pax_global_header00006660000000000000000000000064127444401300014511gustar00rootroot0000000000000052 comment=975870bd714c76cb86f2c1e6fa6f969cc285e0d3 Eagle-master/000077500000000000000000000000001274444013000133635ustar00rootroot00000000000000Eagle-master/.gitignore000066400000000000000000000000161274444013000153500ustar00rootroot00000000000000*.o src/eagle Eagle-master/README.md000066400000000000000000000004661274444013000146500ustar00rootroot00000000000000# Eagle This repository is for developers of the Eagle haplotype phasing software, which is open-source (GNU GPLv3). Most users will wish to download release tarballs (containing compiled executables and full genetic map tables) from the main Eagle website: http://data.broadinstitute.org/alkesgroup/Eagle/ Eagle-master/example/000077500000000000000000000000001274444013000150165ustar00rootroot00000000000000Eagle-master/example/EUR_test.bed000066400000000000000000005630631274444013000172010ustar00rootroot00000000000000l(Ϯ*輈2館.*¢.#̸ꫮ *ο诈诠> ʪ򮫾8*Ϯʺ˺館.㪯⢼#̸꯮+οꯨ꾸 +ʪ򮫾8>* :ʻ꺂+;+ギʯΰ머?::论+/+>/;";+쮺벪/???+?:/;";+쮺벪/???+:/;";*쮺벪/???+?;;/ø/뿾?/ο/;;.쮺øﺪ/뾾??+㾏˺뺾﫿̻+οί껬;:??ꯌ :#󼋎 2싫 .̊8ʺ+: ʪ/(2ʠ*?>Ϻ*ʿΫ򺳻+뫫￯/?.?:+/* /*2<ʪ>*먊.Ȩ"++̫ʫ늣Ê.*꺮*8;*꼪Σ2㬠:+*8.(;*3*:( < **8;*꼪Σ2㬠:+*8.(;*3*:( < **<莿?:ί>>.讪:/>ꯣ;*:+/* /*2<ʪ>*먊.Ȩ"++̫ʫ늣Ê.*꺮*8;*꼪Σ2㬠:+*8.(;*3*:( < **8;*꼪Σ2㬠:+*8.(;*3*:( < **<莿?:ί>>.讪:/㊾ꯣ;*??ʸ莯;(꼪Σ2:+*8.(;*;*:( **?ʸ莯; ꨮ꼪Σ2:+*8.(;*;*;( **?:+諸.* /**2<#ʪ> 몊.Ȩ"++ȫʫ늣.*꺮*?ʸ莯;(꼪Σ2:+*8.(;*;*:( **;:?ο?8ί>>.讪:/㊾ꯣ;*ʸ莯;(꼪Σ2:+*8.(;*;*:( **ʸ莯;(꼪Σ2:+*8.(;*;*:( **?ʸ讯;(꼪Σ2:+*8.(;*;*:( **?8ί>>.讪:/㊾ꯣ;*?;˿̎">ﯻ;/;ˢ>;+:+0ʪ;㪻*?/ 8ꃺ⫊3" 뼺ꮿ:*.???;꯸3>:///ή8ﯺ.??믺;꯺;?:./ή:ﯺ.ʋ**>+㨨"; ;"# .+ +(*(: "/#ˋ/>.3ʺ*((:.ຬ켼"ʋ*>/㨨"*;"# Ψ+ +(:,"+ "#/ξ;??>/>???>̏.:?:+88늲*8莫ຼ̊"?:Ύ/뮳+0;*>>ʪ>"(˫.̳***.?Ͽ>/?>ϯ>????>ϯ>::?늎/ /0:*(¨ :뾋*> (ȣ*+* ,;/믯⣫>뿏>˯+뺣>/?Ͽ>???::?늎/ /0:*(¨ :뾋  (ȣ.+* ,::?눎/ /0:*(¨ :뮋  (ȣ.+* ,?;믯⣫?뿏.˯+ﺫ>??ʿ﫿;Ͽ?;믯ﺣ⣫뿏>˯>;:?視 /⃋2:(‚*:뾋*>*뮈 ̳/;* ,?:>3#꾏ˎ믪ﻣΫ£(»ʯ+ʫ> .0샪"꾋ʈ믢;ʫ8*(*"«*.8˨*ʫ?*+:﫫;>Ȭ˿.ʫ/Ͼ.+ϼϬ2:ﾫ?￾˫?;.>˫;/ﾫ?￾˫?;.>˫;/?//ﯫ;꾯:Ȭ.ʫ/ϻϯ.*ϼ,2:8.+"0"+뻬""+.‹> Ϊ舊껪*몺˪Ȫ8.:ˮ.?8.+"0"+뻬""+.‹> Ϊ舊껪*몺˪Ȫ8.:ˮ.??8/+⏪"0"+뻮""+.‹ ,> Ϊ芊뻪*못˪8.:Ϯ/?믻>Ϻ+*;+,ʫ躪+>./+2;:(<(?+ʸ ﯫ:Ϻ;/ʮ/*<*?+:/*㢮(;ﲫϻ+ﯫ:Ϻ;/ʮ/*<*?+*/*㢮(;ﲫ˻+￫:Ϻ;/ʮ/*<*?/*/*㪪(ﲫ˻/￫:Ϻ;/ʮ/*<*?/*/*㪪(ﲫ˻/;?;?;??;?௻"˲ ;󫻻ʪ.:*<.*/:8⫺ꢃ0, ά;??????+:8?;????>;+;?>? 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( 8몿;+˿ί;;>+#?:?/*Ϋ?.??.?>?>/?;?;?:*:?.?:/;.?????;ﯾ/?>?>ϯ;;??>뺺몮ʻο+.+Ϻ:/뮋*«Ͽ???>??辎(+;*?裿¾Ｚ>Ϡ;+2﮺?辎(+;*?裿¾Ｚ>Ϡ;+2﮺?????/???????κʪ#(+<.8 ʮ>ꪯ.<ʊ( :>.κʪ#(*<.8 ʮ+>ꪯ.<ʊ( :>..8ﻯ ?..8ﻯʮ?..8ﻯ ?..8ﻯ ?.?.8ﻯ ?.ȊΪ+.8 ʮ뿾뮏.<(ú?.κΪ+(.ﯰ8 ʮ>ꪯ.<(ú>.ȊΪ+.8 ʮ뿾뮏.<(ú?..8ﻯ?.?ﮯ묻뺫?˿ ο;Ͽ:;???/ϯ;Ͽ;?/./:#??ϻ?8*,˪.#/3γ>?:β0?ί+뺫ϻ/;Ͽ;?>*辯.>.;뿫+뻫㳺㿨:?믯?과ȿ>?* ;?(*>.:+/;/+:򮾾믫>33>(?* ﾻ?꾫;;?;?;?.⋺⺺(,:>򪿬﫮.ꪯ??ꫀ迾課ʿ++?컏??⪊+‚#㫫ʪϫ((ȫ?#袯; 8.舀> 싺,,?*(: 2**밬;; "*:2++3Ȫ ;"ϫ;ï/㯎,+, (?."+.>*ʿ *+/.??/뼮*ꮮ;,/;㿈 +*?쯺.;/.:??#+뼨**Ϊ誮;:,;¯ #*?:*򾌺*/ ા̲ˣ.ϢȪ #ë 쮈+*+.3>?ϻ;ﮫ.??+???￿Ϯ;κ:?/;>?;??Eagle-master/example/EUR_test.bim000066400000000000000000002125301274444013000172040ustar00rootroot0000000000000021 rs11702480 0.415634 38347375 G A 21 rs7280358 0.415683 38349787 A C 21 rs7282108 0.415721 38352192 A C 21 rs58296537 0.415776 38358682 G C 21 rs150853915 0.415796 38361458 T C 21 rs115711809 0.415803 38362498 G A 21 rs2409872 0.415806 38362985 G A 21 rs11910597 0.415955 38384946 G T 21 rs3761360 0.415964 38386216 G A 21 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ۗ^;nkٻuNjkɖ]_7liӚ~iMAh:A¬VbLuP}96i!sB覾!)U>Ǘ` VAP0ht΂s+ U>Ǘ` VAP8!0N> Qy7LK쭂?΁w.SӭnK74~œ-wm{E5(B.S6mv󞗾4ƹro%@[gMەg|>VrF\y'jؕⶄu7hx* `ж^2Z[rOVaVaTA@۫ 6sAh]3w}7 g5m>6b}O|zT?%==YXs㌟ӆHO*m?CvJx=op߆mH(sI O?>ۤ@Ϩ>ʹڭ犆L=y~_,oP1bn qgMF?7=, ,ߣAK{V=/lSmZT=_B>vb3I0*eE k%ɡOY Eti-8FVOe1>vv|nNi6`ŜJy!w|*mEqC? c_SbvrsB*kC3=?ln_+-C-`ϕSȏ@\+,v:zp4Nӷ͔,]n_r-lA]EoM,kU,yUgz75}oY8b˩,[궶]GSˮ~YԹdץayOw}ziG w3r3-l\6iCZb9d.إ1oNEIa~`Qlf '7?ЎQPV>V}_N-9t_r]1n&xt\m%T/j%C+,vp%smx1+i}:.7'Trp\Z7n8Gj}#nĪhvM?zwhwZN,>[9Oz@vJ~YO*)n?=n鋝Ybo=aO}|&`qcdS,k?pb4brjVSP!7!B LS׋~8JW jkϖ7M$sʱr+ji_y[+Xp29aM,†=&dq[1l޲"[&uAyl&B,2/!׵jl{)oщ19"J.E+r4s0.s_NⴸhWc9OMr4b'%Ƹsn~A=AS?Y87scj[|/'ז"pgyэXn 1ޡn뢕>'5ĵ _:\+ǖX VqG-֧Bkj~2&A-_ee WxVhOa瑼snYxf;gOyZ$лz]h>7hc:v~Ly5'ޱ7Oh//gl4Lxt)'BCP ]ˎ8<;1!"_3#bWqSfgx#~,F|IsK[ߜ{w+M?fCckA8o:/,ܐzaqckLAZLX#r59)MwxeL2o#VykBxZ¯]ꊅ#`w?-sǎNmn6YϺ&r3s{Mja #Rpu:Es~X_ϖp,OlӠz0sstzKbvzPZ?~z6~o_zp׮z05Y6h_zumb~X҃' k,\ƳzXrQ+K}ӷ3+^ګlg9Z2ߴ~lq<Smڟk:<2Lw3-gYʹyPףyWY\ 1c/r`Ӹt4 ĵoC&- \mXZi b6 #O1bOY?Ƒ(/9{],JŰF,`ci Y*K7MA4?djMj]_ vv|J D|={'_&D-Y8YUxpE D&8!0 Bj8.GSaϤ5}%D+]1Giv9q&Z"}jƧd?*82?C[bP9ۇ ,M\M=qzwsK }U$6rG' u>:H]I>|Ox^!^s`S ;wrx5I9ZJ#|E͚/aUƥow247|Gvk|Gx<6/{?6|ݐ~jg{ E|`e{Grvhy. cȱq|19>yNXq>nkƶ3v7cUNVNl瀬Xw>Kǘggh'v)[Wآ+]hsa_88<6!Bi Km0xxk ;wv`}LcZu̮?zsui1~=<>jX6ڪł崅幖Z yOW/33][4?xl?e=7fL"xFOqc\Ѓ #8 -=R.Ah/GM#(%Xӗ56Om+ qúrtE󨶷<ܞU榻ƶ~_cɤJ]tg}I'[Hҷ<~8QJ|xSn m[H5.6f6.tܲUۮ.?JcYq4*OOG_<>߃Ozp$pagAT]7{Ʒ쨱[ /ⱲwqQ4lmqhV=yG+{pq^1QuZ_p-zw%r_sO})og3ϱ5 &$'45ˣgF>o~A s:A?eF{xm_x1Ea|((~FNmƥ-YOk֌2{gǶ8{CVࡍS+nM >  |C4t}o<ž<*6Gkl O^Q$ĭh^Ԛ3|Xa~m,yWAo% _ګhj~07Cw}tWa(.n߳ڷ>u˭V#y9ۘo%]~BCEagle-master/example/example.log000066400000000000000000000075511274444013000171640ustar00rootroot00000000000000 +-----------------------------+ | | | Eagle v2.3 | | July 22, 2016 | | Po-Ru Loh | | | +-----------------------------+ Copyright (C) 2015-2016 Harvard University. Distributed under the GNU GPLv3 open source license. Command line options: ../eagle \ --bfile=EUR_test \ --geneticMapFile=USE_BIM \ --chrom=21 \ --outPrefix=phased \ --numThreads=4 Setting number of threads to 4 === Reading genotype data === Reading fam file: EUR_test.fam Total indivs in PLINK data: Nbed = 379 Total indivs stored in memory: NpreQC = 379 Reading bim file: EUR_test.bim Total snps in PLINK data: Mbed = 2000 Restricting to 1813 SNPs on chrom 21 in region [bpStart,bpEnd] = [0,1e+09] Total SNPs stored in memory: MpreQC = 1813 Allocating 1813 x 379 bytes to temporarily store genotypes Reading genotypes and performing QC filtering on snps and indivs... Reading bed file: EUR_test.bed Expecting 190000 (+3) bytes for 379 indivs, 2000 snps Total post-QC indivs: N = 379 Total post-QC SNPs: M = 1813 MAF spectrum: 0- 5%: 495 5-10%: 290 10-20%: 332 20-30%: 248 30-40%: 234 40-50%: 214 Physical distance range: 9752235 base pairs Genetic distance range: 23.0881 cM Average # SNPs per cM: 79 Auto-selecting --maxBlockLen: 0.25 cM Number of <=(64-SNP, 0.25cM) segments: 68 Average # SNPs per segment: 26 Estimating LD scores using 379 indivs Fraction of heterozygous genotypes: 0.246308 Typical span of default 100-het history length: 5.17 cM Setting --histFactor=1.00 BEGINNING STEP 1 Time for step 1: 0.373152 Time for step 1 MN^2: 0.0242926 Making hard calls (time: 0.0283859) BEGINNING STEP 2 BATCH 1 OF 1 Building hash tables .................................................................. (time: 0.0523882) Phasing samples 1-379 Time for phasing batch: 0.449098 Making hard calls (time: 0.029567) Time for step 2: 0.531062 Time for step 2 MN^2: 0.0591508 BEGINNING STEP 3 (PBWT ITERS) Auto-selecting number of PBWT iterations: setting --pbwtIters to 2 BEGINNING PBWT ITER 1 BATCH 1 OF 10 Phasing samples 1-37 Time for phasing batch: 1.75458 BATCH 2 OF 10 Phasing samples 38-75 Time for phasing batch: 1.59901 BATCH 3 OF 10 Phasing samples 76-113 Time for phasing batch: 1.69437 BATCH 4 OF 10 Phasing samples 114-151 Time for phasing batch: 1.62289 BATCH 5 OF 10 Phasing samples 152-189 Time for phasing batch: 1.59901 BATCH 6 OF 10 Phasing samples 190-227 Time for phasing batch: 1.63321 BATCH 7 OF 10 Phasing samples 228-265 Time for phasing batch: 1.63894 BATCH 8 OF 10 Phasing samples 266-303 Time for phasing batch: 1.57722 BATCH 9 OF 10 Phasing samples 304-341 Time for phasing batch: 1.56258 BATCH 10 OF 10 Phasing samples 342-379 Time for phasing batch: 1.63269 Time for PBWT iter 1: 16.3145 BEGINNING PBWT ITER 2 BATCH 1 OF 10 Phasing samples 1-37 Time for phasing batch: 2.73515 BATCH 2 OF 10 Phasing samples 38-75 Time for phasing batch: 2.58695 BATCH 3 OF 10 Phasing samples 76-113 Time for phasing batch: 2.70714 BATCH 4 OF 10 Phasing samples 114-151 Time for phasing batch: 2.54992 BATCH 5 OF 10 Phasing samples 152-189 Time for phasing batch: 2.51631 BATCH 6 OF 10 Phasing samples 190-227 Time for phasing batch: 2.62562 BATCH 7 OF 10 Phasing samples 228-265 Time for phasing batch: 2.60083 BATCH 8 OF 10 Phasing samples 266-303 Time for phasing batch: 2.4503 BATCH 9 OF 10 Phasing samples 304-341 Time for phasing batch: 2.54366 BATCH 10 OF 10 Phasing samples 342-379 Time for phasing batch: 2.56976 Time for PBWT iter 2: 25.8857 Writing .haps.gz and .sample output Time for writing output: 0.370972 Total elapsed time for analysis = 43.6733 sec Eagle-master/example/example_ref.log000066400000000000000000000054521274444013000200160ustar00rootroot00000000000000 +-----------------------------+ | | | Eagle v2.3 | | July 22, 2016 | | Po-Ru Loh | | | +-----------------------------+ Copyright (C) 2015-2016 Harvard University. Distributed under the GNU GPLv3 open source license. Command line options: ../eagle \ --vcfRef=ref.bcf \ --vcfTarget=target.vcf.gz \ --geneticMapFile=../tables/genetic_map_hg19_withX.txt.gz \ --outPrefix=target.phased Setting number of threads to 1 Warning: The index file is older than the data file: ref.bcf.csi Reference samples: Nref = 169 Target samples: Ntarget = 8 [W::vcf_parse] INFO 'AC' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'AN' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'DP' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'AFR_AF' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'EX_TARGET' is not defined in the header, assuming Type=String SNPs to analyze: M = 430 SNPs in both target and reference SNPs ignored: 0 SNPs in target but not reference 215 SNPs in reference but not target 0 multi-allelic SNPs 0 monomorphic SNPs Missing rate in target genotypes: 0.00116279 Filling in genetic map coordinates using reference file: ../tables/genetic_map_hg19_withX.txt.gz Physical distance range: 3595565 base pairs Genetic distance range: 10.292 cM Average # SNPs per cM: 42 Number of <=(64-SNP, 1cM) segments: 9 Average # SNPs per segment: 47 Fraction of heterozygous genotypes: 0.178114 Typical span of default 100-het history length: 13.44 cM Setting --histFactor=1.00 Auto-selecting number of phasing iterations: setting --pbwtIters to 1 BEGINNING PHASING PHASING ITER 1 OF 1 Phasing target samples ................................................................................ Time for phasing iter 1: 0.23367 Writing vcf.gz output to target.phased.vcf.gz [W::vcf_parse] INFO 'AC' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'AN' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'DP' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'AFR_AF' is not defined in the header, assuming Type=String [W::vcf_parse] INFO 'EX_TARGET' is not defined in the header, assuming Type=String Time for writing output: 0.028584 Total elapsed time for analysis = 9.43616 sec Mean phase confidence of each target individual: ID PHASE_CONFIDENCE HG00403 0.953163 HG00404 0.949485 HG00406 0.927005 HG00407 0.950292 HG00419 0.938822 HG00421 0.93367 HG00422 0.952224 HG00428 0.944651 Eagle-master/example/example_vcf.log000066400000000000000000000065431274444013000200220ustar00rootroot00000000000000 +-----------------------------+ | | | Eagle v2.3 | | July 22, 2016 | | Po-Ru Loh | | | +-----------------------------+ Copyright (C) 2015-2016 Harvard University. Distributed under the GNU GPLv3 open source license. Command line options: ../eagle \ --vcf=EUR_test.vcf.gz \ --geneticMapFile=../tables/genetic_map_hg19_withX.txt.gz \ --chrom=21 \ --outPrefix=phased \ --numThreads=4 Setting number of threads to 4 === Reading genotype data === Reading genotypes for N = 379 samples Read M = 1813 variants Filling in genetic map coordinates using reference file: ../tables/genetic_map_hg19_withX.txt.gz Physical distance range: 9752235 base pairs Genetic distance range: 23.0881 cM Average # SNPs per cM: 79 Auto-selecting --maxBlockLen: 0.25 cM Number of <=(64-SNP, 0.25cM) segments: 68 Average # SNPs per segment: 26 Estimating LD scores using 379 indivs Fraction of heterozygous genotypes: 0.246308 Typical span of default 100-het history length: 5.17 cM Setting --histFactor=1.00 BEGINNING STEP 1 Time for step 1: 0.375713 Time for step 1 MN^2: 0.0244864 Making hard calls (time: 0.028863) BEGINNING STEP 2 BATCH 1 OF 1 Building hash tables .................................................................. (time: 0.0508139) Phasing samples 1-379 Time for phasing batch: 0.437996 Making hard calls (time: 0.029588) Time for step 2: 0.51841 Time for step 2 MN^2: 0.0594165 BEGINNING STEP 3 (PBWT ITERS) Auto-selecting number of PBWT iterations: setting --pbwtIters to 2 BEGINNING PBWT ITER 1 BATCH 1 OF 10 Phasing samples 1-37 Time for phasing batch: 1.77567 BATCH 2 OF 10 Phasing samples 38-75 Time for phasing batch: 1.64262 BATCH 3 OF 10 Phasing samples 76-113 Time for phasing batch: 1.71332 BATCH 4 OF 10 Phasing samples 114-151 Time for phasing batch: 1.61786 BATCH 5 OF 10 Phasing samples 152-189 Time for phasing batch: 1.6091 BATCH 6 OF 10 Phasing samples 190-227 Time for phasing batch: 1.6461 BATCH 7 OF 10 Phasing samples 228-265 Time for phasing batch: 1.651 BATCH 8 OF 10 Phasing samples 266-303 Time for phasing batch: 1.58484 BATCH 9 OF 10 Phasing samples 304-341 Time for phasing batch: 1.59481 BATCH 10 OF 10 Phasing samples 342-379 Time for phasing batch: 1.63671 Time for PBWT iter 1: 16.4721 BEGINNING PBWT ITER 2 BATCH 1 OF 10 Phasing samples 1-37 Time for phasing batch: 2.72875 BATCH 2 OF 10 Phasing samples 38-75 Time for phasing batch: 2.59217 BATCH 3 OF 10 Phasing samples 76-113 Time for phasing batch: 2.72183 BATCH 4 OF 10 Phasing samples 114-151 Time for phasing batch: 2.57471 BATCH 5 OF 10 Phasing samples 152-189 Time for phasing batch: 2.5283 BATCH 6 OF 10 Phasing samples 190-227 Time for phasing batch: 2.64632 BATCH 7 OF 10 Phasing samples 228-265 Time for phasing batch: 2.63781 BATCH 8 OF 10 Phasing samples 266-303 Time for phasing batch: 2.52006 BATCH 9 OF 10 Phasing samples 304-341 Time for phasing batch: 2.53771 BATCH 10 OF 10 Phasing samples 342-379 Time for phasing batch: 2.51691 Time for PBWT iter 2: 26.0046 Writing vcf.gz output to phased.vcf.gz Time for writing output: 0.331217 Total elapsed time for analysis = 52.9965 sec Eagle-master/example/phased.haps.gz000066400000000000000000005736121274444013000175740ustar00rootroot00000000000000[<>%~ Jf1eU2 %˷:n%$%yLM7vj~Wi/:ϝϦ̴:h%NF&FK6YC&9k_jy?z]ëU~a$Яf]e3j;zܳ1p,E$s(hpUտq~DZ d9Dlյ#r#T3769ROKi XUSHt"rVN-췗e|T<[̫1֪D5ǜ;vr;,&q11Y~dP5Q[vBـ:-rJ^#siQz (MuǞC$^>E<4>.s16$ޥ8Jf5.87D<ŵ՜3 :ZA;^T[j+>c+ ea20fxɬ@DU<QYs 1oANUqLfDYnjRQV[^q`#n`Dd]Rk#Q$lH\ yLO}I߯?;}}[|v5^=.y?MuǞC$^@~jm9?#hvlQJD^u@ʛ,[eQ=;Zg?R6{ڬuV (xqM~4iϴ'z^TpSj6lD1*tj/,VFs.﹒u`鈹w[F3[]Zp'4O)kq˼WϷ3ߠKG~+jM 6 Sڡ6c3!cܷV{L1}ѻZ} (8+R:}Zb-JR-P;Zwf_rԚQCٛ"4VG5lMu( 8 Mf9,X#cÙcf1a,f+.m8uE1ukzE[񑙁B-vW2Pj@p-GPOIao}j:9av)<[yٻSDLDY ԁlx%XkCX':]&h҇*>Ŏ~0RS1Z4,Qvj ߹ |10 )}||iP0e3fsI`LdaWT~2yK 5"AXOIao눆b)/ռS KT[xY?NN3'GqOWDCX':]&h҇*>Ŏ~0RS1Z4,Qvj ߹ LM|hsUjƙXaŨkwdbql G+Ud}PkҸ>_Tj{UپkI c_f:hAY1BSByUl6eͭ,d־Ǐ{>D\kwl3 Yކ] OMsn&>!+঄3u,*ꌟ:0YOrE`%Z}R@/-'jH):u Tjs2ٙuZG-s{tc"Q=[qgt.ob )NeOuL>%Y/U<|! 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mpDBCEagle-master/example/run_example.sh000066400000000000000000000011361274444013000176720ustar00rootroot00000000000000../eagle \ --bfile=EUR_test \ --geneticMapFile=USE_BIM \ --chrom=21 \ --outPrefix=phased \ --numThreads=4 \ 2>&1 | tee example.log ### run eagle without any parameters to list options ### typical options for phasing without a reference: # to import genetic map coordinates: --geneticMapFile=tables/genetic_map_hg##.txt.gz # to remove indivs or exclude SNPs: --remove, --exclude # to perform QC on missingness: --maxMissingPerIndiv, --maxMissingPerSnp # to select a region to phase: --bpStart, --bpEnd ### old: # to use Eagle1 algorithm: --v1 # to use Eagle1 fast mode: --v1fast Eagle-master/example/run_example_ref.sh000066400000000000000000000004521274444013000205260ustar00rootroot00000000000000echo 'If pulling from github, change --geneticMapFile to ../tables/genetic_map_hg19_example.txt.gz' echo ../eagle \ --vcfRef=ref.bcf \ --vcfTarget=target.vcf.gz \ --geneticMapFile=../tables/genetic_map_hg19_withX.txt.gz \ --outPrefix=target.phased \ 2>&1 | tee example_ref.log Eagle-master/example/run_example_vcf.sh000066400000000000000000000010251274444013000205250ustar00rootroot00000000000000../eagle \ --vcf=EUR_test.vcf.gz \ --geneticMapFile=../tables/genetic_map_hg19_withX.txt.gz \ --chrom=21 \ --outPrefix=phased \ --numThreads=4 \ 2>&1 | tee example_vcf.log ### run eagle without any parameters to list options ### typical options for phasing without a reference in VCF/BCF mode: # to import genetic map coordinates: --geneticMapFile=tables/genetic_map_hg##.txt.gz # to select a region to phase: --bpStart, --bpEnd ### old: # to use Eagle1 algorithm: --v1 # to use Eagle1 fast mode: --v1fast Eagle-master/example/target.phased.vcf.gz000066400000000000000000000510711274444013000206720ustar00rootroot00000000000000BC]5}[oGW3G#g=,{H%3O-db)RKR?DdUVGTf4-#Qꮨ勿͇|߾~OWߝz훛wW=Np.%/WKNy}r&9__('jlp=Hq>#i(B(#M٤d}GH[l.y$v|!Ďg? 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Eagle-master/src/DipTreePBWT.cpp000066400000000000000000000577731274444013000167320ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include #include #include #include #include #include #include "HapHedge.hpp" #include "NumericUtils.hpp" #include "Timer.hpp" #include "DipTreePBWT.hpp" namespace EAGLE { using std::vector; using std::cout; using std::endl; const int TO_UNKNOWN = -2, TO_NONE = -1; // TO_NONE used in HapPathSplit and HapPrefix // struct HapPathSplit HapPathSplit::HapPathSplit(void) {}; HapPathSplit::HapPathSplit(int _t) : t(_t), relProbLastStop(1), hapPrefixInd(0) { hapPrefixTo[0] = hapPrefixTo[1] = TO_UNKNOWN; }; HapPathSplit::HapPathSplit(int _t, float relProb, int ind) : t(_t), relProbLastStop(relProb), hapPrefixInd(ind) { hapPrefixTo[0] = hapPrefixTo[1] = TO_UNKNOWN; }; // struct HapPath HapPath::HapPath(void) {}; // struct HapPrefix HapPrefix::HapPrefix(void) {}; HapPrefix::HapPrefix(const HapTreeState &_state) { state = _state; //to[0] = to[1] = TO_UNKNOWN; }; // class HapWaves HapWaves::HapWaves(const HapHedgeErr &_hapHedge, const vector &_cMcoords, double _cMexpect, int _histLength, int _beamWidth, float _logPerr, int _tCur) : rng(123), rand01(rng, boost::uniform_01<>()), hapHedge(_hapHedge), cMcoords(_cMcoords), cMexpect(_cMexpect), histLength(_histLength), beamWidth(_beamWidth), pErr(expf(_logPerr)), maxHapPaths(2*beamWidth), maxHapPrefixes(maxHapPaths*histLength*2+1), tCur(_tCur) { curMod = tCur % HAPWAVES_HIST; nextMod = (tCur+1) % HAPWAVES_HIST; for (int p = 0; p < HAPWAVES_HIST; p++) { hapPathSizes[p] = 0; hapPaths[p] = new HapPath[maxHapPaths]; for (int i = 0; i < maxHapPaths; i++) hapPaths[p][i].splitList = new HapPathSplit[histLength]; hapPrefixes[p] = new HapPrefix[maxHapPrefixes]; } // add root of 0th HapTree as cur HapPath hapPaths[curMod][0].cumLogP = 0; hapPaths[curMod][0].splitListLength = 1; hapPaths[curMod][0].splitList[0] = HapPathSplit(tCur); hapPaths[curMod][0].to[0] = hapPaths[0][0].to[1] = TO_UNKNOWN; hapPathSizes[curMod] = 1; hapPrefixes[curMod][0] = HapPrefix(hapHedge.getHapTreeMulti(tCur).getRootState()); hapPrefixSizes[curMod] = 1; } HapWaves::~HapWaves(void) { for (int p = 0; p < HAPWAVES_HIST; p++) { for (int i = 0; i < maxHapPaths; i++) delete[] hapPaths[p][i].splitList; delete[] hapPaths[p]; delete[] hapPrefixes[p]; } } inline double sq(double x) { return x*x; } // use cMcoords and cMexpect (cMexpect>0 => coalescent; cMexpect<0 => Li-Stephens) float HapWaves::recombP(int tCur, int tSplit) const { double p = 0; if (cMexpect > 0) { // coalescent IBD length distribution with mean a = cMexpect double a = cMexpect; double term1 = 1 / sq(1 + (cMcoords[tCur]-cMcoords[tSplit])/a); double term2 = tCur+1 == (int) cMcoords.size() ? 0 : 1 / sq(1 + (cMcoords[tCur+1]-cMcoords[tSplit])/a); p = term1 - term2; } else { // Li-Stephens IBD length distribution with mean a = -cMexpect double a = -cMexpect; double term1 = exp(-(cMcoords[tCur]-cMcoords[tSplit])/a); double term2 = tCur+1 == (int) cMcoords.size() ? 0 : exp(-(cMcoords[tCur+1]-cMcoords[tSplit])/a); p = term1 - term2; } const double minRecombP = 0.000001, maxRecombP = 1.0;//pErr; return std::max(std::min(p, maxRecombP), minRecombP); } // populate hapPrefixes[nextMod] // populate toCumLogP[] in hapPaths[curMod] (but don't populate hapPaths[nextMod]) void HapWaves::computeAllExtensions(const vector &nextPossibleBits) { // add root of next (= new cur) HapTree as beginning of HapPrefix list if (tCur+1 < (int) cMcoords.size()) { hapPrefixes[nextMod][0] = HapPrefix(hapHedge.getHapTreeMulti(tCur+1).getRootState()); hapPrefixSizes[nextMod] = 1; } float mult = hapHedge.getHapTreeMulti(tCur).getInvNhaps(); // iterate over paths for (int i = 0; i < hapPathSizes[curMod]; i++) { float relProbStopNext[2] = {0, 0}; // iterate over splits for (int j = 0; j < hapPaths[curMod][i].splitListLength; j++) { HapPathSplit &split = hapPaths[curMod][i].splitList[j]; // iterate over next possible bits for (int b = 0; b < 2; b++) { if (!((nextPossibleBits[i]>>b)&1)) continue; HapPrefix &hapPrefix = hapPrefixes[curMod][split.hapPrefixInd]; // if extension of hap prefix hasn't been attempted, attempt to perform extension if (split.hapPrefixTo[b] == TO_UNKNOWN) { split.hapPrefixTo[b] = TO_NONE; // default: can't extend (overwrite if path found) hapPrefix.toHetOnlyProb[b] = 0; // try to extend hap prefix: // fill in split.hapPrefixTo[b], hapPrefixes[curMod][split.hapPrefixInd].to*[b] const HapTreeMulti &hapTree = hapHedge.getHapTreeMulti(split.t); HapTreeState state = hapPrefix.state; if (hapTree.next(2*tCur, state, b)) { // can extend to match at het hapPrefix.toHetOnlyProb[b] += mult * state.count; if (hapTree.next(2*tCur+1, state, 0)) { // no err in inter-het region // create and link new HapPrefix node in hapPrefixes[nextMod]; link split.hapPrefixTo[b] = hapPrefixSizes[nextMod]++; hapPrefixes[nextMod][split.hapPrefixTo[b]].state = state; } } } relProbStopNext[b] += split.relProbLastStop * hapPrefix.toHetOnlyProb[b] * recombP(tCur, split.t); } } for (int b = 0; b < 2; b++) { if (!((nextPossibleBits[i]>>b)&1)) continue; float relLogP = -1000; if (relProbStopNext[b] != 0) relLogP = logf(relProbStopNext[b]); hapPaths[curMod][i].toCumLogP[b] = hapPaths[curMod][i].cumLogP + relLogP;// + recombLogPs[tCur]; } } } float HapWaves::getToCumLogProb(int ind, int nextBit) const { return hapPaths[curMod][ind].toCumLogP[nextBit]; } // look up/create extension of hapPaths[curMod][ind] in hapPaths[nextMod] // return index in hapPaths[nextMod] int HapWaves::extendPath(int ind, int nextBit) { HapPath &curHapPath = hapPaths[curMod][ind]; if (curHapPath.to[nextBit] == TO_UNKNOWN) { int nextInd = hapPathSizes[nextMod]++; assert(hapPathSizes[nextMod]<=maxHapPaths); curHapPath.to[nextBit] = nextInd; HapPath &nextHapPath = hapPaths[nextMod][nextInd]; nextHapPath.cumLogP = curHapPath.toCumLogP[nextBit]; float calibP = expf(curHapPath.cumLogP - nextHapPath.cumLogP); int &nSplit = nextHapPath.splitListLength; nSplit = 0; nextHapPath.to[0] = nextHapPath.to[1] = TO_UNKNOWN; for (int j = (curHapPath.splitList[0].t + histLength == tCur+1 ? 1 : 0); j < curHapPath.splitListLength; j++) { const HapPathSplit &curSplit = curHapPath.splitList[j]; if (curSplit.hapPrefixTo[nextBit] != TO_NONE) { nextHapPath.splitList[nSplit++] = HapPathSplit(curSplit.t, curSplit.relProbLastStop * calibP, curSplit.hapPrefixTo[nextBit]); } } nextHapPath.splitList[nSplit++] = HapPathSplit(tCur+1); // restart } return curHapPath.to[nextBit]; } void HapWaves::advance(void) { tCur++; curMod = tCur % HAPWAVES_HIST; nextMod = (tCur+1) % HAPWAVES_HIST; hapPathSizes[nextMod] = 0; hapPrefixSizes[nextMod] = 0; } /* * At any point along a haplotype path (i.e., a sequence of alleles at split sites), * we have stored a "split list" of positions at which the last copied segment could have begun. * We can compute the relative probabilities of these split positions (given the next allele), * which allows us to sample the last copied segment. * * INPUT: (t, hapPathInd, tBit) designating a stored haplotype path extended to tBit at t * - t = position; (t % HAPWAVES_HIST) is index in haplotype paths ending in hom region before t * - hapPathInd = index * - tBit = haplotype bit at t (to which to extend haplotype prefixes in split list) * * OUTPUT: (tStart, state) designating a haplotype segment randomly sampled from the split list * - tStart = start position of copied segment * - state = state corresponding to copied segment in HapTree at tStart */ void HapWaves::sampleLastPrefix(int &tStart, HapTreeState &state, int t, int hapPathInd, int tBit) { assert(tCur+1 - t < HAPWAVES_HIST); // the relevant history shouldn't have been overwritten int tMod = t % HAPWAVES_HIST; const HapPath &hapPath = hapPaths[tMod][hapPathInd]; // compute (unscaled) probabilities of each possible split point in the list float relProbStopNext = 0; vector cumRelProbStopNext(hapPath.splitListLength); for (int j = 0; j < hapPath.splitListLength; j++) { const HapPathSplit &split = hapPath.splitList[j]; const HapPrefix &hapPrefix = hapPrefixes[tMod][split.hapPrefixInd]; // this computation was previously done to determine the relative probabilities // of extending the path to tBit=0 vs. tBit=1 at tree index t (= split site t-1) relProbStopNext += split.relProbLastStop * hapPrefix.toHetOnlyProb[tBit] * recombP(t, split.t); cumRelProbStopNext[j] = relProbStopNext; } float relLogP = -1000; if (relProbStopNext != 0) relLogP = logf(relProbStopNext); assert(hapPaths[tMod][hapPathInd].toCumLogP[tBit] == hapPath.cumLogP + relLogP); // randomly sample a split point float r = rand01(); for (int j = 0; j < hapPath.splitListLength; j++) if (cumRelProbStopNext[j] > r*relProbStopNext || j+1 == hapPath.splitListLength) { const HapPathSplit &split = hapPath.splitList[j]; const HapPrefix &hapPrefix = hapPrefixes[tMod][split.hapPrefixInd]; tStart = split.t; state = hapPrefix.state; return; } } // struct DipTreeNode bool DipTreeNode::operator < (const DipTreeNode &dNode) const { return logP+boostLogP > dNode.logP+dNode.boostLogP; } // class DipTree void DipTree::traceNode(int t, int i) { int from = nodes[t][i].from; if (t>1) traceNode(t-1, from); cout << "(" << (int) nodes[t][i].hapMat << "," << (int) nodes[t][i].hapPat << ") "; } std::pair truncPair(uint64 histMat, uint64 histPat, uint64 histBits) { uint64 mask = histBits>=64ULL ? -1ULL : (1ULL< nextPossibleBits(2*beamWidth); int checkWidth = std::min((int) nodes[tCur].size(), beamWidth); vector reqMats(checkWidth), reqPats(checkWidth); const float logPthresh = 2*logPerr;//logf(0.000001f); for (int i = 0; i < checkWidth; i++) { const DipTreeNode &dNode = nodes[tCur][i]; if (dNode.logP+dNode.boostLogP < nodes[tCur][0].logP+nodes[tCur][0].boostLogP + logPthresh) { checkWidth = i; break; } assert(dNode.hapPathInds[0] < (int) nextPossibleBits.size()); assert(dNode.hapPathInds[1] < (int) nextPossibleBits.size()); if (isFullyConstrained) { char &reqMat = reqMats[i], &reqPat = reqPats[i]; if ((constraints[tCur]>>1) == 0) // no-hom-err constraint reqMat = reqPat = constraints[tCur]&1; else { // rel phase constraint int t = tCur, ind = i; for (int d = 0; d < (constraints[tCur]>>1)-1; d++) ind = nodes[t--][ind].from; reqMat = nodes[t][ind].hapMat ^ (constraints[tCur]&1); reqPat = nodes[t][ind].hapPat ^ (constraints[tCur]&1); } nextPossibleBits[dNode.hapPathInds[0]] |= 1< nextNodes; for (int i = 0; i < checkWidth; i++) { const DipTreeNode &dNode = nodes[tCur][i]; for (char hapMat = 0; hapMat < 2; hapMat++) for (char hapPat = 0; hapPat < 2; hapPat++) { if (!dNode.unequalAnc && hapMat > hapPat) continue; if (isFullyConstrained && (hapMat != reqMats[i] || hapPat != reqPats[i])) continue; if (isOppConstrained && hapMat==hapPat) continue; DipTreeNode nextNode; nextNode.from = i; nextNode.unequalAnc = dNode.unequalAnc || (hapMat != hapPat); nextNode.hapMat = hapMat; nextNode.hapPat = hapPat; nextNode.numErr = dNode.numErr + (genos[tCur]<=2 && hapMat+hapPat != genos[tCur]); nextNode.logP = hapWaves.getToCumLogProb(dNode.hapPathInds[0], hapMat) + hapWaves.getToCumLogProb(dNode.hapPathInds[1], hapPat) + nextNode.numErr * logPerr; nextNode.boostLogP = dNode.boostLogP; if (isFullyConstrained) { nextNode.histMat = dNode.histMat; nextNode.histPat = dNode.histPat; } else { nextNode.histMat = (dNode.histMat<<1ULL) | hapMat; nextNode.histPat = (dNode.histPat<<1ULL) | hapPat; } nextNodes.push_back(nextNode); } } if (!isFullyConstrained) { // compute number of bits of history to use (histLength minus # of fully constrained sites) int histBits = 0; for (int t = tCur; t > std::max(tCur-histLength, 0); t--) if (constraints[t]==OPP_CONSTRAINT || constraints[t]==NO_CONSTRAINT) histBits++; // aggregate DipTree paths that agree exactly in past histLength std::sort(nextNodes.begin(), nextNodes.end()); std::map < std::pair , int > histToInd; for (int i = 0; i < (int) nextNodes.size(); i++) { const DipTreeNode &nextNode = nextNodes[i]; std::pair histPair = truncPair(nextNode.histMat, nextNode.histPat, histBits); std::map < std::pair , int >::iterator it = histToInd.find(histPair); if (it == histToInd.end()) { histToInd[histPair] = nodes[tCur+1].size(); nodes[tCur+1].push_back(nextNode); } else { int j = it->second; float sumLogPj = nodes[tCur+1][j].logP + nodes[tCur+1][j].boostLogP; float sumLogPi = nextNode.logP + nextNode.boostLogP; NumericUtils::logSumExp(sumLogPi, sumLogPj); // prob i += prob existing tCur+1 node j nodes[tCur+1][j].boostLogP += sumLogPi - sumLogPj; // augment boost for existing node j } } //cout << " " << nodes[tCur+1].size() << "/" << nextNodes.size() << std::flush; } else nodes[tCur+1] = nextNodes; // extend hap paths of top beamWidth DipTree nodes (part 2) for (int i = 0; i < std::min((int) nodes[tCur+1].size(), beamWidth); i++) { DipTreeNode &nextNode = nodes[tCur+1][i]; const DipTreeNode &dNode = nodes[tCur][nextNode.from]; nextNode.hapPathInds[0] = hapWaves.extendPath(dNode.hapPathInds[0], nextNode.hapMat); nextNode.hapPathInds[1] = hapWaves.extendPath(dNode.hapPathInds[1], nextNode.hapPat); } hapWaves.advance(); tCur++; float totLogP = nodes[tCur][0].logP + nodes[tCur][0].boostLogP; for (int i = 1; i < (int) nodes[tCur].size(); i++) NumericUtils::logSumExp(totLogP, nodes[tCur][i].logP + nodes[tCur][i].boostLogP); for (int i = 0; i < (int) nodes[tCur].size(); i++) { normProbs[tCur].push_back(expf(nodes[tCur][i].logP + nodes[tCur][i].boostLogP - totLogP)); //traceNode(tCur, i); cout << normProbs[tCur].back() << endl; } } DipTree::DipTree(const HapHedgeErr &_hapHedge, const vector &_genos, const char *_constraints, const vector &_cMcoords, double _cMexpect, int _histLength, int _beamWidth, float _logPerr, int _tCur) : rng(12345), rand01(rng, boost::uniform_01<>()), hapHedge(_hapHedge), hapWaves(_hapHedge, _cMcoords, _cMexpect, _histLength, _beamWidth, _logPerr, _tCur), genos(_genos), constraints(_constraints), histLength(_histLength), beamWidth(_beamWidth), logPerr(_logPerr), tCur(_tCur), T(_hapHedge.getNumTrees()), nodes(T+1), normProbs(T+1) { DipTreeNode dNode; dNode.from = -1; dNode.unequalAnc = 0; dNode.logP = 0; dNode.numErr = 0; dNode.hapPathInds[0] = dNode.hapPathInds[1] = 0; dNode.histMat = 0; dNode.histPat = 0; dNode.boostLogP = 0; nodes[tCur].push_back(dNode); // root of DipTree } // compute probability of AA at hets tCallLoc1 and tCallLoc2 float DipTree::callProbAA(int tCallLoc1, int tCallLoc2, int callLength) { assert(tCallLoc1>0 && tCallLoc20 && tCallLoc > &nodes, int tCallLoc, int t, int ind, int h, bool isFwd) { refHap.tMaskFwd = refHap.tMaskRev = 0; const int maxShift = 8*sizeof(refHap.tMaskFwd); while (t > 0) { // rewind DipTree int t1Bit = h==0 ? nodes[t][ind].hapMat : nodes[t][ind].hapPat; // allele at t-1 int dist = t-1 - tCallLoc; if (dist <= 0) dist--; if (dist < -maxShift) break; else if (dist <= maxShift) { int t1BitShift = t1Bit<<(abs(dist)-1); if (isFwd == (dist > 0)) refHap.tMaskFwd |= t1BitShift; else refHap.tMaskRev |= t1BitShift; } ind = nodes[t--][ind].from; } } /* * INPUT: * - tCallLoc = tree index of left side of interval of interest: (tCallLoc, tCallLoc+1) * - callLength = number of positions to look ahead * - samples = number of random samples to take * - bestHaps = actual indices of Kpbwt haplotypes currently encoded in HapHedgeErr * - isFwd = flag indicating whether output het masks should be little- or big-endian * * OUTPUT: * - vector of sampled reference haplotype pairs */ vector DipTree::sampleRefs(int tCallLoc, int callLength, int samples, const vector &bestHaps, bool isFwd) { if (callLength > HAPWAVES_HIST-5) { cerr << "ERROR in DipTree::sampleRefs(): callLength=" << callLength << ", HAPWAVES_HIST=" << HAPWAVES_HIST << endl; cerr << " To use this callLength, increase HAPWAVES_HIST and recompile" << endl; assert(callLength <= HAPWAVES_HIST-5); } assert(tCallLoc>=0 && tCallLoc ret(samples); for (int s = 0; s < samples; s++) { // randomly sample a DipTree node float r = rand01(); float cumProb = 0; for (int i = 0; i < (int) nodes[tFront].size(); i++) { cumProb += normProbs[tFront][i]; if (cumProb > r*probTot || i+1 == (int) nodes[tFront].size()) { // sample a reference haplotype for each parental path in the sampled DipTree node for (int h = 0; h < 2; h++) { int t = tFront; // current position in DipTree int ind = i; // index into stored DipTree nodes at t int tStart = tFront; // start of last copied haplotype segment (for now, set to tFront) // set ret[s].haps[h].tMask{Fwd,Rev} to use when aligning parental paths to phase calls computeHetMasks(ret[s].haps[h], nodes, tCallLoc, t, ind, h, isFwd); /* traceNode(t, i); cout << "tFront = " << tFront << endl; cout << "tCallLoc: " << tCallLoc << " tStart: " << tStart << " T: " << T << endl; */ HapTreeState state; int tBit = 0; ret[s].haps[h].isEnd = false; // jump backward one copied segment at a time until we get one starting <= tCallLoc while (tStart > tCallLoc) { if (tStart == tCallLoc+1) // prev segment ends in (tCallLoc, tCallLoc+1) ret[s].haps[h].isEnd = true; while (t != tStart) // rewind DipTree from t to tStart (start of last copied segment) ind = nodes[t--][ind].from; tBit = h==0 ? nodes[t][ind].hapMat : nodes[t][ind].hapPat; // allele at tStart-1 ind = nodes[t--][ind].from; // move t back 1; now tBit is allele at t (= tStart-1) // sample previous segment; output is written to (tStart, state) hapWaves.sampleLastPrefix(tStart, state, t, nodes[t][ind].hapPathInds[h], tBit); ret[s].haps[h].tLength = t-tStart; } const HapTreeMulti &hapTree = hapHedge.getHapTreeMulti(tStart); bool tBitExtOK = hapTree.next(2*t, state, tBit); // extend state to bit=tBit @ t if (!tBitExtOK) { cerr << "Internal error in sampleRefs(): Could not extend haplotype" << endl; cerr << " tStart = " << tStart << endl; cerr << " t = " << t << endl; cerr << " tCallLoc = " << tCallLoc << endl; cerr << " tFront = " << tFront << endl; cerr << " T = " << T << endl; cerr << " tBit = " << tBit << endl; cerr << " state.seq = " << state.seq << endl; cerr << " state.node = " << state.node << endl; cerr << " state.count = " << state.count << endl; assert(tBitExtOK); // error out } // randomly sample an actual haplotype from this prefix, moving up to 10 hets ahead for (int m = 2*t+1; m < 2*T && m < 2*t+20; m++) { if (m % 2 == 1) // error bit: extend to 0-err hom region if possible hapTree.nextAtFrac(m, state, 0); else // het bit: randomly choose extension hapTree.nextAtFrac(m, state, rand01()); } /* const HapBitsT &hapBitsT = hapHedge.getHapBitsT(); int refSeq = state.seq; // refSeq's bit at tCallLoc: hapBitsT.getBit(refSeq, 2*tCallLoc) // check tStart..t of refSeq matches geno for (int m = 2*tStart+1; m <= 2*t; m += 2) assert(hapBitsT.getBit(refSeq, m)==0); */ ret[s].haps[h].refSeq = bestHaps[state.seq]; } break; } } } return ret; } } Eagle-master/src/DipTreePBWT.hpp000066400000000000000000000135571274444013000167270ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef DIPTREEPBWT_HPP #define DIPTREEPBWT_HPP #include #include #include #include #include "HapHedge.hpp" namespace EAGLE { struct HapPathSplit { int t; // location of most recent start = tree index (note HapPath goes to tCur >= t) float relProbLastStop; // cumP for path ending just before t, relative to // cumP = exp(cumLogP) for full HapPath ending just before tCur int hapPrefixInd; // index (in HapWaves::hapPrefixes[curMod][.]) // of the HapPrefix starting from t that ends the HapPath int hapPrefixTo[2]; // indices (in HapWaves::hapPrefixes[nextMod][.]) // of the extended HapPrefixes starting from t that have 0 (resp. 1) // at split site tCur (i.e, bit 2*tCur) and no err (i.e., 0) at 2*tCur+1 HapPathSplit(void); HapPathSplit(int _t); // split corresponding to new start at tCur=_t (i.e., root state) HapPathSplit(int _t, float relProb, int ind); }; struct HapPath { float cumLogP; // log(cumP) for this path ending just before tCur int splitListLength; HapPathSplit *splitList; // [max size = histLength] list of prev split points, probs, prefixes int to[2]; // index of extension to bit = 0 (resp. 1) at split site tCur (i.e., HapPath tCur+1) float toCumLogP[2]; // log(cumP) for extended path HapPath(void); }; struct HapPrefix { HapTreeState state; // state in tree getHapTreeMulti(split.t) //int to[2]; float toHetOnlyProb[2]; // probability of extension to bit = 0 (resp. 1) at split site tCur HapPrefix(void); HapPrefix(const HapTreeState &_state); }; struct RefHap { uint refSeq; short tLength; bool isEnd; short tMaskFwd, tMaskRev; }; struct HapPair { RefHap haps[2]; }; // history length to save for sampling ref haps (for in-sample imputation): // needs to be a few splits longer than callLength passed to sampleRefs() #define HAPWAVES_HIST 25 class HapWaves { boost::lagged_fibonacci607 rng; boost::variate_generator > rand01; const HapHedgeErr &hapHedge; const std::vector &cMcoords; const double cMexpect; const int histLength, beamWidth; const float pErr; const int maxHapPaths, maxHapPrefixes; int tCur, curMod, nextMod; int hapPathSizes[HAPWAVES_HIST]; HapPath *hapPaths[HAPWAVES_HIST]; // [max size = 2*beamWidth each] int hapPrefixSizes[HAPWAVES_HIST]; HapPrefix *hapPrefixes[HAPWAVES_HIST]; // [max size = 2*beamWidth * histLength * 2 each] public: HapWaves(const HapHedgeErr &_hapHedge, const std::vector &_cMcoords, double cMexpect, int _histLength, int _beamWidth, float _logPerr, int _tCur); ~HapWaves(void); float recombP(int tCur, int tSplit) const; // populate hapPrefixes[nextMod] // populate toCumLogP[] in hapPaths[curMod] (but don't populate hapPaths[nextMod]) void computeAllExtensions(const std::vector &nextPossibleBits); float getToCumLogProb(int ind, int nextBit) const; // look up/create extension of hapPaths[curMod][ind] in hapPaths[nextMod] // return index in hapPaths[nextMod] int extendPath(int ind, int nextBit); void advance(void); void sampleLastPrefix(int &tStart, HapTreeState &state, int