305196bdbf2f57c5583ed0635d2136a470b40fe7 Mon Sep 17 00:00:00 2001 From: Dave Larson Date: Fri, 19 Jan 2018 14:36:22 -0600 Subject: [PATCH 2/6] Switch to decimal representation of AB prior --- svtyper/statistics.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/svtyper/statistics.py b/svtyper/statistics.py index 0f0ddec..51cc3cd 100644 --- a/svtyper/statistics.py +++ b/svtyper/statistics.py @@ -23,7 +23,7 @@ def log_choose(n, k): def bayes_gt(ref, alt, is_dup): # probability of seeing an alt read with true genotype of of hom_ref, het, hom_alt respectively if is_dup: # specialized logic to handle non-destructive events such as duplications - p_alt = [1e-2, 1/5.0, 1/3.0] + p_alt = [1e-2, 0.2, 1/3.0] else: p_alt = [1e-3, 0.5, 0.9] From 07ed2ba575cd316d83388e56bb30daa341e16f57 Mon Sep 17 00:00:00 2001 From: Dave Larson Date: Fri, 19 Jan 2018 14:54:38 -0600 Subject: [PATCH 3/6] Update test data for new DUP genotyping --- tests/data/example.gt.vcf | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/tests/data/example.gt.vcf b/tests/data/example.gt.vcf index 0c8d68a..e1c2b53 100644 --- a/tests/data/example.gt.vcf +++ b/tests/data/example.gt.vcf @@ -1,5 +1,5 @@ ##fileformat=VCFv4.1 -##fileDate=20161212 +##fileDate=20180119 ##reference=/shared/genomes/b37/full/human_g1k_v37.fasta ##INFO= ##INFO= @@ -337,7 +337,7 @@ 3 178550130 209676 G 749.19 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-744;END=178550874;STR=+-:992;CIPOS=0,0;CIEND=0,0;EVENT=209676;SUP=992;PESUP=779;SRSUP=213;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:200:113:75:37:749.19:-79,-4,-47:74:36:35:4:0:39:31:0.33 3 178567653 209686 A 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-689;END=178568342;STR=+-:77;CIPOS=0,0;CIEND=0,0;EVENT=209686;SUP=77;PESUP=2;SRSUP=75;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:160:160:0:0.00:-0,-48,-159:159:0:78:0:0:81:0:0 3 179654341 210032 C 3131.50 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-462;END=179654803;STR=+-:1342;CIPOS=0,0;CIEND=0,0;EVENT=210032;SUP=1342;PESUP=956;SRSUP=386;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 1/1:200:107:0:107:3131.50:-318,-32,-5:0:106:0:30:6:0:69:1 -3 185628683 211946 G 0.00 . TOOL=LUMPY;SVTYPE=DUP;SVLEN=80531;END=185709214;STR=-+:103;IMPRECISE;CIPOS=-41,1;CIEND=-2,8;EVENT=211946;SUP=103;PESUP=103;SRSUP=0;EVTYPE=PE;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:57:64:60:3:0.00:-2,-7,-14:60:3:0:0:0:60:3:0.048 +3 185628683 211946 G 0.10 . TOOL=LUMPY;SVTYPE=DUP;SVLEN=80531;END=185709214;STR=-+:103;IMPRECISE;CIPOS=-41,1;CIEND=-2,8;EVENT=211946;SUP=103;PESUP=103;SRSUP=0;EVTYPE=PE;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:16:64:60:3:0.10:-2,-3,-7:60:3:0:0:0:60:3:0.048 3 187732908 212594 A 224.62 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-1909;END=187734817;STR=+-:118;IMPRECISE;CIPOS=-2,8;CIEND=-10,1;EVENT=212594;SUP=118;PESUP=118;SRSUP=0;EVTYPE=PE;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:146:56:42:13:224.62:-27,-4,-30:42:13:0:0:0:42:13:0.24 3 189224507 213103 C 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-874;END=189225381;STR=+-:9;CIPOS=0,0;CIEND=0,0;EVENT=213103;SUP=9;PESUP=1;SRSUP=8;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:161:161:0:0.00:-0,-48,-160:160:0:76:0:0:84:0:0 