t, int hapPathInd, int tBit); }; struct DipTreeNode { int from; char unequalAnc, hapMat, hapPat; uint64 histMat, histPat; float boostLogP; float logP; int numErr; int hapPathInds[2]; bool operator < (const DipTreeNode &dNode) const; }; // constraint encoding: const char OPP_CONSTRAINT = -2; // require no het err, i.e., 0|1 or 1|0 const char NO_CONSTRAINT = -1; // relative phase contraints are encoded as (dist=num_splits_to_ref_het<<1)|(rel_phase) // no hom err constraints (i.e., 0|0 at 0, 1|1 at 2) are encoded as 0 or 1 (i.e., dist=0 above) class DipTree { boost::lagged_fibonacci607 rng; boost::variate_generator > rand01; const HapHedgeErr &hapHedge; HapWaves hapWaves; const std::vector &genos; const char *constraints; const int histLength, beamWidth; const float logPerr; int tCur; const int T; std::vector < std::vector > nodes; std::vector < std::vector > normProbs; void traceNode(int t, int i); void advance(void); public: DipTree(const HapHedgeErr &_hapHedge, const std::vector &_genos, const char *_constraints, const std::vector &_cMcoords, double cMexpect, int _histLength, int _beamWidth, float _logPerr, int _tCur); // compute probability of AA at hets tCallLoc1 and tCallLoc2 float callProbAA(int tCallLoc1, int tCallLoc2, int callLength); // compute diploid dosage at tCallLoc float callDosage(int tCallLoc, int callLength); std::vector sampleRefs(int tCallLoc, int callLength, int samples, const std::vector &bestHaps, bool isFwd); }; } #endif Eagle-master/src/Eagle.cpp000066400000000000000000004040461274444013000157030ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include #include #include #include #include #include #include #include #include #include #include #include "omp.h" #include #include "Types.hpp" #include "FileUtils.hpp" #include "MemoryUtils.hpp" #include "NumericUtils.hpp" #include "StringUtils.hpp" #include "Timer.hpp" #include "HapHedge.hpp" #include "Version.hpp" #include "Eagle.hpp" //#define DETAILS namespace EAGLE { using std::vector; using std::string; using std::pair; using std::make_pair; using std::cout; using std::cerr; using std::endl; using std::max; using std::min; const double MEMO_UNSET = -1000; const char noTrioInfo = '`'; const string trio1 = "\033[1;36mo\033[0m"; const string trio2 = "\033[1;31mx\033[0m"; const char IBDx2char = '_'; const char ROHchar = '='; const char wrongChar = '@'; const char conflictChar = '#'; inline uint popcount64(uint64 i) { i = i - ((i >> 1) & 0x5555555555555555); i = (i & 0x3333333333333333) + ((i >> 2) & 0x3333333333333333); i = (i + (i >> 4)) & 0xF0F0F0F0F0F0F0F; return (i * 0x101010101010101) >> 56; } void Eagle::init() { totTicks = 0; extTicks = 0; diphapTicks = 0; lshTicks = 0; lshCheckTicks = 0; dpTicks = 0; dpStaticTicks = 0; dpSwitchTicks = 0; dpUpdateTicks = 0; dpSortTicks = 0; dpUpdateCalls = 0; blipFixTicks = 0; blipPopTicks = 0; blipVoteTicks = 0; blipLshTicks = 0; maskSnps64j = ALIGNED_MALLOC_UCHARS(Mseg64*64); cMs64j = ALIGNED_MALLOC_DOUBLES(Mseg64*64+1); double cMlast = 0; for (uint64 m64 = 0; m64 < Mseg64; m64++) { for (uint64 j = 0; j < seg64cMvecs[m64].size(); j++) { maskSnps64j[m64*64+j] = 1; cMs64j[m64*64+j] = cMlast = seg64cMvecs[m64][j]; } for (uint64 j = seg64cMvecs[m64].size(); j < 64; j++) { maskSnps64j[m64*64+j] = 0; cMs64j[m64*64+j] = cMlast; } } cMs64j[Mseg64*64] = cMlast; haploBits = ALIGNED_MALLOC_UINT64S(Mseg64*2*N); haploBitsT = ALIGNED_MALLOC_UINT64S(2*N*Mseg64); segConfs = ALIGNED_MALLOC_UCHARS(2*N*Mseg64); maskIndivs = vector (N, 1); for (uint wrongBitsA = 0; wrongBitsA < (1U<>k)&1)*homErrCost + ((wrongHetBitsA>>k)&1)*hetErrCost - ((wrongHomBitsB>>k)&1)*homErrCost - ((wrongHetBitsB>>k)&1)*hetErrCost; if (cumDiff < minDiff) minDiff = cumDiff; } } } Eagle::Eagle(uint64 _N, uint64 _Mseg64, const uint64_masks *_genoBits, vector < vector > _seg64cMvecs, const AlleleFreqs *_seg64logPs, vector _invLD64j, const vector &_indivs, const vector &_snps, const string &maskFile, const vector &_isFlipped64j, double _pErr, int runStep2) : N(_N), Nref(0), Mseg64(_Mseg64), genoBits(_genoBits), seg64cMvecs(_seg64cMvecs), seg64logPs(_seg64logPs), invLD64j(_invLD64j), indivs(_indivs), snps(_snps), isFlipped64j(_isFlipped64j), logPerr(log10(_pErr)) { init(); if (runStep2) { phaseConfs = ALIGNED_MALLOC_UCHARS(2*N*Mseg64*64); phaseConfs2 = ALIGNED_MALLOC_UCHARS(2*N*Mseg64*64); tmpHaploBitsT = NULL; } else { phaseConfs = phaseConfs2 = NULL; tmpHaploBitsT = ALIGNED_MALLOC_UINT64S(2*N*Mseg64); memset(tmpHaploBitsT, 0, 2*N*Mseg64*sizeof(tmpHaploBitsT[0])); } if (!maskFile.empty()) { int masked = 0; vector < pair > maskFidIids = FileUtils::readFidIids(maskFile); std::set < pair < string, string> > maskSet(maskFidIids.begin(), maskFidIids.end()); for (uint64 n = 0; n < N; n++) if (maskSet.count(make_pair(indivs[n].famID, indivs[n].indivID))) { maskIndivs[n] = 0; masked++; } cout << "Number of indivs masked: " << masked << endl; } } // constructor for ref-mode Eagle::Eagle(uint64 _Nref, uint64 _Ntarget, uint64 _Mseg64, const uint64_masks *_genoBits, vector < vector > _seg64cMvecs, double _pErr) : N(_Nref+_Ntarget), Nref(_Nref), Mseg64(_Mseg64), genoBits(_genoBits), seg64cMvecs(_seg64cMvecs), logPerr(log10(_pErr)) { init(); isFlipped64j = vector (Mseg64*64); // no flipping in ref mode phaseConfs = phaseConfs2 = NULL; tmpHaploBitsT = ALIGNED_MALLOC_UINT64S(2*(N-Nref)*Mseg64); memset(segConfs, 0, 2*N*Mseg64*sizeof(segConfs[0])); for (uint64 nRef = 0; nRef < Nref; nRef++) for (uint64 m64 = 0; m64 < Mseg64; m64++) { // copy ref haploBits stored in genoBits haploBits[m64*2*N + 2*nRef] = genoBits[m64*N + nRef].is0; haploBits[m64*2*N + 2*nRef+1] = genoBits[m64*N + nRef].is2; for (uint64 nHap = 2*nRef; nHap <= 2*nRef+1; nHap++) haploBitsT[nHap*Mseg64 + m64] = haploBits[m64*2*N + nHap]; } } void Eagle::reallocLRPtoPBWT(void) { // non-ref mode transition: LRP iters 1-2 -> PBWT iters 3+ assert(phaseConfs != NULL); ALIGNED_FREE(phaseConfs2); phaseConfs2 = NULL; ALIGNED_FREE(phaseConfs); phaseConfs = NULL; assert(tmpHaploBitsT == NULL); tmpHaploBitsT = ALIGNED_MALLOC_UINT64S(2*N*Mseg64); } Eagle::~Eagle() { ALIGNED_FREE(segConfs); ALIGNED_FREE(haploBitsT); ALIGNED_FREE(haploBits); if (phaseConfs != NULL) { ALIGNED_FREE(phaseConfs2); ALIGNED_FREE(phaseConfs); } if (tmpHaploBitsT != NULL) { ALIGNED_FREE(tmpHaploBitsT); // allocated only in ref-mode } ALIGNED_FREE(cMs64j); ALIGNED_FREE(maskSnps64j); } inline uint getNonMissingGeno(const uint64_masks &bits, uint64 j) { if (bits.is0 & (1ULL< fail break; uint64 missMask = bits0.is9 | bits1.is9; for (uint64 j = jStart; j != jEnd; j += inc) { uint geno1 = bgetGeno0123(bits1, j); double logBFj = 0; if (!(missMask & (1ULL< maxLogBF) { maxLogBF = curLogBF; if (inc == 1) match.m64jEnd = m64*64+j; else match.m64jStart = m64*64+j; } } } match.logBF += maxLogBF; } double minLogBF = 0, curLogBF = 0; for (uint64 m64j = match.m64jStart; m64j <= match.m64jEnd; m64j++) { curLogBF += workLogBF[m64j]; if (curLogBF < minLogBF) { minLogBF = curLogBF; match.m64jStart = m64j+1; while (!maskSnps64j[match.m64jStart]) match.m64jStart++; } } match.logBF -= minLogBF; //match.logBF -= log10(snpsChecked); match.cMlenInit = cMs64j[match.m64jEnd] - cMs64j[match.m64jStart]; return match; } void Eagle::trim(Match &match, const Match &ref, uint64 n0, int orientation, uint64 trimStart, int inc, double workLogBF[]) const { uint64 n1 = match.n, n2 = ref.n; // find IBDx2; store IBDx2 status in workLogBF (0 or 1) to compute probabilities accordingly double IBDx2logBF = 0; uint64 IBDx2start = trimStart; for (uint64 m64j = trimStart; m64j+1!=match.m64jStart && m64j!=match.m64jEnd+1; m64j += inc) workLogBF[m64j] = 0; // initialize workLogBF to 0 (not IBDx2) in *MATCH* (n1) // check for IBDx2 in *REF* (n2) uint64 m64jLast; // last SNP to check: go beyond end of match to ensure detection of ref IBDx2 if (inc == 1) m64jLast = min(match.m64jEnd + 50ULL, Mseg64*64-1); else m64jLast = max((int) match.m64jStart - 50, 0); for (uint64 m64j = trimStart; m64j!=m64jLast+inc; m64j += inc) { uint g0 = getGeno0123(m64j, n0); uint g2 = getGeno0123(m64j, n2); bool mismatch = false; if (g0 != 3 && g2 != 3) { if (g0 == g2) IBDx2logBF += seg64logPs[m64j].cond[g2][g0] * invLD64j[m64j]; else mismatch = true; } if (mismatch || m64j==m64jLast) { // end of IBDx2 segment if (IBDx2logBF < -1) { // 10:1 IBDx2 #ifdef VERBOSE printf("IBDx2 detected in %d: %.1f-%.1f (%d SNPs)\n", (int) n2, cMs64j[IBDx2start], cMs64j[m64j], (int) (m64j-IBDx2start)); #endif for (uint64 m64j2 = IBDx2start; m64j2 != m64j; m64j2 += inc) workLogBF[m64j2] = 1; } IBDx2logBF = 0; // reset IBDx2start = m64j+inc; } } double maxLogBF = 0, curLogBF = 0; uint64 m64jBest = trimStart; for (uint64 m64j = trimStart; m64j+1!=match.m64jStart && m64j!=match.m64jEnd+1; m64j += inc) { double logBF = 0; uint g0 = getGeno0123(m64j, n0); uint g1 = getGeno0123(m64j, n1); uint g2 = getGeno0123(m64j, n2); if (g0 != 3 && g1 != 3) { uint g0eff = g0; if (g0 == 1 && ref.m64jStart <= m64j && m64j <= ref.m64jEnd && g2 != 3) { // n0 het and n2 (ref) match info available if (g2 != 1) { // n2 hom if (orientation == 1) g0eff = g2; // treat g0 as n2 hom else g0eff = 2-g2; // treat g0 as opp n2 hom } else if (workLogBF[m64j] == 0) { // n0 and n2 both hets and not IBDx2 if (orientation == 1) g0eff = 4; // same orientation as het-het => p(hap=1) = 1-p else g0eff = 5; // opp orientation to het-het => p(hap=1) = p } } double logP_geno1_null = seg64logPs[m64j].cond[g1][3]; double logP_geno1_duo = seg64logPs[m64j].cond[g1][g0eff]; logBF = min(max((logP_geno1_duo - logP_geno1_null) * invLD64j[m64j], logPerr), -logPerr); } curLogBF += logBF; if (curLogBF > maxLogBF) { maxLogBF = curLogBF; m64jBest = m64j; } workLogBF[m64j] = curLogBF; } uint64 m64jTrim = m64jBest; if (inc == 1) match.m64jEnd = m64jTrim; else match.m64jStart = m64jTrim; // conservative trimming: backtrack to 10x higher prob uint m64jTrimCons = trimStart; for (uint64 m64j = trimStart; m64j != m64jBest; m64j += inc) if (workLogBF[m64j] < maxLogBF - log10(10)) m64jTrimCons = m64j; if (inc == 1) match.m64jEndCons = std::min(match.m64jEndCons, m64jTrimCons); else match.m64jStartCons = std::max(match.m64jStartCons, m64jTrimCons); } vector searchSigns(const vector &matches, const vector < vector > &sameEdges, const vector < vector > &oppEdges, const vector &kept) { // process left to right so that when sign choice is arbitrary, adjacent matches have same sign uint V = matches.size(); vector signs(V); vector < pair > order(V); for (uint v = 0; v < V; v++) order[v] = make_pair(matches[v].m64jStart, v); sort(order.begin(), order.end()); uint lastEnd = 0; int lastSign = 1; // sign of farthest-right match seen so far std::queue q; for (uint i = 0; i < V; i++) { uint v = order[i].second; if (!kept[v]) continue; // not used if (signs[v]) continue; // already visited signs[v] = lastSign; q.push(v); while (!q.empty()) { uint u = q.front(); q.pop(); for (uint i = 0; i < sameEdges[u].size(); i++) { uint w = sameEdges[u][i]; if (!kept[w]) continue; if (signs[w]) { if (signs[w] != signs[u]) return vector (); } else { signs[w] = signs[u]; q.push(w); if (matches[w].m64jEnd > lastEnd) { lastEnd = matches[w].m64jEnd; lastSign = signs[w]; } } } for (uint i = 0; i < oppEdges[u].size(); i++) { uint w = oppEdges[u][i]; if (!kept[w]) continue; if (signs[w]) { if (signs[w] == signs[u]) return vector (); } else { signs[w] = -signs[u]; q.push(w); if (matches[w].m64jEnd > lastEnd) { lastEnd = matches[w].m64jEnd; lastSign = signs[w]; } } } } } return signs; } void updateVote(int &votesCur, int votesThresh, int vote) { if (abs(votesCur) >= votesThresh) return; votesCur += vote; } void Eagle::computePhaseConfs(uint64 n0, const vector &matches, const vector &signs, bool cons) { vector < vector > votes(2, vector (Mseg64*64)); vector votesThresh(Mseg64*64); const int votesMax = 1000000; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (maskSnps64j[m64j]) { votesThresh[m64j] = // 2 / log10((1-p)/p) = number of votes needed to get >100:1 odds (int) (2 / fabs(seg64logPs[m64j].cond[0][4] - seg64logPs[m64j].cond[0][5])) + 1; if (!(votesThresh[m64j] < votesMax)) votesThresh[m64j] = votesMax; uint g0 = getGeno0123(m64j, n0); if (g0 == 0) { votes[0][m64j] = votes[1][m64j] = -votesMax; } else if (g0 == 2) { votes[0][m64j] = votes[1][m64j] = votesMax; } else if (g0 == 3) { votes[0][m64j] = votes[1][m64j] = -1; } // missing: default P(1) = p } } vector isIBDx2(Mseg64*64); for (uint i = 0; i < matches.size(); i++) { if (!signs[i]) continue; uint64 start, end; if (cons) { start = std::max(matches[i].m64jStartCons, matches[i].m64jStart); end = std::min(matches[i].m64jEndCons, matches[i].m64jEnd); } else { start = matches[i].m64jStart; end = matches[i].m64jEnd; } #ifdef VERBOSE printf("match %d (%.1f-%.1f)\n", (int) i, cMs64j[start], cMs64j[end]); #endif // find IBDx2 regions vector < pair > IBDx2regions; uint64 m64jFirst = max((int) start - 50, 0); // go beyond ends to detect overhanging IBDx2 uint64 m64jLast = min(end + 50ULL, Mseg64*64-1); double IBDx2logBF = 0; uint64 IBDx2start = m64jFirst; for (uint64 m64j = m64jFirst; m64j <= m64jLast; m64j++) { uint g0 = getGeno0123(m64j, n0); uint g1 = getGeno0123(m64j, matches[i].n); bool mismatch = false; if (g0 != 3 && g1 != 3) { if (g0 == g1) IBDx2logBF += seg64logPs[m64j].cond[g1][g0] * invLD64j[m64j]; else mismatch = true; } if (mismatch || m64j==m64jLast) { // end of IBDx2 segment if (IBDx2logBF < -1) { // 10:1 IBDx2 IBDx2regions.push_back(make_pair(IBDx2start, m64j)); #ifdef VERBOSE printf("IBDx2 detected in %d: %.1f-%.1f (%d SNPs)\n", (int) matches[i].n, cMs64j[IBDx2start], cMs64j[m64j], (int) (m64j-IBDx2start)); #endif } IBDx2logBF = 0; // reset IBDx2start = m64j+1; } } for (uint r = 0; r < IBDx2regions.size(); r++) // set IBDx2 region flags memset(&isIBDx2[IBDx2regions[r].first], 1, IBDx2regions[r].second-IBDx2regions[r].first); // accumulate votes for (uint64 m64j = start; m64j <= end; m64j++) { if (!maskSnps64j[m64j]) continue; uint g0 = getGeno0123(m64j, n0); uint g1 = getGeno0123(m64j, matches[i].n); int vote = 0; if (g1 == 0 || g1 == 2) // n1 hom: IBDx2 status irrelevant; phase determined (votesMax) vote = (g1-1)*votesMax*2; // super strong vote (overrides any previous small votes) else if (g1 == 1 && !isIBDx2[m64j]) // n1 het and not IBDx2; weak phase info vote = 1; if (vote) { int q = (signs[i] == 1); updateVote(votes[q][m64j], votesThresh[m64j], vote); if (g0 == 1) // n0 het: pass info to opp chromosome updateVote(votes[!q][m64j], votesThresh[m64j], -vote); } } for (uint r = 0; r < IBDx2regions.size(); r++) // unset IBDx2 region flags memset(&isIBDx2[IBDx2regions[r].first], 0, IBDx2regions[r].second-IBDx2regions[r].first); } // fast rng: last 16 bits of Marsaglia's MWC uint w = 521288629; if (phaseConfs != NULL) { // need to make hard calls here for (uint i = 0; i < (n0 & 0xff); i++) w=18000*(w&65535)+(w>>16); } for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (maskSnps64j[m64j]) { for (uint64 q = 0; q <= 1; q++) { double phaseConf; if (votes[q][m64j] >= votesMax) phaseConf = 1; else if (votes[q][m64j] <= -votesMax) phaseConf = 0; else { double OR = pow(10.0, fabs(seg64logPs[m64j].cond[0][4] - seg64logPs[m64j].cond[0][5]) * votes[q][m64j]); phaseConf = OR / (1 + OR); } if (phaseConfs != NULL) phaseConfs[(2*n0+q)*Mseg64*64 + m64j] = (uchar) (phaseConf * 255); else { uchar uPhaseConf = (uchar) (phaseConf * 255); if (uPhaseConf == (uchar) 255 || ((w=18000*(w&65535)+(w>>16))&255) < uPhaseConf) tmpHaploBitsT[(2*n0+q)*Mseg64 + (m64j/64)] |= 1ULL<<(m64j&63); } } } else { if (phaseConfs != NULL) phaseConfs[2*n0*Mseg64*64 + m64j] = phaseConfs[(2*n0+1)*Mseg64*64 + m64j] = 0; } } } vector Eagle::trioRelPhase(uint64 n0, uint64 nF1, uint64 nF2) const { bool isParent = false; if (((int) nF1) < 0) { // nF1 is the child; n0 is a parent isParent = true; nF1 = -nF1; } vector trioPhaseVec; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL< unknown; +/-1 => pat/mat if (trioPhase == 0) continue; } vector trioRelPhaseVec(trioPhaseVec.size()-1); for (uint i = 1; i < trioPhaseVec.size(); i++) trioRelPhaseVec[i-1] = (trioPhaseVec[i-1]==0 || trioPhaseVec[i]==0) ? -1 : (trioPhaseVec[i-1]==trioPhaseVec[i] ? 0 : 1); // -1 => unknown; 0 => same; 1 => opp return trioRelPhaseVec; } void Eagle::checkPhase(uint64 n0, uint64 nF1, uint64 nF2, double thresh) const { cout << "checking at thresh=" << thresh << ": "; double lastPhased = cMs64j[0]; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2)&(1ULL< Eagle::checkPhaseConfsPhase(uint64 n0, uint64 nF1, uint64 nF2) const { vector ret; int lastPhased64j = -1; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<= 128; bool phase = hapBit == (trioPhase == 1); if (lastPhased64j != -1 && ret.back() != phase) printf(" %.2f", (cMs64j[lastPhased64j] + cMs64j[m64j]) / 2); lastPhased64j = m64j; ret.push_back(phase); } cout << endl; return ret; } void Eagle::checkHapPhase(uint64 n0, uint64 nF1, uint64 nF2, const uint64 curHaploBitsT[], uint64 m64, uint64 side, vector < vector > votes) const { if ((int) nF1 == -1) return; for (uint64 m64j = (m64-side)*64; m64j < (m64+side+1)*64; m64j++) { if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<>j)&1) == (trioPhase == 1)) //if (((haploBitsT[n1hap*Mseg64 + m64cur]>>j)&1) == (trioPhase == 1)) if (((curHaploBitsT[m64cur]>>j)&1) == (trioPhase == 1)) cout << trio1; else cout << trio2; if (!votes.empty()) cout << "[" << votes[j][(curHaploBitsT[m64cur]>>j)&1] << "|" << votes[j][!((curHaploBitsT[m64cur]>>j)&1)] << ";" << votes[j][((curHaploBitsT[m64cur]>>j)&1)+2] << "|" << votes[j][!((curHaploBitsT[m64cur]>>j)&1)+2] << "]"; } cout << endl; } vector Eagle::checkHapPhase1(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 m64start, uint64 m64end, int sign) const { vector ret; if ((int) nF1 == -1) return ret; cout << "n1hap = " << n1hap << "; m64 = [" << m64start << "," << m64end << "): "; for (uint64 m64j = m64start*64; m64j < m64end*64; m64j++) { if (m64j != m64start*64 && (m64j&63)==0) cout << "|"; if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<>j)&1) == (trioPhase == sign)) { cout << trio1; ret.push_back(0); } else { cout << trio2; ret.push_back(1); } } cout << endl; return ret; } vector Eagle::checkHapPhase1j(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 m64jStart, uint64 m64jEnd, int sign) const { vector ret; if ((int) nF1 == -1) return ret; //cout << "n1hap = " << n1hap << "; m64 = [" << m64start << "," << m64end << "): "; for (uint64 m64j = m64jStart; m64j < m64jEnd; m64j++) { if (m64j != m64jStart && (m64j&63)==0) cout << m64j/64;//"|"; if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<>j)&1) == (trioPhase == sign)) { cout << trio1; ret.push_back(0); } else { cout << trio2; ret.push_back(1); } } //cout << endl; return ret; } vector Eagle::checkHapPhase1jCall(uint64 n0, uint64 nF1, uint64 nF2, uint64 callBitsT[], uint64 m64jStart, uint64 m64jEnd, bool print, int sign) const { vector ret; if ((int) nF1 == -1) return ret; for (uint64 m64j = m64jStart; m64j < m64jEnd; m64j++) { if (m64j != m64jStart && (m64j&63)==0) if (print) cout << m64j/64;//"|"; if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<>j)&1) == (trioPhase == sign)) { if (print) cout << trio1; ret.push_back(0); } else { if (print) cout << trio2; ret.push_back(1); } } if (print) cout << endl; return ret; } int Eagle::checkHapPhase2(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 n2hapA, uint64 n2hapB, uint64 m64, int sign) const { vector ret; if ((int) nF1 == -1) return 0;/*ret*/; uint64 n1is1 = haploBitsT[n1hap*Mseg64 + m64]; uint64 n2is1A = haploBitsT[n2hapA*Mseg64 + m64]; uint64 n2is1B = haploBitsT[n2hapB*Mseg64 + m64]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongHomBitsA = (bits0.is0 & (n1is1 | n2is1A)) | (bits0.is2 & ~(n1is1 & n2is1A)); uint64 wrongHetBitsA = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1A)); uint64 wrongHomBitsB = (bits0.is0 & (n1is1 | n2is1B)) | (bits0.is2 & ~(n1is1 & n2is1B)); uint64 wrongHetBitsB = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1B)); uint score = popcount64(wrongHomBitsB)*homErrCost + popcount64(wrongHetBitsB)*hetErrCost; uint minScore = score; uint64 kSwitch = 0; for (uint64 k = 0; k < 64; k++) { score += ((wrongHomBitsA>>k)&1)*homErrCost + ((wrongHetBitsA>>k)&1)*hetErrCost - ((wrongHomBitsB>>k)&1)*homErrCost - ((wrongHetBitsB>>k)&1)*hetErrCost; if (score < minScore) { minScore = score; kSwitch = k+1; } } cout << "m64 = " << m64 << ": (" << n1hap << "," << n2hapA; if (n2hapA != n2hapB) cout << "-" << n2hapB; cout << ") score = " << minScore << " "; cout << " conf = " << (int) segConfs[n1hap*Mseg64+m64] << "," << (int) segConfs[n2hapA*Mseg64+m64]; if (n2hapA != n2hapB) cout << "-" << (int) segConfs[n2hapB*Mseg64+m64]; cout << " "; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64*64+j; if (!maskSnps64j[m64j]) continue; const uint64_masks &bits0 = genoBits[m64*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<>j)&1) == (trioPhase == sign)) phase = 0; else phase = 1; bool hetErr = ((haploBits[m64*2*N + n1hap]>>j)&1) == ((haploBits[m64*2*N + (j>j)&1); uchar conf1 = 0, conf2 = 0; if (hetErr) { conf1 = phaseConfs[n1hap*Mseg64*64 + m64j]; conf2 = phaseConfs[(j Eagle::checkHaploBits(uint64 n0, uint64 nF1, uint64 nF2, uint64 hapBits, uint64 m64, int pad) const { vector ret; if ((int) nF1 == -1) return ret; bool isParent = false; if (((int) nF1) < 0) { // nF1 is the child; n0 is a parent isParent = true; nF1 = -nF1; } int printed = 0; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64*64+j; if (!maskSnps64j[m64j]) continue; const uint64_masks &bits0 = genoBits[m64*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<= 0) { if (((hapBits>>j)&1) == (trioPhase == 1)) cout << trio1; else cout << trio2; printed++; } ret.push_back(((hapBits>>j)&1) == (trioPhase == 1)); } while (printed < pad) { cout << " "; printed++; } return ret; } pair Eagle::phaseSegHMM(uint64 n0, uint64 n1hap, uint64 n2hapA, uint64 n2hapB, uint64 m64, uint64 &hetErrMask) const { uint64 n1is1 = haploBitsT[n1hap*Mseg64 + m64]; uint64 n2is1A = haploBitsT[n2hapA*Mseg64 + m64]; uint64 n2is1B = haploBitsT[n2hapB*Mseg64 + m64]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongHomBitsA = (bits0.is0 & (n1is1 | n2is1A)) | (bits0.is2 & ~(n1is1 & n2is1A)); uint64 wrongHetBitsA = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1A)); uint64 wrongHomBitsB = (bits0.is0 & (n1is1 | n2is1B)) | (bits0.is2 & ~(n1is1 & n2is1B)); uint64 wrongHetBitsB = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1B)); uint score = popcount64(wrongHomBitsB)*homErrCost + popcount64(wrongHetBitsB)*hetErrCost; uint minScore = score; double cMdiffMax = m64==0 ? 0.0 : cMs64j[m64*64] - cMs64j[m64*64-1]; uint64 kSwitch = 0; uint64 kSeg = seg64cMvecs[m64].size(); for (uint64 k = 0; k < kSeg; k++) { score += ((wrongHomBitsA>>k)&1)*homErrCost + ((wrongHetBitsA>>k)&1)*hetErrCost - ((wrongHomBitsB>>k)&1)*homErrCost - ((wrongHetBitsB>>k)&1)*hetErrCost; double cMdiff = (k+1==kSeg ? cMs64j[(m64+1)*64] : cMs64j[m64*64+k+1]) - cMs64j[m64*64+k]; if (score < minScore || (score == minScore && cMdiff > cMdiffMax)) { minScore = score; cMdiffMax = cMdiff; kSwitch = k+1; } } uint64 phaseBits1 = 0, phaseBits2 = 0; hetErrMask = 0; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64*64+j; if (!maskSnps64j[m64j]) continue; const uint64_masks &bits0 = genoBits[m64*N + n0]; if (bits0.is0&(1ULL<>j)&1; uint64 phase2 = ((haploBits[m64*2*N + (j>j)&1); if (bits0.is9&(1ULL< Eagle::checkSegPhase(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 n2hap, int sign, uint64 m64) const { vector ret; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64*64+j; if (!maskSnps64j[m64j]) continue; const uint64_masks &bits0 = genoBits[m64*N + n0]; if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL<>j)&1; if (sign == -1) hapBit1 = 1-hapBit1; int hapBit2 = (haploBits[m64*2*N + n2hap]>>j)&1; if (sign == 1) hapBit2 = 1-hapBit2; uchar conf1 = phaseConfs[n1hap*Mseg64*64 + m64j]; uchar conf2 = phaseConfs[n2hap*Mseg64*64 + m64j]; //if (hapBit1 != hapBit2) cout << "?[" << (uint) conf1 << "|" << (uint) conf2 << "]"; int hapBitFinal = hapBit1; if (!(conf1 == 0 || conf1 == 255) && (conf2 == 0 || conf2 == 255)) hapBitFinal = hapBit2; */ int hapBitFinal = (int) phaseConfs2[2*n0*Mseg64*64 + m64j] >= 128; if (hapBitFinal == (trioPhase == 1)) { cout << trio1; ret.push_back(0); } else { cout << trio2; ret.push_back(1); } } cout << endl; return ret; } void Eagle::computeSegPhaseConfs(uint64 n0, uint64 n1hap, uint64 n2hap, int sign, uint64 m64, int err) { const double maxOffsetFrac = 0.25, offsetFrac = ((n0&63)-31.5)/31.5 * maxOffsetFrac; uint64 m64jStart, m64jEnd; if (offsetFrac >= 0) { m64jStart = m64==0 ? 0 : m64*64 + (uint) (offsetFrac * seg64cMvecs[m64].size()); m64jEnd = (m64+1)*64 + (m64+1==Mseg64 ? 0 : (uint) (offsetFrac * seg64cMvecs[m64+1].size())); } else { m64jStart = m64==0 ? 0 : (m64-1)*64 + (uint) ((1+offsetFrac) * seg64cMvecs[m64-1].size()); m64jEnd = m64*64 + (m64+1==Mseg64 ? 64 : (uint) ((1+offsetFrac) * seg64cMvecs[m64].size())); } /* cout << "m64 = " << m64 << ": " << m64jStart/64 << "." << (m64jStart&63) << " - " << m64jEnd/64 << "." << (m64jEnd&63) << endl; */ int cropErr = max(err-1, 0); uchar hetConfs[2]; hetConfs[0] = (uchar) cropErr; hetConfs[1] = (uchar) (255-cropErr); for (uint64 m64j = m64jStart; m64j < m64jEnd; m64j++) { if (maskSnps64j[m64j]) { uint64 m64cur = m64j/64; uint64 j = m64j&63; uint g0 = getGeno0123(m64j, n0); if (g0 == 0) phaseConfs2[2*n0*Mseg64*64 + m64j] = phaseConfs2[(2*n0+1)*Mseg64*64 + m64j] = 0; else if (g0 == 2) phaseConfs2[2*n0*Mseg64*64 + m64j] = phaseConfs2[(2*n0+1)*Mseg64*64 + m64j] = 255; else { int hapBit1 = (haploBits[m64cur*2*N + n1hap]>>j)&1; int hapBit2 = (haploBits[m64cur*2*N + n2hap]>>j)&1; if (g0 == 1) { // het (not missing) uchar conf1 = phaseConfs[n1hap*Mseg64*64 + m64j]; uchar conf2 = phaseConfs[n2hap*Mseg64*64 + m64j]; if (!(conf1 == 0 || conf1 == 255) && (conf2 == 0 || conf2 == 255)) hapBit1 = 1-hapBit2; // only use n2hap if n1hap conf <100% and n2hap conf = 100% else hapBit2 = 1-hapBit1; // default: go with n1hap } if (sign == -1) std::swap(hapBit1, hapBit2); phaseConfs2[2*n0*Mseg64*64 + m64j] = hetConfs[hapBit1]; phaseConfs2[(2*n0+1)*Mseg64*64 + m64j] = hetConfs[hapBit2]; } } else phaseConfs2[2*n0*Mseg64*64 + m64j] = phaseConfs2[(2*n0+1)*Mseg64*64 + m64j] = 0; } } string Eagle::computePhaseString(uint64 n0, uint64 nF1, uint64 nF2, const vector &matches, const vector &signs, uint64 start, double cMend, bool cons) const { if ((int) nF1 == -1 || (int) nF2 == -1) return ""; vector starts(matches.size()), ends(matches.size()); for (uint i = 0; i < matches.size(); i++) { if (cons) { starts[i] = std::max(matches[i].m64jStartCons, matches[i].m64jStart); ends[i] = std::min(matches[i].m64jEndCons, matches[i].m64jEnd); } else { starts[i] = matches[i].m64jStart; ends[i] = matches[i].m64jEnd; } } string phase; double lastPhased = cMs64j[start], lastHet = lastPhased; int hetCount = 0, snpCount = 0; for (uint64 m64j = start; m64j < Mseg64*64 && cMs64j[m64j] < cMend; m64j++) { if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; const uint64_masks &bitsF1 = genoBits[m64cur*N + nF1]; const uint64_masks &bitsF2 = genoBits[m64cur*N + nF2]; int trioPhase = 1; // default if ((bitsF1.is0|bitsF2.is2)&(1ULL< 0.5) { char buf[20]; sprintf(buf, "[%.1fcM:%d/%d]", cM-lastPhased, hetCount, snpCount); phase += string(buf); } if (votes1&votes2) phase += conflictChar; else if (trioPhase) { if (votes1) phase += trio1; else phase += trio2; } else phase += noTrioInfo; hetCount = 0; snpCount = 0; lastPhased = cM; } else phase += '?'; lastHet = cMs64j[m64j]; hetCount++; } if (cMend >= cMs64j[Mseg64*64-1]) { double cM = cMs64j[Mseg64*64-1]; for (int tick = (int) (10*lastPhased) + 1; tick < 10*cM; tick++) { if (tick % 10 == 0) phase += (char) ('0' + (tick/10)%10); else if (lastHet <= lastPhased) phase += ROHchar; else phase += IBDx2char; } if (cM-lastPhased > 0.5) { char buf[20]; sprintf(buf, "[%.1fcM:%d/%d]", cM-lastPhased, hetCount, snpCount); phase += string(buf); } } return phase; } void Eagle::printMatch(uint64 n0, uint64 nF1, uint64 nF2, const Match &duoMatch, double memoLogBF[][4]) const { if ((int) nF1 == -1 || (int) nF2 == -1) return; uint64 n1 = duoMatch.n; uint64 x = duoMatch.m64jStart, y = duoMatch.m64jEnd; double logBF = duoMatch.logBF; int same = 0, opp = 0; string phase; double lastPhased = cMs64j[x], maxPhasedGap = 0, lastHet = cMs64j[x], maxHetGap = 0; int hetCount = 0, snpCount = 0, numErr = 0; for (uint m64j = duoMatch.m64jStart; m64j <= duoMatch.m64jEnd; m64j++) { if (!maskSnps64j[m64j]) continue; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; const uint64_masks &bits1 = genoBits[m64cur*N + n1]; const uint64_masks &bitsF1 = genoBits[m64cur*N + nF1]; const uint64_masks &bitsF2 = genoBits[m64cur*N + nF2]; uint64 wrongBits = (bits0.is0 & bits1.is2) | (bits0.is2 & bits1.is0); if (wrongBits&(1ULL< 0.5) { char buf[20]; sprintf(buf, "[%.1fcM:%d/%d]", cM-lastPhased, hetCount, snpCount); phase += string(buf); } if (trioPhased&(1ULL< maxPhasedGap) maxPhasedGap = cM - lastPhased; lastPhased = cM; } else snpCount++; if ((~(bits0.is0|bits0.is2|bits0.is9))&(1ULL< maxHetGap) maxHetGap = cM - lastHet; lastHet = cM; hetCount++; } } double cM = cMs64j[y]; if (cM - lastPhased > maxPhasedGap) maxPhasedGap = cM - lastPhased; lastPhased = cM; if (cM - lastHet > maxHetGap) maxHetGap = cM - lastHet; lastHet = cM; const uint WINDOW = 20; double minLogBFwindow = 0, minLoc = 0; for (uint64 wStart = x; wStart+WINDOW <= y; wStart++) { if (!maskSnps64j[wStart]) continue; double logBFwindow = 0; for (uint64 m64j = wStart; m64j < wStart+WINDOW; m64j++) { const uint64_masks &bits1 = genoBits[m64j/64*N + n1]; uint geno1 = bgetGeno0123(bits1, m64j&63); if (memoLogBF[m64j][geno1] != MEMO_UNSET) logBFwindow += memoLogBF[m64j][geno1]; } if (logBFwindow < minLogBFwindow) { minLogBFwindow = logBFwindow; minLoc = cMs64j[wStart]; } } printf("n0=%-5d n1=%-5d (%s) BF= %.1f cM= %.1f (%.1f-%.1f):", (int) n0, (int) n1, Nref==0 ? indivs[n1].indivID.c_str() : "", logBF, cMs64j[y]-cMs64j[x], cMs64j[x], cMs64j[y]); cout << " (" << numErr << " errs) "; cout << same << "|" << opp; cout << " " << phase; cout << " max gap: " << maxPhasedGap; cout << " max ROH: " << maxHetGap; printf(" min window logBF: %.1f minLoc: %.1fcM", minLogBFwindow, minLoc); cout << endl; } void Eagle::checkTrioErrorRate(uint64 n0, uint64 nF1, uint64 nF2) const { if ((int) nF1 == -1) return; int numOppHom1 = 0, numOppHom2 = 0, numWrongHet = 0, snpCount = 0; for (uint m64j = 0; m64j < Mseg64*64; m64j++) { if (!maskSnps64j[m64j]) continue; snpCount++; uint64 m64cur = m64j/64; uint64 j = m64j&63; const uint64_masks &bits0 = genoBits[m64cur*N + n0]; const uint64_masks &bitsF1 = genoBits[m64cur*N + nF1]; const uint64_masks &bitsF2 = genoBits[m64cur*N + nF2]; uint64 oppHom1 = (bits0.is0 & bitsF1.is2) | (bits0.is2 & bitsF1.is0); uint64 oppHom2 = (bits0.is0 & bitsF2.is2) | (bits0.is2 & bitsF2.is0); uint64 wrongHet = ~(bits0.is0|bits0.is2|bits0.is9) & ((bitsF1.is0&bitsF2.is0) | (bitsF1.is2&bitsF2.is2)); if (oppHom1&(1ULL< topInds[2], vector topIndsLens[2], uint K) const { /* for (uint e = 0; e < 2; e++) { topInds[e] = vector (Mseg64 * K); topIndsLens[e] = vector (Mseg64); } uint *runStarts[2][2]; // [even/odd][max err]; lengths are N for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) runStarts[p][e] = ALIGNED_MALLOC_UINTS(N); uint *runStartFreqs[2][2]; // [even/odd][max err]; lengths are Mseg64+1 (b/c m64+1 can go over) for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) runStartFreqs[p][e] = ALIGNED_MALLOC_UINTS(Mseg64+1); // initialize "prev" p=1 for (uint e = 0; e < 2; e++) { const uint p = 1; memset(runStarts[p][e], 0, N*sizeof(runStarts[p][e][0])); // all runs start at 0 runStartFreqs[p][e][0] = N; memset(&runStartFreqs[p][e][1], 0, Mseg64*sizeof(runStarts[p][e][1])); } for (uint64 m64 = 0; m64 < Mseg64; m64++) { // initialize cur [p=(m64&1)] arrays const uint p = m64&1; for (uint e = 0; e < 2; e++) { memcpy(runStarts[p][e], runStarts[!p][e], N*sizeof(runStarts[p][e][0])); memset(runStartFreqs[p][e], 0, (Mseg64+1)*sizeof(runStartFreqs[p][e][0])); } uint64_masks bits0 = genoBits[m64*N + n0]; for (uint64 n1 = 0; n1 < N; n1++) { const uint64_masks &bits1 = genoBits[m64*N + n1]; uint64 wrongBits = (bits0.is0 & bits1.is2) | (bits0.is2 & bits1.is0); // update cur runStarts based on bit matches if (wrongBits) { if (wrongBits & (wrongBits-1)) // 2+ wrong => fail; move both starts forward runStarts[p][0][n1] = runStarts[p][1][n1] = m64+1; else { // 1 wrong => move 1-err start to 0-err start; fail 0-err runStarts[p][1][n1] = runStarts[p][0][n1]; runStarts[p][0][n1] = m64+1; } } // compute cur runStartFreqs based on (updated) cur runStarts for (uint e = 0; e < 2; e++) runStartFreqs[p][e][runStarts[p][e][n1]]++; } for (uint e = 0; e < 2; e++) for (uint s64 = 0; s64 <= m64; s64++) if ((runStartFreqs[p][e][s64] >= K && m64+1 == Mseg64) || // reached end (runStartFreqs[p][e][s64] < K && runStartFreqs[!p][e][s64] >= K)) { // all n1 s.t. runStarts[p][e][n1] == s64 are in top K starting from s64 // some n1 s.t. runStarts[!p][e][n1] == s64 are in top K starting from s64 uint allPos = 0, somePos = runStartFreqs[p][e][s64]; uint *topIndsChunk = &topInds[e][s64*K]; for (uint64 n1 = 0; n1 < N; n1++) { if (allPos < K && runStarts[p][e][n1] == s64) topIndsChunk[allPos++] = n1; else if (somePos < K && runStarts[!p][e][n1] == s64) topIndsChunk[somePos++] = n1; } topIndsLens[e][s64] = min(somePos, K); } } for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) ALIGNED_FREE(runStartFreqs[p][e]); for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) ALIGNED_FREE(runStarts[p][e]); */ for (uint e = 0; e < 2; e++) { topInds[e] = vector (Mseg64 * K); topIndsLens[e] = vector (Mseg64); } uint *runStarts[2]; // [even/odd]; lengths are N for (uint p = 0; p < 2; p++) runStarts[p] = ALIGNED_MALLOC_UINTS(N); uint *runStartFreqs[2]; // [even/odd]; lengths are Mseg64+1 (b/c m64+1 can go over) for (uint p = 0; p < 2; p++) runStartFreqs[p] = ALIGNED_MALLOC_UINTS(Mseg64+1); // initialize "prev" p=1 { const uint p = 1; memset(runStarts[p], 0, N*sizeof(runStarts[p][0])); // all runs start at 0 runStartFreqs[p][0] = N; memset(&runStartFreqs[p][1], 0, Mseg64*sizeof(runStarts[p][1])); } for (uint64 m64 = 0; m64 < Mseg64; m64++) { // initialize cur [p=(m64&1)] arrays const uint p = m64&1; { memcpy(runStarts[p], runStarts[!p], N*sizeof(runStarts[p][0])); memset(runStartFreqs[p], 0, (Mseg64+1)*sizeof(runStartFreqs[p][0])); } uint64_masks bits0 = genoBits[m64*N + n0]; for (uint64 n1 = 0; n1 < N; n1++) { const uint64_masks &bits1 = genoBits[m64*N + n1]; uint64 wrongBits = (bits0.is0 & bits1.is2) | (bits0.is2 & bits1.is0); // update cur runStarts based on bit matches if (wrongBits) { runStarts[p][n1] = m64+1; } // compute cur runStartFreqs based on (updated) cur runStarts runStartFreqs[p][runStarts[p][n1]]++; } for (uint s64 = 0; s64 <= m64; s64++) if ((runStartFreqs[p][s64] >= K && m64+1 == Mseg64) || // reached end (runStartFreqs[p][s64] < K && runStartFreqs[!p][s64] >= K)) { // all n1 s.t. runStarts[p][n1] == s64 are in top K starting from s64 // some n1 s.t. runStarts[!p][n1] == s64 are in top K starting from s64 uint allPos = 0, somePos = runStartFreqs[p][s64]; uint *topIndsChunk = &topInds[1][s64*K]; for (uint64 n1 = 0; n1 < N; n1++) { if (allPos < K && runStarts[p][n1] == s64) topIndsChunk[allPos++] = n1; else if (somePos < K && runStarts[!p][n1] == s64) topIndsChunk[somePos++] = n1; } topIndsLens[1][s64] = min(somePos, K); } } for (uint p = 0; p < 2; p++) ALIGNED_FREE(runStartFreqs[p]); for (uint p = 0; p < 2; p++) ALIGNED_FREE(runStarts[p]); } void Eagle::findLongDipHap(uint64 n0, vector topInds[2], vector topIndsLens[2], uint K, uint errStart=1) const { uint64 Nhaps = 2*(Nref==0 ? N : Nref); for (uint e = 0; e < 2; e++) { topInds[e] = vector (Mseg64 * K); topIndsLens[e] = vector (Mseg64); } uint *runStarts[2][2]; // [even/odd][max err]; lengths are Nhaps for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) runStarts[p][e] = ALIGNED_MALLOC_UINTS(Nhaps); uint *runStartFreqs[2][2]; // [even/odd][max err]; lengths are Mseg64+1 (b/c m64+1 can go over) for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) runStartFreqs[p][e] = ALIGNED_MALLOC_UINTS(Mseg64+1); // initialize "prev" p=1 for (uint e = 0; e < 2; e++) { const uint p = 1; memset(runStarts[p][e], 0, Nhaps*sizeof(runStarts[p][e][0])); // all runs start at 0 runStartFreqs[p][e][0] = Nhaps; memset(&runStartFreqs[p][e][1], 0, Mseg64*sizeof(runStarts[p][e][1])); } for (uint64 m64 = 0; m64 < Mseg64; m64++) { // initialize cur [p=(m64&1)] arrays const uint p = m64&1; for (uint e = 0; e < 2; e++) { memcpy(runStarts[p][e], runStarts[!p][e], Nhaps*sizeof(runStarts[p][e][0])); memset(runStartFreqs[p][e], 0, (Mseg64+1)*sizeof(runStartFreqs[p][e][0])); } uint64_masks bits0 = genoBits[m64*N + n0]; //uint *runStarts_p_0 = runStarts[p][0], *runStarts_p_1 = runStarts[p][1]; //uint *runStartFreqs_p_0 = runStartFreqs[p][0], *runStartFreqs_p_1 = runStartFreqs[p][1]; for (uint64 n1 = 0; n1 < Nhaps; n1++) { uint64 is1 = haploBits[m64*2*N + n1]; uint64 wrongBits = (bits0.is0 & is1) | (bits0.is2 & ~is1); // update cur runStarts based on bit matches if (wrongBits) { if (wrongBits & (wrongBits-1)) // 2+ wrong => fail; move both starts forward runStarts[p][0][n1] = runStarts[p][1][n1] = m64+1; else { // 1 wrong => move 1-err start to 0-err start; fail 0-err runStarts[p][1][n1] = runStarts[p][0][n1]; runStarts[p][0][n1] = m64+1; } } // compute cur runStartFreqs based on (updated) cur runStarts for (uint e = errStart; e < 2; e++) runStartFreqs[p][e][runStarts[p][e][n1]]++; /* if (wrongBits) { if (wrongBits & (wrongBits-1)) // 2+ wrong => fail; move both starts forward runStarts_p_0[n1] = runStarts_p_1[n1] = m64+1; else { // 1 wrong => move 1-err start to 0-err start; fail 0-err runStarts_p_1[n1] = runStarts_p_0[n1]; runStarts_p_0[n1] = m64+1; } } runStartFreqs_p_0[runStarts_p_0[n1]]++; runStartFreqs_p_1[runStarts_p_1[n1]]++; */ } for (uint e = errStart; e < 2; e++) for (uint s64 = 0; s64 <= m64; s64++) if ((runStartFreqs[p][e][s64] >= K && m64+1 == Mseg64) || // reached end (runStartFreqs[p][e][s64] < K && runStartFreqs[!p][e][s64] >= K)) { // all n1 s.t. runStarts[p][e][n1] == s64 are in top K starting from s64 // some n1 s.t. runStarts[!p][e][n1] == s64 are in top K starting from s64 uint allPos = 0, somePos = runStartFreqs[p][e][s64]; uint *topIndsChunk = &topInds[e][s64*K]; for (uint64 n1 = 0; n1 < Nhaps; n1++) { if (allPos < K && runStarts[p][e][n1] == s64) topIndsChunk[allPos++] = n1; else if (somePos < K && runStarts[!p][e][n1] == s64) topIndsChunk[somePos++] = n1; } topIndsLens[e][s64] = min(somePos, K); } } for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) ALIGNED_FREE(runStartFreqs[p][e]); for (uint p = 0; p < 2; p++) for (uint e = 0; e < 2; e++) ALIGNED_FREE(runStarts[p][e]); } void Eagle::randomlyPhaseTmpHaploBitsT(uint64 n0) { // fast rng: last 16 bits of Marsaglia's MWC uint w = 521288629; for (uint i = 0; i < (n0 & 0xff); i++) w=18000*(w&65535)+(w>>16); uint64 n1 = (n0+1) % N; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) { uint g = getGeno0123(m64j, n0); if (g == 3) g = getGeno0123(m64j, n1); // if missing, try filling with geno of next sample if (g == 3) g = 1; // if still missing, set to het if (g == 0) // nothing to do; tmpHaploBitsT is already cleared in init() ; else if (g == 2) { // set bit in both parental haplotypes for (uint64 q = 0; q <= 1ULL; q++) tmpHaploBitsT[(2*n0+q)*Mseg64 + (m64j/64)] |= 1ULL<<(m64j&63); } else { // set bit in random parental haplotype uint64 q = (w=18000*(w&65535)+(w>>16))&1; tmpHaploBitsT[(2*n0+q)*Mseg64 + (m64j/64)] |= 1ULL<<(m64j&63); } } } pair > Eagle::findLongDipMatches(uint64 n0, uint64 nF1, uint64 nF2) { if (!maskIndivs[n0]) return make_pair(0.0, vector ()); vector topInds[2]; // [max err]; lengths are Mseg64 * K vector topIndsLens[2]; // [max err]; lengths are Mseg64 const uint K = 10; Timer timer; findLongHalfIBD(n0, topInds, topIndsLens, K); double halfIBDtime = timer.update_time(); const double duoMatchThresh = log10(N*10), longMatchMin = 4.0; /***** COMPUTE BAYES FACTORS FOR LONG HALF-IBD REGIONS TO SELECT LONG MATCHES *****/ vector cumTopMatches; vector longMatches; double *workLogBF = ALIGNED_MALLOC_DOUBLES(Mseg64*64); double (*memoLogBF)[4] = (double (*)[4]) ALIGNED_MALLOC(Mseg64*64*4*sizeof(double)); // initialize memo lookup table of logBFs (n1 given n0) for (uint m64j = 0; m64j < Mseg64*64; m64j++) for (uint g = 0; g < 4; g++) memoLogBF[m64j][g] = MEMO_UNSET; for (uint64 m64 = 0; m64 < Mseg64; m64++) { std::set n1s; n1s.insert(n0); // delete previous matches that have ended: sort by greaterEnd and erase range at end sort(cumTopMatches.begin(), cumTopMatches.end(), Match::greaterEnd); for (uint k = 0; k < cumTopMatches.size(); k++) { if (m64 >= cumTopMatches[k].m64jEnd/64) { cumTopMatches.resize(k); break; } else n1s.insert(cumTopMatches[k].n); } // incorporate new matches for (uint e = 0; e < 2; e++) { for (uint k = 0; k < topIndsLens[e][m64]; k++) { uint n1 = topInds[e][m64*K + k]; if (maskIndivs[n1] && !n1s.count(n1)) { n1s.insert(n1); Match duoMatch = computeDuoLogBF(memoLogBF, workLogBF, n0, n1, m64); assert(maskSnps64j[duoMatch.m64jStart]); assert(maskSnps64j[duoMatch.m64jEnd]); if (duoMatch.logBF > duoMatchThresh && duoMatch.cMlenInit >= longMatchMin) { longMatches.push_back(duoMatch); #ifdef VERBOSE printMatch(n0, nF1, nF2, duoMatch, memoLogBF); #endif //retractMatch(n0, duoMatch, memoLogBF); cumTopMatches.push_back(duoMatch); } } } } } #ifdef VERBOSE cout << "num longMatches: " << longMatches.size() << endl; #endif /***** TRIM MATCHES UNTIL CONSISTENT; DETERMINE SAME/OPP ORIENTATION OF PAIRS *****/ const double longMatchMinTrim = 3.0, minSameOppDiff = 0.5, minMatchLenDiff = 0.5; sort(longMatches.begin(), longMatches.end(), Match::greaterLen); vector < vector > sameEdges(longMatches.size()), oppEdges(longMatches.size()); for (uint i = 0; i < longMatches.size(); i++) for (uint j = 0; j < i; j++) { // trim against previous (longer) matches double iLen = cMs64j[longMatches[i].m64jEnd] - cMs64j[longMatches[i].m64jStart]; double jLen = cMs64j[longMatches[j].m64jEnd] - cMs64j[longMatches[j].m64jStart]; // check if too short (after previous trimming) if (iLen < longMatchMinTrim || jLen < longMatchMinTrim) continue; Match &d1 = longMatches[iLen longestOpp + minSameOppDiff || (longestSame == fullOverlap && longestSame > longestOpp)) { sameEdges[i].push_back(j); sameEdges[j].push_back(i); orientation = 1; trimStart = (sameStart+sameEnd)/2; } else if (longestOpp > longestSame + minSameOppDiff || (longestOpp == fullOverlap && longestOpp > longestSame)) { oppEdges[i].push_back(j); oppEdges[j].push_back(i); orientation = -1; trimStart = (oppStart+oppEnd)/2; } if (orientation != 0) { // clearly same or opp // left end if (cMs64j[d1.m64jStart] < cMs64j[d2.m64jStart] - minMatchLenDiff) // d1 extends further trim(d2, d1, n0, orientation, trimStart, -1, workLogBF); // => trim d2 else trim(d1, d2, n0, orientation, trimStart, -1, workLogBF); // right end if (cMs64j[d1.m64jEnd] > cMs64j[d2.m64jEnd] + minMatchLenDiff) // d1 extends further trim(d2, d1, n0, orientation, trimStart, 1, workLogBF); // => trim d2 else trim(d1, d2, n0, orientation, trimStart, 1, workLogBF); #ifdef VERBOSE printf(" --> %.1f (%.1f-%.1f) --> %.1f (%.1f-%.1f)\n", cMs64j[d1.m64jEnd]-cMs64j[d1.m64jStart], cMs64j[d1.m64jStart], cMs64j[d1.m64jEnd], cMs64j[d2.m64jEnd]-cMs64j[d2.m64jStart], cMs64j[d2.m64jStart], cMs64j[d2.m64jEnd]); #endif } else { // can't determine same vs. opp => chop shorter so that matches no longer overlap if (d1.m64jStart < d2.m64jStart) d1.m64jEnd = d2.m64jStart-1; else d1.m64jStart = min(d2.m64jEnd+1ULL, Mseg64*64-1); #ifdef VERBOSE printf(" trimmed first to cM= %.1f (%.1f-%.1f)\n", cMs64j[d1.m64jEnd]-cMs64j[d1.m64jStart], cMs64j[d1.m64jStart], cMs64j[d1.m64jEnd]); #endif } } /***** REDUCE TO SET OF TRIMMED MATCHES WITH CONSISTENT SIGNS *****/ vector kept(longMatches.size()), checked(longMatches.size()); for (uint t = 0; t < longMatches.size(); t++) { // find longest remaining trimmed match uint i = 0; double longest = 0; for (uint iTest = 0; iTest < longMatches.size(); iTest++) if (!checked[iTest]) { const Match &d1 = longMatches[iTest]; if (cMs64j[d1.m64jEnd]-cMs64j[d1.m64jStart] > longest) { longest = cMs64j[d1.m64jEnd]-cMs64j[d1.m64jStart]; i = iTest; } } checked[i] = true; if (longest < longMatchMinTrim) break; if (longMatches[i].n == nF1 || longMatches[i].n == nF2) continue; kept[i] = true; #ifdef VERBOSE const Match &d1 = longMatches[i]; printf("cM= %.1f (%.1f-%.1f)\n", cMs64j[d1.m64jEnd]-cMs64j[d1.m64jStart], cMs64j[d1.m64jStart], cMs64j[d1.m64jEnd]); #endif vector signs = searchSigns(longMatches, sameEdges, oppEdges, kept); if (signs.empty()) { // inconsistent signs kept[i] = false; #ifdef VERBOSE cout << " WARNING: sign inconsistency: eliminating" << endl; #endif } } // compute final signs vector signs = searchSigns(longMatches, sameEdges, oppEdges, kept); #ifdef VERBOSE for (uint i = 0; i < longMatches.size(); i++) if (kept[i]) { const Match &d1 = longMatches[i]; printf("cM= %.1f (%.1f-%.1f): ", vector curMatch(1, d1); vector curSign(1, signs[i]); cMs64j[d1.m64jEnd]-cMs64j[d1.m64jStart], cMs64j[d1.m64jStart], cMs64j[d1.m64jEnd]); cout << computePhaseString(n0, nF1, nF2, curMatch, curSign, d1.m64jStart, cMs64j[d1.m64jEnd]+1e-9, false) << endl; cout << computePhaseString(n0, nF1, nF2, curMatch, curSign, d1.m64jStart, cMs64j[d1.m64jEnd]+1e-9, true) << endl; } cout << endl << endl << "phase: " << computePhaseString(n0, nF1, nF2, longMatches, signs, 0, 1e100, false) << endl; cout << endl << endl << "phase: " << computePhaseString(n0, nF1, nF2, longMatches, signs, 0, 1e100, true) << endl; #endif computePhaseConfs(n0, longMatches, signs, true); if ((int) nF1 != -1 && (int) nF2 != -1) { checkPhase(n0, nF1, nF2, 0.1); checkPhase(n0, nF1, nF2, 0.5); } ALIGNED_FREE(workLogBF); ALIGNED_FREE(memoLogBF); // record longest match length per seg64 for output vector cMs(Mseg64); bool cons = true; for (uint i = 0; i < longMatches.size(); i++) { if (!signs[i]) continue; uint64 start, end; if (cons) { start = std::max(longMatches[i].m64jStartCons, longMatches[i].m64jStart); end = std::min(longMatches[i].m64jEndCons, longMatches[i].m64jEnd); } else { start = longMatches[i].m64jStart; end = longMatches[i].m64jEnd; } for (uint64 m64 = (start+63)/64; m64 < end/64; m64++) cMs[m64] = std::max(cMs[m64], cMs64j[end]-cMs64j[start]); } return make_pair(halfIBDtime, cMs); } int Eagle::numDipHapWrongBits(uint64 m64, uint64 n0, uint64 n1hap) const { uint64 is1 = haploBits[m64*2*N + n1hap]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongBits = (bits0.is0 & is1) | (bits0.is2 & ~is1); return popcount64(wrongBits); } int Eagle::firstDipHapGoodBit(uint64 m64, uint64 n0, uint64 n1hap) const { uint64 is1 = haploBits[m64*2*N + n1hap]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongBits = (bits0.is0 & is1) | (bits0.is2 & ~is1); return wrongBits ? 64 - __builtin_clzll(wrongBits) : 0; // MSB } int Eagle::firstDipHapWrongBit(uint64 m64, uint64 n0, uint64 n1hap) const { if (m64 >= Mseg64) return 0; uint64 is1 = haploBits[m64*2*N + n1hap]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongBits = (bits0.is0 & is1) | (bits0.is2 & ~is1); return popcount64((wrongBits & ~(wrongBits-1))-1); // LSB } struct DipHapSeg { uint n, start, end; DipHapSeg(uint _n, uint _start, uint _end) : n(_n), start(_start), end(_end) {} bool operator < (const DipHapSeg &seg2) const { return end-start > seg2.end-seg2.start || (end-start == seg2.end-seg2.start && n < seg2.n); } }; struct DipHapSegFarther { bool operator() (const DipHapSeg &seg1, const DipHapSeg &seg2) const { return seg1.end > seg2.end || (seg1.end == seg2.end && seg1.n < seg2.n); } }; int Eagle::countSE(const vector &phaseVec) { int ans = 0; for (uint h = 1; h < phaseVec.size(); h++) ans += (phaseVec[h] != phaseVec[h-1]); return ans; } int Eagle::countMajorSE(const vector &phaseVec) { vector phaseVec7; for (uint h7 = 0; h7+7 < phaseVec.size(); h7 += 7) { int votes = 0; for (uint h = h7; h < h7+7; h++) votes += phaseVec[h]; phaseVec7.push_back(votes >= 4); } return countSE(phaseVec7); } double Eagle::findLongHapMatches(uint64 n0, uint64 nF1, uint64 nF2, int iter) { if (!maskIndivs[n0]) return 0; if (Mseg64 < 3U) { cerr << "Too few SNP segments for analysis" << endl; exit(1); } uint seed = n0; // for rand_r() vector topInds[2]; // [max err]; lengths are Mseg64 * K vector topIndsLens[2]; // [max err]; lengths are Mseg64 const uint K = 20; Timer timer; findLongDipHap(n0, topInds, topIndsLens, K); double hapTime = timer.update_time(); /* // VISUALIZE RESULTS for (uint64 m64 = 0; m64 < Mseg64; m64++) { cout << "m64 = " << m64 << endl; int m64xMin = std::max(0, (int) m64-5); int m64xMax = std::min(m64+11, Mseg64); for (int m64x = m64xMin; m64x < m64xMax; m64x++) { int numSnps = 0; for (int j = 0; j < 64; j++) numSnps += maskSnps64j[m64x*64+j]; printf("%2d ", numSnps); } cout << endl; for (uint e = 0; e < 2; e++) { cout << "e = " << e << endl; for (uint k = 0; k < topIndsLens[e][m64]; k++) { uint64 n1hap = topInds[e][m64*K + k]; for (int m64x = m64xMin; m64x < m64xMax; m64x++) { printf("%2d ", numDipHapWrongBits(m64x, n0, n1hap)); } cout << " (" << n1hap << ")" << endl; } } } */ const int maxWrongBits = 3; std::set longDipHapSegs[Mseg64]; const uint maxSegs = (iter == 2 ? 10 : 20); // TODO: increase accuracy with 20? vector lastEnd64(2*N); for (uint64 m64 = 0; m64 < Mseg64; m64++) { //if ((int) nF1 != -1) cout << "m64 = " << m64 << endl; for (uint e = 0; e < 2; e++) { //if ((int) nF1 != -1) cout << "e = " << e << endl; for (uint k = 0; k < topIndsLens[e][m64]; k++) { uint64 n1hap = topInds[e][m64*K + k]; if (!maskIndivs[n1hap/2]) continue; if (n1hap/2 == n0) continue; if (lastEnd64[n1hap] > m64) continue; // find start uint segStart = m64; while ((int) segStart >= 0 && numDipHapWrongBits(segStart, n0, n1hap) <= maxWrongBits) segStart--; segStart++; // find end uint segEnd = m64; while (segEnd < Mseg64 && numDipHapWrongBits(segEnd, n0, n1hap) <= maxWrongBits) segEnd++; //checkHapPhase1(n0, nF1, nF2, n1hap, segStart, segEnd); lastEnd64[n1hap] = segEnd; for (uint64 m64x = segStart; m64x < segEnd; m64x++) { longDipHapSegs[m64x].insert(DipHapSeg(n1hap, segStart, segEnd)); if (longDipHapSegs[m64x].size() > maxSegs) longDipHapSegs[m64x].erase(--longDipHapSegs[m64x].end()); } } } } /* for (uint64 m64 = 0; m64 < Mseg64; m64++) { cout << "m64 = " << m64 << endl; for (std::set ::iterator it = longDipHapSegs[m64].begin(); it != longDipHapSegs[m64].end(); it++) { printf("%2d: %2d-%2d (%d)\n", it->end-it->start, it->start, it->end, it->n); } } */ uint64 curHaploBitsT[Mseg64]; const uint64 side = 1; //const uint numHapHaps = 5; vector errBests(Mseg64); vector < pair > n12hapBests(Mseg64); for (uint64 m64 = 0+side; m64+side < Mseg64; m64++) { /* if ((int) nF1 != -1) { cout << "m64 = " << m64 << endl; for (uint i = 0; i < numHapHaps; i++) printf(" "); } checkHapPhase(n0, nF1, nF2, haploBitsT + 2*n0*Mseg64, m64, side); */ vector < pair > bestHitPairs; uint minWrongBits = 99; for (std::set ::iterator it = longDipHapSegs[m64].begin(); it != longDipHapSegs[m64].end(); it++) { // for each dip-hap long match uint64 n1hap = it->n; // ---------- SLOW ---------- /* std::set < pair > wrongBitsHaps; uint worstInSet = 1<<30; for (uint64 n2hap = 0; n2hap < 2*N; n2hap++) { if (!maskIndivs[n2hap/2]) continue; if (n2hap/2 == n0) continue; if (n2hap/2 == n1hap/2) continue; // opp haps of same indiv uint numWrongBits = 0; for (uint64 m64x = m64-side; m64x <= m64+side; m64x++) { uint64 n1is1 = haploBits[m64x*2*N + n1hap]; uint64 n2is1 = haploBits[m64x*2*N + n2hap]; const uint64_masks &bits0 = genoBits[m64x*N + n0]; uint64 wrongBits = (bits0.is0 & (n1is1 | n2is1)) | (bits0.is2 & ~(n1is1 & n2is1)) | (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1)); numWrongBits += popcount64(wrongBits); } if (numWrongBits < worstInSet) { wrongBitsHaps.insert(make_pair(numWrongBits, n2hap)); if (wrongBitsHaps.size() > numHapHaps) { wrongBitsHaps.erase(--wrongBitsHaps.end()); worstInSet = (--wrongBitsHaps.end())->first; } } } for (std::set < pair >::iterator itH = wrongBitsHaps.begin(); itH != wrongBitsHaps.end(); itH++) printf("%2d ", itH->first); //printf("%2d (%d)\n", itH->first, itH->second); */ // ---------- FAST ---------- if ((int) nF1 != -1) printf("| "); for (uint64 m64x = m64-side; m64x <= m64+side; m64x++) { curHaploBitsT[m64x] = 0; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64x*64+j, bit = 0; if (maskSnps64j[m64j]) { uint g0 = getGeno0123(m64j, n0); if (g0 == 0 || g0 == 3) bit = 0; else if (g0 == 2) bit = 1; else bit = 1-((haploBitsT[n1hap*Mseg64 + m64x]>>j)&1); } curHaploBitsT[m64x] |= bit<second*/n1hap*Mseg64, m64, side); // n1hap is better! } } if (bestHitPairs.empty()) { // keep current phasing errBests[m64] = 99; n12hapBests[m64] = make_pair((uint) n0*2, (uint) n0*2+1); } else { errBests[m64] = minWrongBits; n12hapBests[m64] = bestHitPairs[rand_r(&seed) % bestHitPairs.size()]; } } if ((int) nF1 != -1) cout << endl << "2nd-iter phase:" << endl; int sign = 1; vector signs(Mseg64); uint64 prevInd = side; vector phaseVec; for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint64 curInd = min(max(m64, side), Mseg64-1-side); /*int minWrongBits = 99; for (int diff = - (int) side; diff <= (int) side; diff++) { uint64 m64d = m64+diff; if (m64d >= Mseg64) continue; uint64 n1is1 = haploBitsT[n12hapBests[m64d].first*Mseg64 + m64]; uint64 n2is1 = haploBitsT[n12hapBests[m64d].second*Mseg64 + m64]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongBits = (bits0.is0 & (n1is1 | n2is1)) | (bits0.is2 & ~(n1is1 & n2is1)) | (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1)); int numWrongBits = popcount64(wrongBits); if (numWrongBits < minWrongBits) { minWrongBits = numWrongBits; curInd = m64d; } } */ // best of 3 neighbors doesn't help? vector < pair > offsetMults; if (m64 > side && m64 < Mseg64-side) { // update sign uint64 n1prev = n12hapBests[prevInd].first, n2prev = n12hapBests[prevInd].second; uint64 n1cur = n12hapBests[curInd].first, n2cur = n12hapBests[curInd].second; for (uint64 m64j = (m64-side)*64; m64j < (m64+side)*64; m64j++) { uint h1prev = (haploBitsT[n1prev*Mseg64 + (m64j/64)]>>(m64j&63))&1; uint h2prev = (haploBitsT[n2prev*Mseg64 + (m64j/64)]>>(m64j&63))&1; uint h1cur = (haploBitsT[n1cur*Mseg64 + (m64j/64)]>>(m64j&63))&1; uint h2cur = (haploBitsT[n2cur*Mseg64 + (m64j/64)]>>(m64j&63))&1; if (h1prev + h2prev == 1 && h1cur + h2cur == 1) { int offset = abs((int) (m64j - m64*64)); offsetMults.push_back(make_pair(offset, h1prev == h1cur ? 1 : -1)); } } } if (!offsetMults.empty()) { sort(offsetMults.begin(), offsetMults.end()); int totVotes = min((int) offsetMults.size(), 5), sameVotes = 0; for (int k = 0; k < totVotes; k++) if (offsetMults[k].second == 1) sameVotes++; if (sameVotes < (totVotes+1)/2) sign *= -1; // swap sign } signs[m64] = sign; uint64 n1hap = n12hapBests[curInd].first, n2hap = n12hapBests[curInd].second; computeSegPhaseConfs(n0, n1hap, n2hap, sign, m64, errBests[curInd]); prevInd = curInd; } if ((int) nF1 != -1) { for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint64 curInd = min(max(m64, side), Mseg64-1-side); char usedInd = ' '; if (curInd > m64) usedInd = 'v'; else if (curInd < m64) usedInd = '^'; uint64 n1hap = n12hapBests[curInd].first, n2hap = n12hapBests[curInd].second; int sign = signs[m64]; printf("m64 = %2d err: %2d %c (%6d,%6d) ", (int) m64, (int) errBests[curInd], usedInd, (int) (sign==1 ? n1hap : n2hap), (int) (sign==1 ? n2hap : n1hap)); //cout << closestOffset << endl; vector phaseSeg = checkSegPhase(n0, nF1, nF2, n1hap, n2hap, sign, m64); phaseVec.insert(phaseVec.end(), phaseSeg.begin(), phaseSeg.end()); } printf("# major SE: %2d # tot SE: %2d / %d\n", countMajorSE(phaseVec), countSE(phaseVec), (int) phaseVec.size()-1); fflush(stdout); } /* for (uint64 n1hap = 2*n0; n1hap <= 2*n0+1; n1hap++) { cout << "n0 = " << n0 << "; n1hap = " << n1hap << ": "; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) cout << (int) phaseConfs2[n1hap*Mseg64*64 + m64j] << " "; cout << endl; } */ return hapTime; } inline uint64 pairToULL(pair p) { return ((uint64) p.first<<32ULL)|p.second; } inline pair ullToPair(uint64 ull) { return make_pair((uint) (ull>>32ULL), (uint) ull); } bool Eagle::updateHelper(std::unordered_map &dpTab, uint &dpBestScore, pair cur, pair next, uint score) const { #ifdef RDTSC_TIMING uint64 tscStart = Timer::rdtsc(); #endif /* ---- SLOW ---- if (dpTab.find(pairToULL(next)) == dpTab.end() || dpTab[pairToULL(next)].score > score) dpTab[pairToULL(next)] = DPState(score, cur); */ if (score > dpBestScore + 2*switchCost) return false; DPState &nextState = dpTab[pairToULL(next)]; if (nextState.score == 0 || nextState.score > score) { nextState.score = score; nextState.from = cur; } if (score < dpBestScore) dpBestScore = score; #ifdef RDTSC_TIMING dpUpdateTicks += Timer::rdtsc() - tscStart; dpUpdateCalls++; #endif return true; } uint Eagle::computeStaticScore(uint n0, uint n1hap, uint n2hap, uint64 m64) const { #ifdef RDTSC_TIMING uint64 tscStart = Timer::rdtsc(); #endif uint64 n1is1 = haploBitsT[n1hap*Mseg64 + m64]; uint64 n2is1 = haploBitsT[n2hap*Mseg64 + m64]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongHomBits = (bits0.is0 & (n1is1 | n2is1)) | (bits0.is2 & ~(n1is1 & n2is1)); uint64 wrongHetBits = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1)); uint score = popcount64(wrongHomBits)*homErrCost + popcount64(wrongHetBits)*hetErrCost + segConfs[n1hap*Mseg64+m64] / 5 + segConfs[n2hap*Mseg64+m64] / 5; #ifdef RDTSC_TIMING dpStaticTicks += Timer::rdtsc() - tscStart; #endif return score; } uint Eagle::computeSwitchScore(uint n0, uint n1hap, uint n2hapA, uint n2hapB, uint64 m64) const { #ifdef RDTSC_TIMING uint64 tscStart = Timer::rdtsc(); #endif uint64 n1is1 = haploBitsT[n1hap*Mseg64 + m64]; uint64 n2is1A = haploBitsT[n2hapA*Mseg64 + m64]; uint64 n2is1B = haploBitsT[n2hapB*Mseg64 + m64]; const uint64_masks &bits0 = genoBits[m64*N + n0]; uint64 wrongHomBitsA = (bits0.is0 & (n1is1 | n2is1A)) | (bits0.is2 & ~(n1is1 & n2is1A)); uint64 wrongHetBitsA = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1A)); uint64 wrongHomBitsB = (bits0.is0 & (n1is1 | n2is1B)) | (bits0.is2 & ~(n1is1 & n2is1B)); uint64 wrongHetBitsB = (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1B)); /* ---- SLOW ---- uint score = popcount64(wrongHomBitsB)*homErrCost + popcount64(wrongHetBitsB)*hetErrCost; uint minScore = score; for (uint64 k = 0; k < 64; k++) { score += ((wrongHomBitsA>>k)&1)*homErrCost + ((wrongHetBitsA>>k)&1)*hetErrCost - ((wrongHomBitsB>>k)&1)*homErrCost - ((wrongHetBitsB>>k)&1)*hetErrCost; if (score < minScore) minScore = score; } assert(score == popcount64(wrongHomBitsA)*homErrCost + popcount64(wrongHetBitsA)*hetErrCost); */ uint64 wrongBitsA = wrongHomBitsA | wrongHetBitsA; uint64 wrongBitsB = wrongHomBitsB | wrongHetBitsB; uint64 hetBits = ~(bits0.is0|bits0.is2|bits0.is9); uint mask = (1U<>b))&mask)<<(switchScoreLutBits+switchScoreLutBits)) | ((((uint) (wrongBitsB>>b))&mask)<>b))&mask)); bestScore = min(bestScore, curScore + switchScoreLut[lutInd][0]); curScore += switchScoreLut[lutInd][1]; } curScore = bestScore + segConfs[n1hap*Mseg64+m64] / 5 + segConfs[n2hapA*Mseg64+m64] / 5 + segConfs[n2hapB*Mseg64+m64] / 5; // additional penalty for errors in (n1hap,n2hapB) at end of m64 curScore += ((wrongBitsB & 0xf000000000000000) != 0) + ((wrongBitsB & 0xff00000000000000) != 0) + ((wrongBitsB & 0xffff000000000000) != 0); if (m64+1 < Mseg64) { // additional penalty for errors in (n1hap,n2hapB) at start of m64+1 n1is1 = haploBitsT[n1hap*Mseg64 + m64+1]; n2is1B = haploBitsT[n2hapB*Mseg64 + m64+1]; const uint64_masks &bits0next = genoBits[(m64+1)*N + n0]; wrongBitsB = (bits0next.is0 & (n1is1 | n2is1B)) | (bits0next.is2 & ~(n1is1 & n2is1B)) | (~(bits0next.is0|bits0next.is2|bits0next.is9) & ~(n1is1 ^ n2is1B)); curScore += ((wrongBitsB & 0xf) != 0) + ((wrongBitsB & 0xff) != 0) + ((wrongBitsB & 0xffff) != 0); } #ifdef RDTSC_TIMING dpSwitchTicks += Timer::rdtsc() - tscStart; #endif return curScore; } void Eagle::updateTable(std::unordered_map dpTable[], uint dpBestScores[], uint64 m64, uint64 dist, uint n0, uint n1hapA, uint n2hapA, uint n1hapB, uint n2hapB, uint score) const { if (n1hapB/2 == n2hapB/2) return; // disallow copying both haps from an indiv if ((n1hapA == n1hapB && n2hapA == n2hapB) || (n1hapA != n1hapB && n2hapA != n2hapB)) score += computeStaticScore(n0, n1hapB, n2hapB, m64); else { if (n1hapA == n1hapB) score += computeSwitchScore(n0, n1hapA, n2hapA, n2hapB, m64); else /* (n2hapA == n2hapB) */ score += computeSwitchScore(n0, n2hapA, n1hapA, n1hapB, m64); } if (!updateHelper(dpTable[m64], dpBestScores[m64], make_pair(n1hapA, n2hapA), make_pair(n1hapB, n2hapB), score)) return; for (uint64 m64x = m64+1; m64x < m64+dist && m64x < Mseg64; m64x++) { score += computeStaticScore(n0, n1hapB, n2hapB, m64x); if (!updateHelper(dpTable[m64x], dpBestScores[m64x], make_pair(n1hapB, n2hapB), make_pair(n1hapB, n2hapB), score)) return; } } void updateErrHits(vector &hitVec, uint64 &bestErrLoc, uint64 errLoc, uint n2hap) { if (errLoc > bestErrLoc) { bestErrLoc = errLoc; hitVec.resize(1, n2hap); } else if (errLoc == bestErrLoc) hitVec.push_back(n2hap); } void Eagle::safeInsert(std::set &refHapSet, uint n1hap, uint n0) const { if (!maskIndivs[n1hap/2]) return; if (n1hap/2 == n0) return; refHapSet.insert(n1hap); } vector < pair > Eagle::findGoodSegs(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap) const { vector < pair > goodSegs; uint64 firstGood = 0; for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint64_masks bits0 = genoBits[m64*N + n0]; uint64_masks bitsF1 = genoBits[m64*N + nF1]; uint64_masks bitsF2 = genoBits[m64*N + nF2]; uint64 is0 = bits0.is0 | (~(bits0.is0|bits0.is2|bits0.is9) & ((bitsF1.is0 & ~bitsF2.is0) | (~bitsF1.is2 & bitsF2.is2))); uint64 is2 = bits0.is2 | (~(bits0.is0|bits0.is2|bits0.is9) & ((bitsF1.is2 & ~bitsF2.is2) | (~bitsF1.is0 & bitsF2.is0))); uint64 is1 = haploBits[m64*2*N + n1hap]; uint64 wrongBits = (is0 & is1) | (is2 & ~is1); if (wrongBits) { uint64 firstWrong = m64*64 + popcount64((wrongBits & ~(wrongBits-1))-1); if (firstWrong - firstGood >= 64) goodSegs.push_back(make_pair(firstGood, firstWrong)); firstGood = m64*64 + (wrongBits ? 64 - __builtin_clzll(wrongBits) : 0); } } goodSegs.push_back(make_pair(firstGood, Mseg64*64)); return goodSegs; } void Eagle::updateFarHaps(vector < pair > &farHaps, uint n1hap, uint m64jStart, uint m64jEnd) const { const double cMminLen = 1.0; if (cMs64j[m64jEnd] - cMs64j[m64jStart] < cMminLen) return; //cout << m64jStart/64 << "." << (m64jStart&63) << "-" << m64jEnd/64 << "." << (m64jEnd&63) << " "; if (m64jEnd > farHaps[m64jStart].first) { farHaps[m64jStart].first = m64jEnd; farHaps[m64jStart].second = n1hap; } } double Eagle::runHMM(uint64 n0, uint64 nF1, uint64 nF2, int iter, uint beamWidth, uint maxHapStates) { if (!maskIndivs[n0]) return 0; if (Mseg64 < 3U) { cerr << "Too few SNP segments for analysis" << endl; exit(1); } uint seed = n0; // for rand_r() /***** FIND LONGEST DIP-HAP MATCHES *****/ #ifdef RDTSC_TIMING uint64 tscStart = Timer::rdtsc(); #endif vector topInds[2]; // [max err]; lengths are Mseg64 * K vector topIndsLens[2]; // [max err]; lengths are Mseg64 const uint K = 100; Timer timer; findLongDipHap(n0, topInds, topIndsLens, K, iter >= 4 ? 0 : 1); double hapTime = timer.update_time(); #ifdef RDTSC_TIMING diphapTicks += Timer::rdtsc() - tscStart; #endif /* // VISUALIZE RESULTS for (uint64 m64 = 0; m64 < Mseg64; m64++) { cout << "m64 = " << m64 << endl; int m64xMin = std::max(0, (int) m64-5); int m64xMax = std::min(m64+11, Mseg64); for (int m64x = m64xMin; m64x < m64xMax; m64x++) { int numSnps = 0; for (int j = 0; j < 64; j++) numSnps += maskSnps64j[m64x*64+j]; printf("%2d ", numSnps); } cout << endl; for (uint e = 0; e < 2; e++) { cout << "e = " << e << endl; for (uint k = 0; k < topIndsLens[e][m64]; k++) { uint64 n1hap = topInds[e][m64*K + k]; for (int m64x = m64xMin; m64x < m64xMax; m64x++) { printf("%2d ", numDipHapWrongBits(m64x, n0, n1hap)); } cout << " (" << n1hap << ")" << endl; } } } */ /***** EXTEND DIP-HAP MATCHES TO OBTAIN LONGEST MATCHES COVERING EACH SEG *****/ #ifdef RDTSC_TIMING uint64 tscExtStart = Timer::rdtsc(); #endif const int maxWrongBits = 1; std::set longDipHapSegsForward[Mseg64]; const uint maxSegs = std::max(50U, maxHapStates/4); vector lastEnd64(2*N); for (uint64 m64 = 0; m64 < Mseg64; m64++) { #ifdef DETAILS if ((int) nF1 != -1) cout << "m64 = " << m64 << endl; #endif for (uint e = 0; e < 2; e++) { #ifdef DETAILS if ((int) nF1 != -1) cout << "e = " << e << endl; #endif for (uint k = 0; k < topIndsLens[e][m64]; k++) { uint64 n1hap = topInds[e][m64*K + k]; if (!maskIndivs[n1hap/2]) continue; if (n1hap/2 == n0) continue; if (lastEnd64[n1hap] > m64) continue; // find start uint segStart = m64; while ((int) segStart >= 0 && numDipHapWrongBits(segStart, n0, n1hap) <= maxWrongBits) segStart--; if ((int) segStart < 0) segStart = 0; //segStart++; NEW: start one chunk before! uint segStart64j = segStart*64 + firstDipHapGoodBit(segStart, n0, n1hap); // find end uint segEnd = m64+1; while (segEnd < Mseg64 && numDipHapWrongBits(segEnd, n0, n1hap) <= maxWrongBits) segEnd++; uint segEnd64j = segEnd*64 + firstDipHapWrongBit(segEnd, n0, n1hap); #ifdef DETAILS checkHapPhase1(n0, nF1, nF2, n1hap, segStart, segEnd); #endif lastEnd64[n1hap] = segEnd; for (uint64 m64x = segStart; m64x+1 /* extend forward */ < segEnd; m64x++) { longDipHapSegsForward[m64x].insert(DipHapSeg(n1hap, segStart64j, segEnd64j)); if (longDipHapSegsForward[m64x].size() > maxSegs) longDipHapSegsForward[m64x].erase(--longDipHapSegsForward[m64x].end()); } } } } #ifdef RDTSC_TIMING extTicks += Timer::rdtsc() - tscExtStart; #endif /***** COMPILE SET OF REFERENCE HAPLOTYPES FOR EACH TRANSITIONS AT EACH SEG *****/ std::set refHapSets[Mseg64]; vector refHapVecs[Mseg64]; vector < pair > refHapOppPairs[Mseg64]; const uint numTopShort = maxHapStates/4, numTopLong = maxHapStates/4, minRefHaps = maxHapStates/4; const uint64 side = 1; uint64 curHaploBitsT[Mseg64]; for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint cumTop = 0; // dip-hap hits starting at m64 and m64+1 for (uint64 m64x = m64; m64x < m64+2 && m64x < Mseg64; m64x++) for (uint e = 1; e != -1U; e--) { cumTop += numTopShort / 4; for (uint k = 0; k < topIndsLens[e][m64] && refHapSets[m64].size() < cumTop; k++) { uint n1hap = topInds[e][m64*K + k]; if (segConfs[n1hap*Mseg64+m64] < 5 && (m64+1==Mseg64 || segConfs[n1hap*Mseg64+m64+1] < 5)) safeInsert(refHapSets[m64], n1hap, n0); } } // long dip hap covering m64, m64+1 cumTop += numTopLong; for (std::set ::iterator it = longDipHapSegsForward[m64].begin(); it != longDipHapSegsForward[m64].end() && refHapSets[m64].size() < cumTop; it++) { uint n1hap = it->n; if (segConfs[n1hap*Mseg64+m64] < 5 && (m64+1==Mseg64 || segConfs[n1hap*Mseg64+m64+1] < 5)) safeInsert(refHapSets[m64], n1hap, n0); } #ifdef DETAILS cout << "m64 = " << m64 << ": " << refHapSets[m64].size() << endl; #endif /***** AUGMENT REFERENCE HAPLOTYPE SET WITH COMPLEMENTS *****/ vector refHapVec(refHapSets[m64].begin(), refHapSets[m64].end()); if (m64+1 >= side && m64+1+side < Mseg64) { // look up m64+1 in LSH for (uint k1 = 0; k1 < refHapVec.size(); k1++) { uint64 n1hap = refHapVec[k1]; // require no err on right part of m64 uint64 m64errMaskMax = 1ULL<<((uint64) rand_r(&seed)&63); for (uint64 m64x = m64+1-side; m64x <= m64+1+side; m64x++) { curHaploBitsT[m64x] = 0; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64x*64+j, bit = 0; if (maskSnps64j[m64j]) { uint g0 = getGeno0123(m64j, n0); if (g0 == 0 || g0 == 3) bit = 0; else if (g0 == 2) bit = 1; else bit = 1-((haploBitsT[n1hap*Mseg64 + m64x]>>j)&1); } curHaploBitsT[m64x] |= bit< hits[3]; // n2haps with 1st err at [1]: m64+1; [2]: m64+2 (allow 1@m64+1) vector bestErrLocs(3); // farthest error locations seen for (uint h = 0; h < hashLookups[m64+1].size(); h++) { // for each hashing uint numHits; #ifdef RDTSC_TIMING uint64 tscLshStart = Timer::rdtsc(); #endif const uint *lenHapInds = hashLookups[m64+1][h].query(computeHash(curHaploBitsT, hashBits[m64+1][h])); #ifdef RDTSC_TIMING lshTicks += Timer::rdtsc() - tscLshStart; uint64 tscLshCheckStart = Timer::rdtsc(); #endif if (lenHapInds == NULL) numHits = 0; else numHits = lenHapInds[0]; for (uint k = 1; k <= numHits; k++) { uint64 n2hap = lenHapInds[k]; if (!maskIndivs[n2hap/2]) continue; if (n2hap/2 == n0) continue; if (n2hap/2 == n1hap/2) continue; // opp haps of same indiv int errFail = 0, err1 = 0; // err1: 1 err in m64+1 uint64 err1Loc = 0, err2Loc = 0; for (uint64 m64x = m64; m64x <= m64+2; m64x++) { uint64 n1is1 = haploBitsT[n1hap*Mseg64 + m64x]; uint64 n2is1 = haploBitsT[n2hap*Mseg64 + m64x]; const uint64_masks &bits0 = genoBits[m64x*N + n0]; uint64 wrongBits = (bits0.is0 & (n1is1 | n2is1)) | (bits0.is2 & ~(n1is1 & n2is1)) | (~(bits0.is0|bits0.is2|bits0.is9) & ~(n1is1 ^ n2is1)); if (m64x == m64) { if (wrongBits >= m64errMaskMax) { // not perfect in right part of m64 errFail = 2; // fail break; } } else if (m64x == m64+1) { if (wrongBits & (wrongBits-1)) { // 2+ err errFail = 1; // fail err1Loc = (wrongBits & ~(wrongBits-1))-1; // LSB-1: big is good break; } else if (wrongBits != 0) err1 = 1; } else { err2Loc = (wrongBits & ~(wrongBits-1))-1; // LSB-1: big is good } } if (!errFail) { // did not fail if (err2Loc != 0) err2Loc -= err1; // slightly worse to have 1 error in m64+1 updateErrHits(hits[2], bestErrLocs[2], err2Loc, n2hap); } else if (errFail == 1) updateErrHits(hits[1], bestErrLocs[1], err1Loc, n2hap); } #ifdef RDTSC_TIMING lshCheckTicks += Timer::rdtsc() - tscLshCheckStart; #endif if (bestErrLocs[2] == -1ULL) break; // early exit if perfect match found } //checkHapPhase1(n0, nF1, nF2, refHapVec[k1], m64, min(m64+3, Mseg64)); uint64 n2hap = -1ULL; for (int xLoc = 2; xLoc >= 0; xLoc--) if (!hits[xLoc].empty()) { n2hap = hits[xLoc][rand_r(&seed) % hits[xLoc].size()]; //cout << "2." << popcount64(bestErrLocs[2]) << ": "; break; } if (n2hap != -1ULL) { #ifdef DETAILS checkHapPhase1(n0, nF1, nF2, n2hap, m64, min(m64+3, Mseg64)); #endif safeInsert(refHapSets[m64], n2hap, n0); refHapOppPairs[m64].push_back(make_pair((uint) n1hap, (uint) n2hap)); } } } // make sure at least some ref haps are chosen: relax earlier conf filter for (std::set ::iterator it = longDipHapSegsForward[m64].begin(); it != longDipHapSegsForward[m64].end() && refHapSets[m64].size() < minRefHaps/2; it++) safeInsert(refHapSets[m64], it->n, n0); for (uint64 m64x = m64; m64x < m64+2 && m64x < Mseg64; m64x++) for (uint e = 0; e < 2; e++) for (uint k = 0; k < topIndsLens[e][m64] && refHapSets[m64].size() < minRefHaps; k++) safeInsert(refHapSets[m64], topInds[e][m64*K + k], n0); refHapVecs[m64] = vector (refHapSets[m64].begin(), refHapSets[m64].end()); //cout << "m64 = " << m64 << ": " << refHapSets[m64].size() << endl; } #ifdef DETAILS // TEMPORARY: CHECKING TRIO HAP - REF HAP MATCHES std::set longTrioHapHapSegsForward[2][Mseg64]; uint longestTrioHaps[2][Mseg64]; memset(&longestTrioHaps[0][0], 0, 2*Mseg64*sizeof(longestTrioHaps[0][0])); for (int p = 0; p < 2; p++) { cout << "Checking trio hap - ref hap matches" << endl; for (uint64 n1hap = 0; n1hap < 2*N; n1hap++) { if (n1hap % 10000 == 0) cout << "at " << n1hap << endl; if (!maskIndivs[n1hap/2]) continue; if (n1hap/2 == n0) continue; vector < pair > goodSegs = findGoodSegs(n0, p==0?nF1:nF2, p==0?nF2:nF1, n1hap); for (uint s = 0; s < goodSegs.size(); s++) for (uint64 m64x = (goodSegs[s].first + 32) / 64; m64x < (goodSegs[s].second + 32) / 64; m64x++) { if (goodSegs[s].second - goodSegs[s].first > longestTrioHaps[p][m64x]) { longTrioHapHapSegsForward[p][m64x].insert(DipHapSeg(n1hap, goodSegs[s].first, goodSegs[s].second)); if (longTrioHapHapSegsForward[p][m64x].size() > 10) { longTrioHapHapSegsForward[p][m64x].erase(--longTrioHapHapSegsForward[p][m64x].end()); longestTrioHaps[p][m64x] = ((--longTrioHapHapSegsForward[p][m64x].end())->end) - ((--longTrioHapHapSegsForward[p][m64x].end())->start); } } } } } #endif /***** RUN HMM (BEAM SEARCH) *****/ std::unordered_map dpTable[Mseg64]; uint dpBestScores[Mseg64]; for (uint64 m64 = 0; m64 < Mseg64; m64++) dpBestScores[m64] = 1<<30; pair finalHapPairs[Mseg64]; vector bestPathScores(Mseg64); #ifdef RDTSC_TIMING uint64 tscDpStart = Timer::rdtsc(); #endif for (uint64 m64 = 0; m64 <= Mseg64; m64++) { // find best from prev #ifdef RDTSC_TIMING uint64 tscDpSortStart = Timer::rdtsc(); #endif vector curStates; if (m64 == 0) curStates.push_back(DPState(0, make_pair(-1U, -1U))); if (m64 > 0) { uint maxDiffScore = 2*switchCost; uint bestScore = dpBestScores[m64-1]; // prune best states to beamWidth (via bucket sort) vector < vector > curStateBuckets(maxDiffScore+1); for (std::unordered_map ::iterator it = dpTable[m64-1].begin(); it != dpTable[m64-1].end(); it++) if (it->second.score <= bestScore + maxDiffScore) curStateBuckets[it->second.score - bestScore].push_back(it->first); for (uint dScore = 0; dScore <= maxDiffScore && curStates.size() < beamWidth; dScore++) { //if (curStates.size() + curStateBuckets[dScore].size() > beamWidth) //sort(curStateBuckets[dScore].begin(), curStateBuckets[dScore].end()); for (uint k = 0; k < curStateBuckets[dScore].size() && curStates.size() < beamWidth; k++) curStates.push_back(DPState(bestScore+dScore, ullToPair(curStateBuckets[dScore][k]))); } /* ---- SLOW ---- for (std::unordered_map ::iterator it = dpTable[m64-1].begin(); it != dpTable[m64-1].end(); it++) if (it->second.score <= bestScore + maxDiffScore) curStates.push_back(DPState(it->second.score, ullToPair(it->first))); // .from = prev sort(curStates.begin(), curStates.end()); */ } #ifdef RDTSC_TIMING dpSortTicks += Timer::rdtsc() - tscDpSortStart; #endif if (m64 < Mseg64) { const vector &refHapVec = refHapVecs[m64]; uint Kref = refHapVec.size(); // iterate through best in beam if (m64 > 0) { for (uint s = 0; s < curStates.size() && s < beamWidth; s++) { uint n1hap = curStates[s].from.first, n2hap = curStates[s].from.second; uint score = curStates[s].score; // continue updateTable(dpTable, dpBestScores, m64, 1, n0, n1hap, n2hap, n1hap, n2hap, score); } for (uint s = 0; s < curStates.size() && s < beamWidth; s++) { uint n1hap = curStates[s].from.first, n2hap = curStates[s].from.second; uint score = curStates[s].score; // switch n1hap or n2hap for (uint k = 0; k < Kref; k++) { updateTable(dpTable, dpBestScores, m64, 3, n0, n1hap, n2hap, refHapVec[k], n2hap, score+switchCost); updateTable(dpTable, dpBestScores, m64, 3, n0, n1hap, n2hap, n1hap, refHapVec[k], score+switchCost); } } } // clean start (from curStates[0]) if (m64 == 0) { for (uint k1 = 0; k1 < Kref; k1++) for (uint k2 = k1+1; k2 < Kref; k2++) updateTable(dpTable, dpBestScores, m64, 3, n0, curStates[0].from.first, curStates[0].from.second, refHapVec[k1], refHapVec[k2], curStates[0].score+2*switchCost); } else { // only try clean start from opp pairs for (uint k12 = 0; k12 < refHapOppPairs[m64].size(); k12++) updateTable(dpTable, dpBestScores, m64, 3, n0, curStates[0].from.first, curStates[0].from.second, refHapOppPairs[m64][k12].first, refHapOppPairs[m64][k12].second, curStates[0].score+3*switchCost); } } else { // finished; backtrack through DP table finalHapPairs[Mseg64-1] = curStates[0].from; bestPathScores[Mseg64-1] = curStates[0].score; for (int m64x = Mseg64-2; m64x >= 0; m64x--) { finalHapPairs[m64x] = dpTable[m64x+1][pairToULL(finalHapPairs[m64x+1])].from; //cout << "m64 = " << m64x << ": n1hap = " << finalHapPairs[m64x].first << ", n2hap = " << finalHapPairs[m64x].second << " score = " << dpTable[m64x+1][pairToULL(finalHapPairs[m64x+1])].score << endl; bestPathScores[m64x] = dpTable[m64x+1][pairToULL(finalHapPairs[m64x+1])].score; } } } #ifdef RDTSC_TIMING dpTicks += Timer::rdtsc() - tscDpStart; #endif /***** FIND TRANSITIONS WITHIN 64-SNP CHUNKS *****/ uint64 hmmHaploBitsT[2][Mseg64], fixHaploBitsT[2][Mseg64], hetErrMasks[Mseg64], uncertainMasks[Mseg64]; vector phaseVec; vector n1haps, n2haps, n3haps, signs; for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint64 n1hap, n2hap, n3hap; int sign; if (m64 == 0) { n1hap = finalHapPairs[m64].first; n2hap = n3hap = finalHapPairs[m64].second; sign = 1; } else if (finalHapPairs[m64].first == finalHapPairs[m64-1].first) { n1hap = finalHapPairs[m64].first; n2hap = finalHapPairs[m64-1].second; n3hap = finalHapPairs[m64].second; sign = 1; } else if (finalHapPairs[m64].second == finalHapPairs[m64-1].second) { n1hap = finalHapPairs[m64].second; n2hap = finalHapPairs[m64-1].first; n3hap = finalHapPairs[m64].first; sign = -1; } else { // restart n1hap = finalHapPairs[m64].first; n2hap = n3hap = finalHapPairs[m64].second; sign = 1; } n1haps.push_back(n1hap); n2haps.push_back(n2hap); n3haps.push_back(n3hap); signs.push_back(sign); pair phaseBits = phaseSegHMM(n0, n1hap, n2hap, n3hap, m64, hetErrMasks[m64]); hmmHaploBitsT[0][m64] = phaseBits.first; hmmHaploBitsT[1][m64] = phaseBits.second; if (sign == -1) std::swap(hmmHaploBitsT[0][m64], hmmHaploBitsT[1][m64]); //checkHapPhase(n0, nF1, nF2, hmmHaploBitsT[0], m64, 0); //vector phaseSeg = checkHapPhase2(n0, nF1, nF2, n1hap, n2hap, n3hap, m64, sign); //cout << endl; //phaseVec.insert(phaseVec.end(), phaseSeg.begin(), phaseSeg.end()); } /***** DETECT AND FIX BLIPS BASED ON HAPLOTYPE FREQUENCIES *****/ for (uint64 m64 = 0; m64 < Mseg64; m64++) { #ifdef RDTSC_TIMING uint64 tscBlipFixStart = Timer::rdtsc(); #endif vector < vector > votes(64, vector (4)); uint64 m64mid = min(max(m64, side), Mseg64-1-side); std::unordered_set seen; //cout << "m64 = " << m64 << endl; for (int