3 189363422 213158 T 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-7487;END=189370909;STR=+-:132;IMPRECISE;CIPOS=-1,11;CIEND=0,0;EVENT=213158;SUP=132;PESUP=132;SRSUP=0;EVTYPE=PE;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:129:129:0:0.00:-0,-39,-128:128:0:58:0:0:70:0:0 From c0d100f26148fd9197739c4fd63e59a5e36023e2 Mon Sep 17 00:00:00 2001 From: Dave Larson Date: Fri, 19 Jan 2018 14:56:48 -0600 Subject: [PATCH 4/6] Identify two most likely genotypes Prepare for changing genotype calculation by caching the two most likely genotypes instead of just the most likely. --- svtyper/classic.py | 3 ++- svtyper/singlesample.py | 3 ++- 2 files changed, 4 insertions(+), 2 deletions(-) diff --git a/svtyper/classic.py b/svtyper/classic.py index 5b6f580..385287b 100755 --- a/svtyper/classic.py +++ b/svtyper/classic.py @@ -433,7 +433,8 @@ def sv_genotype(bam_string, QR = int(split_weight * ref_seq) + int(disc_weight * ref_span) QA = int(split_weight * alt_splitters) + int(disc_weight * alt_span) gt_lplist = bayes_gt(QR, QA, is_dup) - gt_idx = gt_lplist.index(max(gt_lplist)) + best, second_best = sorted([ (i, e) for i, e in enumerate(gt_lplist) ], key=lambda(x): x[1], reverse=True)[0:2] + gt_idx = best[0] # print log probabilities of homref, het, homalt if debug: diff --git a/svtyper/singlesample.py b/svtyper/singlesample.py index 0620232..ca8d02a 100644 --- a/svtyper/singlesample.py +++ b/svtyper/singlesample.py @@ -413,7 +413,8 @@ def bayesian_genotype(breakpoint, counts, split_weight, disc_weight, debug): # the actual bayesian calculation and decision gt_lplist = bayes_gt(QR, QA, is_dup) - gt_idx = gt_lplist.index(max(gt_lplist)) + best, second_best = sorted([ (i, e) for i, e in enumerate(gt_lplist) ], key=lambda(x): x[1], reverse=True)[0:2] + gt_idx = best[0] # print log probabilities of homref, het, homalt if debug: From 6d1488987cfb5eee19389d4ded47e539bf7d491f Mon Sep 17 00:00:00 2001 From: Dave Larson Date: Fri, 19 Jan 2018 14:59:07 -0600 Subject: [PATCH 5/6] Change genotype quality calculation The genotype quality calculation is still capped at 200, but is now reported as the ratio between the most likely and second most likely calls. This calculation should be more numerically stable than the previous and more accurate. --- svtyper/classic.py | 5 +- svtyper/singlesample.py | 5 +- tests/data/example.gt.vcf | 160 +++++++++++++++++++------------------- 3 files changed, 82 insertions(+), 88 deletions(-) diff --git a/svtyper/classic.py b/svtyper/classic.py index 385287b..95f4e18 100755 --- a/svtyper/classic.py +++ b/svtyper/classic.py @@ -469,10 +469,7 @@ def sv_genotype(bam_string, if gt_sum > 0: gt_sum_log = math.log(gt_sum, 10) sample_qual = abs(-10 * (gt_lplist[0] - gt_sum_log)) # phred-scaled probability site is non-reference in this sample - if 1 - (10**gt_lplist[gt_idx] / 10**gt_sum_log) == 0: - phred_gq = 200 - else: - phred_gq = abs(-10 * math.log(1 - (10**gt_lplist[gt_idx] / 10**gt_sum_log), 10)) + phred_gq = min(-10 * (second_best[1] - best[1]), 200) var.genotype(sample.name).set_format('GQ', int(phred_gq)) var.genotype(sample.name).set_format('SQ', sample_qual) var.qual += sample_qual diff --git a/svtyper/singlesample.py b/svtyper/singlesample.py index ca8d02a..49da119 100644 --- a/svtyper/singlesample.py +++ b/svtyper/singlesample.py @@ -451,10 +451,7 @@ def bayesian_genotype(breakpoint, counts, split_weight, disc_weight, debug): if gt_sum > 0: gt_sum_log = math.log(gt_sum, 10) sample_qual = abs(-10 * (gt_lplist[0] - gt_sum_log)) # phred-scaled probability site is non-reference in this sample - if 1 - (10**gt_lplist[gt_idx] / 10**gt_sum_log) == 0: - phred_gq = 200 - else: - phred_gq = abs(-10 * math.log(1 - (10**gt_lplist[gt_idx] / 10**gt_sum_log), 10)) + phred_gq = min(-10 * (second_best[1] - best[1]), 200) result['formats']['GQ'] = int(phred_gq) result['formats']['SQ'] = sample_qual result['qual'] += sample_qual diff --git a/tests/data/example.gt.vcf b/tests/data/example.gt.vcf index e1c2b53..4f29b72 100644 --- a/tests/data/example.gt.vcf +++ b/tests/data/example.gt.vcf @@ -140,39 +140,39 @@ ##contig= ##contig= #CHROM POS ID REF ALT QUAL FILTER INFO FORMAT NA12878 -2 2798774 72354 C 1743.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-467;END=2799241;STR=+-:840;CIPOS=0,0;CIEND=0,0;EVENT=72354;SUP=840;PESUP=608;SRSUP=232;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 1/1:146:60:0:60:1743.00:-177,-18,-3:0:59:0:15:4:0:39:1 +2 2798774 72354 C 1743.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-467;END=2799241;STR=+-:840;CIPOS=0,0;CIEND=0,0;EVENT=72354;SUP=840;PESUP=608;SRSUP=232;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 1/1:150:60:0:60:1743.00:-177,-18,-3:0:59:0:15:4:0:39:1 2 3732805 72623 C 755.39 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-5222;END=3738027;STR=+-:212;CIPOS=0,0;CIEND=0,0;EVENT=72623;SUP=212;PESUP=192;SRSUP=20;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:200:81:46:34:755.39:-77,-1,-24:45:33:21:2:4:24:26:0.42 2 6400508 73459 C 0.00 . 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TOOL=LUMPY;SVTYPE=DEL;SVLEN=-120;END=30935094;STR=+-:8;CIPOS=0,0;CIEND=0,0;EVENT=81625;SUP=8;PESUP=1;SRSUP=7;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:62:62:0:0.00:-0,-19,-62:62:0:62:0:0:0:0:0 +2 30934974 81625 C 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-120;END=30935094;STR=+-:8;CIPOS=0,0;CIEND=0,0;EVENT=81625;SUP=8;PESUP=1;SRSUP=7;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:186:62:62:0:0.00:-0,-19,-62:62:0:62:0:0:0:0:0 2 33224462 82677 A 749.25 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-2829;END=33227291;STR=+-:357;CIPOS=0,0;CIEND=0,0;EVENT=82677;SUP=357;PESUP=263;SRSUP=94;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:200:102:66:36:749.25:-78,-3,-40:65:35:33:11:2:32:21:0.35 -2 34523656 83127 G 1277.09 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-2062;END=34525718;STR=+-:1031;CIPOS=0,0;CIEND=0,0;EVENT=83127;SUP=1031;PESUP=719;SRSUP=312;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:153:117:61:55:1277.09:-129,-1,-29:60:54:28:17:2:32:34:0.47 +2 34523656 83127 G 1277.09 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-2062;END=34525718;STR=+-:1031;CIPOS=0,0;CIEND=0,0;EVENT=83127;SUP=1031;PESUP=719;SRSUP=312;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:200:117:61:55:1277.09:-129,-1,-29:60:54:28:17:2:32:34:0.47 