opp = 0; opp < 2; opp++) for (uint h = 0; h < min((uint) hashLookups[m64mid].size(), 10U); h++) { // for each hash uint numHits; #ifdef RDTSC_TIMING uint64 tscBlipLshStart = Timer::rdtsc(); #endif const uint *lenHapInds = hashLookups[m64mid][h].query(computeHash(hmmHaploBitsT[opp], hashBits[m64mid][h])); #ifdef RDTSC_TIMING blipLshTicks += Timer::rdtsc() - tscBlipLshStart; #endif if (lenHapInds == NULL) numHits = 0; else numHits = lenHapInds[0]; for (uint k = 1; k <= min(numHits, 25U); k++) { uint64 nXhap = lenHapInds[k]; if (!maskIndivs[nXhap/2]) continue; if (nXhap/2 == n0) continue; if (seen.count(nXhap)) continue; seen.insert(nXhap); #ifdef RDTSC_TIMING uint64 tscBlipPopStart = Timer::rdtsc(); #endif int errs = 0; for (uint64 m64x = m64mid-side; m64x <= m64mid+side; m64x++) { const uint64_masks &bits0 = genoBits[m64x*N + n0]; errs += popcount64((hmmHaploBitsT[opp][m64x] ^ haploBitsT[nXhap*Mseg64+m64x]) & ~bits0.is9); } #ifdef RDTSC_TIMING blipPopTicks += Timer::rdtsc() - tscBlipPopStart; uint64 tscBlipVoteStart = Timer::rdtsc(); #endif if (errs <= 2) { //checkHapPhase(n0, nF1, nF2, haploBitsT + nXhap*Mseg64, m64mid, side); for (uint64 j = 0; j < 64; j++) votes[j][(((haploBitsT[nXhap*Mseg64+m64]>>j)&1)^opp) + 2*opp]++; } #ifdef RDTSC_TIMING blipVoteTicks += Timer::rdtsc() - tscBlipVoteStart; #endif } } fixHaploBitsT[0][m64] = hmmHaploBitsT[0][m64]; fixHaploBitsT[1][m64] = hmmHaploBitsT[1][m64]; const uint64_masks &bits0 = genoBits[m64*N + n0]; for (uint64 j = 0; j < 64; j++) { if ((bits0.is0|bits0.is2|bits0.is9)&(1ULL< relVoteDiff) { fixHaploBitsT[0][m64] &= ~(1ULL< "; checkHapPhase(n0, nF1, nF2, fixHaploBitsT[0], m64, 0); } cout << " "; checkHapPhase(n0, nF1, nF2, hmmHaploBitsT[0], m64, 0, votes); } */ } // set phaseConfs2: 0|255 unless hetErr or flip or miss; 1|254 at those sites uchar *phaseConfsHap0, *phaseConfsHap1; if (Nref) { // allocate temp arrays for phaseConfs2 haplotype confidences phaseConfsHap0 = ALIGNED_MALLOC_UCHARS(Mseg64*64); phaseConfsHap1 = ALIGNED_MALLOC_UCHARS(Mseg64*64); } else { phaseConfsHap0 = phaseConfs2 + 2*n0*Mseg64*64; phaseConfsHap1 = phaseConfs2 + (2*n0+1)*Mseg64*64; } uchar hapConfs[2][2]; hapConfs[0][0] = 0; hapConfs[0][1] = 255; // [0][*]: not uncertain hapConfs[1][0] = 1; hapConfs[1][1] = 254; // [1][*]: uncertain for (uint64 m64 = 0; m64 < Mseg64; m64++) { uncertainMasks[m64] = hetErrMasks[m64] | (fixHaploBitsT[0][m64] ^ hmmHaploBitsT[0][m64]) | genoBits[m64*N + n0].is9; for (uint64 j = 0; j < 64; j++) { uint64 m64j = m64*64 + j; bool uncertain = (uncertainMasks[m64]>>j)&1; phaseConfsHap0[m64j] = hapConfs[uncertain][(fixHaploBitsT[0][m64]>>j)&1]; phaseConfsHap1[m64j] = hapConfs[uncertain][(fixHaploBitsT[1][m64]>>j)&1]; } } #ifdef CHECK_TRUE_DIP_HAP /***** CHECK TRUE BEST DIP-HAP: ARE THEY RESPECTED BY FINAL PHASE? *****/ cout << "CHECK TRUE BEST DIP-HAP: ARE THEY RESPECTED BY FINAL PHASE?" << endl; std::set segsOutput; for (uint64 m64 = 0; m64 < Mseg64; m64++) for (int p = 0; p < 2; p++) { //cout << "m64 = " << m64 << " true longest cover, parent " << p+1 << endl; for (std::set ::iterator it = longTrioHapHapSegsForward[p][m64].begin(); it != longTrioHapHapSegsForward[p][m64].end(); it++) { if (!segsOutput.count(*it)) { segsOutput.insert(*it); /* cout << "n1hap = " << it->n << "; m64 = [" << it->start/64 << "." << (it->start&63) << "," << it->end/64 << "." << (it->end&63) << "): "; cout << ((std::find(refHapVecs[m64].begin(), refHapVecs[m64].end(), it->n) != refHapVecs[m64].end()) ? "YES" : "\033[1;33mNO\033[0m") << endl;//" "; */ //checkHapPhase1j(n0, nF1, nF2, it->n, it->start, it->end); cout << endl; vector ret = checkHapPhase1jCall(n0, nF1, nF2, fixHaploBitsT[p], it->start, it->end, false); if (find(ret.begin(), ret.end(), 0) != ret.end() && find(ret.begin(), ret.end(), 1) != ret.end()) checkHapPhase1jCall(n0, nF1, nF2, fixHaploBitsT[p], it->start, it->end, true); } break; } } #endif /***** POST-PROCESS: FIND LONG DIP-HAP MATCHES ALMOST CONSISTENT WITH PHASING *****/ vector < pair > farHaps(Mseg64*64); for (uint64 m64 = 0; m64 < Mseg64; m64++) { //cout << "m64 = " << m64 << ":" << endl; for (uint e = 0; e < 2; e++) { //cout << "e = " << e << ":" << endl; for (uint k = 0; k < topIndsLens[e][m64] && k < 10U /*TODO*/; k++) { uint64 n1hap = topInds[e][m64*K + k]; // TODO: save this info from earlier if (!maskIndivs[n1hap/2]) continue; if (n1hap/2 == n0) continue; // find start uint segStart = m64; while ((int) segStart >= 0 && numDipHapWrongBits(segStart, n0, n1hap) <= maxWrongBits) segStart--; if ((int) segStart < 0) segStart = 0; uint segStart64j = segStart*64 + firstDipHapGoodBit(segStart, n0, n1hap); // find end uint segEnd = m64+1; while (segEnd < Mseg64 && numDipHapWrongBits(segEnd, n0, n1hap) <= maxWrongBits) segEnd++; uint segEnd64j = segEnd*64 + firstDipHapWrongBit(segEnd, n0, n1hap); vector err64j(1, segStart64j); bool foundHet = false, prevPhase = false; for (uint64 m64j = segStart64j; m64j < segEnd64j; m64j++) if (maskSnps64j[m64j]) { uint64 m64 = m64j/64, j = m64j&63; uint g0 = getGeno0123(m64j, n0); // TODO: speed up bool relPhase = ((haploBitsT[n1hap*Mseg64+m64] ^ fixHaploBitsT[0][m64])>>j)&1; if (g0 == 1) { if (!foundHet) foundHet = true; else if (relPhase != prevPhase) err64j.push_back(m64j); prevPhase = relPhase; } else if (g0 == 0 || g0 == 2) { if (relPhase) { // dip-hap err err64j.push_back(m64j); err64j.push_back(m64j); } } } err64j.push_back(segEnd64j); /* // output post-process debug info cout << "true: "; checkHapPhase1j(n0, nF1, nF2, n1hap, segStart64j, segEnd64j); cout << endl; cout << "call: "; checkHapPhase1jCall(n0, nF1, nF2, fixHaploBitsT[0], segStart64j, segEnd64j, true); cout << "err vs. call:"; for (uint i = 0; i < err64j.size(); i++) { cout << " " << err64j[i]/64 << "." << (err64j[i]&63); printf("(%.2f)", cMs64j[err64j[i]]); } cout << endl; */ const double cMconsecMin = 1.5, cMendMin = 1.5; uint iStart = 0; for (uint i = 1; i < err64j.size(); i++) { double cMseg = cMs64j[err64j[i]] - cMs64j[err64j[i-1]]; if (i == iStart+1) { // piece ending at err64j[i] is first in new chunk if (cMseg < cMendMin) // no good; can't start yet iStart = i; } else { double cMprev = cMs64j[err64j[i-1]] - cMs64j[err64j[i-2]]; if (cMprev < cMconsecMin && cMseg < cMconsecMin) { // consec short => split // deal with chunk that just ended at either err64j[i-2] or err64j[i-1] if (cMprev < cMendMin) // last is too short updateFarHaps(farHaps, n1hap, err64j[iStart], err64j[i-2]); else updateFarHaps(farHaps, n1hap, err64j[iStart], err64j[i-1]); // deal with beginning of next chunk if (cMseg < cMendMin) iStart = i; else iStart = i-1; } } if (i+1 == err64j.size()) { if (cMseg < cMendMin) updateFarHaps(farHaps, n1hap, err64j[iStart], err64j[i-1]); else updateFarHaps(farHaps, n1hap, err64j[iStart], err64j[i]); } } //cout << endl; } } } uint farEnd = 0; vector hapSegs; for (uint64 segStart64j = 0; segStart64j < Mseg64*64; segStart64j++) if (farHaps[segStart64j].first > farEnd) { farEnd = farHaps[segStart64j].first; hapSegs.push_back(DipHapSeg(farHaps[segStart64j].second, segStart64j, farEnd)); } std::set postSwitches; for (uint i = 0; i < hapSegs.size(); i++) { uint64 n1hap = hapSegs[i].n, segStart64j = hapSegs[i].start, segEnd64j = hapSegs[i].end; uint64 useStart64j = (i==0 || hapSegs[i-1].end < segStart64j) ? segStart64j : (hapSegs[i-1].end + segStart64j)/2; uint64 useEnd64j = (i+1==hapSegs.size() || segEnd64j < hapSegs[i+1].start) ? segEnd64j : (segEnd64j + hapSegs[i+1].start)/2; /* // output post-process debug info double cMstart = cMs64j[segStart64j], cMend = cMs64j[segEnd64j]; if ((int) nF1 != -1) { updateFarHaps(farHaps, n1hap, segStart64j, segEnd64j); // just to print cout << endl; cout << "true: "; checkHapPhase1j(n0, nF1, nF2, n1hap, segStart64j, segEnd64j); cout << endl; cout << "call: "; checkHapPhase1jCall(n0, nF1, nF2, fixHaploBitsT[0], segStart64j, segEnd64j, true); printf("%.2f-%.2f cM; ", cMstart, cMend); cout << "use " << useStart64j/64 << "." << (useStart64j&63) << "-" << useEnd64j/64 << "." << (useEnd64j&63) << endl; } */ vector numSinceSwitches; vector switchLocs; bool foundHet = false, prevPhase = false; int numSinceSwitch = 0; for (uint64 m64j = segStart64j; m64j < segEnd64j; m64j++) if (maskSnps64j[m64j]) { uint64 m64 = m64j/64, j = m64j&63; uint g0 = getGeno0123(m64j, n0); // TODO: speed up if (g0 == 1) { numSinceSwitch++; bool relPhase = ((haploBitsT[n1hap*Mseg64+m64] ^ fixHaploBitsT[0][m64])>>j)&1; if (!foundHet) foundHet = true; else if (relPhase != prevPhase) { numSinceSwitches.push_back(numSinceSwitch); switchLocs.push_back(m64j); numSinceSwitch = 0; } prevPhase = relPhase; } } numSinceSwitches.push_back(numSinceSwitch); for (uint s = 0; s < switchLocs.size(); s++) if (numSinceSwitches[s] > 2 && numSinceSwitches[s+1] > 2 && useStart64j <= switchLocs[s] && switchLocs[s] < useEnd64j) { uint64 m64j = switchLocs[s]; /* output post-process debug info if ((int) nF1 != -1) { cout << "SUGGEST SWITCH: " << m64j/64 << "." << (m64j&63); printf("(%.2f; split %.2f=%.2f+%.2f)", cMs64j[m64j], cMend-cMstart, cMs64j[m64j]-cMstart, cMend-cMs64j[m64j]); } */ postSwitches.insert(m64j); } } // apply switches int sign = 1; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { uint64 m64 = m64j/64, j = m64j&63; if (postSwitches.count(m64j)) sign = -sign; if (sign == -1) { uint64 tmp = (fixHaploBitsT[0][m64] ^ fixHaploBitsT[1][m64]) & (1ULL<= 128; hapBits[1] = (int) phaseConfsHap1[m64j] >= 128; for (uint64 h = 0; h <= 1ULL; h++) { uint64 nTargetHap = 2*(n0-Nref) + h; tmpHaploBitsT[nTargetHap*Mseg64 + (m64j/64)] |= hapBits[h]<<(m64j&63); } } ALIGNED_FREE(phaseConfsHap1); ALIGNED_FREE(phaseConfsHap0); } if ((int) nF1 != -1) { // final output cout << "3rd-iter phase:" << endl; for (uint64 m64 = 0; m64 < Mseg64; m64++) { /* checkHaploBits(n0, nF1, nF2, hmmHaploBitsT[0][m64], m64); if (fixHaploBitsT[0][m64] != hmmHaploBitsT[0][m64]) { cout << " -> "; checkHaploBits(n0, nF1, nF2, fixHaploBitsT[0][m64], m64); } */ vector phaseSeg = checkHaploBits(n0, nF1, nF2, fixHaploBitsT[0][m64], m64, -1); //cout << endl; phaseVec.insert(phaseVec.end(), phaseSeg.begin(), phaseSeg.end()); } printf("# major SE: %2d # tot SE: %2d / %d\n", countMajorSE(phaseVec), countSE(phaseVec), (int) phaseVec.size()-1); fflush(stdout); } #ifdef RDTSC_TIMING totTicks += Timer::rdtsc() - tscStart; #endif return hapTime; } void Eagle::writePhaseConfs(const string &tmpPhaseFile) const { FILE *fout = fopen(tmpPhaseFile.c_str(), "wb"); fwrite(phaseConfs, 1, 2*N*Mseg64*64, fout); fclose(fout); } void Eagle::readPhaseConfs(const string &tmpPhaseFile) { FILE *fout = fopen(tmpPhaseFile.c_str(), "rb"); fread(phaseConfs, 1, 2*N*Mseg64*64, fout); fclose(fout); } void Eagle::cpPhaseConfs(uint64 n0start, uint64 n0end) { memcpy(phaseConfs + 2*n0start*Mseg64*64, phaseConfs2 + 2*n0start*Mseg64*64, 2*(n0end-n0start)*Mseg64*64); } void Eagle::cpTmpHaploBitsT(uint64 n0start, uint64 n0end) { memcpy(haploBitsT + 2*n0start*Mseg64, tmpHaploBitsT + 2*n0start*Mseg64, 2*(n0end-n0start)*Mseg64 * sizeof(haploBitsT[0])); for (uint64 nHap = 2*n0start; nHap < 2*n0end; nHap++) for (uint64 m64 = 0; m64 < Mseg64; m64++) haploBits[m64*2*N + nHap] = haploBitsT[nHap*Mseg64 + m64]; } void Eagle::outputSE(const vector &children, const vector &nF1s, const vector &nF2s, int step) const { if (children.empty()) return; vector majorSEs, totSEs; vector majorSErates, totSErates; for (uint att = 0; att < children.size(); att++) { printf("Switch error locations (step %d):", step); vector phaseVec = checkPhaseConfsPhase(children[att], nF1s[att], nF2s[att]); majorSEs.push_back(countMajorSE(phaseVec)); totSEs.push_back(countSE(phaseVec)); majorSErates.push_back(majorSEs.back() * 100.0 / (phaseVec.size()-1)); totSErates.push_back(totSEs.back() * 100.0 / (phaseVec.size()-1)); printf("# major SE: %2d # tot SE: %2d / %d (step %d)\n", majorSEs.back(), totSEs.back(), (int) phaseVec.size()-1, step); } sort(majorSEs.begin(), majorSEs.end()); sort(totSEs.begin(), totSEs.end()); int useTrios = 70; printf("%d-trio avg # major SE: %.2f avg # tot SE: %.2f (step %d)\n", useTrios, std::accumulate(majorSEs.begin(), majorSEs.begin()+useTrios, 0) / (double) useTrios, std::accumulate(totSEs.begin(), totSEs.begin()+useTrios, 0) / (double) useTrios, step); sort(majorSErates.begin(), majorSErates.end()); sort(totSErates.begin(), totSErates.end()); printf("median major SE rate: %.2f%% median tot SE rate: %.2f%% (step %d)\n", majorSErates[(nF1s.size()-1)/2], totSErates[(nF1s.size()-1)/2], step); fflush(stdout); } void Eagle::writeHapsGzSample(const string &prefix) const { FileUtils::AutoGzOfstream hapsGzOut; hapsGzOut.openOrExit(prefix + ".haps.gz"); uint64 m = 0; // index in snps vector for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (!maskSnps64j[m64j]) continue; hapsGzOut << snps[m].chrom << " " << snps[m].ID << " " << snps[m].physpos << " " << snps[m].allele1 << " " << snps[m].allele2; for (uint64 n0 = 0; n0 < N; n0++) { int hapBit1, hapBit2; if (phaseConfs != NULL) { hapBit1 = (int) phaseConfs[2*n0*Mseg64*64 + m64j] < 128; hapBit2 = (int) phaseConfs[(2*n0+1)*Mseg64*64 + m64j] < 128; } else { hapBit1 = !((haploBits[(m64j/64)*2*N + 2*n0]>>(m64j&63))&1); hapBit2 = !((haploBits[(m64j/64)*2*N + 2*n0+1]>>(m64j&63))&1); } if (isFlipped64j[m64j]) { hapBit1 = !hapBit1; hapBit2 = !hapBit2; } hapsGzOut << " " << hapBit1 << " " << hapBit2; } hapsGzOut << endl; m++; } hapsGzOut.close(); FileUtils::AutoGzOfstream sampleOut; sampleOut.openOrExit(prefix + ".sample"); sampleOut << std::setprecision(3); sampleOut << "ID_1 ID_2 missing" << endl; sampleOut << "0 0 0" << endl; for (uint64 n0 = 0; n0 < N; n0++) { /* int ctrMiss = 0, ctrTot = 0; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) { ctrTot++; ctrMiss += getGeno0123(m64j, n0)==3; } */ double missing = 0;//ctrMiss / (double) ctrTot; sampleOut << indivs[n0].famID << " " << indivs[n0].indivID << " " << missing << endl; } sampleOut.close(); } void bcf_hdr_append_eagle_version(bcf_hdr_t *hdr, int argc, char **argv) { kstring_t str = {0,0,0}; const char cmd[] = "eagle"; ksprintf(&str,"##%sVersion=%s+htslib-%s\n", cmd, EAGLE_VERSION, hts_version()); bcf_hdr_append(hdr,str.s); str.l = 0; ksprintf(&str,"##%sCommand=%s", cmd, "eagle"); int i; for (i=1; i mostRecentPloidy(N-Nref, 2); while (bcf_read(htsTmp, hdr, rec) >= 0) { int chrom = StringUtils::bcfNameToChrom(bcf_hdr_id2name(hdr, rec->rid), 1, chromX); int ntgt_gt = bcf_get_genotypes(hdr, rec, &tgt_gt, &mtgt_gt); int bp = rec->pos+1; if (bpStart <= bp && bp <= bpEnd) { // check if within output region for (int i = 0; i < (int) (N-Nref); i++) { int ploidy = 2; int *ptr = tgt_gt + i*ploidy; if (chrom != chromX || (bcf_gt_is_missing(ptr[0]) && mostRecentPloidy[i] == 2) || ptr[1] != bcf_int32_vector_end) { // diploid... be careful about missing '.' mostRecentPloidy[i] = 2; bool missing = false; int minIdx = 1000, maxIdx = 0; for (int j = 0; j < ploidy; j++) { if ( bcf_gt_is_missing(ptr[j]) ) { // missing allele missing = true; } else { int idx = bcf_gt_allele(ptr[j]); // allele index minIdx = std::min(minIdx, idx); maxIdx = std::max(maxIdx, idx); } } if (!missing && minIdx == maxIdx) { // hom => same allele ptr[0] = ptr[1] = bcf_gt_phased(minIdx); } else if (!missing && minIdx > 0) { // ALT1/ALT2 het => don't phase ptr[0] = ptr[1] = bcf_gt_missing; } else { // REF/ALT* het => phase as called by Eagle if (missing && noImpMissing) { // don't call alleles ptr[0] = ptr[1] = bcf_gt_missing; } else { for (int j = 0; j < ploidy; j++) { uint64 nTargetHap = 2*i + j; int altIdx = missing ? 1 : maxIdx; int hapBit = (tmpHaploBitsT[nTargetHap*Mseg64+(m64j/64)]>>(m64j&63))&1; if (isFlipped64j[m64j]) hapBit = !hapBit; int idx = hapBit ? altIdx : 0; ptr[j] = bcf_gt_phased(idx); // convert allele index to bcf value (phased) } } } } else { // haploid mostRecentPloidy[i] = 1; if ( bcf_gt_is_missing(ptr[0]) && !noImpMissing ) { // missing allele int j = 0; uint64 nTargetHap = 2*i + j; int altIdx = 1; int hapBit = (tmpHaploBitsT[nTargetHap*Mseg64+(m64j/64)]>>(m64j&63))&1; if (isFlipped64j[m64j]) hapBit = !hapBit; int idx = hapBit ? altIdx : 0; ptr[j] = bcf_gt_phased(idx); // convert allele index to bcf value (phased) } } } bcf_update_genotypes(hdr, rec, tgt_gt, ntgt_gt); bcf_write(out, hdr, rec); } m64j++; if ((m64j&63) == seg64cMvecs[m64j/64].size()) m64j = (m64j + 64ULL) & ~63ULL; // move to next segment } assert(m64j == Mseg64*64); free(tgt_gt); bcf_destroy(rec); bcf_hdr_destroy(hdr); hts_close(out); hts_close(htsTmp); remove(tmpFile.c_str()); } // write phased output in non-ref mode // differences from the above (ref-mode) are as follows: // - does not take noImpMissing arg // - checks chrom // - does not increment m64j outside the bpStart-bpEnd region // - does not delete tmpFile (now vcfFile with original input) void Eagle::writeVcfNonRef(const string &vcfFile, const string &outFile, int inputChrom, int chromX, double bpStart, double bpEnd, const string &writeMode, int argc, char **argv) const { htsFile *htsIn = hts_open(vcfFile.c_str(), "r"); htsFile *out = hts_open(outFile.c_str(), writeMode.c_str()); bcf_hdr_t *hdr = bcf_hdr_read(htsIn); bcf_hdr_append_eagle_version(hdr, argc, argv); bcf_hdr_write(out, hdr); bcf1_t *rec = bcf_init1(); int mtgt_gt = 0, *tgt_gt = NULL; uint64 m64j = 0; // SNP index; update to correspond to current record vector mostRecentPloidy(N-Nref, 2); while (bcf_read(htsIn, hdr, rec) >= 0) { // check CHROM int chrom = StringUtils::bcfNameToChrom(bcf_hdr_id2name(hdr, rec->rid), 1, chromX); if (inputChrom != 0) { if (chrom != inputChrom) { continue; } } int bp = rec->pos+1; if (bpStart <= bp && bp <= bpEnd) { // check if within output region int ntgt_gt = bcf_get_genotypes(hdr, rec, &tgt_gt, &mtgt_gt); for (int i = 0; i < (int) (N-Nref); i++) { int ploidy = 2; int *ptr = tgt_gt + i*ploidy; if (chrom != chromX || (bcf_gt_is_missing(ptr[0]) && mostRecentPloidy[i] == 2) || ptr[1] != bcf_int32_vector_end) { // diploid... be careful about missing '.' mostRecentPloidy[i] = 2; bool missing = false; int minIdx = 1000, maxIdx = 0; // (shouldn't matter; SNPs should be biallelic) for (int j = 0; j < ploidy; j++) { if ( bcf_gt_is_missing(ptr[j]) ) { // missing allele missing = true; } else { int idx = bcf_gt_allele(ptr[j]); // allele index minIdx = std::min(minIdx, idx); maxIdx = std::max(maxIdx, idx); } } if (!missing && minIdx == maxIdx) { // hom => same allele ptr[0] = ptr[1] = bcf_gt_phased(minIdx); } else if (!missing && minIdx > 0) { // ALT1/ALT2 het => don't phase (shouldn't happen) ptr[0] = ptr[1] = bcf_gt_missing; } else { // REF/ALT* het => phase as called by Eagle for (int j = 0; j < ploidy; j++) { uint64 nTargetHap = 2*i + j; int altIdx = missing ? 1 : maxIdx; int hapBit = (tmpHaploBitsT[nTargetHap*Mseg64+(m64j/64)]>>(m64j&63))&1; if (isFlipped64j[m64j]) hapBit = !hapBit; int idx = hapBit ? altIdx : 0; ptr[j] = bcf_gt_phased(idx); // convert allele index to bcf value (phased) } } } else { // haploid mostRecentPloidy[i] = 1; if ( bcf_gt_is_missing(ptr[0]) ) { // missing allele int j = 0; uint64 nTargetHap = 2*i + j; int altIdx = 1; int hapBit = (tmpHaploBitsT[nTargetHap*Mseg64+(m64j/64)]>>(m64j&63))&1; if (isFlipped64j[m64j]) hapBit = !hapBit; int idx = hapBit ? altIdx : 0; ptr[j] = bcf_gt_phased(idx); // convert allele index to bcf value (phased) } } } bcf_update_genotypes(hdr, rec, tgt_gt, ntgt_gt); bcf_write(out, hdr, rec); m64j++; if ((m64j&63) == seg64cMvecs[m64j/64].size()) m64j = (m64j + 64ULL) & ~63ULL; // move to next segment } } assert(m64j == Mseg64*64); free(tgt_gt); bcf_destroy(rec); bcf_hdr_destroy(hdr); hts_close(out); hts_close(htsIn); } void Eagle::makeHardCalls(uint64 n0start, uint64 n0end, uint seed) { // fast rng: last 16 bits of Marsaglia's MWC uint w = 521288629; for (uint i = 0; i < seed % 12345; i++) w=18000*(w&65535)+(w>>16); //memset(haploBits, 0, 2*N*Mseg64*sizeof(haploBits[0])); memset(segConfs + 2*n0start*Mseg64, 0, 2*(n0end-n0start)*Mseg64*sizeof(segConfs[0])); for (uint64 nHap = 2*n0start; nHap < 2*n0end; nHap++) for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if ((m64j&63)==0) haploBits[(m64j/64)*2*N + nHap] = 0; uchar phaseConf = phaseConfs[nHap*Mseg64*64 + m64j]; segConfs[nHap*Mseg64+m64j/64] = max(segConfs[nHap*Mseg64+m64j/64], min(phaseConf, (uchar) (255-phaseConf))); if (phaseConf == (uchar) 255 || ((w=18000*(w&65535)+(w>>16))&255) < phaseConf) haploBits[(m64j/64)*2*N + nHap] |= 1ULL<<(m64j&63); if ((m64j&63)==63) haploBitsT[nHap*Mseg64 + (m64j/64)] = haploBits[(m64j/64)*2*N + nHap]; } } uint Eagle::computeHash(const uint64 *curHaploBitsT, const uint64 *curHashBits, uint B) const { uint hash = 0; for (uint b = 0; b < B; b++) hash |= ((curHaploBitsT[curHashBits[b]>>6]>>(curHashBits[b]&63))&1)< &curHashBits) const { return computeHash(curHaploBitsT, &curHashBits[0], curHashBits.size()); } double Eagle::computeLogHetP(uint64 m64j) const { assert(Nref!=0); // only call this function when in ref-mode int sumHaps = 0; for (uint64 nHap = 0; nHap < 2*Nref; nHap++) sumHaps += (haploBits[(m64j/64)*2*N + nHap]>>(m64j&63))&1; double p = sumHaps / (2.0 * Nref); p = std::min(p, 1-p); return log10(p); } void Eagle::initRefIter(int refIter) { uint64 Ntarget = N - Nref; if (refIter > 1) { // copy tmpHaploBitsT from previous iter -> haploBits, haploBitsT memcpy(haploBitsT + 2*Nref*Mseg64, tmpHaploBitsT, 2*Ntarget*Mseg64*sizeof(tmpHaploBitsT[0])); for (uint64 nHap = 2*Nref; nHap < 2*N; nHap++) // copy transpose for (uint64 m64 = 0; m64 < Mseg64; m64++) haploBits[m64*2*N + nHap] = haploBitsT[nHap*Mseg64 + m64]; } // clear tmpHaploBitsT (temp storage of phased target haplotypes) memset(tmpHaploBitsT, 0, 2*Ntarget*Mseg64*sizeof(tmpHaploBitsT[0])); } // input arg iter = non-ref mode iter (ref mode iter 1 = non-ref mode iter 3) void Eagle::buildHashTables(int iter, int batch, int seed) { std::srand(1000000*seed + 1000*iter + batch); // seed random_shuffle const uint maxValuesPerKey = 99; const uint baseLSH = 10, bonusLSH = iter > 2 ? 4 : 0; const uint numLSH = baseLSH + bonusLSH; const uint maxBits = 32; const double minLogHetP = log10(0.02); hashLookups = vector < vector > (Mseg64, vector (numLSH)); hashBits = vector < vector < vector > > (Mseg64, vector < vector > (numLSH)); const double reduction = (iter == 2 ? 0 : 0.05); const uint64 side = 1; for (uint64 m64 = 0+side; m64+side < Mseg64; m64++) { for (uint h = 0; h < numLSH; h++) { vector m64js; if (h < baseLSH) { // standard hash regions: 3x down to 2x m64 for (uint64 m64j = (uint64) ((m64-side+reduction*h)*64); m64j < (uint64) ((m64+side+1-reduction*h)*64); m64j++) if (maskSnps64j[m64j] && (Nref==0 ? seg64logPs[m64j].cond[1][3] : computeLogHetP(m64j)) > minLogHetP) m64js.push_back(m64j); } else { // small hash regions int offStart = 0, offEnd = 0; switch (h-baseLSH) { case 0: offStart = -32; offEnd = 32; break; case 1: offStart = 0; offEnd = 64; break; case 2: offStart = -32; offEnd = 0; break; case 3: offStart = 0; offEnd = 32; break; } for (uint64 m64j = (uint64) (m64*64 + offStart); m64j < (uint64) (m64*64 + offEnd); m64j++) if (maskSnps64j[m64j]) m64js.push_back(m64j); } if (m64js.empty()) for (uint64 m64j = (m64-side)*64; m64j < (m64+side+1)*64; m64j++) if (maskSnps64j[m64j]) m64js.push_back(m64j); uint bitsInHash = (h < baseLSH ? maxBits-h : 24); // randomly select SNPs m64j to use in hash uint m64jInd = m64js.size(); for (uint b = 0; b < bitsInHash; b++) { // choose next SNP (in random order); if at end, reshuffle if (m64jInd == m64js.size()) { std::random_shuffle(m64js.begin(), m64js.end()); m64jInd = 0; } hashBits[m64][h].push_back(m64js[m64jInd++]); } } } uint64 nRefHaps = 2*((Nref!=0 && iter==3) ? Nref : N); // ref-mode iter 1 -> iter 3 vector < vector > keyVecs(omp_get_max_threads(), vector (nRefHaps)); #pragma omp parallel for for (uint64 m64 = 0+side; m64 < Mseg64-side; m64++) { cout << "." << std::flush; for (uint h = 0; h < numLSH; h++) { // compute hashes vector &keyVec = keyVecs[omp_get_thread_num()]; for (uint64 nHap = 0; nHap < nRefHaps; nHap++) // in ref-mode, only use ref keyVec[nHap] = maskIndivs[nHap/2] ? computeHash(haploBitsT + nHap*Mseg64, &hashBits[m64][h][0], hashBits[m64][h].size()) : -1U; hashLookups[m64][h].init(keyVec, maxValuesPerKey); } } } const uint64 *Eagle::getHaploBitsT(void) const { return haploBitsT; } uint64 Eagle::getNlib(int iter) const { return ((Nref!=0 && iter==3) ? Nref : N); } uint64 Eagle::getMseg64(void) const { return Mseg64; } const uchar *Eagle::getMaskSnps64j(void) const { return maskSnps64j; } double Eagle::computeHetRate(void) const { uint64 homCtr = 0, totCtr = 0; for (uint64 m64 = 0; m64 < Mseg64; m64++) for (uint64 n = Nref; n < N; n++) { // ref genoBits aren't initialized! const uint64_masks &bits = genoBits[m64*N + n]; homCtr += popcount64(bits.is0 | bits.is2); totCtr += popcount64(~bits.is9); } return 1 - homCtr / (double) totCtr; } } Eagle-master/src/Eagle.hpp000066400000000000000000000253061274444013000157060ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef EAGLE_HPP #define EAGLE_HPP //#define RDTSC_TIMING #include #include #include #include #include "Types.hpp" #include "GenoData.hpp" #include "HapHedge.hpp" #include "StaticMultimap.hpp" namespace EAGLE { struct Match { uint n, m64jStart, m64jEnd, m64jStartCons, m64jEndCons; // [m64jStart..m64jEnd] double logBF, cMlenInit; bool operator < (const Match &m2) const { return logBF > m2.logBF; } Match() : n(0), m64jStart(0), m64jEnd(0), m64jStartCons(0), m64jEndCons(1<<30), logBF(0) {} Match(uint _n, uint _m64jStart, uint _m64jEnd, double _logBF) : n(_n), m64jStart(_m64jStart), m64jEnd(_m64jEnd), m64jStartCons(0), m64jEndCons(1<<30), logBF(_logBF) {} static bool greaterEnd(const Match &m1, const Match &m2) { return m1.m64jEnd > m2.m64jEnd || (m1.m64jEnd == m2.m64jEnd && m1.logBF > m2.logBF); } static bool greaterLen(const Match &m1, const Match &m2) { return m1.cMlenInit > m2.cMlenInit || (m1.cMlenInit == m2.cMlenInit && m1.logBF > m2.logBF); } }; struct DPState { uint score; std::pair from; DPState() : score(0), from(std::make_pair(0U, 0U)) {} DPState(uint _score, std::pair _from) : score(_score), from(_from) {} bool operator < (const DPState &state2) const { return score < state2.score || (score==state2.score && from < state2.from); } }; class Eagle { public: mutable uint64 totTicks, extTicks, diphapTicks, lshTicks, lshCheckTicks, dpTicks, dpStaticTicks, dpSwitchTicks, dpSortTicks, dpUpdateTicks, dpUpdateCalls, blipFixTicks, blipPopTicks, blipVoteTicks, blipLshTicks; private: static const uint homErrCost = 1, hetErrCost = 2, switchCost = 3; static const uint switchScoreLutBits = 5; char switchScoreLut[1<<(3*switchScoreLutBits)][2]; const uint64 N, Nref; // Nref = 0 if not in ref-mode const uint64 Mseg64; // number of <=64-SNP chunks const uint64_masks *genoBits; // [[MATRIX]]: M64 x N (is0 and is2 64-bit masks) const std::vector > seg64cMvecs; uchar *maskSnps64j; // M64x64 binary vector indicating SNPs to use double *cMs64j; // M64x64+1 cM coordinates uchar *phaseConfs, *phaseConfs2; // [[MATRIX]]: 2N x M64x64 uint64 *haploBits; // [[MATRIX]]: M64 x 2N (is1 for hard calls) uint64 *haploBitsT; // [[MATRIX]]: 2N x M64 (is1 for hard calls) uint64 *tmpHaploBitsT; // [[MATRIX]]: 2Ntarget x M64 (temp storage for target haps in ref-mode) uchar *segConfs; // [[MATRIX]]: 2N x M64 std::vector < std::vector > hashLookups; std::vector < std::vector < std::vector > > hashBits; const AlleleFreqs *seg64logPs; const std::vector invLD64j; // M64x64 LD-based weights for evaluating match evidence const std::vector indivs; const std::vector snps; // M-vector std::vector maskIndivs; // N-vector: 0 to ignore indivs (e.g., relatives) std::vector isFlipped64j; // in non-ref mode, SNPs are internally flipped to 0=A2=major const double logPerr; // genotype error rate void init(void); uint getGeno0123(uint64 m64j, uint64 n) const; void retractMatch(uint n0, Match &match, double memoLogBF[][4]) const; Match computeDuoLogBF(double memoLogBF[][4], double workLogBF[], uint64 n0, uint64 n1, uint64 m64cur) const; void trim(Match &match, const Match &ref, uint64 n0, int orientation, uint64 trimStart, int inc, double workLogBF[]) const; std::string computePhaseString(uint64 n0, uint64 nF1, uint64 nF2, const std::vector &matches, const std::vector &signs, uint64 start, double cMend, bool cons) const; void printMatch(uint64 n0, uint64 nF1, uint64 nF2, const Match &duoMatch, double memoLogBF[][4]) const; void findLongHalfIBD(uint64 n0, std::vector topInds[2], std::vector topIndsLens[2], uint K) const; std::vector findMinErrDipHap(uint64 n0, uint K, bool useTargetHaps) const; void findLongDipHap(uint64 n0, std::vector topInds[2], std::vector topIndsLens[2], uint K, uint errStart) const; void computePhaseConfs(uint64 n0, const std::vector &matches, const std::vector &signs, bool cons); std::vector trioRelPhase(uint64 n0, uint64 nF1, uint64 nF2) const; void checkPhase(uint64 n0, uint64 nF1, uint64 nF2, double thresh) const; std::vector checkPhaseConfsPhase(uint64 n0, uint64 nF1, uint64 nF2) const; void checkHapPhase(uint64 n0, uint64 nF1, uint64 nF2, const uint64 curHaploBitsT[], uint64 m64, uint64 side, std::vector < std::vector > votes=std::vector < std::vector > ()) const; std::vector checkHapPhase1(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 m64start, uint64 m64end, int sign=1) const; std::vector checkHapPhase1j(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 m64jStart, uint64 m64jEnd, int sign=1) const; std::vector checkHapPhase1jCall(uint64 n0, uint64 nF1, uint64 nF2, uint64 callBitsT[], uint64 m64jStart, uint64 m64jEnd, bool print, int sign=1) const; int checkHapPhase2(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 n2hap, uint64 n3hap, uint64 m64, int sign) const; std::vector checkHaploBits(uint64 n0, uint64 nF1, uint64 nF2, uint64 hapBits, uint64 m64, int pad=0) const; std::pair phaseSegHMM(uint64 n0, uint64 n1hap, uint64 n2hap, uint64 n3hap, uint64 m64, uint64 &hetErrMask) const; std::vector checkSegPhase(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap, uint64 n2hap, int sign, uint64 m64) const; void computeSegPhaseConfs(uint64 n0, uint64 n1hap, uint64 n2hap, int sign, uint64 m64, int err); int numDipHapWrongBits(uint64 m64, uint64 n0, uint64 n1hap) const; int firstDipHapGoodBit(uint64 m64, uint64 n0, uint64 n1hap) const; int firstDipHapWrongBit(uint64 m64, uint64 n0, uint64 n1hap) const; uint computeHash(const uint64 *curHaploBitsT, const uint64 *curHashBits, uint B) const; uint computeHash(const uint64 *curHaploBitsT, const std::vector &curHashBits) const; bool updateHelper(std::unordered_map &dpTab, uint &dpBestScore, std::pair cur, std::pair next, uint score) const; uint computeStaticScore(uint n0, uint n1hap, uint n2hap, uint64 m64) const; uint computeSwitchScore(uint n0, uint n1hap, uint n2hapA, uint n2hapB, uint64 m64) const; void updateTable(std::unordered_map dpTable[], uint dpBestScores[], uint64 m64, uint64 dist, uint n0, uint n1hapA, uint n2hapA, uint n1hapB, uint n2hapB, uint score) const; void safeInsert(std::set &refHapSet, uint n1hap, uint n0) const; std::vector < std::pair > findGoodSegs(uint64 n0, uint64 nF1, uint64 nF2, uint64 n1hap) const; void updateFarHaps(std::vector < std::pair > &farHaps, uint n1hap, uint m64jStart, uint m64jEnd) const; double computeLogHetP(uint64 m64j) const; public: Eagle(uint64 _N, uint64 _Mseg64, const uint64_masks *_genoBits, std::vector < std::vector > _seg64cMvecs, const AlleleFreqs *_seg64freqs, std::vector _invLD64j, const std::vector &_indivs, const std::vector &_snps, const std::string &maskFile, const std::vector &isFlipped64j, double _pErr, int runStep2); // constructor for ref-mode Eagle(uint64 _Nref, uint64 _Ntarget, uint64 _Mseg64, const uint64_masks *_genoBits, std::vector < std::vector > _seg64cMvecs, double _pErr); void reallocLRPtoPBWT(void); ~Eagle(); void checkTrioErrorRate(uint64 n0, uint64 nF1, uint64 nF2) const; void randomlyPhaseTmpHaploBitsT(uint64 n0); std::pair > findLongDipMatches(uint64 n0, uint64 nF1, uint64 nF2); double findLongHapMatches(uint64 n0, uint64 nF1, uint64 nF2, int iter); double runHMM(uint64 n0, uint64 nF1, uint64 nF2, int iter, uint beamWidth, uint maxHapStates); std::vector computeRefIsMono(const std::vector &bestHaps) const; float runPBWT(uint64 n0, uint64 nF1, uint64 nF2, int Kpbwt, double cMexpect, double histFactor, bool runReverse, bool useTargetHaps, bool impMissing); float runPBWT(uint64 n0, uint64 nF1, uint64 nF2, int Kpbwt, double cMexpect, double histFactor, bool runReverse, bool useTargetHaps, bool impMissing, int usePS, const std::vector < std::pair > &conPS); void imputeMissing(const HapHedge &hapHedge, uint64 n0); void writePhaseConfs(const std::string &tmpPhaseFile) const; void readPhaseConfs(const std::string &tmpPhaseFile); void cpPhaseConfs(uint64 n0start, uint64 n0end); void cpTmpHaploBitsT(uint64 n0start, uint64 n0end); void outputSE(const std::vector &children, const std::vector &nF1s, const std::vector &nF2s, int step) const; void writeHapsGzSample(const std::string &prefix) const; void writeVcf(const std::string &tmpFile, const std::string &outFile, int chromX, double bpStart, double bpEnd, const std::string &writeMode, bool noImpMissing, int argc, char**argv) const; void writeVcfNonRef(const std::string &vcfFile, const std::string &outFile, int inputChrom, int chromX, double bpStart, double bpEnd, const std::string &writeMode, int argc, char **argv) const; void makeHardCalls(uint64 n0start, uint64 n0end, uint seed); void initRefIter(int refIter); void buildHashTables(int iter, int batch, int seed); const uint64 *getHaploBitsT(void) const; uint64 getNlib(int iter) const; uint64 getMseg64(void) const; const uchar *getMaskSnps64j(void) const; double computeHetRate(void) const; static int countSE(const std::vector &phaseVec); static int countMajorSE(const std::vector &phaseVec); }; } #endif Eagle-master/src/EagleImpMiss.cpp000066400000000000000000000225141274444013000172010ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include "HapHedge.hpp" #include "MemoryUtils.hpp" #include "NumericUtils.hpp" #include "Eagle.hpp" namespace EAGLE { using std::cout; using std::endl; using std::vector; using std::string; #define HAP_BEAM_WIDTH 16 struct ProbMaskBundle { float logTotProb; int numTop; float probs[HAP_BEAM_WIDTH]; uint64 masks[HAP_BEAM_WIDTH]; }; struct MultMaskState { float mult; // 1/Nhaps * pErr^numErrs uint64 mask; HapTreeState state; char rmActive[2]; inline int count(void) const { return state.count - rmActive[0] - rmActive[1]; } inline float multCount(void) const { if (mult == 0) return 0; else return mult * count(); } bool operator < (const MultMaskState &mms) const { return multCount() > mms.multCount(); } }; void advance(const HapTree &hapTree, const uchar rmHaps[], const uchar hap[], const uchar missing[], MultMaskState states[HAP_BEAM_WIDTH], int m, float pErr) { MultMaskState nextStates[2*HAP_BEAM_WIDTH]; int numNext = 0; // impose pruning thresh (TODO: test) const float minP = states[0].multCount() * pErr * pErr; for (int k = 0; k < HAP_BEAM_WIDTH && states[k].multCount() > minP; k++) for (int b = 0; b < 2; b++) { HapTreeState nextState = states[k].state; if (hapTree.next(m, nextState, b)) { if (missing[m]) { nextStates[numNext].mult = states[k].mult; nextStates[numNext].mask = (states[k].mask<<1)|b; } else { nextStates[numNext].mult = states[k].mult * (b==hap[m] ? 1 : pErr); nextStates[numNext].mask = states[k].mask; } nextStates[numNext].state = nextState; nextStates[numNext].rmActive[0] = states[k].rmActive[0] && ((rmHaps[m]&1)==b); nextStates[numNext].rmActive[1] = states[k].rmActive[1] && ((rmHaps[m]>>1)==b); numNext++; } } std::sort(nextStates, nextStates + numNext); memcpy(states, nextStates, std::min(numNext, HAP_BEAM_WIDTH) * sizeof(states[0])); // copy best if (numNext < HAP_BEAM_WIDTH) states[numNext].mult = 0; } string logProbToStr(float f) { f /= log(10); char buf[100]; sprintf(buf, "%.2fe%d", pow(10, f - floor(f)), (int) floor(f)); return buf; } // rmHaps: 2-bit phased genotypes for haplotype pair to ignore... or NULL if none (ref mode) // recombLogPs[T+1]: [0,T] = 0; [1..T-1] = logP for recomb in (t-0.5,t+0.5) void impMissing(const HapHedge &hapHedge, const uchar *rmHaps, uchar hap[], const uchar missing[], const float recombLogPs[], float pErr) { const int maxExt = 500; const int M = hapHedge.getM(); const int skip = hapHedge.getSkip(); const int T = hapHedge.getNumTrees(); const int dtMax = maxExt / skip; ProbMaskBundle *topPrefixes = (ProbMaskBundle *) calloc(T * dtMax, sizeof(topPrefixes[0])); // calloc => numTop initialized to 0 vector fwdLogProbs(T+1, -1000000), bwdLogProbs(T+1, -1000000); fwdLogProbs[0] = 0; bwdLogProbs[T] = 0; MultMaskState states[HAP_BEAM_WIDTH]; // compute haplotype prefix beams; compute fwdLogProbs for (int t = 0; t < T; t++) { const HapTree &hapTree = hapHedge.getHapTree(t); states[0].mask = 0; states[0].state = hapTree.getRootState(); if (rmHaps == NULL) { states[0].mult = hapTree.getInvNhaps(); states[0].rmActive[0] = states[0].rmActive[1] = 0; } else { states[0].mult = 1 / (1/hapTree.getInvNhaps()-2); // removing 2 haps states[0].rmActive[0] = states[0].rmActive[1] = 1; } for (int k = 1; k < HAP_BEAM_WIDTH; k++) states[k].mult = 0; int m = t*skip; int dtMiss = 0; for (int dt = 0; dt 64) break; // impose pruning threshold (TODO: test) float dtPrevBestProb = (dt==0 ? 0 : topPrefixes[t*dtMax + (dt-1)].probs[0]); float minP = dtPrevBestProb * pErr * pErr * expf(recombLogPs[t+dt]); // rel to previous float totProb = 0; ProbMaskBundle &bundle = topPrefixes[t*dtMax + dt]; bundle.numTop = 0; //cout << "t = " << t << ", dt = " << dt << ":" << endl; for (int k = 0; k < HAP_BEAM_WIDTH && states[k].multCount() > minP; k++) { float prob = states[k].multCount(); totProb += prob; bundle.numTop++; bundle.probs[k] = prob; bundle.masks[k] = states[k].mask; //cout << " prob = " << prob << ", mask = " << states[k].mask << endl; } if (bundle.numTop == 0) break; bundle.logTotProb = logf(totProb); // compute fwdLogProbs NumericUtils::logSumExp(fwdLogProbs[t+dt+1], fwdLogProbs[t] + bundle.logTotProb + recombLogPs[t+dt+1]); //cout << endl; } //cout << endl; } // count missing sites int numMiss = 0; vector tMiss; for (int t = 0; t < T; t++) { tMiss.push_back(numMiss); int m = t*skip; int mEnd = std::min(m + skip, M); for (; m < mEnd; m++) if (missing[m]) numMiss++; } // initialize log probs for missing sites float allLogProb01s[numMiss][2]; for (int i = 0; i < numMiss; i++) for (int b = 0; b < 2; b++) allLogProb01s[i][b] = -1000000; // compute bwdLogProbs; compute log probs at missing sites (using saved haplotype prefix beams) for (int t = T-1; t >= 0; t--) { int m = t*skip; int dtMiss = 0; for (int dt = 0; dt>(dtMiss-1-i))&1] += bundle.probs[k]; for (int i = 0; i < dtMiss; i++) for (int b = 0; b < 2; b++) if (prob01s[i][b] != 0) NumericUtils::logSumExp(allLogProb01s[tMiss[t]+i][b], fwdLogProbs[t] + logf(prob01s[i][b]) + bwdLogProbs[t+dt+1]); } } // impute missing sites numMiss = 0; for (int m = 0; m < M; m++) if (missing[m]) { hap[m] = (allLogProb01s[numMiss][1] > allLogProb01s[numMiss][0]); numMiss++; } /* for (int t = 0; t <= T; t++) cout << "fwdProbs[" << t << "]: " << logProbToStr(fwdLogProbs[t]) << endl; for (int t = 0; t <= T; t++) cout << "bwdProbs[" << t << "]: " << logProbToStr(bwdLogProbs[t]) << endl; for (int i = 0; i < numMiss; i++) { cout << "missing site " << i << ":"; for (int b = 0; b < 2; b++) cout << " " << logProbToStr(allLogProb01s[i][b]); cout << endl; } */ free(topPrefixes); } void Eagle::imputeMissing(const HapHedge &hapHedge, uint64 n0) { int M = hapHedge.getM(), skip = hapHedge.getSkip(), T = hapHedge.getNumTrees(); const HapBitsT &hapBitsT = hapHedge.getHapBitsT(); uchar *rmHaps = NULL; if (2*n0 < (uint64) hapBitsT.getNhaps()) { // set rmHaps rmHaps = ALIGNED_MALLOC_UCHARS(M * sizeof(rmHaps[0])); for (int m = 0; m < M; m++) rmHaps[m] = hapBitsT.getBit(2*n0, m) | (hapBitsT.getBit(2*n0+1, m)<<1); } vector missing(M); int m = 0; vector cMtreeStarts; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) { if (m % skip == 0) cMtreeStarts.push_back(cMs64j[m64j]); missing[m++] = (genoBits[m64j/64 * N + n0].is9>>(m64j&63))&1; } cMtreeStarts.push_back(cMs64j[Mseg64*64]); vector recombLogPs(T+1); const double cMswitch = 2.0; for (int t = 1; t < T; t++) { double cMdelta = (cMtreeStarts[t+1] - cMtreeStarts[t-1]) / 2; recombLogPs[t] = log(std::max(1 - exp(-cMdelta / cMswitch), 1e-6)); //cout << exp(recombLogPs[t]) << " " << std::flush; } //cout << endl; for (uint64 nHap = 2*(n0-Nref); nHap <= 2*(n0-Nref)+1; nHap++) { vector hap(M); m = 0; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) hap[m++] = (tmpHaploBitsT[nHap*Mseg64 + m64j/64]>>(m64j&63))&1; impMissing(hapHedge, rmHaps, &hap[0], &missing[0], &recombLogPs[0], pow(10.0, logPerr)); m = 0; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) { uint64 bit = 1ULL<<(m64j&63); if (hap[m]) tmpHaploBitsT[nHap*Mseg64 + m64j/64] |= bit; else tmpHaploBitsT[nHap*Mseg64 + m64j/64] &= ~bit; m++; } } if (rmHaps != NULL) ALIGNED_FREE(rmHaps); } } Eagle-master/src/EagleMain.cpp000066400000000000000000000576541274444013000165210ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include "omp.h" #include #include "Eagle.hpp" #include "EagleParams.hpp" #include "GenoData.hpp" #include "HapHedge.hpp" #include "SyncedVcfData.hpp" #include "Timer.hpp" #include "StringUtils.hpp" #include "Version.hpp" using namespace EAGLE; using namespace std; //#define LOCAL_TEST //#define OLD_IMP_MISSING void adjustHistFactor(double &histFactor, double hetRate, double snpRate) { if (histFactor == 0) { if (snpRate * hetRate == 0) histFactor = 1; else { // compute how far (in cM) default 100 hets will typically span double cMdefaultHist = 100 / snpRate / hetRate; printf("Typical span of default 100-het history length: %.2f cM\n", cMdefaultHist); const double cMminHist = 1.0; histFactor = max(1.0, min(20.0, cMminHist / cMdefaultHist)); printf("Setting --histFactor=%.2f\n", histFactor); if (histFactor != 1) printf("Typical span of %d-het history length: %.2f cM\n", (int) (100*histFactor), cMdefaultHist*histFactor); cout << flush; } } } void phaseWithRef(EagleParams ¶ms, Timer &timer, double t0, int argc, char **argv) { string tmpFile = params.outPrefix + ".unphased." + params.vcfOutSuffix; string outFile = params.outPrefix + "." + params.vcfOutSuffix; vector < vector < pair > > conPSall; double snpRate; SyncedVcfData vcfData(params.vcfRef, params.vcfTarget, params.allowRefAltSwap, params.chrom, params.chromX, params.bpStart-params.bpFlanking, params.bpEnd+params.bpFlanking, params.geneticMapFile, params.cMmax==0 ? 1 : params.cMmax, tmpFile, params.vcfWriteMode, params.usePS, conPSall, snpRate); Eagle eagle(vcfData.getNref(), vcfData.getNtarget(), vcfData.getMseg64(), vcfData.getGenoBits(), vcfData.getSeg64cMvecs(), params.pErr); double hetRate = eagle.computeHetRate(); cout << "Fraction of heterozygous genotypes: " << hetRate << endl; if (params.usePBWT) adjustHistFactor(params.histFactor, hetRate, snpRate); uint64 Nref = vcfData.getNref(), Ntarget = vcfData.getNtarget(); int iters = params.pbwtIters; if (params.noImpMissing) iters = 1; if (iters == 0) { if (Ntarget < Nref/2) iters = 1; else if (Ntarget < 2*Nref) iters = 2; else iters = 3; cout << endl << "Auto-selecting number of phasing iterations: setting --pbwtIters to " << iters << endl << endl; } cout << endl << "BEGINNING PHASING" << endl; vector confs(Ntarget); for (int iter = 1; iter <= iters; iter++) { double t23 = timer.get_time(); timer.update_time(); double timeMN2 = 0, timeImpMissing = 0; cout << endl << "PHASING ITER " << iter << " OF " << iters << endl << endl; eagle.initRefIter(iter); if (params.usePBWT) { // run PBWT algorithm HapBitsT *hapBitsTptr = NULL; HapHedge *hapHedgePtr = NULL; #ifdef OLD_IMP_MISSING if (!params.noImpMissing) { cout << "Making HapHedge" << endl; hapBitsTptr = new HapBitsT(eagle.getHaploBitsT(), 2*eagle.getNlib(2+iter), eagle.getMseg64(), eagle.getMaskSnps64j()); int skip = 25; hapHedgePtr = new HapHedge(*hapBitsTptr, skip); cout << "Built PBWT on " << hapBitsTptr->getNhaps() << " haplotypes" << endl; cout << "Time for HapHedge: " << timer.update_time() << endl; } #endif cout << endl << "Phasing target samples" << endl; int numPhased = 0; const int dots = 80; #pragma omp parallel for reduction(+:timeImpMissing) schedule(dynamic, 4) for (uint i = Nref; i < Nref+Ntarget; i++) { int nF1 = -1, nF2 = -1; if (params.trioCheck) { if ((i-Nref)%3 == 0) { // child nF1 = i+1; nF2 = i+2; } else if ((i-Nref)%3 == 1) { // parent 1 nF1 = -(i-1); nF2 = i+1; } else { // parent 2 nF1 = -(i-2); nF2 = i-1; } } confs[i-Nref] = eagle.runPBWT (i, nF1, nF2, params.Kpbwt/(iter1, !params.noImpMissing, params.usePS, conPSall[i-Nref]); #ifdef OLD_IMP_MISSING if (!params.noImpMissing) { Timer tim; eagle.imputeMissing(*hapHedgePtr, i); timeImpMissing += tim.update_time(); } #endif #pragma omp critical(NUM_PHASED) { numPhased++; int newDots = numPhased * dots / Ntarget - (numPhased-1) * dots / Ntarget; if (newDots) cout << string(newDots, '.') << flush; } } #ifdef OLD_IMP_MISSING if (!params.noImpMissing) { delete hapHedgePtr; delete hapBitsTptr; } #endif } else { // run LRP algorithm cout << "Building hash tables" << endl; eagle.buildHashTables(2+iter, 0, params.seed); // in ref mode, first iter is 3 cout << " (time: " << timer.update_time() << ")" << endl; cout << endl << "Phasing target samples" << endl; #pragma omp parallel for reduction(+:timeMN2) schedule(dynamic, 4) for (uint i = Nref; i < Nref+Ntarget; i++) timeMN2 += eagle.runHMM(i, -1, -1, 3, params.beamWidth4, params.maxHapStates); } cout << endl << "Time for phasing iter " << iter << ": " << (timer.get_time()-t23) << endl; if (!params.usePBWT) cout << "Time for phasing iter " << iter << " MN^2: " << timeMN2 / params.numThreads << endl; #ifdef OLD_IMP_MISSING else if (!params.noImpMissing) cout << "Time for phasing iter " << iter << " impMissing: " << timeImpMissing / params.numThreads << endl; #endif } /***** FINAL OUTPUT *****/ timer.update_time(); cout << "Writing " << params.vcfOutSuffix << " output to " << outFile << endl; eagle.writeVcf(tmpFile, outFile, params.chromX, params.bpStart, params.bpEnd, params.vcfWriteMode, params.noImpMissing, argc, argv); cout << "Time for writing output: " << timer.update_time() << endl; cout << "Total elapsed time for analysis = " << (timer.get_time()-t0) << " sec" << endl; cout << endl; cout << "Mean phase confidence of each target individual:" << endl; cout << "ID" << "\t" << "PHASE_CONFIDENCE" << endl; for (uint i = Nref; i < Nref+Ntarget; i++) { cout << vcfData.getTargetID(i-Nref) << "\t" << confs[i-Nref] << endl; } } int main(int argc, char *argv[]) { Timer timer; double t0 = timer.get_time(); cout << " +-----------------------------+" << endl; cout << " | |" << endl; cout << " | Eagle v"; printf("%-19s|\n", EAGLE_VERSION); cout << " | "; printf("%-26s|\n", EAGLE_VERSION_DATE); cout << " | Po-Ru Loh |" << endl; cout << " | |" << endl; cout << " +-----------------------------+" << endl; cout << endl; cout << "Copyright (C) 2015-2016 Harvard University." << endl; cout << "Distributed under the GNU GPLv3 open source license." << endl << endl; //cout << "Boost version: " << BOOST_LIB_VERSION << endl; //cout << endl; printf("Command line options:\n\n"); printf("%s ", argv[0]); for (int i = 1; i < argc; i++) { if (strlen(argv[i]) >= 2 && argv[i][0] == '-' && argv[i][1] == '-') printf("\\\n "); bool hasSpace = false; for (uint j = 0; j < strlen(argv[i]); j++) if (isspace(argv[i][j])) hasSpace = true; if (hasSpace) { if (argv[i][0] == '-') { bool foundEquals = false; for (uint j = 0; j < strlen(argv[i]); j++) { printf("%c", argv[i][j]); if (argv[i][j] == '=' && !foundEquals) { printf("\""); foundEquals = true; } } printf("\" "); } else printf("\"%s\" ", argv[i]); } else printf("%s ", argv[i]); } cout << endl << endl; EagleParams params; if (!params.processCommandLineArgs(argc, argv)) { cerr << "Aborting due to error processing command line arguments" << endl; exit(1); } cout << "Setting number of threads to " << params.numThreads << endl; omp_set_num_threads(params.numThreads); if (!params.vcfRef.empty()) { // use reference haplotypes phaseWithRef(params, timer, t0, argc, argv); return 0; } cout << endl << "=== Reading genotype data ===" << endl << endl; GenoData genoData; if (!params.vcfFile.empty()) genoData.initVcf(params.vcfFile, params.chrom, params.chromX, params.bpStart, params.bpEnd, params.geneticMapFile, params.noMapCheck, params.cMmax); else genoData.initBed(params.famFile, params.bimFile, params.bedFile, params.chrom, params.bpStart, params.bpEnd, params.geneticMapFile, params.excludeFiles, params.removeFiles, params.maxMissingPerSnp, params.maxMissingPerIndiv, params.noMapCheck, params.cMmax); vector invLD64j = genoData.computeInvLD64j(1000); if (!params.usePBWT) { // Eagle v1 algorithm params.pbwtOnly = false; // should already be false params.runStep2 = 1; } else { // PBWT algorithm // if SNP density is >1000 SNPs/Mb, don't run Steps 1+2 (even if --pbwtOnly is not set) int bpSpan = genoData.getSnps().back().physpos - genoData.getSnps()[0].physpos; double snpsPerMb = genoData.getSnps().size() / (bpSpan*1e-6); if (snpsPerMb > 1000) params.pbwtOnly = true; if (params.pbwtOnly) params.runStep2 = 0; // if --runStep2 hasn't yet been set, SNP density must be low; run Step 2 unless too few chunks if (params.runStep2 != 0 && params.runStep2 != 1) params.runStep2 = (genoData.getMseg64() >= 3U); // can't run Step 2 with < 3 SNP segments } Eagle eagle(genoData.getN(), genoData.getMseg64(), genoData.getGenoBits(), genoData.getSeg64cMvecs(), genoData.getSeg64logPs(), invLD64j, genoData.getIndivs(), genoData.getSnps(), params.maskFile, genoData.getIsFlipped64j(), params.pErr, params.runStep2); double hetRate = eagle.computeHetRate(); cout << "Fraction of heterozygous genotypes: " << hetRate << endl; if (params.usePBWT) adjustHistFactor(params.histFactor, hetRate, genoData.computeSnpRate()); map > trioIIDs; vector children, nF1s, nF2s; uint N = genoData.getN(); double timeMN2 = 0; #ifdef LOCAL_TEST { ifstream //finTrios("/groups/price/poru/HSPH_SVN/data/GERA/phasing/eur.CEU_gt_0.9.trios_indep.fam"); finTrios("/groups/price/UKBiobank/download/ukb4777_trios.fam"); if (finTrios) { string FID, IID, s1, s2, s3, s4; while (finTrios >> FID >> IID >> s1 >> s2 >> s3 >> s4) trioIIDs[IID] = make_pair(s1, s2); for (uint i = 0; i < N; i++) { int nF1 = -1, nF2 = -1; if (trioIIDs.find(genoData.getIndiv(i).indivID) == trioIIDs.end()) continue; pair parents = trioIIDs[genoData.getIndiv(i).indivID]; for (uint iF = 0; iF < N; iF++) if (genoData.getIndiv(iF).indivID == parents.first || genoData.getIndiv(iF).indivID == parents.second) { if (nF1 == -1) nF1 = iF; else nF2 = iF; } if (nF1 != -1 && nF2 != -1) { children.push_back(i); nF1s.push_back(nF1); nF2s.push_back(nF2); } } cout << "Identified " << children.size() << " trio children" << endl; } } #endif if (params.iter == 0) { if (params.outPrefix == "") { cerr << "ERROR: --outPrefix must be specified" << endl; exit(1); } /***** RUN STEP 1 *****/ if (!params.pbwtOnly) { cout << endl << "BEGINNING STEP 1" << endl << endl; double t1 = timer.get_time(); timer.update_time(); timeMN2 = 0; for (uint att = 0; att < min(9U, (uint) children.size()); att++) // run on trio children eagle.findLongDipMatches(children[att], nF1s[att], nF2s[att]); #pragma omp parallel for reduction(+:timeMN2) schedule(dynamic, 4) for (uint i = 0; i < N; i++) { //cout << StringUtils::itos(i)+"\n" << flush; timeMN2 += eagle.findLongDipMatches(i, -1, -1).first; //cout << StringUtils::itos(-i)+"\n" << flush; } if (!params.tmpPhaseConfsPrefix.empty()) eagle.writePhaseConfs(params.tmpPhaseConfsPrefix+".step1.bin"); cout << "Time for step 1: " << (timer.get_time()-t1) << endl; cout << "Time for step 1 MN^2: " << timeMN2 / params.numThreads << endl; eagle.outputSE(children, nF1s, nF2s, 1); } else { // use PBWT only => phase randomly cout << endl << "SKIPPED STEP 1" << endl; #pragma omp parallel for reduction(+:timeMN2) schedule(dynamic, 4) for (uint i = 0; i < N; i++) eagle.randomlyPhaseTmpHaploBitsT(i); } if (params.runStep2) { // running step 2 => Step 1 phase confs were saved to phaseConfs cout << endl << "Making hard calls" << flush; timer.update_time(); eagle.makeHardCalls(0, N, params.seed); cout << " (time: " << timer.update_time() << ")" << endl << endl; } else { // not running Step 2 => Step 1 phase calls were saved to tmpHaploBitsT eagle.cpTmpHaploBitsT(0, N); } /***** RUN STEPS 2-4 (STEP 4 = STEP 3a in paper) *****/ for (int step = 2; step <= (params.usePBWT ? (1+params.runStep2) : 4); step++) { cout << endl << "BEGINNING STEP " << step << endl << endl; double t23 = timer.get_time(); timer.update_time(); timeMN2 = 0; const uint64 numBatches = step == 2 ? 1 : 10; const uint64 runBatches = step <= 3 ? numBatches : (uint64) (numBatches * params.fracStep4); for (uint64 b = 1; b <= runBatches; b++) { cout << "BATCH " << b << " OF " << runBatches << endl; cout << "Building hash tables" << endl; eagle.buildHashTables(step, b, params.seed); cout << " (time: " << timer.update_time() << ")" << endl; if (b == 1) for (uint att = 0; att < min(9U, (uint) children.size()); att++) // run on trio children step == 2 ? eagle.findLongHapMatches(children[att], nF1s[att], nF2s[att], step) : eagle.runHMM(children[att], nF1s[att], nF2s[att], step, step==3 ? params.beamWidth3 : params.beamWidth4, params.maxHapStates); uint iStart = (b-1)*N/numBatches, iEnd = b*N/numBatches; cout << endl << "Phasing samples " << (iStart+1) << "-" << iEnd << endl; #pragma omp parallel for reduction(+:timeMN2) schedule(dynamic, 4) for (uint i = iStart; i < iEnd; i++) { //if (step == 3) cout << StringUtils::itos(i)+"\n" << flush; timeMN2 += step == 2 ? eagle.findLongHapMatches(i, -1, -1, step) : eagle.runHMM(i, -1, -1, step, step==3 ? params.beamWidth3 : params.beamWidth4, params.maxHapStates); //if (step == 3) cout << StringUtils::itos(-i)+"\n" << flush; } eagle.cpPhaseConfs(iStart, iEnd); cout << "Time for phasing batch: " << timer.update_time() << endl; cout << endl << "Making hard calls" << flush; eagle.makeHardCalls(iStart, iEnd, params.seed + step); cout << " (time: " << timer.update_time() << ")" << endl << endl; } if (!params.tmpPhaseConfsPrefix.empty()) eagle.writePhaseConfs(params.tmpPhaseConfsPrefix+".step"+StringUtils::itos(step)+".bin"); cout << "Time for step " << step << ": " << (timer.get_time()-t23) << endl; cout << "Time for step " << step << " MN^2: " << timeMN2 / params.numThreads << endl; eagle.outputSE(children, nF1s, nF2s, step); } if (params.usePBWT) { // run PBWT iters if (!params.runStep2) // didn't run Step 2 => didn't allocate phaseConfs cout << endl << "SKIPPED STEP 2" << endl; else // ran Step 2 => allocated phaseConfs; didn't allocate tmpHaploBitsT eagle.reallocLRPtoPBWT(); cout << endl << endl << "BEGINNING STEP 3 (PBWT ITERS)" << endl << endl; int iters = params.pbwtIters; if (iters == 0) { iters = 2 + params.pbwtOnly; cout << "Auto-selecting number of PBWT iterations: setting --pbwtIters to " << iters << endl << endl; } for (int iter = 1; iter <= iters; iter++) { cout << endl << "BEGINNING PBWT ITER " << iter << endl << endl; double t23 = timer.get_time(); timer.update_time(); double timeImpMissing = 0; int skip = 16; int Kpbwt = params.Kpbwt; bool runReverse = true; if (iter < iters) { // run rougher computation Kpbwt >>= (iters-iter); skip *= 2; runReverse = false; } const uint64 numBatches = 10; for (uint64 b = 1; b <= numBatches; b++) { cout << "BATCH " << b << " OF " << numBatches << endl; #ifdef OLD_IMP_MISSING cout << endl << "Making HapHedge" << endl; HapBitsT hapBitsT(eagle.getHaploBitsT(), 2*eagle.getNlib(2+iter), eagle.getMseg64(), eagle.getMaskSnps64j()); HapHedge hapHedge(hapBitsT, skip); cout << "Built PBWT on " << hapBitsT.getNhaps() << " haplotypes" << endl; cout << "Time for HapHedge: " << timer.update_time() << endl; #endif if (b == 1) for (uint att = 0; att < min(9U, (uint) children.size()); att++) // run on trios eagle.runPBWT(children[att], nF1s[att], nF2s[att], Kpbwt, params.expectIBDcM, params.histFactor, runReverse, true, false); uint iStart = (b-1)*N/numBatches, iEnd = b*N/numBatches; cout << endl << "Phasing samples " << (iStart+1) << "-" << iEnd << endl; #pragma omp parallel for reduction(+:timeImpMissing) schedule(dynamic, 4) for (uint i = iStart; i < iEnd; i++) { eagle.runPBWT(i, -1, -1, Kpbwt, params.expectIBDcM, params.histFactor, runReverse, true, true); #ifdef OLD_IMP_MISSING Timer tim; eagle.imputeMissing(hapHedge, i); timeImpMissing += tim.update_time(); #endif } eagle.cpTmpHaploBitsT(iStart, iEnd); cout << "Time for phasing batch: " << timer.update_time() << endl << endl; } cout << "Time for PBWT iter " << iter << ": " << (timer.get_time()-t23) << endl; #ifdef OLD_IMP_MISSING cout << "Time for PBWT iter " << iter << " impMissing: " << timeImpMissing / params.numThreads << endl; #endif //eagle.outputSE(children, nF1s, nF2s, step); // currently requires phaseConfs } } /***** FINAL OUTPUT *****/ if (!params.vcfFile.empty()) { string outFile = params.outPrefix + "." + params.vcfOutSuffix; cout << "Writing " << params.vcfOutSuffix << " output to " << outFile << endl; eagle.writeVcfNonRef(params.vcfFile, outFile, params.chrom, params.chromX, params.bpStart, params.bpEnd, params.vcfWriteMode, argc, argv); } else { cout << "Writing .haps.gz and .sample output" << endl; timer.update_time(); eagle.writeHapsGzSample(params.outPrefix); } cout << "Time for writing output: " << timer.update_time() << endl; } else if (params.iter == 1) { // PERFORM 1ST-ITER PHASING FOR A SMALL SUBSET ONLY (FOR TESTING) double t1 = timer.get_time(); timer.update_time(); timeMN2 = 0; map longestFreqs; int tot = 0; int att = 0, maxAtt = 10; for (uint i = 0; i < N; i++) { int nF1 = -1, nF2 = -1; if (trioIIDs.find(genoData.getIndiv(i).indivID) == trioIIDs.end()) continue; cout << "Testing n0 = " << i << ": " << genoData.getIndiv(i).famID << " " << genoData.getIndiv(i).indivID << endl; pair parents = trioIIDs[genoData.getIndiv(i).indivID]; for (uint iF = 0; iF < N; iF++) if (genoData.getIndiv(iF).indivID == parents.first || genoData.getIndiv(iF).indivID == parents.second) { cout << "Parent n1: " << iF << endl; if (nF1 == -1) nF1 = iF; else nF2 = iF; } eagle.checkTrioErrorRate(i, nF1, nF2); pair > ret = eagle.findLongDipMatches(i, nF1, nF2); timeMN2 += ret.first; for (uint j = 0; j < ret.second.size(); j++) { longestFreqs[(int) ret.second[j]]++; tot++; } att++; if (att == maxAtt) break; } int cum = 0; for (map ::iterator it = longestFreqs.begin(); it != longestFreqs.end(); it++) { cum += it->second; cout << it->first << " cM: " << it->second << " cum: " << (double) cum/tot << endl; } cout << "Time for step 1: " << (timer.get_time()-t1) << endl; cout << "Time for step 1 MN^2: " << timeMN2 / params.numThreads << endl; } else { // iter > 1 (FOR TESTING) cout << "Reading phase confidences" << endl; eagle.readPhaseConfs(/*"test_UKBiobank/eagle_305_chr10_small_iter2_bsub.tmpPhaseConfs.bin"*/params.tmpPhaseConfsPrefix+".step"+StringUtils::itos(params.iter-1)+".bin"); timer.update_time(); cout << "Making hard calls" << endl; eagle.makeHardCalls(0, N, params.seed); cout << "Time for hard calls: " << timer.update_time() << endl; /* global PBWT cout << "Making forward HapHedge" << endl; HapBitsT hapBitsFwdT(eagle.getHaploBitsT(), 2*eagle.getNlib(params.iter), eagle.getMseg64(), eagle.getMaskSnps64j()); int skip = 1; HapHedge hapHedgeFwd(hapBitsFwdT, skip); cout << "Making backward HapHedge" << endl; HapBitsT hapBitsBwdT(hapBitsFwdT, -1); HapHedge hapHedgeBwd(hapBitsBwdT, skip); cout << "Time for HapHedge: " << timer.update_time() << endl; */ #define USE_PBWT #ifndef USE_PBWT cout << "Building hash tables" << endl; eagle.buildHashTables(params.iter, 1, params.seed); cout << endl << "Time for hash tables: " << timer.update_time() << endl; #else eagle.reallocLRPtoPBWT(); #endif int att = 0, maxAtt = N; for (uint i = 0; i < N; i++) { int nF1 = -1, nF2 = -1; if (trioIIDs.find(genoData.getIndiv(i).indivID) == trioIIDs.end()) continue; cout << "Testing n0 = " << i << ": " << genoData.getIndiv(i).famID << " " << genoData.getIndiv(i).indivID << endl; pair parents = trioIIDs[genoData.getIndiv(i).indivID]; for (uint iF = 0; iF < N; iF++) if (genoData.getIndiv(iF).indivID == parents.first || genoData.getIndiv(iF).indivID == parents.second) { cout << "Parent n1: " << iF << endl; if (nF1 == -1) nF1 = iF; else nF2 = iF; } eagle.checkTrioErrorRate(i, nF1, nF2); #ifdef USE_PBWT eagle.runPBWT(i, nF1, nF2, params.Kpbwt, params.expectIBDcM, params.histFactor, true, false, !params.noImpMissing); #else timeMN2 += params.iter == 2 ? eagle.findLongHapMatches(i, nF1, nF2, params.iter) : eagle.runHMM(i, nF1, nF2, params.iter, params.iter==3 ? params.beamWidth3 : params.beamWidth4, params.maxHapStates/*, &hapHedgeFwd, &hapHedgeBwd*/); #endif att++; if (att == maxAtt) break; } cout << "Time for step minus init: " << timer.update_time() << endl; cout << "Time for MN^2: " << timeMN2 / (params.iter == 0 ? params.numThreads : 1) << endl; #ifdef RDTSC_TIMING printf("%.1f%% of time in dip-hap\n", 100*eagle.diphapTicks / (double) eagle.totTicks); printf("%.1f%% of time in ext\n", 100*eagle.extTicks / (double) eagle.totTicks); printf("%.1f%% of time in LSH\n", 100*eagle.lshTicks / (double) eagle.totTicks); printf("%.1f%% of time in LSH hit checks\n", 100*eagle.lshCheckTicks / (double) eagle.totTicks); printf("%.1f%% of time in DP\n", 100*eagle.dpTicks / (double) eagle.totTicks); printf(" rel %.1f%% in sort\n", 100*eagle.dpSortTicks / (double) eagle.dpTicks); printf(" rel %.1f%% in update\n", 100*eagle.dpUpdateTicks / (double) eagle.dpTicks); printf(" rel %.1f%% in computeStatic\n", 100*eagle.dpStaticTicks / (double) eagle.dpTicks); printf(" rel %.1f%% in computeSwitch\n", 100*eagle.dpSwitchTicks / (double) eagle.dpTicks); printf("%.1f%% of time in blip fix\n", 100*eagle.blipFixTicks / (double) eagle.totTicks); printf(" rel %.1f%% in LSH\n", 100*eagle.blipLshTicks / (double) eagle.blipFixTicks); printf(" rel %.1f%% in popcount\n", 100*eagle.blipPopTicks / (double) eagle.blipFixTicks); printf(" rel %.1f%% in vote update\n", 100*eagle.blipVoteTicks / (double) eagle.blipFixTicks); cout << "Number of update calls: " << eagle.dpUpdateCalls << endl; #endif } cout << "Total elapsed time for analysis = " << (timer.get_time()-t0) << " sec" << endl; } Eagle-master/src/EaglePBWT.cpp000066400000000000000000000710231274444013000163730ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include #include "DipTreePBWT.hpp" #include "HapHedge.hpp" #include "NumericUtils.hpp" #include "Timer.hpp" #include "Types.hpp" #include "Eagle.hpp" namespace EAGLE { using std::vector; using std::cout; using std::endl; struct ProbInd { float prob; int ind1, ind2; ProbInd(float _prob=0, int _ind1=0, int _ind2=0) : prob(_prob), ind1(_ind1), ind2(_ind2) {} bool operator < (const ProbInd &pi) const { return std::min(prob, 1-prob) < std::min(pi.prob, 1-pi.prob); } }; inline int popcount64_012(uint64 i) { if (i == 0) return 0; else if ((i & (i-1ULL)) == 0) return 1; else return 2; } vector Eagle::findMinErrDipHap(uint64 n0, uint K, bool useTargetHaps) const { uint64 Nhaps = 2*((Nref==0 || useTargetHaps) ? N : Nref); if (K > Nhaps) K = Nhaps; vector bestHaps; bestHaps.reserve(K); if (K == Nhaps) { for (uint64 nHap = 0; nHap < Nhaps; nHap++) if (nHap/2 != n0) bestHaps.push_back(nHap); } else { vector < pair > hapErrInds(Nhaps); vector genoBitsT(Mseg64); for (uint64 m64 = 0; m64 < Mseg64; m64++) genoBitsT[m64] = genoBits[m64*N + n0]; for (uint64 nHap = 0; nHap < Nhaps; nHap++) { uint numErrs = (nHap/2 == n0 ? 1000000 : 0); for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint64 is1 = haploBitsT[nHap*Mseg64 + m64]; uint64 wrongBits = (genoBitsT[m64].is0 & is1) | (genoBitsT[m64].is2 & ~is1); numErrs += popcount64_012(wrongBits); } hapErrInds[nHap].first = numErrs; hapErrInds[nHap].second = nHap; } std::sort(hapErrInds.begin(), hapErrInds.end()); for (uint k = 0; k < K; k++) if (hapErrInds[k].second/2 != n0) bestHaps.push_back(hapErrInds[k].second); } return bestHaps; } vector Eagle::computeRefIsMono(const vector &bestHaps) const { vector refIsMono(Mseg64*64, true); vector anyIs0(Mseg64), anyIs1(Mseg64); for (uint i = 0; i < bestHaps.size(); i++) { uint64 nHap = bestHaps[i]; for (uint64 m64 = 0; m64 < Mseg64; m64++) { uint64 is1 = haploBitsT[nHap*Mseg64 + m64]; anyIs0[m64] |= ~is1; anyIs1[m64] |= is1; } } for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { if (maskSnps64j[m64j]) { uint64 m64 = m64j/64, j = m64j&63; refIsMono[m64j] = !((anyIs0[m64]>>j)&1) || !((anyIs1[m64]>>j)&1); } } return refIsMono; } float Eagle::runPBWT(uint64 n0, uint64 nF1, uint64 nF2, int Kpbwt, double cMexpect, double histFactor, bool runReverse, bool useTargetHaps, bool impMissing) { vector < pair > noConPS; return runPBWT(n0, nF1, nF2, Kpbwt, cMexpect, histFactor, runReverse, useTargetHaps, impMissing, 0, noConPS); } float Eagle::runPBWT(uint64 n0, uint64 nF1, uint64 nF2, int Kpbwt, double cMexpect, double histFactor, bool runReverse, bool useTargetHaps, bool impMissing, int usePS, const vector < pair > &conPS) { Timer timer; vector m64jInds(Mseg64*64+1); const int SPEED_FACTOR = 1; const float lnPerr = logf(powf(10.0f, logPerr)); const int CALL_LENGTH_FACTOR = 1; bool print = (int) nF1 != -1; /***** SELECT BEST REFERENCE HAPLOTYPES *****/ if (print) cout << "selecting " << Kpbwt << " ref haps... " << std::flush; vector bestHaps = findMinErrDipHap(n0, Kpbwt, useTargetHaps); // find sites at which only one allele is represented in bestHaps => can't be used as split vector refIsMono = computeRefIsMono(bestHaps); // size = Mseg64*64 if (print) cout << " done " << timer.update_time() << endl; /***** PROCESS TARGET GENOTYPES *****/ // create vectors of genos, genoBits, and hets vector genos64j(Mseg64*64); vector hets64j, refMonoHets64j; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) { genos64j[m64j] = getGeno0123(m64j, n0); if (maskSnps64j[m64j] && genos64j[m64j]==1) { if (!refIsMono[m64j]) hets64j.push_back(m64j); else refMonoHets64j.push_back(m64j); } } vector tgtGenoBits(Mseg64); for (uint64 m64 = 0; m64 < Mseg64; m64++) tgtGenoBits[m64] = genoBits[m64*N + n0]; vector pbwtBitsFine(Mseg64); float conf = 0; // find split sites (for PBWT HapTree starts): hets and occasionally inter-het sites vector < pair > tCallLocs; vector tHomLocs; vector splits64j; const double cMmaxSplit = 0.5; if (!hets64j.empty()) { splits64j.push_back(hets64j[0]); for (uint64 h = 1; h < hets64j.size(); h++) { int lastCallLoc = splits64j.size(); // old het ind + 1: tree indices are split indices + 1 for (uint64 m64j = hets64j[h-1]+1; m64j <= hets64j[h]; m64j++) if (maskSnps64j[m64j] && !refIsMono[m64j] && genos64j[m64j] <= 2) if (m64j == hets64j[h] || cMs64j[m64j] > cMs64j[splits64j.back()] + cMmaxSplit) { splits64j.push_back(m64j); if (m64j < hets64j[h]) tHomLocs.push_back(splits64j.size()); // hom ind + 1 } int nextCallLoc = splits64j.size(); // new het ind + 1 tCallLocs.push_back(make_pair(lastCallLoc, nextCallLoc)); } } else { // all hom or missing or mono in ref; put in splits as necessary for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j] && !refIsMono[m64j] && genos64j[m64j] <= 2) if (splits64j.empty() || cMs64j[m64j] > cMs64j[splits64j.back()] + cMmaxSplit) { splits64j.push_back(m64j); tHomLocs.push_back(splits64j.size()); // hom ind + 1 } } if (print) { cout << "num hets (poly in best haps): " << hets64j.size(); cout << " num hets (mono in best haps): " << refMonoHets64j.size(); cout << " num splits: " << splits64j.size() << endl; } // allocate storage for reference haplotype samples (to use for impMissing and singleton hets) const int samples = 10; vector < vector > refSamples[2]; refSamples[0].resize(splits64j.size()+1); refSamples[1].resize(splits64j.size()+1); // store which inter-split chunks contain at least one missing site vector tHasMissing(splits64j.size()+1); // "missing" = missing or singleton het for (int t = 0; t <= (int) splits64j.size(); t++) { uint64 m64jPrev = t==0 ? -1ULL : splits64j[t-1]; uint64 m64jNext = t==(int) splits64j.size() ? Mseg64*64 : splits64j[t]; for (uint64 m64j = m64jPrev+1; m64j < m64jNext; m64j++) if (maskSnps64j[m64j] && ((genos64j[m64j] == 3 && impMissing) || // missing (genos64j[m64j] == 1 && refIsMono[m64j]))) // singleton het tHasMissing[t] = true; } // create vector of genos at split sites (padded on left and right to match hapBitsT) vector splitGenos; splitGenos.push_back(0); // pad on left with 0 (to match hapBitsT) for (uint64 s = 0; s < splits64j.size(); s++) splitGenos.push_back(genos64j[splits64j[s]]); splitGenos.push_back(0); // pad on right with 0 (to match hapBitsT) // check for 0 or 1 het (warn) if (hets64j.size() <= 1) { cerr << "WARNING: Sample " << n0-Nref+1 << " (1-indexed) has a het count of " << hets64j.size() << endl; } // compute recombination probabilities vector cMcoords(splits64j.size()+2); for (uint64 s = 0; s <= splits64j.size(); s++) { uint64 splitStart = (s == 0 ? 0 : splits64j[s-1]); uint64 splitStop = (s == splits64j.size() ? Mseg64*64 : splits64j[s]); cMcoords[s] = cMs64j[splitStart]; cMcoords[s+1] = cMs64j[splitStop]; int homs = 0; for (uint64 m64j = splitStart+1; m64j < splitStop; m64j++) if (genos64j[m64j] == 0 || genos64j[m64j] == 2) homs++; } /**** BUILD PBWT DATA STRUCTURE *****/ // create HapBitsT encoding of ref hets and hom errs if (print) cout << "making HapBitsT... " << std::flush; HapBitsT hapBitsT(haploBitsT, Mseg64, splits64j, splitGenos, tgtGenoBits, bestHaps); if (print) cout << " done " << timer.update_time() << endl; // create HapHedge PBWT data structure if (print) cout << "making HapHedge... " << std::flush; HapHedgeErr *hapHedgePtr = new HapHedgeErr(hapBitsT); if (print) cout << " done " << timer.update_time() << endl; //hapHedgePtr->printTree(0); /***** RUN COARSE (UNCONSTRAINED) DIPTREE SEARCH *****/ // initialize DipTree object if (print) cout << "making DipTree (unconstr)... " << std::flush; vector constraints(splitGenos.size(), NO_CONSTRAINT); vector splitInds(Mseg64*64+1); // index map for FORMAT:PS constraints if (usePS) { // populate splitInds: 1-based indices t=1..T-2 in splits64j[t-1] of 1-based SNPs m+1 for (uint64 m64j = 0, m = 0, t = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) { m++; m64jInds[m] = m64j; if (t < splits64j.size() && splits64j[t]==m64j) { t++; splitInds[m] = t; } else splitInds[m] = 0; } // set constraints for fast search for (uint c = 0; c < conPS.size(); c++) if (splitInds[conPS[c].first] && splitInds[abs(conPS[c].second)]) constraints[splitInds[conPS[c].first]] = ((splitInds[conPS[c].first]-splitInds[abs(conPS[c].second)])<<1)|(conPS[c].second<0); } const int histLengthFast = 30*histFactor, pbwtBeamWidthFast = 30/SPEED_FACTOR; DipTree dipTreeFast(*hapHedgePtr, splitGenos, &constraints[0], cMcoords, cMexpect, histLengthFast, pbwtBeamWidthFast, lnPerr, 0); if (print) cout << " done " << timer.update_time() << endl; // explore search space; make phase calls if (print) cout << "making phase calls (uncon)... " << std::flush; const int callLengthFast = 10*CALL_LENGTH_FACTOR; const float minFix = 0.5f, maxFix = 0.9f, fixThresh = 0.01f; vector probInds; vector pbwtBitsFast(Mseg64); uint64 lastBit = 0; for (uint64 i = 0; i < tCallLocs.size(); i++) { float probAA = dipTreeFast.callProbAA(tCallLocs[i].first, tCallLocs[i].second, callLengthFast); ProbInd probInd(probAA, tCallLocs[i].first, tCallLocs[i].second); if (probAA < 0.5f) lastBit = !lastBit; uint64 m64j = hets64j[i+1]; pbwtBitsFast[m64j/64] |= lastBit<<(m64j&63); if (i > 0) { // try calling rel phase vs. 2 hets back (in case prev het is err) float probAA2 = dipTreeFast.callProbAA(tCallLocs[i-1].first, tCallLocs[i].second, callLengthFast); ProbInd probInd2(probAA2, tCallLocs[i-1].first, tCallLocs[i].second); if (probInd2 < probInd) probInd = probInd2; } probInds.push_back(probInd); } int T = splitGenos.size(); // splits64j.size()+2; tree indices are split indices + 1 vector revConstraints(T, NO_CONSTRAINT); // set relative phase constraints for most confident hets std::sort(probInds.begin(), probInds.end()); //float fracFixed = 0; for (int f = 0; f < minFix*probInds.size() || (f < maxFix*probInds.size() && (probInds[f].prob < fixThresh || probInds[f].prob > 1-fixThresh)) || (f < (int) probInds.size() && (probInds[f].prob==0 || probInds[f].prob==1)); f++) { //fracFixed = (f+1.0f) / probInds.size(); constraints[probInds[f].ind2] = // het constraint: fix relative phase of ind2 wrt ind1 revConstraints[T-1-probInds[f].ind1] = ((probInds[f].ind2 - probInds[f].ind1)<<1) | (probInds[f].prob < 0.5f); if (constraints[probInds[f].ind1] == NO_CONSTRAINT) constraints[probInds[f].ind1] = OPP_CONSTRAINT; // set to -2 = "start of het block" revConstraints[T-1-probInds[f].ind2] = OPP_CONSTRAINT; } // make hom dosage calls (and divide by 2 to sort properly: uncertainty = dist from 0 or 1) probInds.clear(); for (uint64 i = 0; i < tHomLocs.size(); i++) probInds.push_back(ProbInd(dipTreeFast.callDosage(tHomLocs[i], callLengthFast) / 2, tHomLocs[i])); std::sort(probInds.begin(), probInds.end()); for (int f = 0; f < minFix*probInds.size() || (f < maxFix*probInds.size() && (probInds[f].prob < fixThresh || probInds[f].prob > 1-fixThresh)) || (f < (int) probInds.size() && (probInds[f].prob==0 || probInds[f].prob==1)); f++) constraints[probInds[f].ind1] = revConstraints[T-1-probInds[f].ind1] = (probInds[f].prob >= 0.5f); // hom constraint: no err allowed if (print) cout << " done " << timer.update_time() << endl; //cout << "frac fixed: " << fracFixed << endl; // set constraints for fine search if (usePS == 2) { for (uint c = 0; c < conPS.size(); c++) if (splitInds[conPS[c].first] && splitInds[abs(conPS[c].second)]) constraints[splitInds[conPS[c].first]] = revConstraints[T-1-splitInds[abs(conPS[c].second)]] = ((splitInds[conPS[c].first]-splitInds[abs(conPS[c].second)])<<1)|(conPS[c].second<0); } /***** RUN FINE (CONSTRAINED) DIPTREE SEARCH *****/ // initialize DipTree object if (print) cout << "making DipTree (constrained)..." << std::flush; const int histLengthFine = 100*histFactor, pbwtBeamWidthFine = 50/SPEED_FACTOR; DipTree dipTreeFine(*hapHedgePtr, splitGenos, &constraints[0], cMcoords, cMexpect, histLengthFine, pbwtBeamWidthFine, lnPerr, 0); if (print) cout << " done " << timer.update_time() << endl; // explore search space; make phase calls if (print) cout << "making phase calls (constr)... " << std::flush; const int callLengthFine = 20*CALL_LENGTH_FACTOR; const int callLengthSample = 20; // sample refs (BEFORE callProbAA: sampleRefs needs recent history that gets overwritten) for (int t = 0; t < T-1; t++) if (tHasMissing[t]) refSamples[0][t] = dipTreeFine.sampleRefs(t, callLengthSample, samples, bestHaps, true); vector probAAsCur; lastBit = 0; for (uint64 i = 0; i < tCallLocs.size(); i++) { float probAA = dipTreeFine.callProbAA(tCallLocs[i].first, tCallLocs[i].second, callLengthFine); probAAsCur.push_back(probAA); conf += std::max(probAA, 1-probAA); if (probAA < 0.5f) lastBit = !lastBit; uint64 m64j = hets64j[i+1]; pbwtBitsFine[m64j/64] |= lastBit<<(m64j&63); } conf /= tCallLocs.size(); if (print) cout << " done " << timer.update_time() << endl; delete hapHedgePtr; if (runReverse) { // create HapBitsT encoding of ref hets and hom errs if (print) cout << "making revHapBitsT... " << std::flush; HapBitsT revHapBitsT(hapBitsT, -2); if (print) cout << " done " << timer.update_time() << endl; // create HapHedge PBWT data structure if (print) cout << "making revHapHedge... " << std::flush; HapHedgeErr revHapHedge(revHapBitsT); if (print) cout << " done " << timer.update_time() << endl; vector revSplitGenos(splitGenos); std::reverse(revSplitGenos.begin(), revSplitGenos.end()); vector revcMcoords(T); for (int t = 0; t < T; t++) revcMcoords[t] = cMcoords[T-1] - cMcoords[T-1-t]; // initialize DipTree object if (print) cout << "making revDipTree (constr)... " << std::flush; DipTree revDipTreeFine(revHapHedge, revSplitGenos, &revConstraints[0], revcMcoords, cMexpect, histLengthFine, pbwtBeamWidthFine, lnPerr, 0); if (print) cout << " done " << timer.update_time() << endl; // explore search space; make phase calls if (print) cout << "making rev phase calls (con)..." << std::flush; // sample refs (BEFORE callProbAA: sampleRefs needs recent history that gets overwritten) for (int t = T-2; t >= 0; t--) if (tHasMissing[t]) refSamples[1][t] = revDipTreeFine.sampleRefs(T-2-t, callLengthSample, samples, bestHaps, false); vector revPbwtBitsFine(Mseg64); lastBit = 0; for (int i = tCallLocs.size()-1; i >= 0; i--) { float probAA = revDipTreeFine.callProbAA(T-1-tCallLocs[i].second, T-1-tCallLocs[i].first, callLengthFine); if (probAA + probAAsCur[i] < 1) lastBit = !lastBit; uint64 m64j = hets64j[i]; revPbwtBitsFine[m64j/64] |= lastBit<<(m64j&63); } if (print) cout << " done " << timer.update_time() << endl; pbwtBitsFine = revPbwtBitsFine; } // trio analysis output if (print) { /* for (uint64 m64 = 0; m64 < Mseg64; m64++) { checkHaploBits(n0, nF1, nF2, pbwtBitsFast[m64], m64, 25); checkHaploBits(n0, nF1, nF2, pbwtBitsFine[m64], m64, 25); cout << endl; } */ vector phaseVec; for (uint64 m64 = 0; m64 < Mseg64; m64++) { vector phaseSeg = checkHaploBits(n0, nF1, nF2, pbwtBitsFast[m64], m64, -1); phaseVec.insert(phaseVec.end(), phaseSeg.begin(), phaseSeg.end()); } printf("FAST# major SE: %2d # tot SE: %2d / %d\n", countMajorSE(phaseVec), countSE(phaseVec), (int) phaseVec.size()-1); phaseVec.clear(); for (uint64 m64 = 0; m64 < Mseg64; m64++) { vector phaseSeg = checkHaploBits(n0, nF1, nF2, pbwtBitsFine[m64], m64, -1); phaseVec.insert(phaseVec.end(), phaseSeg.begin(), phaseSeg.end()); } printf("FINE# major SE: %2d # tot SE: %2d / %d\n", countMajorSE(phaseVec), countSE(phaseVec), (int) phaseVec.size()-1); // check accuracy of fast calls vector trioRelPhaseVec = trioRelPhase(n0, nF1, nF2); const int NUM_CALL_LENGTHS = 2; int callLengths[NUM_CALL_LENGTHS] = {10, 20/*, 50, 100*/}; for (int l = 0; l < NUM_CALL_LENGTHS; l++) { cout << "callLength = " << callLengths[l] << endl; vector probAAs; for (uint64 i = 0; i < tCallLocs.size(); i++) probAAs.push_back(dipTreeFast.callProbAA(tCallLocs[i].first, tCallLocs[i].second, callLengths[l])); vector < vector > probCorFastSlow; for (uint i = 0; i < probAAs.size(); i++) if (trioRelPhaseVec[i] >= 0) { vector tmp(4); tmp[0] = std::min(probAAs[i], 1-probAAs[i]); tmp[1] = (probAAs[i] > 0.5f) == !trioRelPhaseVec[i]; tmp[2] = (probAAsCur[i] > 0.5f) == !trioRelPhaseVec[i]; probCorFastSlow.push_back(tmp); } std::sort(probCorFastSlow.begin(), probCorFastSlow.end()); const int NUM_PCTS = 7; int pcts[NUM_PCTS] = {50, 80, 90, 95, 98, 99, 100}; for (int p = 0; p < NUM_PCTS; p++) { int pct = pcts[p]; uint iCut = probCorFastSlow.size()*pct/100; int numErrs = 0, numErrsCur = 0; for (uint i = 0; i < iCut; i++) { if (probCorFastSlow[i][1] == 0) numErrs++; if (probCorFastSlow[i][2] == 0) numErrsCur++; } printf(" len=%d,cut=%d%%: p opp = %f, %d errs, %d cur / %d calls\n", callLengths[l], pct, probCorFastSlow[iCut-1][0], numErrs, numErrsCur, iCut); } } } // write phase calls uint64 nTargetHap = 2*(n0-Nref); uint64 nTargetOpp = 2*(n0-Nref) + 1; for (uint64 m64 = 0; m64 < Mseg64; m64++) { tmpHaploBitsT[nTargetHap*Mseg64 + m64] = pbwtBitsFine[m64]; tmpHaploBitsT[nTargetOpp*Mseg64 + m64] = ~pbwtBitsFine[m64]; } // set hom bits for (uint64 m64 = 0; m64 < Mseg64; m64++) { for (uint64 j = 0; j < 64ULL; j++) { uint64 m64j = m64*64+j; if (maskSnps64j[m64j]) { if (genos64j[m64j] == 0) { tmpHaploBitsT[nTargetHap*Mseg64 + m64] &= ~(1ULL< miss64j; for (uint64 m64j = m64jPrev+1; m64j < m64jNext; m64j++) if (genos64j[m64j] == 3 && impMissing) // missing miss64j.push_back(m64j); // orient each hap pair wrt called phase if (!hets64j.empty()) for (int fb = 0; fb < 2; fb++) { for (int s = 0; s < samples; s++) { double cMmid; if (t==0) cMmid = cMs64j[splits64j[t]]; else if (t==(int) splits64j.size()) cMmid = cMs64j[splits64j[t-1]]; else cMmid = (cMs64j[splits64j[t-1]] + cMs64j[splits64j[t]]) / 2; vector < pair > cMdistSigns; for (int i = 15; i >= 0; i--) if ((((refSamples[fb][t][s].haps[0].tMaskRev ^ refSamples[fb][t][s].haps[1].tMaskRev)>>i)&1) && splitGenos[t-i]==1) { uint64 m64j = splits64j[t-i-1]; cMdistSigns.push_back(make_pair(fabs(cMs64j[m64j]-cMmid), ((refSamples[fb][t][s].haps[0].tMaskRev>>i)&1) == ((pbwtBitsFine[m64j/64]>>(m64j&63))&1))); } for (int i = 0; i < 16; i++) if ((((refSamples[fb][t][s].haps[0].tMaskFwd ^ refSamples[fb][t][s].haps[1].tMaskFwd)>>i)&1) && splitGenos[t+i+1]==1) { uint64 m64j = splits64j[t+i]; cMdistSigns.push_back(make_pair(fabs(cMs64j[m64j]-cMmid), ((refSamples[fb][t][s].haps[0].tMaskFwd>>i)&1) == ((pbwtBitsFine[m64j/64]>>(m64j&63))&1))); } if (!cMdistSigns.empty()) { sort(cMdistSigns.begin(), cMdistSigns.end()); if (!cMdistSigns[0].second) std::swap(refSamples[fb][t][s].haps[0], refSamples[fb][t][s].haps[1]); } } } // for each haplotype in turn, call missing sites (and save mean hap length) double hMeanLens[2]; for (int h = 0; h < 2; h++) { vector endRefs[2]; vector nonEndRefs[2], nonEndLens[2]; // split sampled haplotypes into buckets: those that end in (t,t+1) and those that don't for (int fb = 0; fb < 2; fb++) for (int s = 0; s < samples; s++) { if (refSamples[fb][t][s].haps[h].isEnd) endRefs[fb].push_back(refSamples[fb][t][s].haps[h].refSeq); else { nonEndRefs[fb].push_back(refSamples[fb][t][s].haps[h].refSeq); nonEndLens[fb].push_back(refSamples[fb][t][s].haps[h].tLength); } } // initialize allele dosages int nMiss = miss64j.size(); double alleleDoses[nMiss][2]; for (int m = 0; m < nMiss; m++) alleleDoses[m][0] = alleleDoses[m][1] = 0; // process non-ends: call using longer of fwd, rev ref samples double meanLens[2] = {0, 0}; for (int fb = 0; fb < 2; fb++) if (!nonEndLens[fb].empty()) meanLens[fb] = std::accumulate(nonEndLens[fb].begin(), nonEndLens[fb].end(), 0) / (double) nonEndLens[fb].size(); int fbLong = meanLens[0] > meanLens[1] ? 