2 34965729 83280 A 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-1539;END=34967268;STR=+-:86;CIPOS=0,0;CIEND=0,0;EVENT=83280;SUP=86;PESUP=61;SRSUP=25;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:127:127:0:0.00:-0,-38,-126:126:0:61:0:0:65:0:0 2 35007246 83301 G 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-578;END=35007824;STR=+-:16;CIPOS=0,0;CIEND=0,0;EVENT=83301;SUP=16;PESUP=0;SRSUP=16;EVTYPE=SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:147:147:0:0.00:-0,-44,-146:146:0:69:0:0:77:0:0 -2 35772266 83555 A 305.71 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-52;END=35772318;STR=+-:109;CIPOS=0,0;CIEND=0,0;EVENT=83555;SUP=109;PESUP=1;SRSUP=108;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:131:39:24:14:305.71:-32,-1,-15:24:14:24:14:0:0:0:0.37 -2 40446947 85115 T 155.73 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-125;END=40447072;STR=+-:100;CIPOS=0,0;CIEND=0,0;EVENT=85115;SUP=100;PESUP=0;SRSUP=100;EVTYPE=SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:149:39:29:9:155.73:-19,-3,-21:29:9:29:9:0:0:0:0.24 +2 35772266 83555 A 305.71 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-52;END=35772318;STR=+-:109;CIPOS=0,0;CIEND=0,0;EVENT=83555;SUP=109;PESUP=1;SRSUP=108;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:132:39:24:14:305.71:-32,-1,-15:24:14:24:14:0:0:0:0.37 +2 40446947 85115 T 155.73 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-125;END=40447072;STR=+-:100;CIPOS=0,0;CIEND=0,0;EVENT=85115;SUP=100;PESUP=0;SRSUP=100;EVTYPE=SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:155:39:29:9:155.73:-19,-3,-21:29:9:29:9:0:0:0:0.24 2 41238369 85376 A 0.00 . TOOL=LUMPY;SVTYPE=DEL;SVLEN=-11934;END=41250303;STR=+-:41;CIPOS=0,0;CIEND=0,0;EVENT=85376;SUP=41;PESUP=29;SRSUP=12;EVTYPE=PE,SR;PRIN GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/0:200:135:135:0:0.00:-0,-40,-134:134:0:60:0:0:74:0:0 2 41775966 85577 T 0.00 . 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TOOL=LUMPY;SVTYPE=BND;STR=++:74;IMPRECISE;CIPOS=0,0;CIEND=-1,2;MATEID=894054_1;EVENT=894054;SUP=74;PESUP=73;SRSUP=1;EVTYPE=PE,SR GT:GQ:DP:RO:AO:SQ:GL:QR:QA:RS:AS:ASC:RP:AP:AB 0/1:65:39:32:6:65.75:-12,-5,-26:32:6:0:0:0:32:6:0.16 From 8ed6810e8bf62600cb1ccc2fcca1f48b24000f37 Mon Sep 17 00:00:00 2001 From: Dave Larson Date: Fri, 19 Jan 2018 15:03:33 -0600 Subject: [PATCH 6/6] Update to 0.5.0 This release incorporates the following changes: - Duplication genotyping model has been adjusted. The new model is more sensitive and should better reflect genotyping uncertainty. - Genotype quality calculations have been improved. If you have filtering scripts relying on genotype quality (and/or site quality for DUPs) you may need to recalibrate them before applying to this version. --- svtyper/version.py | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/svtyper/version.py b/svtyper/version.py index 14af72d..6501800 100644 --- a/svtyper/version.py +++ b/svtyper/version.py @@ -1,2 +1,2 @@ __author__ = "Colby Chiang (colbychiang@wustl.edu)" -__version__ = "v0.4.0" +__version__ = "v0.5.0"