0 : 1; for (uint k = 0; k < nonEndRefs[fbLong].size(); k++) { int refSeq = nonEndRefs[fbLong][k]; for (int m = 0; m < nMiss; m++) alleleDoses[m][(haploBitsT[refSeq*Mseg64+miss64j[m]/64]>>(miss64j[m]&63))&1] += 1; } // compute mean lengths including ends=0 for phasing singletons later for (int fb = 0; fb < 2; fb++) meanLens[fb] = std::accumulate(nonEndLens[fb].begin(), nonEndLens[fb].end(), 0) / (double) samples; hMeanLens[h] = std::max(meanLens[0], meanLens[1]); // set to max of fwd, rev // process ends: find most likely recombination points at which fwd and rev haps meet if (!endRefs[0].empty() && !endRefs[1].empty()) { for (uint k = 0; k < endRefs[0].size() && k < endRefs[1].size(); k++) { int refSeqFwd = endRefs[0][k], refSeqRev = endRefs[1][k]; int errFwd = 0, errRev = 0; for (uint64 m64j = m64jPrev+1; m64j < m64jNext; m64j++) { if ((genos64j[m64j] == 0 || genos64j[m64j] == 2) && (((haploBitsT[refSeqRev*Mseg64+m64j/64]>>(m64j&63))&1) != genos64j[m64j]/2)) errRev++; } // find recombination points that minimize errors (usually 0 errors) int minErr = 1<<30; vector cMdiffs; vector revStarts; for (uint64 m64j = m64jPrev; m64j < m64jNext; m64j++) { if (m64j != m64jPrev) { // update err counts if ((genos64j[m64j] == 0 || genos64j[m64j] == 2) && (((haploBitsT[refSeqFwd*Mseg64+m64j/64]>>(m64j&63))&1) != genos64j[m64j]/2)) errFwd++; if ((genos64j[m64j] == 0 || genos64j[m64j] == 2) && (((haploBitsT[refSeqRev*Mseg64+m64j/64]>>(m64j&63))&1) != genos64j[m64j]/2)) errRev--; } // rev starts at m64j+1 double cMdiff = cMs64j[m64j+1] - (m64j==-1ULL ? 0 : cMs64j[m64j]) + 1e-9; if (errFwd+errRev < minErr) { minErr = errFwd+errRev; cMdiffs.clear(); revStarts.clear(); } if (errFwd+errRev == minErr) { cMdiffs.push_back(cMdiff); revStarts.push_back(m64j+1); } } // augment dosages proportionally to cMdiffs (btwn consecutive SNPs) at recomb points double cMtot = std::accumulate(cMdiffs.begin(), cMdiffs.end(), 0.0); for (int m = 0; m < nMiss; m++) { double cMcum = 0; for (uint x = 0; x < revStarts.size(); x++) { if (miss64j[m] < revStarts[x]) cMcum += cMdiffs[x]; else break; } alleleDoses[m][(haploBitsT[refSeqFwd*Mseg64+miss64j[m]/64]>>(miss64j[m]&63))&1] += cMcum / cMtot; alleleDoses[m][(haploBitsT[refSeqRev*Mseg64+miss64j[m]/64]>>(miss64j[m]&63))&1] += 1 - cMcum / cMtot; } } } // make final calls for (int m = 0; m < nMiss; m++) { uint64 m64 = miss64j[m]/64, j = miss64j[m]&63; if (alleleDoses[m][0] >= alleleDoses[m][1]) tmpHaploBitsT[(nTargetHap+h)*Mseg64 + m64] &= ~(1ULL<= 0; i--) { if ((((refSamples[fb][t][s].haps[h].tMaskRev ^ refSamples[fb][t][s].haps[1-h].tMaskRev)>>i)&1) && splitGenos[t-i]==1) { uint64 m64j = splits64j[t-i-1]; cout << (((refSamples[fb][t][s].haps[h].tMaskRev>>i)&1) == ((pbwtBitsFine[m64j/64]>>(m64j&63))&1) ? "+" : "-"); } else cout << "."; } cout << "|"; for (int i = 0; i < 16; i++) { if ((((refSamples[fb][t][s].haps[h].tMaskFwd ^ refSamples[fb][t][s].haps[1-h].tMaskFwd)>>i)&1) && splitGenos[t+i+1]==1) { uint64 m64j = splits64j[t+i]; cout << (((refSamples[fb][t][s].haps[h].tMaskFwd>>i)&1) == ((pbwtBitsFine[m64j/64]>>(m64j&63))&1) ? "+" : "-"); } else cout << "."; } cout << " "; } cout << endl; } } } */ if (print && usePS) { int correct = 0; for (uint c = 0; c < conPS.size(); c++) { int m1 = conPS[c].first, m2 = abs(conPS[c].second), isOpp = conPS[c].second<0; uint m64j1 = m64jInds[m1], m64j2 = m64jInds[m2]; assert(genos64j[m64j1]==1 && genos64j[m64j2]==1); correct += (uint) isOpp == (((pbwtBitsFine[m64j1/64]>>(m64j1&63))&1) ^ ((pbwtBitsFine[m64j2/64]>>(m64j2&63))&1)); } cout << "constraints respected: " << correct << " / " << conPS.size() << endl; } return conf; } } Eagle-master/src/EagleParams.cpp000066400000000000000000000354011274444013000170420ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include "StringUtils.hpp" #include "FileUtils.hpp" #include "EagleParams.hpp" #include namespace EAGLE { using std::vector; using std::string; using std::cout; using std::cerr; using std::endl; // populates members; error-checks bool EagleParams::processCommandLineArgs(int argc, char *argv[]) { vector removeFileTemplates, excludeFileTemplates; string chromStr; // allow "X" namespace po = boost::program_options; po::options_description commonOptions; commonOptions.add_options() ("geneticMapFile", po::value(&geneticMapFile)->required(), "HapMap genetic map provided with download: tables/genetic_map_hg##.txt.gz") // "chr pos rate(cM/Mb) map(cM)" ("outPrefix", po::value(&outPrefix)->required(), "prefix for output files") ("numThreads", po::value(&numThreads)->default_value(1), "number of computational threads") ; po::options_description nonRefMode ("Input options for phasing without a reference"); nonRefMode.add_options() // genotype data parameters ("bfile", po::value(), "prefix of PLINK .fam, .bim, .bed files") ("bfilegz", po::value(), "prefix of PLINK .fam.gz, .bim.gz, .bed.gz files") ("fam", po::value(&famFile), "PLINK .fam file (note: file names ending in .gz are auto-decompressed)") ("bim", po::value(&bimFile), "PLINK .bim file") ("bed", po::value(&bedFile), "PLINK .bed file") ("vcf", po::value(&vcfFile), "[compressed] VCF/BCF file containing input genotypes") ("remove", po::value< vector >(&removeFileTemplates), "file(s) listing individuals to ignore (no header; FID IID must be first two columns)") ("exclude", po::value< vector >(&excludeFileTemplates), "file(s) listing SNPs to ignore (no header; SNP ID must be first column)") ("maxMissingPerSnp", po::value(&maxMissingPerSnp)->default_value(0.1, "0.1"), "QC filter: max missing rate per SNP") ("maxMissingPerIndiv", po::value(&maxMissingPerIndiv)->default_value(0.1, "0.1"), "QC filter: max missing rate per person") ; po::options_description refMode ("Input/output options for phasing using a reference panel"); refMode.add_options() ("vcfRef", po::value(&vcfRef), "tabix-indexed [compressed] VCF/BCF file for reference haplotypes") ("vcfTarget", po::value(&vcfTarget), "tabix-indexed [compressed] VCF/BCF file for target genotypes") ("vcfOutFormat", po::value(&vcfOutFormat)->default_value("z"), "b|u|z|v: compressed BCF (b), uncomp BCF (u), compressed VCF (z), uncomp VCF (v)") ("noImpMissing", "disable imputation of missing ./. target genotypes") ("allowRefAltSwap", "allow swapping of REF/ALT in target vs. ref VCF") ; po::options_description bothModes("Region selection options"); bothModes.add_options() ("chrom", po::value(&chromStr)->default_value("0"), "chromosome to analyze (if input has many)") ("bpStart", po::value(&bpStart)->default_value(0), "minimum base pair position to analyze") ("bpEnd", po::value(&bpEnd)->default_value(1e9, "1e9"), "maximum base pair position to analyze") ("bpFlanking", po::value(&bpFlanking)->default_value(0), "(ref-mode only) flanking region to use during phasing but discard in output") ; po::options_description algOptions("Algorithm options"); algOptions.add_options() ("Kpbwt", po::value(&Kpbwt)->default_value(10000), "number of conditioning haplotypes") // TODO: throw error if set in --v1 mode ("pbwtIters", po::value(&pbwtIters)->default_value(0), "number of PBWT phasing iterations (0=auto)") ("expectIBDcM", po::value(&expectIBDcM)->default_value(2, "2.0"), "expected length of haplotype copying (cM)") ("histFactor", po::value(&histFactor)->default_value(0, "0"), "history length multiplier (0=auto)") ("genoErrProb", po::value(&pErr)->default_value(0.003, "0.003"), "estimated genotype error probability") ("pbwtOnly", "in non-ref mode, use only PBWT iters (automatic for sequence data)") ("v1", "use Eagle1 phasing algorithm (instead of default Eagle2 algorithm)") ; po::options_description hidden("Hidden options"); hidden.add_options() ("help,h", "print help message with typical options") // experimental options ("usePS", po::value(&usePS)->default_value(0), "use FORMAT:PS phase constraints in target VCF: 1=soft, 2=harder") ("runStep2", po::value(&runStep2)->default_value(-1), "enable/disable Step 2 of non-ref algorithm (-1=auto)") ("chromX", po::value(&chromX)->default_value(23), "maximum chromosome number (chrX)") // Eagle1 advanced options ("v1fast", "Eagle1 fast mode: --maxBlockLen=0.3, --maxStatePairsStep4=100, --fracStep4=0.5") ("maxBlockLen", po::value(&cMmax)->default_value(0), "max length (in cM units) of a SNP block; increase to trade accuracy for speed (0=auto)") ("maxStatePairsStep3", po::value(&beamWidth3)->default_value(100), "maximum state pairs per position in dynamic programming (HMM-like) search (step 3)") ("maxStatePairsStep4", po::value(&beamWidth4)->default_value(200), "maximum state pairs per position in dynamic programming (HMM-like) search (step 4)") ("fracStep4", po::value(&fracStep4)->default_value(1), "fraction of samples to re-phase in 4th step") ("seed", po::value(&seed)->default_value(0), "random seed (ignored in ref-mode)") // error-checking ("noMapCheck", "disable automatic check of genetic map scale") // testing options ("iter", po::value(&iter)->default_value(0), "iter to run") ("maskFile", po::value(&maskFile), "indivs to mask (e.g., relatives)") ("tmpPhaseConfsPrefix", po::value(&tmpPhaseConfsPrefix), "prefix for tmp files of phase confidences") ("maxHapStates", po::value(&maxHapStates)->default_value(80), "maximum copying haplotype states per position in dynamic programming search") ("trioCheck", "flag to output trio check; assumes target samples are in child,mat,pat order") ; po::options_description visible("Options"); visible.add(commonOptions).add(nonRefMode).add(refMode).add(bothModes).add(algOptions); po::options_description all("All options"); all.add(commonOptions).add(nonRefMode).add(refMode).add(bothModes).add(algOptions).add(hidden); all.add_options() ("bad-args", po::value< vector >(), "bad args") ; po::positional_options_description positional_desc; positional_desc.add("bad-args", -1); // for error-checking command line po::variables_map vm; po::command_line_parser cmd_line(argc, argv); cmd_line.options(all); cmd_line.style(po::command_line_style::default_style ^ po::command_line_style::allow_guessing); cmd_line.positional(positional_desc); try { po::store(cmd_line.run(), vm); if (vm.count("help")) { cout << endl; cout << visible << endl; exit(0); } po::notify(vm); // throws an error if there are any problems usePBWT = !vm.count("v1"); pbwtOnly = vm.count("pbwtOnly"); if (pbwtOnly && !usePBWT) { cerr << "ERROR: --pbwtOnly cannot be specified if using the --v1 algorithm" << endl; return false; } trioCheck = vm.count("trioCheck"); if (vm.count("bfile") + vm.count("bfilegz") + (vm.count("fam") || vm.count("bim") || vm.count("bed")) + vm.count("vcf") + (vm.count("vcfRef") || vm.count("vcfTarget")) != 1) { cerr << "ERROR: Use exactly one of the --bfile, --bfilegz, --fam,bim,bed, --vcf, or" << endl << " --vcfRef,vcfTarget input formats" << endl; return false; } if (vm.count("bfile")) { string bfile = vm["bfile"].as(); famFile = bfile + ".fam"; bimFile = bfile + ".bim"; bedFile = bfile + ".bed"; } if (vm.count("bfilegz")) { string bfile = vm["bfilegz"].as(); famFile = bfile + ".fam.gz"; bimFile = bfile + ".bim.gz"; bedFile = bfile + ".bed.gz"; } if (vm.count("bad-args")) { cerr << "ERROR: Unknown options:"; vector bad_args = vm["bad-args"].as< vector >(); for (uint i = 0; i < bad_args.size(); i++) cerr << " " << bad_args[i]; cerr << endl; return false; } noMapCheck = vm.count("noMapCheck"); noImpMissing = vm.count("noImpMissing"); allowRefAltSwap = vm.count("allowRefAltSwap"); if (vm.count("vcfRef") || vm.count("vcfTarget") || vm.count("vcf")) { // VCF mode if (vm.count("vcf")) { // non-ref mode if (noImpMissing) { cerr << "ERROR: --noImpMissing is only supported in ref-mode" << endl; return false; } if (bpFlanking != 0) { cerr << "ERROR: --bpFlanking is only supported in ref-mode" << endl; return false; } } else { // ref-mode if (vcfRef.empty()) { cerr << "ERROR: --vcfRef must be specified in reference-based phasing mode" << endl; return false; } if (vcfTarget.empty()) { cerr << "ERROR: --vcfTarget must be specified in reference-based phasing mode" << endl; return false; } if (pbwtIters > 1 && noImpMissing) { cerr << "ERROR: --pbwtIters cannot be greater than 1 if --noImpMissing is set" << endl; return false; } } // vcf input checks for both ref and non-ref mode if (geneticMapFile == "USE_BIM") { cerr << "ERROR: --geneticMapFile must be specified when using VCF/BCF input" << endl; return false; } if (!removeFileTemplates.empty() || !excludeFileTemplates.empty() || maxMissingPerSnp != 0.1 || maxMissingPerIndiv != 0.1) { cerr << "ERROR: --remove, --exclude, --maxMissingPerSnp, --maxMissingPerIndiv" << " are not supported for VCF/BCF input or in reference mode" << endl; return false; } if (vcfOutFormat == "b") { vcfOutSuffix = "bcf"; vcfWriteMode = "wb"; } else if (vcfOutFormat == "u") { vcfOutSuffix = "bcf"; vcfWriteMode = "wbu"; } else if (vcfOutFormat == "z") { vcfOutSuffix = "vcf.gz"; vcfWriteMode = "wz"; } else if (vcfOutFormat == "v") { vcfOutSuffix = "vcf"; vcfWriteMode = "w"; } else { cerr << "ERROR: --vcfOutFormat must be one of {b,u,z,v}" << endl; return false; } if (bpFlanking < 0) { cerr << "ERROR: --bpFlanking cannot be negative" << endl; return false; } } else { // non-ref mode if (famFile.empty()) { cerr << "ERROR: fam file must be specified either using --fam or --bfile" << endl; return false; } if (bimFile.empty()) { cerr << "ERROR: bim file must be specified either using --bim or --bfile" << endl; return false; } if (bedFile.empty()) { cerr << "ERROR: bed file must be specified either using --bed or --bfile" << endl; return false; } if (noImpMissing) { cerr << "ERROR: --noImpMissing is only supported in ref-mode" << endl; return false; } if (bpFlanking != 0) { cerr << "ERROR: --bpFlanking is only supported in ref-mode" << endl; return false; } } removeFiles = StringUtils::expandRangeTemplates(removeFileTemplates); excludeFiles = StringUtils::expandRangeTemplates(excludeFileTemplates); if (!(0 <= maxMissingPerSnp && maxMissingPerSnp <= 1)) { cerr << "ERROR: --maxMissingPerSnp must be between 0 and 1" << endl; return false; } if (!(0 <= maxMissingPerIndiv && maxMissingPerIndiv <= 1)) { cerr << "ERROR: --maxMissingPerIndiv must be between 0 and 1" << endl; return false; } chrom = StringUtils::bcfNameToChrom(chromStr.c_str(), 0, chromX); // checks for range if (pbwtIters < 0 || pbwtIters > 3) { cerr << "ERROR: --pbwtIters must be either 0=auto, 1, 2, or 3" << endl; return false; } // check advanced options if (vm.count("v1fast")) { cMmax = 0.5; beamWidth3 = 100; beamWidth4 = 100; fracStep4 = 0.5; } if ((cMmax != 0 && cMmax < 0.1) || cMmax > 1.0) { cerr << "ERROR: --maxBlockLen must be 0=auto or between 0.1 and 1 cM" << endl; return false; } if (beamWidth3 < 10 || beamWidth3 > 1000) { cerr << "ERROR: --maxStatePairsStep3 must be between 10 and 1000" << endl; return false; } if (beamWidth4 < 10 || beamWidth4 > 1000) { cerr << "ERROR: --maxStatePairsStep4 must be between 10 and 1000" << endl; return false; } if (maxHapStates < 40 || maxHapStates > 1000) { cerr << "ERROR: --maxHapStates must be between 40 and 1000" << endl; return false; } if (fracStep4 < 0.0 || fracStep4 > 1.0) { cerr << "ERROR: --fracStep4 must be between 0.0 and 1.0" << endl; return false; } if (pErr < 1e-6 || pErr > 0.1) { cerr << "ERROR: --genoErrProb must be between 0.000001 and 0.1" << endl; return false; } // check that all files specified are readable/writeable FileUtils::requireEmptyOrReadable(famFile); FileUtils::requireEmptyOrReadable(bimFile); FileUtils::requireEmptyOrReadable(bedFile); FileUtils::requireEmptyOrReadable(vcfRef); FileUtils::requireEmptyOrReadable(vcfTarget); if (geneticMapFile != "USE_BIM") { vector reqHeader; reqHeader.push_back("chr"); reqHeader.push_back("position"); reqHeader.push_back("COMBINED_rate(cM/Mb)"); reqHeader.push_back("Genetic_Map(cM)"); if (FileUtils::parseHeader(geneticMapFile, " \t") != reqHeader) { cerr << "ERROR: --geneticMapFile must have four columns with names:" << endl << " chr position COMBINED_rate(cM/Mb) Genetic_Map(cM)" << endl; return false; } } FileUtils::requireEachEmptyOrReadable(removeFiles); FileUtils::requireEachEmptyOrReadable(excludeFiles); } catch (po::error &e) { cerr << "ERROR: " << e.what() << endl << endl; cerr << visible << endl; return false; } return true; } } Eagle-master/src/EagleParams.hpp000066400000000000000000000047201274444013000170470ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef EAGLEPARAMS_HPP #define EAGLEPARAMS_HPP #include #include #include "Types.hpp" namespace EAGLE { class EagleParams { public: // main input files std::string famFile, bimFile, bedFile, vcfFile, vcfRef, vcfTarget; int chrom, chromX; // optional reference map file for filling in genpos std::string geneticMapFile; std::vector removeFiles; // list(s) of indivs to remove std::vector excludeFiles; // list(s) of SNPs to exclude double bpStart, bpEnd, bpFlanking; std::string outPrefix; // .haps.gz .sample std::string vcfOutFormat, vcfOutSuffix, vcfWriteMode; // outFormat b|u|z|v -> outSuffix bcf|bcf|vcf.gz|vcf, writeMode wb|wbu|wz|w bool noImpMissing; int usePS; // use FORMAT:PS phase constraints: 1=soft, 2=harder bool allowRefAltSwap; // in reference-based phasing mode bool usePBWT; bool pbwtOnly; // in non-ref mode, don't run Steps 1 or 2 int runStep2; // in non-ref mode, do/don't run Step 2 int pbwtIters; double expectIBDcM; // expected length of an IBD segment (for transition probabilities) double histFactor; // history length multiplier // QC params double maxMissingPerSnp, maxMissingPerIndiv; int numThreads; double cMmax; int beamWidth3, beamWidth4; int maxHapStates; double fracStep4; double pErr; uint seed; bool noMapCheck; int Kpbwt; // testing int iter; std::string tmpPhaseConfsPrefix; std::string maskFile; // list of indivs to mask (e.g., relatives) bool trioCheck; // populates members; error-checks bool processCommandLineArgs(int argc, char *argv[]); }; } #endif Eagle-master/src/FileUtils.cpp000066400000000000000000000136761274444013000165730ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include "StringUtils.hpp" #include "FileUtils.hpp" #include "Types.hpp" #include #include namespace FileUtils { using std::string; using std::vector; using std::cerr; using std::endl; void openOrExit(std::ifstream &stream, const string &file, std::ios_base::openmode mode) { stream.open(file.c_str(), mode); if (!stream) { cerr << "ERROR: Unable to open file: " << file << endl; exit(1); } } void openWritingOrExit(std::ofstream &stream, const string &file, std::ios_base::openmode mode) { stream.open(file.c_str(), mode); if (!stream) { cerr << "ERROR: Unable to open file for writing: " << file << endl; exit(1); } } void requireEmptyOrReadable(const std::string &file) { if (file.empty()) return; std::ifstream fin; fin.open(file.c_str()); if (!fin) { cerr << "ERROR: Unable to open file: " << file << endl; exit(1); } fin.close(); } void requireEachEmptyOrReadable(const std::vector &fileList) { for (uint i = 0; i < fileList.size(); i++) requireEmptyOrReadable(fileList[i]); } void requireEmptyOrWriteable(const std::string &file) { if (file.empty()) return; std::ofstream fout; fout.open(file.c_str(), std::ios::out|std::ios::app); if (!fout) { cerr << "ERROR: Output file is not writeable: " << file << endl; exit(1); } fout.close(); } vector parseHeader(const string &fileName, const string &delimiters) { AutoGzIfstream fin; fin.openOrExit(fileName); string header; getline(fin, header); vector split = StringUtils::tokenizeMultipleDelimiters(header, delimiters); fin.close(); return split; } int lookupColumnInd(const string &fileName, const string &delimiters, const string &columnName) { vector headers = parseHeader(fileName, delimiters); int columnInd = -1; for (uint c = 0; c < headers.size(); c++) if (headers[c] == columnName) columnInd = c; // first column is snp ID, treated separately if (columnInd == -1) { cerr << "WARNING: Column " << columnName << " not found in headers of " << fileName << endl; //exit(1); } return columnInd; } double readDoubleNanInf(std::istream &stream) { string str; stream >> str; double x; sscanf(str.c_str(), "%lf", &x); return x; } vector < std::pair > readFidIids(const string &file) { vector < std::pair > ret; AutoGzIfstream fin; fin.openOrExit(file); string FID, IID, line; while (fin >> FID >> IID) { if (FID.empty() || IID.empty()) { cerr << "ERROR: In file " << file << endl; cerr << " unable to read FID and IID; check format" << endl; exit(1); } ret.push_back(make_pair(FID, IID)); getline(fin, line); } fin.close(); return ret; } int AutoGzIfstream::lineCount(const std::string &file) { AutoGzIfstream fin; fin.openOrExit(file); int ctr = 0; string line; while (getline(fin, line)) ctr++; return ctr; } /***** AutoGzIfstream class implementation *****/ void AutoGzIfstream::openOrExit(const std::string &file, std::ios_base::openmode mode) { fin.open(file.c_str(), mode); if (!fin) { cerr << "ERROR: Unable to open file: " << file << endl; exit(1); } if ((int) file.length() > 3 && file.substr(file.length()-3) == ".gz") boost_in.push(boost::iostreams::gzip_decompressor()); boost_in.push(fin); } void AutoGzIfstream::close() { fin.close(); boost_in.reset(); } AutoGzIfstream::operator bool() const { return boost_in; } AutoGzIfstream& AutoGzIfstream::read(char *s, std::streamsize n) { boost_in.read(s, n); return *this; } int AutoGzIfstream::get() { return boost_in.get(); } double AutoGzIfstream::readDoubleNanInf() { return FileUtils::readDoubleNanInf(boost_in); } void AutoGzIfstream::clear() { boost_in.clear(); } AutoGzIfstream& AutoGzIfstream::seekg(std::streamoff off, std::ios_base::seekdir way) { boost_in.seekg(off, way); return *this; } AutoGzIfstream& getline(AutoGzIfstream& in, std::string &s) { std::getline(in.boost_in, s); return in; } /***** AutoGzOfstream class implementation *****/ void AutoGzOfstream::openOrExit(const std::string &file, std::ios_base::openmode mode) { fout.open(file.c_str(), mode); if (!fout) { cerr << "ERROR: Unable to open file: " << file << endl; exit(1); } if ((int) file.length() > 3 && file.substr(file.length()-3) == ".gz") boost_out.push(boost::iostreams::gzip_compressor()); boost_out.push(fout); } void AutoGzOfstream::close() { boost_out.reset(); } AutoGzOfstream& AutoGzOfstream::operator << (std::ostream&(*manip)(std::ostream&)) { manip(boost_out); return *this; } void AutoGzOfstream::unsetf(std::ios_base::fmtflags mask) { boost_out.unsetf(mask); } AutoGzOfstream::operator bool() const { return boost_out; } } Eagle-master/src/FileUtils.hpp000066400000000000000000000057211274444013000165700ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef FILEUTILS_HPP #define FILEUTILS_HPP #include #include #include #include "StringUtils.hpp" #include namespace FileUtils { void openOrExit(std::ifstream &stream, const std::string &file, std::ios_base::openmode mode=std::ios::in); void openWritingOrExit(std::ofstream &stream, const std::string &file, std::ios_base::openmode mode=std::ios::out); void requireEmptyOrReadable(const std::string &file); void requireEachEmptyOrReadable(const std::vector &fileList); void requireEmptyOrWriteable(const std::string &file); std::vector parseHeader(const std::string &fileName, const std::string &delimiters); int lookupColumnInd(const std::string &fileName, const std::string &delimiters, const std::string &columnName); double readDoubleNanInf(std::istream &stream); std::vector < std::pair > readFidIids(const std::string &file); class AutoGzIfstream { boost::iostreams::filtering_istream boost_in; std::ifstream fin; public: static int lineCount(const std::string &file); void openOrExit(const std::string &file, std::ios_base::openmode mode=std::ios::in); void close(); template AutoGzIfstream& operator >> (T &x) { boost_in >> x; return *this; } operator bool() const; AutoGzIfstream& read(char *s, std::streamsize n); int get(); double readDoubleNanInf(); void clear(); AutoGzIfstream& seekg(std::streamoff off, std::ios_base::seekdir way); friend AutoGzIfstream& getline(AutoGzIfstream& in, std::string &s); }; AutoGzIfstream& getline(AutoGzIfstream& in, std::string &s); class AutoGzOfstream { boost::iostreams::filtering_ostream boost_out; std::ofstream fout; public: void openOrExit(const std::string &file, std::ios_base::openmode mode=std::ios::out); void close(); template AutoGzOfstream& operator << (const T &x) { boost_out << x; return *this; } AutoGzOfstream& operator << (std::ostream&(*manip)(std::ostream&)); void unsetf(std::ios_base::fmtflags); operator bool() const; }; } #endif Eagle-master/src/GenoData.cpp000066400000000000000000000732611274444013000163510ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include #include #include "Types.hpp" #include "FileUtils.hpp" #include "MemoryUtils.hpp" #include "MapInterpolater.hpp" #include "LapackConst.hpp" #include "GenoData.hpp" namespace EAGLE { using std::vector; using std::string; using std::cout; using std::cerr; using std::endl; using FileUtils::getline; int GenoData::plinkChromCode(const string &chrom) { if (isdigit(chrom[0])) return atoi(chrom.c_str()); if (chrom == "X") return 23; if (chrom == "Y") return 24; if (chrom == "XY") return 25; if (chrom == "MT") return 26; return -1; } // set indivsPreQC, NpreQC // return bedIndivRemoved vector GenoData::processIndivs(const string &famFile, const vector &removeFiles) { std::map FID_IID_to_ind; string line; vector bedIndivs; cout << "Reading fam file: " << famFile << endl; FileUtils::AutoGzIfstream fin; fin.openOrExit(famFile); while (getline(fin, line)) { std::istringstream iss(line); IndivInfoX indiv; if (!(iss >> indiv.famID >> indiv.indivID >> indiv.paternalID >> indiv.maternalID >> indiv.sex >> indiv.pheno)) { cerr << "ERROR: Incorrectly formatted fam file: " << famFile << endl; cerr << "Line " << bedIndivs.size()+1 << ":" << endl; cerr << line << endl; cerr << "Unable to input 6 values (4 string, 1 int, 1 double)" << endl; exit(1); } string combined_ID = indiv.famID + " " + indiv.indivID; if (FID_IID_to_ind.find(combined_ID) != FID_IID_to_ind.end()) { cerr << "ERROR: Duplicate individual in fam file at line " << bedIndivs.size()+1 << endl; exit(1); } FID_IID_to_ind[combined_ID] = bedIndivs.size(); bedIndivs.push_back(indiv); } fin.close(); uint64 Nbed = bedIndivs.size(); cout << "Total indivs in PLINK data: Nbed = " << Nbed << endl; // process individuals to remove vector bedIndivRemoved(Nbed); for (uint f = 0; f < removeFiles.size(); f++) { const string &removeFile = removeFiles[f]; cout << "Reading remove file (indivs to remove): " << removeFile << endl; fin.openOrExit(removeFile); int lineCtr = 0; int numRemoved = 0; int numAbsent = 0; while (getline(fin, line)) { lineCtr++; std::istringstream iss(line); string FID, IID; if (!(iss >> FID >> IID)) { cerr << "ERROR: Incorrectly formatted remove file: " << removeFile << endl; cerr << "Line " << lineCtr << ":" << endl; cerr << line << endl; cerr << "Unable to input FID and IID" << endl; exit(1); } string combined_ID = FID + " " + IID; if (FID_IID_to_ind.find(combined_ID) == FID_IID_to_ind.end()) { if (numAbsent < 5) cerr << "WARNING: Unable to find individual to remove: " << combined_ID << endl; numAbsent++; } else if (!bedIndivRemoved[FID_IID_to_ind[combined_ID]]) { bedIndivRemoved[FID_IID_to_ind[combined_ID]] = true; numRemoved++; } } fin.close(); cout << "Removed " << numRemoved << " individual(s)" << endl; if (numAbsent) cerr << "WARNING: " << numAbsent << " individual(s) not found in data set" << endl; } for (uint64 nbed = 0; nbed < Nbed; nbed++) if (!bedIndivRemoved[nbed]) indivsPreQC.push_back(bedIndivs[nbed]); NpreQC = indivsPreQC.size(); cout << "Total indivs stored in memory: NpreQC = " << NpreQC << endl; return bedIndivRemoved; } vector GenoData::readBimFile(const string &bimFile) { vector ret; string line; FileUtils::AutoGzIfstream fin; fin.openOrExit(bimFile); int numOutOfOrder = 0; while (getline(fin, line)) { std::istringstream iss(line); SnpInfoX snp; string chrom_str; if (!(iss >> chrom_str >> snp.ID >> snp.genpos >> snp.physpos >> snp.allele1 >> snp.allele2)) { cerr << "ERROR: Incorrectly formatted bim file: " << bimFile << endl; cerr << "Line " << ret.size()+1 << ":" << endl; cerr << line << endl; cerr << "Unable to input 6 values (2 string, 1 double, 1 int, 2 string)" << endl; exit(1); } snp.chrom = plinkChromCode(chrom_str); if (snp.chrom == -1) { cerr << "ERROR: Unknown chromosome code in bim file: " << bimFile << endl; cerr << "Line " << ret.size()+1 << ":" << endl; cerr << line << endl; exit(1); } if (!ret.empty() && (snp.chrom < ret.back().chrom || (snp.chrom == ret.back().chrom && (snp.physpos <= ret.back().physpos || snp.genpos < ret.back().genpos)))) { if (numOutOfOrder < 5) { cerr << "WARNING: Out-of-order snp in bim file: " << bimFile << endl; cerr << "Line " << ret.size()+1 << ":" << endl; cerr << line << endl; } numOutOfOrder++; //exit(1); } ret.push_back(snp); } if (numOutOfOrder) cerr << "WARNING: Total number of out-of-order snps in bim file: " << numOutOfOrder << endl; fin.close(); // TODO: exit with error or sort SNPs? return ret; } // set snpsPreQC, MpreQC // return bedSnpExcluded vector GenoData::processSnps(const string &bimFile, int chrom, double bpStart, double bpEnd, const vector &excludeFiles) { FileUtils::AutoGzIfstream fin; string line; // read bim file cout << "Reading bim file: " << bimFile << endl; vector bedSnps = readBimFile(bimFile); uint64 Mbed = bedSnps.size(); cout << "Total snps in PLINK data: Mbed = " << Mbed << endl; vector bedSnpExcluded(Mbed); if (chrom == 0) { if (bedSnps[0].chrom != bedSnps.back().chrom) { cerr << "ERROR: Only one chromosome may be analyzed at a time; use --chrom" << endl; exit(1); } else chrom = bedSnps[0].chrom; } uint64 MbedOnChrom = 0; for (uint64 mbed = 0; mbed < Mbed; mbed++) { if (bedSnps[mbed].chrom != chrom || bedSnps[mbed].physpos < bpStart || bedSnps[mbed].physpos > bpEnd) bedSnpExcluded[mbed] = true; else MbedOnChrom++; } if (MbedOnChrom < Mbed) { cout << "Restricting to " << MbedOnChrom << " SNPs on chrom " << chrom << " in region [bpStart,bpEnd] = [" << bpStart << "," << bpEnd << "]" << endl; } // create dictionary rsID -> index in full bed snp list std::map rsID_to_ind; for (uint64 mbed = 0; mbed < Mbed; mbed++) { if (rsID_to_ind.find(bedSnps[mbed].ID) != rsID_to_ind.end()) { cerr << "WARNING: Duplicate snp ID " << bedSnps[mbed].ID << " -- masking duplicate" << endl; bedSnpExcluded[mbed] = true; } else rsID_to_ind[bedSnps[mbed].ID] = mbed; } // TODO: also limit SNP density (e.g., Omni 2.5M) and/or MAF? // process snps to exclude for (uint f = 0; f < excludeFiles.size(); f++) { const string &excludeFile = excludeFiles[f]; cout << "Reading exclude file (SNPs to exclude): " << excludeFile << endl; fin.openOrExit(excludeFile); int numExcluded = 0; int numAbsent = 0; while (getline(fin, line)) { std::istringstream iss(line); string rsID; iss >> rsID; if (rsID_to_ind.find(rsID) == rsID_to_ind.end()) { if (numAbsent < 5) cerr << "WARNING: Unable to find SNP to exclude: " << rsID << endl; numAbsent++; } else if (!bedSnpExcluded[rsID_to_ind[rsID]]) { bedSnpExcluded[rsID_to_ind[rsID]] = true; numExcluded++; } } fin.close(); cout << "Excluded " << numExcluded << " SNP(s)" << endl; if (numAbsent) cerr << "WARNING: " << numAbsent << " SNP(s) not found in data set" << endl; } for (uint64 mbed = 0; mbed < Mbed; mbed++) if (!bedSnpExcluded[mbed]) snpsPreQC.push_back(bedSnps[mbed]); MpreQC = snpsPreQC.size(); cout << "Total SNPs stored in memory: MpreQC = " << MpreQC << endl; return bedSnpExcluded; } void GenoData::processMap(vector &snpsVec, const string &geneticMapFile, bool noMapCheck) { // fill in map if external file provided if (geneticMapFile != "USE_BIM") { cout << "Filling in genetic map coordinates using reference file:" << endl; cout << " " << geneticMapFile << endl; Genetics::MapInterpolater mapInterpolater(geneticMapFile); for (uint64 m = 0; m < snpsVec.size(); m++) snpsVec[m].genpos = mapInterpolater.interp(snpsVec[m].chrom, snpsVec[m].physpos); } else { // check map and rescale if in cM units: calculate d(genpos)/d(physpos) double scale = (snpsVec.back().genpos - snpsVec[0].genpos) / (snpsVec.back().physpos - snpsVec[0].physpos); if (0.5e-6 < scale && scale < 3e-6) { cerr << "WARNING: Genetic map appears to be in cM units; rescaling by 0.01" << endl; for (uint64 m = 0; m < snpsVec.size(); m++) snpsVec[m].genpos *= 0.01; } else if (!(0.5e-8 < scale && scale < 3e-8)) { if (noMapCheck) { cerr << "WARNING: Genetic map appears wrong based on overall cM/Mb" << endl; cerr << " Proceeding anyway because --noMapCheck is set" << endl; } else { cerr << "ERROR: Genetic map appears wrong based on overall cM/Mb" << endl; cerr << " To proceed anyway, set --noMapCheck" << endl; exit(1); } } } } inline double log10safe(double x) { return x > 0 ? log10(x) : -1000; } void GenoData::buildGenoBits(uchar *genosPreQC, const vector &genos2bit, double cMmax) { const uint segMin = 16; vector preQCsnpInds; vector cMvec; for (uint64 m = 0; m < MpreQC; m++) if (snpsPreQC[m].passQC) { if (preQCsnpInds.size() == 64 || (preQCsnpInds.size() >= segMin && snpsPreQC[m].genpos > snpsPreQC[preQCsnpInds[0]].genpos + cMmax/100)) { seg64preQCsnpInds.push_back(preQCsnpInds); seg64cMvecs.push_back(cMvec); preQCsnpInds.clear(); cMvec.clear(); } preQCsnpInds.push_back(m); cMvec.push_back(100 * snpsPreQC[m].genpos); } seg64preQCsnpInds.push_back(preQCsnpInds); seg64cMvecs.push_back(cMvec); Mseg64 = seg64preQCsnpInds.size(); cout << "Number of <=(64-SNP, " << cMmax << "cM) segments: " << Mseg64 << endl; cout << "Average # SNPs per segment: " << M / Mseg64 << endl; isFlipped64j = vector (Mseg64*64); genoBits = ALIGNED_MALLOC_UINT64_MASKS(Mseg64 * N); memset(genoBits, 0, Mseg64 * N * sizeof(genoBits[0])); seg64logPs = (AlleleFreqs *) ALIGNED_MALLOC(Mseg64*64 * sizeof(AlleleFreqs)); for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) for (uint g1 = 0; g1 <= 2; g1++) for (uint g0 = 0; g0 <= 3; g0++) seg64logPs[m64j].cond[g1][g0] = NAN; for (uint64 m64 = 0; m64 < Mseg64; m64++) { for (uint64 j = 0; j < seg64preQCsnpInds[m64].size(); j++) { uint64 m = seg64preQCsnpInds[m64][j]; // m, n indices are preQC int genoCounts[3]; genoCounts[0] = genoCounts[1] = genoCounts[2] = 0; for (uint64 n = 0; n < NpreQC; n++) if (indivsPreQC.empty() || indivsPreQC[n].passQC) { uchar geno = genosPreQC != NULL ? genosPreQC[m * NpreQC + n] : (genos2bit[2*(m * NpreQC + n)] + 2*genos2bit[2*(m * NpreQC + n)+1]); if (geno <= 2) genoCounts[geno]++; } uchar is0geno = 0, is2geno = 2; if (genoCounts[2] > genoCounts[0]) { isFlipped64j[m64*64+j] = true; is0geno = 2; is2geno = 0; std::swap(genoCounts[0], genoCounts[2]); } uint64 nPostQC = 0; for (uint64 n = 0; n < NpreQC; n++) if (indivsPreQC.empty() || indivsPreQC[n].passQC) { uchar geno = genosPreQC != NULL ? genosPreQC[m * NpreQC + n] : (genos2bit[2*(m * NpreQC + n)] + 2*genos2bit[2*(m * NpreQC + n)+1]); genoBits[m64 * N + nPostQC].is0 |= ((uint64) (geno == is0geno))< 2))< p(hap=1) = 1-p af.cond[2][4] = log10safe((1-p) * p2 / (p1half + p2)); af.cond[1][4] = log10safe((1-p) * p1half / (p1half + p2) + p * p1half / (p0 + p1half)); af.cond[0][4] = log10safe(p * p0 / (p0 + p1half)); // opp orientation to het-het => p(hap=1) = p af.cond[2][5] = log10safe(p * p2 / (p1half + p2)); af.cond[1][5] = log10safe(p * p1half / (p1half + p2) + (1-p) * p1half / (p0 + p1half)); af.cond[0][5] = log10safe((1-p) * p0 / (p0 + p1half)); if (p > 0.55) { cerr << "INTERNAL ERROR: Minor/major allele coding bug" << endl; exit(1); } } for (uint64 n = 0; n < N; n++) for (uint64 j = seg64preQCsnpInds[m64].size(); j < 64; j++) genoBits[m64*N+n].is9 |= 1ULL< &indivInds) const { uint64 m64 = m64j/64, j = m64j&63, jBit = 1ULL< GenoData::computeInvLD64j(uint64 NsubMax) const { uint64 Mchr = Mseg64*64; vector chipLDscores(Mchr, 1.0); uint64 step = std::max(N / NsubMax, 1ULL); vector indivInds; for (uint64 n = 0; n < N && indivInds.size() < NsubMax; n += step) indivInds.push_back(n); uint64 Nsub = indivInds.size(); cout << "Estimating LD scores using " << Nsub << " indivs" << endl; // allocate memory uchar *chrMaskSnps = ALIGNED_MALLOC_UCHARS(Mchr); memset(chrMaskSnps, 0, Mchr * sizeof(chrMaskSnps[0])); float *chrNormalizedGenos = ALIGNED_MALLOC_FLOATS(Mchr * Nsub); memset(chrNormalizedGenos, 0, Mchr * Nsub * sizeof(chrNormalizedGenos[0])); const int mBlock = 64; float *dotProds = ALIGNED_MALLOC_FLOATS(Mchr * mBlock); // fill and normalize genotypes for (uint64 mchr = 0; mchr < Mchr; mchr++) { if ((mchr&63) < seg64cMvecs[mchr/64].size()) chrMaskSnps[mchr] = fillSnpSubRowNorm1(chrNormalizedGenos + mchr*Nsub, mchr, indivInds); else chipLDscores[mchr] = 0; } uint64 mchrWindowStart = 0; for (uint64 mchr0 = 0; mchr0 < Mchr; mchr0 += mBlock) { // sgemm to compute r2s uint64 mBlockCrop = std::min(Mchr, mchr0+mBlock) - mchr0; while ((mchrWindowStart&63) >= seg64cMvecs[mchrWindowStart/64].size() || seg64cMvecs[mchrWindowStart/64][mchrWindowStart&63] + 1 < seg64cMvecs[mchr0/64][mchr0&63]) mchrWindowStart++; uint64 prevWindowSize = mchr0+mBlockCrop-1 - mchrWindowStart; // [mchrWindowStart..mchr0+mBlockCrop-1) x [mchr0..mchr0+mBlockCrop) { char TRANSA_ = 'T'; char TRANSB_ = 'N'; int M_ = prevWindowSize; int N_ = mBlockCrop; int K_ = Nsub; float ALPHA_ = 1; float *A_ = chrNormalizedGenos + mchrWindowStart*Nsub; int LDA_ = Nsub; float *B_ = chrNormalizedGenos + mchr0*Nsub; int LDB_ = Nsub; float BETA_ = 0; float *C_ = dotProds; int LDC_ = prevWindowSize; SGEMM_MACRO(&TRANSA_, &TRANSB_, &M_, &N_, &K_, &ALPHA_, A_, &LDA_, B_, &LDB_, &BETA_, C_, &LDC_); } for (uint64 mPlus = 0; mPlus < mBlockCrop; mPlus++) { uint64 m = mchr0 + mPlus; if (!chrMaskSnps[m]) continue; for (uint64 mPlus2 = 0; mchrWindowStart+mPlus2 < mchr0+mPlus; mPlus2++) { uint64 m2 = mchrWindowStart + mPlus2; if (!chrMaskSnps[m2]) continue; float adjR2 = dotProdToAdjR2(dotProds[mPlus2 + mPlus*prevWindowSize], Nsub); chipLDscores[m] += adjR2; chipLDscores[m2] += adjR2; } } } ALIGNED_FREE(dotProds); ALIGNED_FREE(chrNormalizedGenos); ALIGNED_FREE(chrMaskSnps); for (uint mchr = 0; mchr < Mchr; mchr++) chipLDscores[mchr] = 1/chipLDscores[mchr]; return chipLDscores; // reciprocals taken above } void GenoData::printRange(void) const { int physRange = snps.back().physpos - snps[0].physpos; double cMrange = 100*(snps.back().genpos - snps[0].genpos); cout << "Physical distance range: " << physRange << " base pairs" << endl; cout << "Genetic distance range: " << cMrange << " cM" << endl; cout << "Average # SNPs per cM: " << (int) (M/cMrange+0.5) << endl; if (physRange == 0 || cMrange == 0) { cerr << "ERROR: Physical and genetic distance ranges must be positive" << endl; cerr << " First SNP: chr=" << snps[0].chrom << " pos=" << snps[0].physpos << " cM=" << 100*snps[0].genpos << endl; cerr << " Last SNP: chr=" << snps.back().chrom << " pos=" << snps.back().physpos << " cM=" << 100*snps.back().genpos << endl; exit(1); } } double GenoData::computeSnpRate(void) const { double cMrange = 100*(snps.back().genpos - snps[0].genpos); return M/cMrange; } /** * reads indiv info from fam file, snp info from bim file * allocates memory, reads genotypes, and does QC */ void GenoData::initBed(const string &famFile, const string &bimFile, const string &bedFile, int chrom, double bpStart, double bpEnd, const string &geneticMapFile, const vector &excludeFiles, const vector &removeFiles, double maxMissingPerSnp, double maxMissingPerIndiv, bool noMapCheck, double cMmax) { // indivsPreQC (without --remove indivs) vector bedIndivRemoved = processIndivs(famFile, removeFiles); // snpsPreQC (restricted to chrom:bpStart-bpEnd and without --exclude snps) vector bedSnpExcluded = processSnps(bimFile, chrom, bpStart, bpEnd, excludeFiles); processMap(snpsPreQC, geneticMapFile, noMapCheck); // modify snpsPreQC // allocate genotypes cout << "Allocating " << MpreQC << " x " << NpreQC << " bytes to temporarily store genotypes" << endl; uchar *genosPreQC = ALIGNED_MALLOC_UCHARS(MpreQC * NpreQC); // temporary cout << "Reading genotypes and performing QC filtering on snps and indivs..." << endl; // open bed file const uint64 Nbed = bedIndivRemoved.size(), Mbed = bedSnpExcluded.size(); cout << "Reading bed file: " << bedFile << endl; cout << " Expecting " << Mbed * ((Nbed+3)>>2) << " (+3) bytes for " << Nbed << " indivs, " << Mbed << " snps" << endl; FileUtils::AutoGzIfstream fin; fin.openOrExit(bedFile, std::ios::in | std::ios::binary); uchar header[3]; fin.read((char *) header, 3); if (!fin || header[0] != 0x6c || header[1] != 0x1b || header[2] != 0x01) { cerr << "ERROR: Incorrect first three bytes of bed file: " << bedFile << endl; exit(1); } // read genos + QC snps (and record indiv miss rates) vector numMissingPerIndiv(NpreQC); uchar *bedLineIn = ALIGNED_MALLOC_UCHARS((Nbed+3)>>2); int numSnpsFailedQC = 0; uint64 m = 0; for (uint64 mbed = 0; mbed < Mbed; mbed++) { uchar *genoLine = genosPreQC + m*NpreQC; readBedLine(fin, bedLineIn, genoLine, bedIndivRemoved, !bedSnpExcluded[mbed]); if (!bedSnpExcluded[mbed]) { snpsPreQC[m].MAF = computeMAF(genoLine, NpreQC); snpsPreQC[m].miss = computeSnpMissing(genoLine, NpreQC); snpsPreQC[m].passQC = snpsPreQC[m].miss <= maxMissingPerSnp; if (snpsPreQC[m].passQC) { for (uint64 n = 0; n < NpreQC; n++) numMissingPerIndiv[n] += genoLine[n] == 9; } else { if (numSnpsFailedQC < 5) cout << "Filtering snp " << snpsPreQC[mbed].ID << ": " << snpsPreQC[m].miss << " missing" << endl; numSnpsFailedQC++; } m++; } } ALIGNED_FREE(bedLineIn); if (numSnpsFailedQC) cout << "Filtered " << numSnpsFailedQC << " SNPs with > " << maxMissingPerSnp << " missing" << endl; if (!fin || fin.get() != EOF) { cerr << "ERROR: Wrong file size or reading error for bed file: " << bedFile << endl; exit(1); } fin.close(); // select subset of snps passing QC for (uint64 m = 0; m < MpreQC; m++) if (snpsPreQC[m].passQC) snps.push_back(snpsPreQC[m]); M = snps.size(); // QC indivs for missingness int numIndivsFailedQC = 0; for (uint64 n = 0; n < NpreQC; n++) { indivsPreQC[n].miss = numMissingPerIndiv[n] / (double) M; indivsPreQC[n].passQC = indivsPreQC[n].miss <= maxMissingPerIndiv; if (!indivsPreQC[n].passQC) { if (numIndivsFailedQC < 5) cout << "Filtering indiv " << indivsPreQC[n].famID << " " << indivsPreQC[n].indivID << ": " << numMissingPerIndiv[n] << "/" << M << " missing" << endl; numIndivsFailedQC++; } } if (numIndivsFailedQC) cout << "Filtered " << numIndivsFailedQC << " indivs with > " << maxMissingPerIndiv << " missing" << endl; // select subset of indivs passing QC for (uint64 n = 0; n < NpreQC; n++) if (indivsPreQC[n].passQC) indivs.push_back(indivsPreQC[n]); N = indivs.size(); cout << endl; cout << "Total post-QC indivs: N = " << N << endl; cout << "Total post-QC SNPs: M = " << M << endl; cout << "MAF spectrum: " << endl; const double mafBounds6[7] = {0, 0.05, 0.1, 0.2, 0.3, 0.4, 0.500001}; vector mafBinCounts(6); for (uint64 m = 0; m < M; m++) for (int b = 0; b < 6; b++) if (mafBounds6[b] <= snps[m].MAF && snps[m].MAF < mafBounds6[b+1]) mafBinCounts[b]++; for (int b = 0; b < 6; b++) printf(" %2.0f-%2.0f%%: %7d\n", 100*mafBounds6[b], 100*mafBounds6[b+1], mafBinCounts[b]); printRange(); if (cMmax == 0) { cMmax = std::min(1.0, std::max(N / 1e5, 0.25)); cout << "Auto-selecting --maxBlockLen: " << cMmax << " cM" << endl; } vector nullVec; buildGenoBits(genosPreQC, nullVec, cMmax); ALIGNED_FREE(genosPreQC); } /** * reads genotypes from VCF/BCF file * does not save indiv info (will be reread from VCF during output) * only saves chrom, physpos, genpos in snp info (rest will be reread from VCF during output) * allocates memory, reads genotypes, and restricts to region if specified; does not do QC */ void GenoData::initVcf(const string &vcfFile, const int inputChrom, const int chromX, double bpStart, double bpEnd, const string &geneticMapFile, bool noMapCheck, double cMmax) { htsFile *fin = hts_open(vcfFile.c_str(), "r"); bcf_hdr_t *hdr = bcf_hdr_read(fin); bcf1_t *rec = bcf_init1(); int mgt = 0, *gt = NULL; NpreQC = bcf_hdr_nsamples(hdr); cout << "Reading genotypes for N = " << NpreQC << " samples" << endl; vector genos2bit; int wantChrom = inputChrom; // might be 0; if so, update // read genos; save chrom and physpos for each SNP while (bcf_read(fin, hdr, rec) >= 0) { // check CHROM int chrom = StringUtils::bcfNameToChrom(bcf_hdr_id2name(hdr, rec->rid), 1, chromX); if (wantChrom == 0) wantChrom = chrom; // if --chrom was not specified, set to first if (chrom != wantChrom) { // only allow multi-chrom file if --chrom has been specified if (inputChrom == 0) { cerr << "ERROR: File contains data for >1 chromosome; specify one with --chrom" << endl; exit(1); } else continue; } // check if POS is within selected region int bp = rec->pos+1; if (!(bpStart <= bp && bp <= bpEnd)) continue; // check for multi-allelics (TODO: ignore with warning and don't phase in output) if (rec->n_allele > 2) { cerr << "ERROR: Multi-allelic site found (i.e., ALT contains multiple alleles)" << endl; cerr << " Either drop or split (bcftools norm -m) multi-allelic variants" << endl; exit(1); } // add chrom and bp to SNP list SnpInfoX snp; snp.chrom = chrom; snp.physpos = bp; snpsPreQC.push_back(snp); // read genotypes int ngt = bcf_get_genotypes(hdr, rec, >, &mgt); if (ngt != 2 * (int) NpreQC) { cerr << "ERROR: Samples are not diploid" << endl; exit(1); } for (int i = 0; i < (int) NpreQC; i++) { int ploidy = 2; int *ptr = gt + i*ploidy; uchar geno = 0; bool missing = false; for (int j = 0; j < ploidy; j++) { if ( ptr[j]==bcf_int32_vector_end ) { if (j == 0) { cerr << "ERROR: ptr[0]==bcf_int32_vector_end... zero ploidy?" << endl; exit(1); } else { // 2nd of ploidy==2 genotypes is set to bcf_int32_vector_end => haploid if ( missing ) continue; // missing diploid genotype can be written in VCF as "." else if (wantChrom == chromX) // X chromosome => haploid ok geno *= 2; // encode as diploid homozygote else { cerr << "ERROR: Haploid genotype found" << endl; exit(1); } } } else { if ( bcf_gt_is_missing(ptr[j]) ) // missing allele missing = true; else geno += bcf_gt_allele(ptr[j]); // 0=REF, 1=ALT (multi-allelics prohibited) } } if (missing) geno = 3; genos2bit.push_back(geno&1); genos2bit.push_back(geno>>1); } } free(gt); bcf_destroy(rec); bcf_hdr_destroy(hdr); hts_close(fin); cout << "Read M = " << snpsPreQC.size() << " variants" << endl; processMap(snpsPreQC, geneticMapFile, noMapCheck); // modify snpsPreQC // don't perform QC; use all SNPs MpreQC = snpsPreQC.size(); for (uint64 m = 0; m < MpreQC; m++) snpsPreQC[m].passQC = true; snps = snpsPreQC; M = snps.size(); // don't perform QC; use all samples N = NpreQC; printRange(); if (cMmax == 0) { cMmax = std::min(1.0, std::max(N / 1e5, 0.25)); cout << "Auto-selecting --maxBlockLen: " << cMmax << " cM" << endl; } buildGenoBits(NULL, genos2bit, cMmax); } GenoData::~GenoData() { ALIGNED_FREE(seg64logPs); ALIGNED_FREE(genoBits); } /** * assumes Nbed = bedIndivRemoved.size() * reads (Nbed+3)>>2 bytes into bedLineIn * stores sum(!bedIndivRemoved) bytes into genoLine if loadGenoLine == true */ void GenoData::readBedLine(FileUtils::AutoGzIfstream &fin, uchar bedLineIn[], uchar genoLine[], vector &bedIndivRemoved, bool storeGenoLine) { uint64 Nbed = bedIndivRemoved.size(); fin.read((char *) bedLineIn, (Nbed+3)>>2); if (storeGenoLine) { const uchar bedToGeno[4] = {2, 9, 1, 0}; uint64 n = 0; for (uint64 nbed = 0; nbed < Nbed; nbed++) if (!bedIndivRemoved[nbed]) genoLine[n++] = bedToGeno[(bedLineIn[nbed>>2]>>((nbed&3)<<1))&3]; } } double GenoData::computeAlleleFreq(const uchar genoLine[], uint64 genoN) { double sum = 0; int num = 0; for (uint64 n = 0; n < genoN; n++) if (genoLine[n] != 9) { sum += genoLine[n]; num++; } return 0.5 * sum / num; } double GenoData::computeMAF(const uchar genoLine[], uint64 genoN) { double alleleFreq = computeAlleleFreq(genoLine, genoN); return std::min(alleleFreq, 1.0-alleleFreq); } double GenoData::computeSnpMissing(const uchar genoLine[], uint64 genoN) { double sum = 0; int num = 0; for (uint64 n = 0; n < genoN; n++) { sum += (genoLine[n] == 9); num++; } return sum / num; } const vector &GenoData::getSnps(void) const { return snps; } uint64 GenoData::getN(void) const { return N; } uint64 GenoData::getMseg64(void) const { return Mseg64; } const uint64_masks *GenoData::getGenoBits(void) const { return genoBits; } vector > GenoData::getSeg64cMvecs(void) const { return seg64cMvecs; } const AlleleFreqs *GenoData::getSeg64logPs(void) const { return seg64logPs; } IndivInfoX GenoData::getIndiv(uint64 n) const { return indivs[n]; } const vector &GenoData::getIndivs(void) const { return indivs; } const vector &GenoData::getIsFlipped64j(void) const { return isFlipped64j; } }; Eagle-master/src/GenoData.hpp000066400000000000000000000120611274444013000163450ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef GENODATA_HPP #define GENODATA_HPP #include #include #include #include #include "Types.hpp" #include "FileUtils.hpp" namespace EAGLE { struct SnpInfoX { int chrom; std::string ID; double genpos; // Morgans int physpos; std::string allele1, allele2; double MAF; // note: MAFs are computed on preQC indivs double miss; bool passQC; }; struct IndivInfoX { std::string famID; std::string indivID; std::string paternalID; std::string maternalID; int sex; // (1=male; 2=female; other=unknown) double pheno; double miss; bool passQC; }; struct AlleleFreqs { double cond[3][6]; /* double dip[3]; double hap[2]; */ }; class GenoData : boost::noncopyable { private: uint64 NpreQC, MpreQC; // # of indivs/snps in fam/bim file not in --remove/exclude file(s) uint64 N, M; // post-QC std::vector indivsPreQC, indivs; // [VECTOR]: NpreQC, N std::vector snpsPreQC, snps; // [VECTOR]: MpreQC, M uint64 Mseg64; // number of <=64-SNP chunks uint64_masks *genoBits; // [[MATRIX]]: M64 x N (is0, is2, is9 64-bit masks; 3 bits/base) std::vector > seg64cMvecs; std::vector > seg64preQCsnpInds; AlleleFreqs *seg64logPs; std::vector isFlipped64j; std::vector processIndivs(const std::string &famFile, const std::vector &removeFiles); std::vector processSnps(const std::string &bimFile, int chrom, double bpStart, double bpEnd, const std::vector &excludeFiles); void processMap(std::vector &snpsVec, const std::string &geneticMapFile, bool noMapCheck); void buildGenoBits(uchar *genosPreQC, const std::vector &genos2bit, double cMmax); bool fillSnpSubRowNorm1(float x[], uint64 m64j, const std::vector &indivInds) const; public: /** * reads indiv info from fam file, snp info from bim file * allocates memory, reads genotypes, and does QC * assumes numbers of bim and bed files match */ void initBed(const std::string &famFile, const std::string &bimFile, const std::string &bedFile, int chrom, double bpStart, double bpEnd, const std::string &geneticMapFile, const std::vector &excludeFiles, const std::vector &removeFiles, double maxMissingPerSnp, double maxMissingPerIndiv, bool noMapCheck, double cMmax); /** * reads genotypes from VCF/BCF file * does not save indiv info (will be reread from VCF during output) * only saves chrom, physpos, genpos in snp info (rest will be reread from VCF during output) * allocates memory, reads genotypes, and restricts to region if specified; does not do QC */ void initVcf(const std::string &vcfFile, const int inputChrom, const int chromX, double bpStart, double bpEnd, const std::string &geneticMapFile, bool noMapCheck, double cMmax); void printRange(void) const; ~GenoData(); static int plinkChromCode(const std::string &chrom); static std::vector readBimFile(const std::string &bimFile); /** * assumes Nbed = bedIndivRemoved.size() * reads (Nbed+3)>>2 bytes into bedLineIn * stores sum(!bedIndivRemoved) bytes into genoLine if storeGenoLine == true */ static void readBedLine(FileUtils::AutoGzIfstream &fin, uchar bedLineIn[], uchar genoLine[], std::vector &bedIndivRemoved, bool storeGenoLine); static double computeAlleleFreq(const uchar genoLine[], uint64 genoN); static double computeMAF(const uchar genoLine[], uint64 genoN); static double computeSnpMissing(const uchar genoLine[], uint64 genoN); const std::vector &getSnps(void) const; uint64 getN(void) const; uint64 getMseg64(void) const; const uint64_masks *getGenoBits(void) const; std::vector > getSeg64cMvecs(void) const; const AlleleFreqs *getSeg64logPs(void) const; IndivInfoX getIndiv(uint64 n) const; std::vector computeInvLD64j(uint64 NsubMax) const; const std::vector &getIndivs(void) const; const std::vector &getIsFlipped64j(void) const; double computeSnpRate(void) const; }; } #endif Eagle-master/src/HapHedge.cpp000066400000000000000000000477241274444013000163410ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include "MemoryUtils.hpp" #include "Types.hpp" #include "HapHedge.hpp" namespace EAGLE { using std::vector; using std::string; using std::cout; using std::endl; void HapBitsT::setBit(uint64 n, uint64 m) { haploBitsT[n*M64 + (m>>6)] |= 1ULL<<(m&63); } #ifdef TEST_VS HapBitsT::HapBitsT(const vector &_hapBitsVS) : hapBitsVS(_hapBitsVS), Nhaps(hapBitsVS.size()), M(hapBitsVS[0].length()) {} int HapBitsT::getBit(uint64 n, uint64 m) const { return hapBitsVS[n][m]-'0'; } HapBitsT::~HapBitsT(void) { } #else HapBitsT::HapBitsT(const uint64 *_haploBitsT, uint64 _Nhaps, uint64 Mseg64, const uchar maskSnps64j[]) { Nhaps = _Nhaps; M = 0; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) M++; M64 = (M+63)/64; haploBitsT = ALIGNED_MALLOC_UINT64S(Nhaps * M64); memset(haploBitsT, 0, Nhaps * M64 * sizeof(haploBitsT[0])); for (uint64 n = 0; n < Nhaps; n++) { uint64 mCur = 0; for (uint64 m64j = 0; m64j < Mseg64*64; m64j++) if (maskSnps64j[m64j]) { if ((_haploBitsT[n*Mseg64 + (m64j>>6)]>>(m64j&63))&1) setBit(n, mCur); mCur++; } } } inline int popcount64_01(uint64 i) { return i!=0; } inline int popcount64_012(uint64 i) { if (i == 0) return 0; else if ((i & (i-1ULL)) == 0) return 1; else return 2; } HapBitsT::HapBitsT(const uint64 *inBitsT, uint64 Mseg64, const vector &splits64j, const vector &splitGenos, const vector &tgtGenoBits, const vector &bestHaps) { Nhaps = bestHaps.size(); M = 2*(splits64j.size()+2); M64 = (M+63)/64; haploBitsT = ALIGNED_MALLOC_UINT64S(Nhaps * M64); memset(haploBitsT, 0, Nhaps * M64 * sizeof(haploBitsT[0])); for (uint k = 0; k < bestHaps.size(); k++) { uint64 n = bestHaps[k]; if (k+1>6); m64 <= (homStop>>6); m64++) { uint64 mask = -1ULL; if (m64 == (homStart>>6)) mask &= (-1ULL>>(homStart&63))<<(homStart&63); if (m64 == (homStop>>6)) mask &= (-1ULL>>(63-(homStop&63))); numErrsA += popcount64_01(mask&((tgtGenoBits[m64].is0 & inBitsT[n*Mseg64 + m64]) | (tgtGenoBits[m64].is2 & ~inBitsT[n*Mseg64 + m64]))); numErrsB += popcount64_01(mask&((tgtGenoBits[m64].is0 & inBitsT[(n+1)*Mseg64 + m64]) | (tgtGenoBits[m64].is2 & ~inBitsT[(n+1)*Mseg64 + m64]))); if (numErrsA && numErrsB) break; } if (numErrsA) setBit(k, 2*h+1); if (numErrsB) setBit(k+1, 2*h+1); // set bits at split int splitA = 0, splitB = 0, splitGeno = 0; if (h < splits64j.size()) { splitA = (inBitsT[n*Mseg64 + (splits64j[h]>>6)]>>(splits64j[h]&63))&1; splitB = (inBitsT[(n+1)*Mseg64 + (splits64j[h]>>6)]>>(splits64j[h]&63))&1; splitGeno = splitGenos[h]; if (splitA) setBit(k, 2*(h+1)); if (splitB) setBit(k+1, 2*(h+1)); } // check for double-IBD if (numErrsA || numErrsB || splitA+splitB != splitGeno || h==splits64j.size()) { if (h > hLastDiff+20) { for (uint h2 = hLastDiff+1; h2 < h; h2++) { setBit(k, 2*h2+1); setBit(k+1, 2*h2+1); } } else if (h > hLastDiff+10) { uint64 kMask = hLastErrA >= hLastErrB ? k : k+1; for (uint h2 = hLastDiff+1; h2 < h; h2++) setBit(kMask, 2*h2+1); } hLastDiff = h; } if (numErrsA) hLastErrA = h; if (numErrsB) hLastErrB = h; } k++; } else { // process lone reference haplotype for (uint64 h = 0; h <= splits64j.size(); h++) { // set hom uint64 homStart = (h == 0 ? 0 : splits64j[h-1]+1); uint64 homStop = (h == splits64j.size() ? Mseg64*64 : splits64j[h]) - 1; int numErrs = 0; for (uint64 m64 = (homStart>>6); m64 <= (homStop>>6); m64++) { uint64 mask = -1ULL; if (m64 == (homStart>>6)) mask &= (-1ULL>>(homStart&63))<<(homStart&63); if (m64 == (homStop>>6)) mask &= (-1ULL>>(63-(homStop&63))); numErrs += popcount64_01(mask&((tgtGenoBits[m64].is0 & inBitsT[n*Mseg64 + m64]) | (tgtGenoBits[m64].is2 & ~inBitsT[n*Mseg64 + m64]))); if (numErrs) break; } if (numErrs) setBit(k, 2*h+1); // set bit at split if (h < splits64j.size() && ((inBitsT[n*Mseg64+(splits64j[h]>>6)]>>(splits64j[h]&63))&1)) setBit(k, 2*(h+1)); } } } } const unsigned char flipByte[] = { 0x00, 0x80, 0x40, 0xC0, 0x20, 0xA0, 0x60, 0xE0, 0x10, 0x90, 0x50, 0xD0, 0x30, 0xB0, 0x70, 0xF0, 0x08, 0x88, 0x48, 0xC8, 0x28, 0xA8, 0x68, 0xE8, 0x18, 0x98, 0x58, 0xD8, 0x38, 0xB8, 0x78, 0xF8, 0x04, 0x84, 0x44, 0xC4, 0x24, 0xA4, 0x64, 0xE4, 0x14, 0x94, 0x54, 0xD4, 0x34, 0xB4, 0x74, 0xF4, 0x0C, 0x8C, 0x4C, 0xCC, 0x2C, 0xAC, 0x6C, 0xEC, 0x1C, 0x9C, 0x5C, 0xDC, 0x3C, 0xBC, 0x7C, 0xFC, 0x02, 0x82, 0x42, 0xC2, 0x22, 0xA2, 0x62, 0xE2, 0x12, 0x92, 0x52, 0xD2, 0x32, 0xB2, 0x72, 0xF2, 0x0A, 0x8A, 0x4A, 0xCA, 0x2A, 0xAA, 0x6A, 0xEA, 0x1A, 0x9A, 0x5A, 0xDA, 0x3A, 0xBA, 0x7A, 0xFA, 0x06, 0x86, 0x46, 0xC6, 0x26, 0xA6, 0x66, 0xE6, 0x16, 0x96, 0x56, 0xD6, 0x36, 0xB6, 0x76, 0xF6, 0x0E, 0x8E, 0x4E, 0xCE, 0x2E, 0xAE, 0x6E, 0xEE, 0x1E, 0x9E, 0x5E, 0xDE, 0x3E, 0xBE, 0x7E, 0xFE, 0x01, 0x81, 0x41, 0xC1, 0x21, 0xA1, 0x61, 0xE1, 0x11, 0x91, 0x51, 0xD1, 0x31, 0xB1, 0x71, 0xF1, 0x09, 0x89, 0x49, 0xC9, 0x29, 0xA9, 0x69, 0xE9, 0x19, 0x99, 0x59, 0xD9, 0x39, 0xB9, 0x79, 0xF9, 0x05, 0x85, 0x45, 0xC5, 0x25, 0xA5, 0x65, 0xE5, 0x15, 0x95, 0x55, 0xD5, 0x35, 0xB5, 0x75, 0xF5, 0x0D, 0x8D, 0x4D, 0xCD, 0x2D, 0xAD, 0x6D, 0xED, 0x1D, 0x9D, 0x5D, 0xDD, 0x3D, 0xBD, 0x7D, 0xFD, 0x03, 0x83, 0x43, 0xC3, 0x23, 0xA3, 0x63, 0xE3, 0x13, 0x93, 0x53, 0xD3, 0x33, 0xB3, 0x73, 0xF3, 0x0B, 0x8B, 0x4B, 0xCB, 0x2B, 0xAB, 0x6B, 0xEB, 0x1B, 0x9B, 0x5B, 0xDB, 0x3B, 0xBB, 0x7B, 0xFB, 0x07, 0x87, 0x47, 0xC7, 0x27, 0xA7, 0x67, 0xE7, 0x17, 0x97, 0x57, 0xD7, 0x37, 0xB7, 0x77, 0xF7, 0x0F, 0x8F, 0x4F, 0xCF, 0x2F, 0xAF, 0x6F, 0xEF, 0x1F, 0x9F, 0x5F, 0xDF, 0x3F, 0xBF, 0x7F, 0xFF }; uint64 reverse64(uint64 v) { return ((uint64) flipByte[v & 0xff] << 56ULL) | ((uint64) flipByte[(v >> 8) & 0xff] << 48ULL) | ((uint64) flipByte[(v >> 16) & 0xff] << 40ULL) | ((uint64) flipByte[(v >> 24) & 0xff] << 32ULL) | ((uint64) flipByte[(v >> 32) & 0xff] << 24ULL) | ((uint64) flipByte[(v >> 40) & 0xff] << 16ULL) | ((uint64) flipByte[(v >> 48) & 0xff] << 8ULL) | flipByte[v >> 56]; } HapBitsT::HapBitsT(const HapBitsT &hapBitsFwdT, int dir) : Nhaps(hapBitsFwdT.getNhaps()), M(hapBitsFwdT.getM()), M64((M+63)/64) { assert(dir<0); // reverse existing HapBitsT haploBitsT = ALIGNED_MALLOC_UINT64S(Nhaps * M64); memset(haploBitsT, 0, Nhaps * M64 * sizeof(haploBitsT[0])); if (dir == -1) { // simple reversal for (uint64 n = 0; n < Nhaps; n++) for (uint64 m = 0; m < M; m++) if (hapBitsFwdT.getBit(n, m)) setBit(n, M-1-m); } else { // repad 0 xyz 0 0 -> 0 zyx 0 0 uint64 Mtrim = M-1, Mtrim64 = (Mtrim+63)/64, offset = Mtrim&63; for (uint64 n = 0; n < Nhaps; n++) { /* for (uint64 m = 1; m < M-2; m++) if (hapBitsFwdT.getBit(n, m)) setBit(n, M-2-m); */ for (uint64 m64 = 0; m64 < Mtrim64; m64++) { uint64 fwdBits = offset==0 ? hapBitsFwdT.getBits64(n, Mtrim64-1-m64) : ((m64>offset) : 0) | (hapBitsFwdT.getBits64(n, Mtrim64-1-m64)<<(64-offset))); //assert(haploBitsT[n * M64 + m64] == reverse64(fwdBits)); haploBitsT[n * M64 + m64] = reverse64(fwdBits); } } } } int HapBitsT::getBit(uint64 n, uint64 m) const { return (haploBitsT[n*M64 + (m>>6)]>>(m&63))&1; } uint64 HapBitsT::getBits64(uint64 n, uint64 m64) const { return haploBitsT[n*M64 + m64]; } HapBitsT::~HapBitsT(void) { ALIGNED_FREE(haploBitsT); } #endif int HapBitsT::getNhaps(void) const { return Nhaps; } int HapBitsT::getM(void) const { return M; } int d, a, count, up, left, right; WorkTreeNode::WorkTreeNode(int _d, int _a, int _count, int _up, int _left, int _right) : d(_d), a(_a), count(_count), up(_up), left(_left), right(_right) {} void dfsPreOrder(WorkTreeNode workNodes[], HapTreeNode *nodes, int &pos, int cur) { if (cur == -1) return; nodes[pos].mSplit = workNodes[cur].d; int left = workNodes[cur].left; nodes[pos].count0 = 1 + (left==-1 ? 0 : workNodes[left].count); nodes[pos].seq1 = workNodes[cur].a; pos++; dfsPreOrder(workNodes, nodes, pos, workNodes[cur].left); dfsPreOrder(workNodes, nodes, pos, workNodes[cur].right); } void dfsPreOrderMulti(WorkTreeNode workNodes[], HapTreeMultiNode *nodes, int &pos, int cur) { if (cur == -1) return; int curPos = pos; nodes[curPos].mSplit = workNodes[cur].d; nodes[curPos].count0 = workNodes[cur].count; nodes[curPos].node0 = curPos+1; nodes[curPos].seq1 = workNodes[cur].a; pos++; dfsPreOrderMulti(workNodes, nodes, pos, workNodes[cur].left); if (pos == curPos+1) { // no next node 0 nodes[curPos].node0 = -1; /* MEMORY-SAVING ALTERNATIVE: use 1 bit (sign of state.count) to encode next node nodes[curPos].count0 = -nodes[curPos].count0; */ } nodes[curPos].node1 = pos; dfsPreOrderMulti(workNodes, nodes, pos, workNodes[cur].right); if (pos == nodes[curPos].node1) // no next node 1 nodes[curPos].node1 = -1; } HapTree::HapTree(const HapBitsT &_hapBitsT, int a[], int d[]) : hapBitsT(_hapBitsT), Nhaps(hapBitsT.getNhaps()), invNhaps(1.0f/Nhaps) { seq0 = a[0]; nodes = (HapTreeNode *) ALIGNED_MALLOC((Nhaps-1) * sizeof(nodes[0])); WorkTreeNode *workNodes = (WorkTreeNode *) ALIGNED_MALLOC(Nhaps * sizeof(workNodes[0])); // perform in-order traversal workNodes[0] = WorkTreeNode(-1, a[0], 0, -1, -1, -1); for (int n = 1; n < Nhaps; n++) { if (d[n] >= d[n-1]) { workNodes[n] = WorkTreeNode(d[n], a[n], 1, n-1, -1, -1); workNodes[n-1].right = n; } else { int cur = n-1, up = workNodes[cur].up; while (d[n] < workNodes[up].d) { workNodes[up].count += workNodes[cur].count; cur = up; up = workNodes[cur].up; } workNodes[n] = WorkTreeNode(d[n], a[n], workNodes[cur].count+1, up, cur, -1); workNodes[cur].up = n; workNodes[up].right = n; } } int cur = Nhaps-1, up = workNodes[cur].up; while (up != -1) { workNodes[up].count += workNodes[cur].count; cur = up; up = workNodes[cur].up; } // perform pre-order traversal int pos = 0; dfsPreOrder(workNodes, nodes, pos, workNodes[0].right); ALIGNED_FREE(workNodes); } HapTree::~HapTree(void) { ALIGNED_FREE(nodes); } float HapTree::getInvNhaps(void) const { return invNhaps; } HapTreeState HapTree::getRootState(void) const { HapTreeState h; h.seq = seq0; h.node = 0; h.count = Nhaps; return h; } bool HapTree::next(int m, HapTreeState &state, int nextBit) const { if (state.count == 1 || nodes[state.node].mSplit > m) { return hapBitsT.getBit(state.seq, m) == nextBit; } else { if (nextBit == 0) { state.count = nodes[state.node++].count0; } else { state.seq = nodes[state.node].seq1; int c0 = nodes[state.node].count0; state.node += c0; state.count -= c0; } return true; } } HapTreeMulti::HapTreeMulti(const HapBitsT &_hapBitsT, SortDiv ad[], int M, WorkTreeNode workNodes[]) : hapBitsT(_hapBitsT), Nhaps(hapBitsT.getNhaps()), invNhaps(1.0f/Nhaps) { // perform in-order traversal workNodes[0] = WorkTreeNode(-1, ad[0].a, 0, -1, -1, -1); int n = 0, nextMult = 1, uniqHaps = Nhaps; for (int nHap = 1; nHap < Nhaps; nHap++) { if (ad[nHap].d == M) { // sequence is identical to previous; merge nextMult++; uniqHaps--; } else { n++; if (ad[nHap].d >= workNodes[n-1].d) { workNodes[n] = WorkTreeNode(ad[nHap].d, ad[nHap].a, nextMult, n-1, -1, -1); workNodes[n-1].right = n; } else { int cur = n-1, up = workNodes[cur].up; int leftCount = nextMult; while (ad[nHap].d < workNodes[up].d) { leftCount += workNodes[cur].count; cur = up; up = workNodes[cur].up; } leftCount += workNodes[cur].count; workNodes[n] = WorkTreeNode(ad[nHap].d, ad[nHap].a, leftCount, up, cur, -1); workNodes[cur].up = n; workNodes[up].right = n; } nextMult = 1; } } nodes = (HapTreeMultiNode *) ALIGNED_MALLOC((uniqHaps-1) * sizeof(nodes[0])); rootState.seq = ad[0].a; rootState.node = workNodes[0].right==-1?-1:0; rootState.count = Nhaps; int pos = 0; dfsPreOrderMulti(workNodes, nodes, pos, workNodes[0].right); } HapTreeMulti::~HapTreeMulti(void) { ALIGNED_FREE(nodes); } float HapTreeMulti::getInvNhaps(void) const { return invNhaps; } HapTreeState HapTreeMulti::getRootState(void) const { return rootState; } bool HapTreeMulti::next(int m, HapTreeState &state, int nextBit) const { if (state.node == -1 || nodes[state.node].mSplit > m) { return hapBitsT.getBit(state.seq, m) == nextBit; } else { if (nextBit == 0) { state.count = nodes[state.node].count0; state.node = nodes[state.node].node0; /* MEMORY-SAVING ALTERNATIVE: use 1 bit (sign of state.count) to encode next node if (state.count > 0) state.node++; else { state.node = -1; state.count = -state.count; } */ } else { state.count -= nodes[state.node].count0; /* MEMORY-SAVING ALTERNATIVE: use 1 bit (sign of state.count) to encode next node state.count -= abs(nodes[state.node].count0); */ state.seq = nodes[state.node].seq1; state.node = nodes[state.node].node1; // update last: overwrites state.node! } return true; } } void HapTreeMulti::nextAtFrac(int m, HapTreeState &state, double nextFrac) const { // see above for MEMORY-SAVING ALTERNATIVES if (state.node == -1 || nodes[state.node].mSplit > m) { return; } else { if (nodes[state.node].count0 >= nextFrac * state.count) { // nextBit = 0 state.count = nodes[state.node].count0; state.node = nodes[state.node].node0; } else { state.count -= nodes[state.node].count0; state.seq = nodes[state.node].seq1; state.node = nodes[state.node].node1; // update last: overwrites state.node! } } } // for debugging void HapTreeMulti::dfsPrint(string curPrefix, int m, int M, const HapTreeState &state) const { if (m > M) return; cout << "m = " << m << ", prefix = " << curPrefix << ": count = " << state.count << endl; for (int b = 0; b < 2; b++) { HapTreeState nextState = state; if (next(m, nextState, b)) dfsPrint(curPrefix + (char) ('0'+b), m+1, M, nextState); } } HapHedge::HapHedge(const HapBitsT &_hapBitsT, int _skip/*, const vector &treeStarts*/) : hapBitsT(_hapBitsT), skip(_skip), T((hapBitsT.getM()+skip-1) / skip) { treePtrs = new HapTree *[T]; int N = hapBitsT.getNhaps(), M = hapBitsT.getM(); // initialize work arrays int *a1 = new int[N], *d1 = new int[N], *a = new int[N], *b = new int[N], *d = new int[N], *e = new int[N]; for (int n = 0; n < N; n++) { a1[n] = n; d1[n] = M; } for (int m = M-1; m >= 0; m--) { // compute sort order and divergence array int u = 0, v = 0, p = m, q = m; for (int n = 0; n < N; n++) { if (d1[n] < p) p = d1[n]; if (d1[n] < q) q = d1[n]; if (hapBitsT.getBit(a1[n], m) == 0) { a[u] = a1[n]; d[u] = p; u++; p = M; } else { b[v] = a1[n]; e[v] = q; v++; q = M; } } memcpy(a1, a, u * sizeof(a1[0])); memcpy(a1+u, b, v * sizeof(a1[0])); memcpy(d1, d, u * sizeof(d1[0])); memcpy(d1+u, e, v * sizeof(d1[0])); // perform pre-order traversal and store to HapTree if (m % skip == 0) { treePtrs[m/skip] = new HapTree(hapBitsT, a1, d1); } } delete[] a1; delete[] d1; delete[] a; delete[] b; delete[] d; delete[] e; } HapHedge::~HapHedge(void) { for (int t = 0; t < T; t++) delete treePtrs[t]; delete[] treePtrs; } const HapTree &HapHedge::getHapTree(int t) const { return *treePtrs[t]; }; int HapHedge::getM(void) const { return hapBitsT.getM(); } int HapHedge::getSkip(void) const { return skip; } int HapHedge::getNumTrees(void) const { return T; } const HapBitsT &HapHedge::getHapBitsT(void) const { return hapBitsT; } HapHedgeErr::HapHedgeErr(const HapBitsT &_hapBitsT) : hapBitsT(_hapBitsT), T((hapBitsT.getM()+1) / 2) { treePtrs = new HapTreeMulti *[T]; int N = hapBitsT.getNhaps(), M = hapBitsT.getM(); // initialize work arrays SortDiv *ad = new SortDiv[N+1], *ad1 = new SortDiv[N+1]; // N+1 for convenience below WorkTreeNode *workNodes = (WorkTreeNode *) ALIGNED_MALLOC(N * sizeof(workNodes[0])); for (int n = 0; n <= N; n++) { // N+1 for convenience below ad[n].a = n; ad[n].d = M; } uint64 *curBits64 = new uint64[N]; uchar *curBits8 = new uchar[N]; // N-byte buffer hopefully fits in L1 cache for random access for (int m = M-1; m >= 0; m--) { if (m == M-1 || (m&63) == 63) { // move current 64-bit m-block for each sample to curBits64 for (int n = 0; n < N; n++) curBits64[n] = hapBitsT.getBits64(n, m>>6); } //uint64 curBit64 = 1ULL<<(m&63); if (m == M-1 || (m&7) == 7) { // move current 8-bit m-block for each sample to curBits8 uint64 shift = (m&63)&~7; for (int n = 0; n < N; n++) curBits8[n] = (uchar) (curBits64[n]>>shift); } uchar curBit8 = 1<<(m&7); // compute sort order and divergence array int u = 0, v = 0, p = m, q = m; if (m % 2 != 1) { for (int n = 0; n < N; n++) { int a_n = ad[n].a; if (/*curBits64[a_n] & curBit64*/curBits8[a_n] & curBit8) { ad1[v].a = a_n; ad1[v].d = q; v++; q = ad[n+1].d; if (q < p) p = q; } else { ad[u].a = a_n; ad[u].d = p; u++; p = ad[n+1].d; if (p < q) q = p; } } } else { for (int n = 0; n < N; n++) { int a_n = ad[n].a; if (/*curBits64[a_n] & curBit64*/curBits8[a_n] & curBit8) { ad1[v].a = a_n; ad1[v].d = M; v++; q = ad[n+1].d; if (q < p) p = q; } else { ad[u].a = a_n; ad[u].d = p; u++; p = ad[n+1].d; if (p < q) q = p; } } ad1[0].d = m; } memcpy(ad+u, ad1, v * sizeof(ad[0])); // perform pre-order traversal and store to HapTree if (m % 2 == 0) treePtrs[m/2] = new HapTreeMulti(hapBitsT, ad, M, workNodes); } delete[] curBits8; delete[] curBits64; ALIGNED_FREE(workNodes); delete[] ad1; delete[] ad; } HapHedgeErr::~HapHedgeErr(void) { for (int t = 0; t < T; t++) delete treePtrs[t]; delete[] treePtrs; } const HapTreeMulti &HapHedgeErr::getHapTreeMulti(int t) const { return *treePtrs[t]; }; int HapHedgeErr::getNumTrees(void) const { return T; } const HapBitsT &HapHedgeErr::getHapBitsT() const { return hapBitsT; } // for debugging void HapHedgeErr::printTree(int t) const { treePtrs[t]->dfsPrint("", 2*t, 2*T, treePtrs[t]->getRootState()); } } Eagle-master/src/HapHedge.hpp000066400000000000000000000076521274444013000163420ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef HAPHEDGE_HPP #define HAPHEDGE_HPP #include #include "Types.hpp" using namespace std; namespace EAGLE { struct HapTreeState { int seq, node, count; }; struct SortDiv { int a, d; }; class HapBitsT { #ifdef TEST_VS const std::vector &hapBitsVS; #endif uint64 *haploBitsT; uint64 Nhaps, M, M64; void setBit(uint64 n, uint64 m); public: #ifdef TEST_VS HapBitsT(const std::vector &_hapBitsVS); #else HapBitsT(const uint64 *_haploBitsT, uint64 _Nhaps, uint64 Mseg64, const uchar maskSnps64j[]); HapBitsT(const uint64 *inBitsT, uint64 Mseg64, const std::vector &splits64j, const std::vector &splitGenos, const std::vector &tgtGenoBits, const std::vector &bestHaps); HapBitsT(const HapBitsT &hapBitsFwdT, int dir); // reverse constructor (dir must equal -1) uint64 getBits64(uint64 n, uint64 m64) const; #endif ~HapBitsT(void); int getBit(uint64 n, uint64 m) const; int getNhaps(void) const; int getM(void) const; }; struct HapTreeNode { int mSplit, count0, seq1; }; struct HapTreeMultiNode { int mSplit, count0, node0, seq1, node1; // MEMORY-SAVING ALTERNATIVE: use 1 bit (sign of state.count) vs. node0 to encode next node }; struct WorkTreeNode { int d, a, count, up, left, right; WorkTreeNode(int _d, int _a, int _count, int _up, int _left, int _right); }; class HapTree { const HapBitsT &hapBitsT; const int Nhaps; float invNhaps; int seq0; // lexicographically first ref seq HapTreeNode *nodes; // [Nhaps-1] public: HapTree(const HapBitsT &_hapBitsT, int a[], int d[]); ~HapTree(void); float getInvNhaps(void) const; HapTreeState getRootState(void) const; bool next(int m, HapTreeState &state, int nextBit) const; }; class HapTreeMulti { const HapBitsT &hapBitsT; const int Nhaps; float invNhaps; HapTreeState rootState; HapTreeMultiNode *nodes; // [Nhaps-1] public: HapTreeMulti(const HapBitsT &_hapBitsT, SortDiv ad[], int M, WorkTreeNode workNodes[]); ~HapTreeMulti(void); float getInvNhaps(void) const; HapTreeState getRootState(void) const; bool next(int m, HapTreeState &state, int nextBit) const; void nextAtFrac(int m, HapTreeState &state, double nextFrac) const; void dfsPrint(std::string curPrefix, int m, int M, const HapTreeState &state) const; }; class HapHedge { const HapBitsT &hapBitsT; const int skip, T; HapTree **treePtrs; public: HapHedge(const HapBitsT &_hapBitsT, int skip/*, const std::vector &treeStarts*/); ~HapHedge(void); const HapTree &getHapTree(int t) const; int getM(void) const; int getSkip(void) const; int getNumTrees(void) const; const HapBitsT &getHapBitsT(void) const; }; class HapHedgeErr { const HapBitsT &hapBitsT; const int T; HapTreeMulti **treePtrs; public: HapHedgeErr(const HapBitsT &_hapBitsT); ~HapHedgeErr(void); const HapTreeMulti &getHapTreeMulti(int t) const; int getNumTrees(void) const; const HapBitsT &getHapBitsT() const; void printTree(int t) const; }; } #endif Eagle-master/src/LapackConst.hpp000066400000000000000000000050301274444013000170630ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef LAPACKCONST_HPP #define LAPACKCONST_HPP #ifdef USE_MKL #include "mkl.h" #define DGER_MACRO dger #define DGEMV_MACRO dgemv #define DGEMM_MACRO dgemm #define SGEMM_MACRO sgemm #define DGELS_MACRO dgels #define DGESVD_MACRO dgesvd #else extern "C" int dgesvd_(char *jobu, char *jobvt, int *m, int *n, double *a, int *lda, double *s, double *u, int *ldu, double *vt, int *ldvt, double *work, int *lwork, int *info); extern "C" int dgemv_(char *TRANS, int *M, int *N, double *ALPHA, double *A, int *LDA, const double *X, int *INCX, double *BETA, double *Y, int *INCY); extern "C" int dger_(int *M, int *N, double *ALPHA, double *X, int *INCX, const double *Y, int *INCY, double *A, int *LDA); extern "C" int dgemm_(char *TRANSA, char *TRANSB, int *M, int *N, int *K, double *ALPHA, const double *A, int *LDA, const double *B, int *LDB, double *BETA, double *C, int *LDC); extern "C" int sgemm_(char *TRANSA, char *TRANSB, int *M, int *N, int *K, float *ALPHA, const float *A, int *LDA, const float *B, int *LDB, float *BETA, float *C, int *LDC); extern "C" int dgels_(char *TRANS, int *M, int *N, int *NRHS, double *A, int *LDA, double *B, int *LDB, double *WORK, int *LWORK, int *INFO); #define DGER_MACRO dger_ #define DGEMV_MACRO dgemv_ #define DGEMM_MACRO dgemm_ #define SGEMM_MACRO sgemm_ #define DGELS_MACRO dgels_ #define DGESVD_MACRO dgesvd_ #endif /* namespace LapackConst { #ifndef USE_MKL #ifdef USE_MKL inline CBLAS_TRANSPOSE lapackTransToMKL(char trans) { return (trans=='N'||trans=='n') ? CblasNoTrans : CblasTrans; } #endif void dgemm_wrap(char TRANSA, char TRANSB, int M, int N, int K, double ALPHA, const double *A, int LDA, const double *B, int LDB, double BETA, double *C, int LDC); } */ #endif Eagle-master/src/Makefile000066400000000000000000000051221274444013000156120ustar00rootroot00000000000000# build options: # 1. cmd line: linking = dynamic (default), static-except-glibc (recommended release), static # 2. cmd line: debug = false (default => -O2), true (-g) ### modify these paths to local BLAS, Boost and htslib install directories LBLAS = -lopenblas # alternatively -llapack (just need sgemm_) BLAS_DIR = /opt/openblas/0.2.14/lib BOOST_INSTALL_DIR = /home/pl88/boost_1_58_0/install HTSLIB_DIR = /groups/price/poru/external_software/htslib/htslib-1.3 ### these paths are used only for static linking ZLIB_STATIC_DIR = /opt/zlib-1.2.8/lib # probably unnecessary on most systems GLIBC_STATIC_DIR = /home/pl88/glibc-static/usr/lib64 ifeq ($(strip ${linking}),) linking = dynamic endif CC = g++ ifeq (${debug},true) CFLAGS += -g else CFLAGS += -O2 endif ifeq (${prof},true) CFLAGS += -g -pg LFLAGS += -pg endif CFLAGS += -std=c++0x -msse -msse2 -fopenmp -Wall LFLAGS += -fopenmp # add BLAS lib path ifneq ($(strip ${BLAS_DIR}),) LPATHS += -L${BLAS_DIR} ifeq (${linking},dynamic) LPATHS += -Wl,-rpath,${BLAS_DIR} endif endif # add Boost include and lib paths ifneq ($(strip ${BOOST_INSTALL_DIR}),) CPATHS += -I${BOOST_INSTALL_DIR}/include LPATHS += -L${BOOST_INSTALL_DIR}/lib ifeq (${linking},dynamic) LPATHS += -Wl,-rpath,${BOOST_INSTALL_DIR}/lib endif endif # add htslib include and lib paths ifneq ($(strip ${HTSLIB_DIR}),) CPATHS += -I${HTSLIB_DIR} LPATHS += -L${HTSLIB_DIR} ifeq (${linking},dynamic) LPATHS += -Wl,-rpath,${HTSLIB_DIR} endif endif # add zlib.a path for static linking on Orchestra ifneq ($(strip ${ZLIB_STATIC_DIR}),) ifneq (${linking},dynamic) LPATHS += -L${ZLIB_STATIC_DIR} endif endif # add flags for static linking; build LAPACK/MKL component of link line ifeq (${linking},static) LFLAGS += -static LPATHS += -L${GLIBC_STATIC_DIR} -L${ZLIB_STATIC_DIR} else ifeq (${linking},static-except-glibc) LFLAGS += -static-libgcc -static-libstdc++ LPATHS += -L${ZLIB_STATIC_DIR} endif # build link line (minus flags) LLIBS = -lhts -lboost_program_options -lboost_iostreams -lz ${LBLAS} ifeq (${linking},static-except-glibc) L = ${LPATHS} -Wl,-Bstatic ${LLIBS} -Wl,-Bdynamic -lpthread -lm else L = ${LPATHS} ${LLIBS} -lpthread -lm endif T = eagle O = DipTreePBWT.o Eagle.o EagleImpMiss.o EagleParams.o EaglePBWT.o FileUtils.o GenoData.o HapHedge.o MapInterpolater.o MemoryUtils.o NumericUtils.o StaticMultimap.o StringUtils.o SyncedVcfData.o Timer.o OMAIN = EagleMain.o $O .PHONY: clean $T: ${OMAIN} ${CC} ${LFLAGS} -o $T ${OMAIN} $L %.o: %.cpp ${CC} ${CFLAGS} ${CPATHS} -o $@ -c $< EagleMain.o: Version.hpp Eagle.o: Version.hpp all: $T clean: rm -f *.o rm -f $T Eagle-master/src/MapInterpolater.cpp000066400000000000000000000056071274444013000177740ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include "MapInterpolater.hpp" #include "FileUtils.hpp" namespace Genetics { using std::vector; using std::string; using std::pair; using std::make_pair; using std::map; using std::cout; using std::cerr; using std::endl; using FileUtils::getline; const string MapInterpolater::MAP_FILE_HEADER = "chr position COMBINED_rate(cM/Mb) Genetic_Map(cM)"; MapInterpolater::MapInterpolater(const string &geneticMapFile) { if (geneticMapFile.empty()) return; chrBpToRateGen[make_pair(0, 0)] = make_pair(0.0, 0.0); // sentinel at beginning string line; FileUtils::AutoGzIfstream fin; fin.openOrExit(geneticMapFile); getline(fin, line); if (line != MAP_FILE_HEADER) { cerr << "ERROR: Wrong format of reference map " << geneticMapFile << endl; cerr << " Expecting header: " << MAP_FILE_HEADER << endl; exit(1); } int chr0 = 0, bp0 = 0; double gen0 = 0; int chr, bp; double rate, gen; while (fin >> chr >> bp >> rate >> gen) { if (chr == chr0) chrBpToRateGen[make_pair(chr, bp)] = make_pair((gen-gen0)/(1e-6*(bp-bp0)), gen); chr0 = chr; bp0 = bp; gen0 = gen; } chrBpToRateGen[make_pair(chr, bp+1e9)] = make_pair(1.0, gen+1e3); // sentinel at end } // returns interpolated genetic position in Morgans double MapInterpolater::interp(int chr, int bp) const { if (chrBpToRateGen.empty()) return 0; map < pair , pair >::const_iterator ubIter = chrBpToRateGen.upper_bound(make_pair(chr, bp)); // map record > (chr, bp) if (ubIter == chrBpToRateGen.end()) { cerr << "ERROR: Chromosome " << chr << " is not in genetic map" << endl; exit(1); } int ubChr = ubIter->first.first; int ubBp = ubIter->first.second; double ubRate = ubIter->second.first; double ubGen = ubIter->second.second; if (chr == ubChr) return 0.01 * (ubGen + 1e-6 * ubRate * (bp-ubBp)); // interpolate interval else return 0.01 * (--ubIter)->second.second; // end of previous chromosome } } Eagle-master/src/MapInterpolater.hpp000066400000000000000000000025461274444013000200000ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef MAPINTERPOLATER_HPP #define MAPINTERPOLATER_HPP #include #include #include namespace Genetics { class MapInterpolater { std::map < std::pair , std::pair > chrBpToRateGen; static const std::string MAP_FILE_HEADER; public: // input file format: chr position COMBINED_rate(cM/Mb) Genetic_Map(cM) // (Oxford map format preceded by chr column) MapInterpolater(const std::string &geneticMapFile); // returns interpolated genetic position in Morgans double interp(int chr, int bp) const; }; } #endif Eagle-master/src/MemoryUtils.cpp000066400000000000000000000025671274444013000171610ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include "MemoryUtils.hpp" #include "Types.hpp" void *ALIGNED_MALLOC(uint64 size) { #ifdef USE_MKL_MALLOC void *p = mkl_malloc(size, MEM_ALIGNMENT); #else void *p = _mm_malloc(size, MEM_ALIGNMENT); #endif // TODO: change to assert() or dispense with altogether and change ALIGNED_MALLOC to macro? if (p == NULL) { std::cerr << "ERROR: Failed to allocate " << size << " bytes" << std::endl; exit(1); } else if ((uint64) p & 0xf) { std::cerr << "ERROR: Memory alignment of " << size << " bytes failed" << std::endl; exit(1); } return p; } Eagle-master/src/MemoryUtils.hpp000066400000000000000000000033751274444013000171640ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef MEMORYUTILS_HPP #define MEMORYUTILS_HPP #include "Types.hpp" #define MEM_ALIGNMENT 64 //#define ALIGNED_MALLOC(size) mkl_malloc(size, MEM_ALIGNMENT) //#define ALIGNED_MALLOC(size) _mm_malloc(size, MEM_ALIGNMENT) void *ALIGNED_MALLOC(uint64 size); #ifdef USE_MKL_MALLOC #include #define ALIGNED_FREE mkl_free #else #include #define ALIGNED_FREE _mm_free #endif #define ALIGNED_MALLOC_DOUBLES(numDoubles) (double *) ALIGNED_MALLOC((numDoubles)*sizeof(double)) #define ALIGNED_MALLOC_FLOATS(numFloats) (float *) ALIGNED_MALLOC((numFloats)*sizeof(float)) #define ALIGNED_MALLOC_UCHARS(numUchars) (uchar *) ALIGNED_MALLOC((numUchars)*sizeof(uchar)) #define ALIGNED_MALLOC_UINTS(numUints) (uint *) ALIGNED_MALLOC((numUints)*sizeof(uint)) #define ALIGNED_MALLOC_UINT64S(numUint64s) (uint64 *) ALIGNED_MALLOC((numUint64s)*sizeof(uint64)) #define ALIGNED_MALLOC_UINT64_MASKS(numUint64_masks) (uint64_masks *) ALIGNED_MALLOC((numUint64_masks)*sizeof(uint64_masks)) #endif Eagle-master/src/NumericUtils.cpp000066400000000000000000000066721274444013000173140ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include "NumericUtils.hpp" namespace NumericUtils { double sum(const double x[], uint64 N) { double ans = 0; for (uint64 n = 0; n < N; n++) ans += x[n]; return ans; } double mean(const std::vector &x) { uint64 N = x.size(); return sum(&x[0], N) / N; } // takes into account that some 0 values may indicate missing/ignored: divide out by Nused, not N double mean(const double x[], uint64 N, uint64 Nused) { return sum(x, N) / Nused; } // regress y on x, assuming both have been 0-centered (so 0-filled missing values ok) double regCoeff(const double y[], const double x[], uint64 N) { /* WRONG! if not mean-centered already, need to mask missing indivs in loop double xbar = mean(x, N, Nused); double ybar = mean(y, N, Nused); cout << "xbar: " << xbar << " ybar: " << ybar << endl; double numer = 0, denom = 0; for (uint64 n = 0; n < N; n++) { numer += (x[n]-xbar) * (y[n]-ybar); denom += sq(x[n]-xbar); } */ double numer = 0, denom = 0; for (uint64 n = 0; n < N; n++) { numer += x[n] * y[n]; denom += sq(x[n]); } return numer / denom; } double dot(const double x[], const double y[], uint64 N) { double ans = 0; for (uint64 n = 0; n < N; n++) ans += x[n] * y[n]; return ans; } double norm2(const double x[], uint64 N) { double ans = 0; for (uint64 n = 0; n < N; n++) ans += sq(x[n]); return ans; } void normalize(double x[], uint64 N) { double scale = 1.0 / sqrt(norm2(x, N)); for (uint64 n = 0; n < N; n++) x[n] *= scale; } std::pair meanStdDev(const double x[], uint64 N) { double mu = 0, s2 = 0; for (uint64 n = 0; n < N; n++) mu += x[n]; mu /= N; for (uint64 n = 0; n < N; n++) s2 += sq(x[n]-mu); s2 /= (N-1); return std::make_pair(mu, sqrt(s2)); } std::pair meanStdErr(const double x[], uint64 N) { std::pair ret = meanStdDev(x, N); ret.second /= sqrt((double) N); return ret; } std::pair meanStdDev(const std::vector &x) { return meanStdDev(&x[0], x.size()); } std::pair meanStdErr(const std::vector &x) { return meanStdErr(&x[0], x.size()); } void logSumExp(float &x, float y) { float big, diff; if (x > y) { big = x; diff = y-x; } else { big = y; diff = x-y; } if (diff < -10) x = big; // a < 1e-4 * b => ignore a else if (diff < -5) x = big + expf(diff); // a < 1e-2 * b => use 1st-order Taylor expansion else x = big + logf(1.0f + expf(diff)); } } Eagle-master/src/NumericUtils.hpp000066400000000000000000000035141274444013000173110ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef NUMERICUTILS_HPP #define NUMERICUTILS_HPP #include #include #include #include "Types.hpp" namespace NumericUtils { inline double sq(double x) { return x*x; } double sum(const double x[], uint64 N); double mean(const std::vector &x); // takes into account that some 0 values may indicate missing/ignored: divide out by Nused, not N double mean(const double x[], uint64 N, uint64 Nused); // regress y on x, assuming both have been 0-centered (so 0-filled missing values ok) double regCoeff(const double y[], const double x[], uint64 N); double dot(const double x[], const double y[], uint64 N); double norm2(const double x[], uint64 N); void normalize(double x[], uint64 N); void logSumExp(float &x, float y); std::pair meanStdDev(const double x[], uint64 N); std::pair meanStdErr(const double x[], uint64 N); std::pair meanStdDev(const std::vector &x); std::pair meanStdErr(const std::vector &x); } #endif Eagle-master/src/StaticMultimap.cpp000066400000000000000000000074421274444013000176250ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include "MemoryUtils.hpp" #include "Types.hpp" #include "StaticMultimap.hpp" namespace EAGLE { using std::vector; using std::map; using std::min; using std::swap; uint randMWC(uint &z, uint &w, uint mod) { z=36969*(z&65535)+(z>>16); w=18000*(w&65535)+(w>>16); return ((z<<16)+w) % mod; } StaticMultimap::StaticMultimap() : initialized(false) {} // for value=[0..len(keyVec)), keyVec[value] = key // ignore if key == -1 // only store up to maxValuesPerKey (if more values, choose randomly) StaticMultimap::StaticMultimap(const vector &keyVec, uint maxValuesPerKey) { init(keyVec, maxValuesPerKey); } void StaticMultimap::init(const vector &keyVec, uint maxValuesPerKey) { // populate tmp map: non-ignored key -> indices i with keyVec[i]=key map < uint, vector > tmpMap; for (uint i = 0; i < keyVec.size(); i++) if (keyVec[i] != -1U) tmpMap[keyVec[i]].push_back(i); // iterate through tmp map to determine total number of values to keep (chop at max) nKeys = tmpMap.size(); nValues = 0; for (map < uint, vector >::iterator it = tmpMap.begin(); it != tmpMap.end(); it++) nValues += min((uint) it->second.size(), maxValuesPerKey); // allocate arrays keys = ALIGNED_MALLOC_UINTS(nKeys); startInds = ALIGNED_MALLOC_UINTS(nKeys); lenValues = ALIGNED_MALLOC_UINTS(nKeys + nValues); // initialize Marsaglia's MWC uint z = 362436069, w = 521288629; // iterate through tmp map to randomly select and store up to maxValuesPerKey uint keysPos = 0, lenValuesPos = 0; for (map < uint, vector >::iterator it = tmpMap.begin(); it != tmpMap.end(); it++) { keys[keysPos] = it->first; // store key startInds[keysPos] = lenValuesPos; // store address of record in storage array keysPos++; vector &values = it->second; if (values.size() > maxValuesPerKey) // randomly move maxValuesPerKey elements to front for (uint j = 0; j < maxValuesPerKey; j++) swap(values[j], values[j + randMWC(z, w, values.size() - j)]); uint nValuesCurKey = min((uint) values.size(), maxValuesPerKey); lenValues[lenValuesPos++] = nValuesCurKey; // store length as first entry of record for (uint j = 0; j < nValuesCurKey; j++) // store list of values lenValues[lenValuesPos++] = values[j]; } initialized = true; } StaticMultimap::~StaticMultimap() { if (initialized) { ALIGNED_FREE(lenValues); ALIGNED_FREE(startInds); ALIGNED_FREE(keys); } } // returns pointer to record: list size followed by list // returns NULL if key not found const uint *StaticMultimap::query(uint key) const { uint lo = 0, hi = nKeys; // condition: keys[lo] <= key < keys[hi] (hi = nKeys ok) while (lo+1. */ #ifndef STATICMULTIMAP_HPP #define STATICMULTIMAP_HPP #include #include "Types.hpp" namespace EAGLE { class StaticMultimap { private: uint nKeys, nValues; uint *keys; // [VECTOR]: nKeys uint *startInds; // [VECTOR]: nKeys uint *lenValues; // [VECTOR]: nKeys + nValues (each record: list size followed by list) bool initialized; public: StaticMultimap(); // for value=[0..len(keyVec)), keyVec[value] = key // ignore if key == -1 // only store up to maxValuesPerKey (if more values, choose randomly) StaticMultimap(const std::vector &keyVec, uint maxValuesPerKey); void init(const std::vector &keyVec, uint maxValuesPerKey); ~StaticMultimap(); // returns pointer to record: list size followed by list // returns NULL if key not found const uint *query(uint key) const; }; } #endif Eagle-master/src/StringUtils.cpp000066400000000000000000000114031274444013000171440ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include #include #include "StringUtils.hpp" namespace StringUtils { using std::vector; using std::string; using std::cout; using std::cerr; using std::endl; int stoi(const string &s) { int i; if (sscanf(s.c_str(), "%d", &i) == 0) { cerr << "ERROR: Could not parse integer from string: " << s << endl; exit(1); } return i; } double stod(const string &s) { double d; sscanf(s.c_str(), "%lf", &d); return d; } string itos(int i) { std::ostringstream oss; oss << i; return oss.str(); } string findDelimiters(const string &s, const string &c) { string delims; for (uint p = 0; p < s.length(); p++) if (c.find(s[p], 0) != string::npos) delims += s[p]; return delims; } // will not return blanks vector tokenizeMultipleDelimiters(const string &s, const string &c) { uint p = 0; vector ans; string tmp; while (p < s.length()) { tmp = ""; while (p < s.length() && c.find(s[p], 0) != string::npos) p++; while (p < s.length() && c.find(s[p], 0) == string::npos) { tmp += s[p]; p++; } if (tmp != "") ans.push_back(tmp); } return ans; } void rangeErrorExit(const string &str, const string &delims) { cerr << "ERROR: Invalid delimiter sequence for specifying range: " << endl; cerr << " Template string: " << str << endl; cerr << " Delimiter sequence found: " << delims << endl; cerr << "Range in must have format {start:end} with no other " << RANGE_DELIMS << " chars" << endl; exit(1); } // basic range template: expand "{start:end}" to vector with one entry per range element // if end==start-1, will return empty vector expandRangeTemplate(const string &str) { vector ret; string delims = findDelimiters(str, RANGE_DELIMS); if (delims.empty()) ret.push_back(str); else if (delims == RANGE_DELIMS) { vector tokens = tokenizeMultipleDelimiters(str, RANGE_DELIMS); for (int i = 0; i < (int) str.size(); i++) if (str[i] == ':' && (str[i-1] == '{' || str[i+1] == '}')) rangeErrorExit(str, delims); int startInd = (str[0] != RANGE_DELIMS[0]), endInd = startInd+1; string prefix, suffix; if (str[0] != RANGE_DELIMS[0]) prefix = tokens[0]; if (str[str.length()-1] != RANGE_DELIMS[2]) suffix = tokens.back(); int start = StringUtils::stoi(tokens[startInd]), end = StringUtils::stoi(tokens[endInd]); if (start > end+1 || end > start+1000000) { cerr << "ERROR: Invalid range in template string: " << str << endl; cerr << " Start: " << start << endl; cerr << " End: " << end << endl; exit(1); } for (int i = start; i <= end; i++) ret.push_back(prefix + itos(i) + suffix); } else rangeErrorExit(str, delims); return ret; } vector expandRangeTemplates(const vector &rangeTemplates) { vector expanded; for (uint i = 0; i < rangeTemplates.size(); i++) { vector range = expandRangeTemplate(rangeTemplates[i]); expanded.insert(expanded.end(), range.begin(), range.end()); } return expanded; } int bcfNameToChrom(const char *nameBuf, int chromMin, int chromX) { int chrom; int startPos = 0; if (strlen(nameBuf)>3 && tolower(nameBuf[0])=='c' && tolower(nameBuf[1])=='h' && tolower(nameBuf[2])=='r') startPos = 3; // allow prefix "chr" if ((int) strlen(nameBuf) == startPos + 1 && toupper(nameBuf[startPos])=='X') chrom = chromX; else { sscanf(nameBuf + startPos, "%d", &chrom); if (!isdigit(nameBuf[startPos]) || !(chrom >= chromMin && chrom <= chromX)) { cerr << "ERROR: Invalid chromosome: " << nameBuf << endl; cerr << " Chromosome number must be between " << chromMin << " and --chromX (= " << chromX << ")" << endl; exit(1); } } return chrom; } } Eagle-master/src/StringUtils.hpp000066400000000000000000000031761274444013000171610ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef STRINGUTILS_HPP #define STRINGUTILS_HPP #include #include namespace StringUtils { const std::string RANGE_DELIMS = "{:}"; // must have 3 chars int stoi(const std::string &s); double stod(const std::string &s); std::string itos(int i); std::string findDelimiters(const std::string &s, const std::string &c); // will not return blanks std::vector tokenizeMultipleDelimiters(const std::string &s, const std::string &c); // basic range template: expand "{start:end}" to vector with one entry per range element // if end==start-1, will return empty std::vector expandRangeTemplate(const std::string &str); std::vector expandRangeTemplates(const std::vector &rangeTemplates); int bcfNameToChrom(const char *nameBuf, int chromMin, int chromX); } #endif Eagle-master/src/SyncedVcfData.cpp000066400000000000000000000437001274444013000173400ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include #include #include #include #include #include #include "Types.hpp" #include "MemoryUtils.hpp" #include "MapInterpolater.hpp" #include "StringUtils.hpp" #include "SyncedVcfData.hpp" namespace EAGLE { using std::vector; using std::string; using std::pair; using std::make_pair; using std::cout; using std::cerr; using std::endl; void process_ref_genotypes(int nsmpl, int ngt, int32_t *gt, bool allowHaploid, bool refAltSwap, vector &hapsRef, int &numMissing, int &numUnphased, uint &w) { numMissing = numUnphased = 0; if (ngt != 2*nsmpl) { cerr << "ERROR: ref ploidy != 2 (ngt != 2*nsmpl): ngt=" << ngt << ", nsmpl=" << nsmpl << endl; exit(1); } int ploidy = ngt/nsmpl; for (int i=0; i haploid if ( missing ) continue; // missing diploid genotype can be written in VCF as "." else if (allowHaploid) { // X chromosome => haploid ok haps[j] = haps[j-1]; // encode as diploid homozygote unphased = false; } else { cerr << "ERROR: ref genotypes contain haploid sample" << endl; exit(1); } } } else { if ( bcf_gt_is_missing(ptr[j]) ) { // missing allele missing = true; } else { int idx = bcf_gt_allele(ptr[j]); // allele index haps[j] = (idx >= 1); // encode REF allele -> 0, ALT allele(s) -> 1 if ( j==1 && !bcf_gt_is_phased(ptr[j]) ) unphased = true; } } } if (missing) { haps[0] = haps[1] = 0; // set both alleles to REF allele numMissing++; } else if (unphased) { if (haps[0] != haps[1] && ((w=18000*(w&65535)+(w>>16))&1)) std::swap(haps[0], haps[1]); // randomize phasing numUnphased++; } if (refAltSwap) { // target REF/ALT are swapped relative to reference REF/ALT haps[0] = !haps[0]; haps[1] = !haps[1]; } hapsRef.push_back(haps[0]); hapsRef.push_back(haps[1]); } } void process_target_genotypes(int nsmpl, int ngt, int32_t *gt, bool allowHaploid, vector &genosTarget, int &numMissing) { numMissing = 0; if (ngt != 2*nsmpl) { cerr << "ERROR: target ploidy != 2 (ngt != 2*nsmpl): ngt=" << ngt << ", nsmpl=" << nsmpl << endl; exit(1); } int ploidy = ngt/nsmpl; for (int i=0; i haploid if ( missing ) continue; // missing diploid genotype can be written in VCF as "." else if (allowHaploid) // X chromosome => haploid ok g *= 2; // encode as diploid homozygote else { cerr << "ERROR: target genotypes contain haploid sample" << endl; exit(1); } } } else { if ( bcf_gt_is_missing(ptr[j]) ) { // missing allele missing = true; } else { int idx = bcf_gt_allele(ptr[j]); // allele index if (idx > 1) { cerr << "ERROR: multi-allelic site found in target; should have been filtered" << endl; exit(1); } g += idx; } } } if (missing) { g = 9; numMissing++; } genosTarget.push_back(g); } } vector < pair > SyncedVcfData::processVcfs (const string &vcfRef, const string &vcfTarget, bool allowRefAltSwap, int chrom, int chromX, double bpStart, double bpEnd, vector &hapsRef, vector &genosTarget, const string &tmpFile, const string &writeMode, int usePS, vector < vector < pair > > &conPSall) { vector < pair > chrBps; bcf_srs_t *sr = bcf_sr_init(); sr->require_index = 1; if ( chrom!=0 ) { kstring_t str = {0,0,0}; ksprintf(&str,"%d:%d-%d",chrom,(uint32_t)bpStart,(uint32_t)bpEnd); if ( bcf_sr_set_regions(sr, str.s, 0)!=0 ) { cerr << "ERROR: failed to initialize the region:" << str.s; exit(1); } free(str.s); } // By default, the synced reader requires that CHR, POS and ALT are the same // in both files. If this is too strict and SNP/indel/all lines with the same // position should be considered as matching, uncomment: // // sr->collapse = COLLAPSE_SNPS|COLLAPSE_INDELS; // // See also examples in bcftools/vcfisec etc. if (allowRefAltSwap) sr->collapse = COLLAPSE_SNPS; if (!bcf_sr_add_reader(sr, vcfRef.c_str())) { cerr << "ERROR: Could not open " << vcfRef << " for reading: " << bcf_sr_strerror(sr->errnum) << endl; exit(1); } if (!bcf_sr_add_reader(sr, vcfTarget.c_str())) { cerr << "ERROR: Could not open " << vcfTarget << " for reading: " << bcf_sr_strerror(sr->errnum) << endl; exit(1); } bcf_hdr_t *ref_hdr = bcf_sr_get_header(sr, 0); bcf_hdr_t *tgt_hdr = bcf_sr_get_header(sr, 1); // Open VCF for writing, "-" stands for standard output // wbu .. uncompressed BCF // wb .. compressed BCF // wz .. compressed VCF // w .. uncompressed VCF htsFile *out = hts_open(tmpFile.c_str(), writeMode.c_str()); // Print the VCF header bcf_hdr_write(out, tgt_hdr); Nref = bcf_hdr_nsamples(ref_hdr); Ntarget = bcf_hdr_nsamples(tgt_hdr); conPSall.resize(Ntarget); std::map bpToSyncedIndex1; // bp -> 1-based index (m+1) // Read target sample IDs targetIDs.resize(Ntarget); for (uint i = 0; i < Ntarget; i++) targetIDs[i] = tgt_hdr->samples[i]; cout << endl; cout << "Reference samples: Nref = " << Nref << endl; cout << "Target samples: Ntarget = " << Ntarget << endl; M = 0; uint MtargetOnly = 0, MrefOnly = 0, MmultiAllelic = 0, Mmonomorphic = 0; uint MwithMissingRef = 0, MwithUnphasedRef = 0, MnotInRegion = 0, MnotOnChrom = 0; uint MrefAltError = 0, numRefAltSwaps = 0; uint64 GmissingRef = 0, GunphasedRef = 0, GmissingTarget = 0; uint w = 521288629; // fast rng: Marsaglia's MWC int mref_gt = 0, *ref_gt = NULL; int mtgt_gt = 0, *tgt_gt = NULL; int mtgt_ps = 0, *tgt_ps = NULL; int Mps = 0; uint64 err_ps = 0, good_ps = 0; int prev_rid = -1; // chromosome BCF id and human-readable numeric id while ( bcf_sr_next_line(sr) ) { bcf1_t *ref = bcf_sr_get_line(sr, 0); bcf1_t *tgt = bcf_sr_get_line(sr, 1); if ( !ref ) { //fprintf(stderr, "onlyT .. %s:%d\n", bcf_seqname(tgt_hdr, tgt), tgt->pos+1); MtargetOnly++; continue; } if ( !tgt ) { //fprintf(stderr, "onlyR .. %s:%d\n", bcf_seqname(ref_hdr, ref), ref->pos+1); MrefOnly++; continue; } //fprintf(stderr, "match .. %s:%d\n", bcf_seqname(ref_hdr, ref), ref->pos+1); // filter out multi-allelic and monomorphic markers int ntgt_gt = bcf_get_genotypes(tgt_hdr, tgt, &tgt_gt, &mtgt_gt); if (tgt->n_allele > 2) { MmultiAllelic++; continue; } if (tgt->n_allele < 2) { Mmonomorphic++; continue; } bool refAltSwap = false; if (allowRefAltSwap) { // perform further error-checking if (tgt->n_allele != 2 || ref->n_allele != 2) { MrefAltError++; continue; } bcf_unpack(tgt, BCF_UN_STR); // unpack thru ALT bcf_unpack(ref, BCF_UN_STR); // unpack thru ALT /* printf("tgt REF=%s, ALT=%s ref REF=%s, ALT=%s\n", tgt->d.allele[0], tgt->d.allele[1], ref->d.allele[0], ref->d.allele[1]); */ if (strcmp(tgt->d.allele[0], ref->d.allele[0]) == 0 && strcmp(tgt->d.allele[1], ref->d.allele[1]) == 0) { refAltSwap = false; } else if (strcmp(tgt->d.allele[0], ref->d.allele[1]) == 0 && strcmp(tgt->d.allele[1], ref->d.allele[0]) == 0) { refAltSwap = true; numRefAltSwaps++; } else { MrefAltError++; continue; } } // Check the chromosome: if region was requested (chrom is set), synced // reader already positioned us in the right region. Otherwise, we process // only the first chromosome in the file and quit if ( prev_rid<0 ) { prev_rid = tgt->rid; if ( !chrom ) // learn the human-readable id { chrom = StringUtils::bcfNameToChrom(bcf_hdr_id2name(tgt_hdr, tgt->rid), 1, chromX); } } if ( prev_rid!=tgt->rid ) break; M++; // SNP passes checks bpToSyncedIndex1[tgt->pos+1] = M; // TODO: be careful about duplicate bp (multiallelics?) // append chromosome number and base pair coordinate to chrBps chrBps.push_back(make_pair(chrom, tgt->pos+1)); // process reference haplotypes: append 2*Nref entries (0/1 pairs) to hapsRef[] // check for missing/unphased ref genos (missing -> REF allele; unphased -> random phase) int nref_gt = bcf_get_genotypes(ref_hdr, ref, &ref_gt, &mref_gt); int numMissing, numUnphased; process_ref_genotypes(Nref, nref_gt, ref_gt, chrom==chromX, refAltSwap, hapsRef, numMissing, numUnphased, w); if (numMissing) MwithMissingRef++; if (numUnphased) MwithUnphasedRef++; GmissingRef += numMissing; GunphasedRef += numUnphased; // process target genotypes: append Ntarget entries (0/1/2/9) to genosTarget[] process_target_genotypes(Ntarget, ntgt_gt, tgt_gt, chrom==chromX, genosTarget, numMissing); GmissingTarget += numMissing; // process target PS field if (usePS && bcf_get_format_int32(tgt_hdr, tgt, "PS", &tgt_ps, &mtgt_ps) >= 0) { Mps++; for (uint i = 0; i < Ntarget; i++) if (tgt_ps[i] != bcf_int32_missing) { std::map ::iterator it = bpToSyncedIndex1.find(abs(tgt_ps[i])); if (it == bpToSyncedIndex1.end() || genosTarget[(M-1)*Ntarget + i] != 1 || genosTarget[(it->second-1)*Ntarget + i] != 1) err_ps++; else { conPSall[i].push_back(make_pair((int) M, it->second * (tgt_ps[i]>0 ? 1 : -1))); good_ps++; } } } // print the record bcf_write(out, tgt_hdr, tgt); } bcf_sr_destroy(sr); hts_close(out); free(ref_gt); free(tgt_gt); cout << "SNPs to analyze: M = " << M << " SNPs in both target and reference" << endl; if (Mps) { cout << " " << Mps << " SNPs with FORMAT:PS field" << endl; cout << good_ps << " usable FORMAT:PS constraints" << endl; cout << err_ps << " unusable FORMAT:PS constraints" << endl; } if (numRefAltSwaps) cerr << "--> WARNING: REF/ALT were swapped in " << numRefAltSwaps << " of these SNPs <--" << endl; cout << endl; cout << "SNPs ignored: " << MtargetOnly << " SNPs in target but not reference" << endl; if (MtargetOnly > M/10U) cerr << " --> WARNING: Check REF/ALT agreement between target and ref <--" << endl; cout << " " << MrefOnly << " SNPs in reference but not target" << endl; if (MnotOnChrom) cout << " " << MnotOnChrom << " SNPs not in specified chrom" << endl; if (MnotInRegion) cout << " " << MnotInRegion << " SNPs not in selected region (+ flanks)" << endl; cout << " " << MmultiAllelic << " multi-allelic SNPs" << endl; cout << " " << Mmonomorphic << " monomorphic SNPs" << endl; if (MrefAltError) cout << " " << MrefAltError << " SNPs with REF/ALT matching errors" << endl; cout << endl; if (MwithMissingRef) { cerr << "WARNING: Reference contains missing genotypes (set to reference allele)" << endl; cerr << " Fraction of sites with missing data: " << MwithMissingRef / (double) M << endl; cerr << " Fraction of ref genotypes missing: " << GmissingRef / (double) M / Nref << endl; } if (MwithUnphasedRef) { cerr << "WARNING: Reference contains unphased genotypes (set to random phase)" << endl; cerr << " Fraction of sites with unphased data: " << MwithUnphasedRef / (double) M << endl; cerr << " Fraction of ref genotypes unphased: " << GunphasedRef / (double) M / Nref << endl; } cout << "Missing rate in target genotypes: " << GmissingTarget / (double) M / Ntarget << endl; cout << endl; if (M <= 1U) { cerr << endl << "ERROR: Target and ref have too few matching SNPs (M = " << M << ")" << endl; exit(1); } return chrBps; } vector SyncedVcfData::processMap(vector < pair > &chrBps, const string &geneticMapFile) { cout << "Filling in genetic map coordinates using reference file:" << endl; cout << " " << geneticMapFile << endl; Genetics::MapInterpolater mapInterpolater(geneticMapFile); vector cMs(chrBps.size()); for (uint64 m = 0; m < chrBps.size(); m++) cMs[m] = 100 * mapInterpolater.interp(chrBps[m].first, chrBps[m].second); return cMs; } void SyncedVcfData::buildGenoBits(const vector &hapsRef, const vector &genosTarget, const vector &cMs, double cMmax) { const uint segMin = 16; vector snpInds; vector cMvec; vector < vector > seg64snpInds; for (uint64 m = 0; m < M; m++) { if (cMvec.size() == 64 || (cMvec.size() >= segMin && cMs[m] > cMvec[0] + cMmax)) { seg64snpInds.push_back(snpInds); seg64cMvecs.push_back(cMvec); snpInds.clear(); cMvec.clear(); } snpInds.push_back(m); cMvec.push_back(cMs[m]); } seg64snpInds.push_back(snpInds); seg64cMvecs.push_back(cMvec); Mseg64 = seg64snpInds.size(); cout << "Number of <=(64-SNP, " << cMmax << "cM) segments: " << Mseg64 << endl; cout << "Average # SNPs per segment: " << M / Mseg64 << endl; uint64 N = Nref + Ntarget; genoBits = ALIGNED_MALLOC_UINT64_MASKS(Mseg64 * N); memset(genoBits, 0, Mseg64 * N * sizeof(genoBits[0])); for (uint64 m64 = 0; m64 < Mseg64; m64++) { for (uint64 j = 0; j < seg64snpInds[m64].size(); j++) { uint64 m = seg64snpInds[m64][j]; for (uint64 n = 0; n < Nref; n++) { // store haploBits for ref haplotypes in genoBits bool haps0 = hapsRef[m * 2*Nref + 2*n]; bool haps1 = hapsRef[m * 2*Nref + 2*n+1]; genoBits[m64 * N + n].is0 |= ((uint64) haps0)< > > &conPSall, double &snpRate) { // perform synced read vector hapsRef; // M*2*Nref vector genosTarget; // M*Ntarget vector < pair > chrBps = processVcfs(vcfRef, vcfTarget, allowRefAltSwap, chrom, chromX, bpStart, bpEnd, hapsRef, genosTarget, tmpFile, writeMode, usePS, conPSall); // interpolate genetic coordinates vector cMs = processMap(chrBps, geneticMapFile); uint64 physRange = 0; double cMrange = 0; for (uint64 m = 0; m+1 < chrBps.size(); m++) if (chrBps[m+1].first == chrBps[m].first) { physRange += chrBps[m+1].second - chrBps[m].second; cMrange += cMs[m+1] - cMs[m]; } cout << "Physical distance range: " << physRange << " base pairs" << endl; cout << "Genetic distance range: " << cMrange << " cM" << endl; cout << "Average # SNPs per cM: " << (int) (M/cMrange + 0.5) << endl; snpRate = M/cMrange; if (physRange == 0 || cMrange == 0) { cerr << "ERROR: Physical and genetic distance ranges must be positive" << endl; cerr << " First SNP: chr=" << chrBps[0].first << " pos=" << chrBps[0].second << " cM=" << cMs[0] << endl; cerr << " Last SNP: chr=" << chrBps.back().first << " pos=" << chrBps.back().second << " cM=" << cMs.back() << endl; exit(1); } buildGenoBits(hapsRef, genosTarget, cMs, cMmax); } SyncedVcfData::~SyncedVcfData() { ALIGNED_FREE(genoBits); } uint64 SyncedVcfData::getNref(void) const { return Nref; } uint64 SyncedVcfData::getNtarget(void) const { return Ntarget; } uint64 SyncedVcfData::getMseg64(void) const { return Mseg64; } const uint64_masks *SyncedVcfData::getGenoBits(void) const { return genoBits; } vector > SyncedVcfData::getSeg64cMvecs(void) const { return seg64cMvecs; } const string &SyncedVcfData::getTargetID(int n) const { return targetIDs[n]; } }; Eagle-master/src/SyncedVcfData.hpp000066400000000000000000000057061274444013000173510ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef SYNCEDVCFDATA_HPP #define SYNCEDVCFDATA_HPP #include #include #include #include #include "Types.hpp" namespace EAGLE { class SyncedVcfData : boost::noncopyable { private: uint64 Nref, Ntarget, M; // N = Nref + Ntarget uint64 Mseg64; // number of <=64-SNP chunks uint64_masks *genoBits; // [[MATRIX]]: M64 x N (is0, is2, is9 64-bit masks; 3 bits/base) // n = [0..Nref) contain ref haploBits in is0, is2 // n = [Nref..Nref+Ntarget) contain target genoBits std::vector > seg64cMvecs; std::vector targetIDs; std::vector < std::pair > processVcfs (const std::string &vcfRef, const std::string &vcfTarget, bool allowRefAltSwap, int chrom, int chromX, double bpStart, double bpEnd, std::vector &hapsRef, std::vector &genosTarget, const std::string &tmpFile, const std::string &writeMode, int usePS, std::vector < std::vector < std::pair > > &conPSall); std::vector processMap(std::vector < std::pair > &chrBps, const std::string &geneticMapFile); void buildGenoBits(const std::vector &hapsRef, const std::vector &genosTarget, const std::vector &cMs, double cMmax); public: /** * reads ref+target vcf data * writes target[isec] to tmpFile * fills in cM coordinates and seg64cMvecs, genoBits */ SyncedVcfData(const std::string &vcfRef, const std::string &vcfTarget, bool allowRefAltSwap, int chrom, int chromX, double bpStart, double bpEnd, const std::string &geneticMapFile, double cMmax, const std::string &tmpFile, const std::string &writeMode, int usePS, std::vector < std::vector < std::pair > > &conPSall, double &snpRate); ~SyncedVcfData(); uint64 getNref(void) const; uint64 getNtarget(void) const; uint64 getMseg64(void) const; const uint64_masks *getGenoBits(void) const; std::vector > getSeg64cMvecs(void) const; const std::string &getTargetID(int n) const; }; } #endif Eagle-master/src/Timer.cpp000066400000000000000000000025531274444013000157430ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #include #include #include "Timer.hpp" Timer::Timer(void) { update_time(); } double Timer::update_time(void) { struct timeval tv; gettimeofday(&tv, NULL); prevtime = curtime; curtime = tv.tv_sec + 1e-6 * tv.tv_usec; return curtime - prevtime; } unsigned long long Timer::rdtsc(void) { unsigned int hi, lo; __asm__ __volatile__ ("rdtsc" : "=a"(lo), "=d"(hi)); return ((unsigned long long) lo) | (((unsigned long long) hi)<<32); } double Timer::get_time(void) { struct timeval tv; gettimeofday(&tv, NULL); return tv.tv_sec + 1e-6 * tv.tv_usec; } Eagle-master/src/Timer.hpp000066400000000000000000000017611274444013000157500ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef TIMER_HPP #define TIMER_HPP class Timer { private: double prevtime, curtime; public: static unsigned long long rdtsc(void); Timer(void); double update_time(void); double get_time(void); }; #endif Eagle-master/src/Types.hpp000066400000000000000000000017521274444013000157740ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef TYPES_HPP #define TYPES_HPP typedef unsigned char uchar; typedef unsigned int uint; typedef unsigned long long uint64; typedef long long int64; struct uint64_masks { uint64 is0, is2, is9; }; #endif Eagle-master/src/Version.hpp000066400000000000000000000016371274444013000163170ustar00rootroot00000000000000/* This file is part of the Eagle haplotype phasing software package developed by Po-Ru Loh. Copyright (C) 2015-2016 Harvard University. This program is free software: you can redistribute it and/or modify it under the terms of the GNU General Public License as published by the Free Software Foundation, either version 3 of the License, or (at your option) any later version. This program is distributed in the hope that it will be useful, but WITHOUT ANY WARRANTY; without even the implied warranty of MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the GNU General Public License for more details. You should have received a copy of the GNU General Public License along with this program. If not, see . */ #ifndef VERSION_HPP #define VERSION_HPP const char EAGLE_VERSION[] = "2.3"; const char EAGLE_VERSION_DATE[] = "July 22, 2016"; #endif Eagle-master/tables/000077500000000000000000000000001274444013000146355ustar00rootroot00000000000000Eagle-master/tables/README.txt000066400000000000000000000003121274444013000163270ustar00rootroot00000000000000NOTE: This directory contains only a small piece of a genetic map to run the provided example. Full genetic maps can be downloaded at: http://data.broadinstitute.org/alkesgroup/Eagle/downloads/tables/ Eagle-master/tables/genetic_map_hg19_example.txt.gz000066400000000000000000025726251274444013000226560ustar00rootroot00000000000000,Wtˎ&˒7SP~R ZzjPOH[n/vާVane_?O?__/RH=6-YgZ_Qy4W.}\j]d΋ڥie R}ؾ՞C[OkZ>~@g[XsuAkyR]os[Ki<ɱ=gIǶ]f;ϵL_Ѹ#W i}χ3;vB}Laؒ&Vfu6^wn_-a{z=Gv#<@{QU_0[)V~a[jm mmKe6`g)j`b9Ys]M$a^{:YH߶yڤ>ŝuuMܶnUE{1B6nh^elۍ]/Ԯj95۫lp۴6sn{oA!`]K˖YBcegrq?|K$}f}i`~k Xr4k[X}ҷf|MZAmQ퇿2oZ?A>MGf 8A"}/)}H,6}KS˰uBe?ԲTvޫ|uÐx\^Y:#7CKOc*flWjۼH3' ]>[C2}/uؾޗ6EȽ훵8~ݬjU.]zf{ ž@Z=[nBڼ]{1"m4(i+H3,vw+fR m3@]g;J);Ҟ}پ>ڲO|(uE{6+b1_ڧjg9${`mq!mڷXF;RDG5QJtרT:VEoȾb&;zjc ik HiǶ UҐ۞,ĶHU!3!9J*cavq}SÌѹYՑd?h2 ikGfIXȃ\p}O~hlL'>FC(H]Ǻ үWgc 9ab=Ҳͺ!zvۋf#{QzjXO lM;8XSY 5˴dz[%5Ɗ\YެY2S_ }bؒnkmGt籯OxMZL[H'+vLRZ>r ڃGIvlǫl 1j^#]=wW#mOa[ihiq^n;F_C3 za4^5!{ JeV׻{-P3p Wb]ocmUNM!%};fmgIU3(f v263ںH;d嵘UdhOT_&- kH;80|Humoy&v8rBQm.6q70^B#' ٪o/<{6tM{1$Y쥎Ueb i/Yc@dqj/!l}lq=Gţ!rݓX `f*.٧Y|S{I4Oif6q.d:7k۫1gf!"Hszt P 5se殘XFyh6о1Kf{iz!lYg'ް}ΫH3+vr4/"AHdX6Btrg{,ߧ#s ,Xw'+n|զ/Ҷîk;&͋4D>AmhsRbz;. @a7nk6RsV"n%liTp̐\}˾vX5TbɶEi+hgfSp2>~ݎ-hfE}j*Շ2foy%c+/-/ƃB3z q]4Q[ɐ8f5l+EDߢ)d%Iٟ5v[mg4i%7gLqY"26}8/RV--g5k.m$/#K:ĻH/,`N"yTd/K+.Y/.S4b"epݖ2-4 - SU a>g*m>LOg+00ʊJΘOck15o"g+eZ0/.lV c; %ǔ?g_VV>™hā\rpUڻom78%uŮ`83AA̶ݗ9`S! *͑8sҶ#-e֯J+z(v?4N(1"IH=ސ7Is)P*݁d_~dvʁ7XԀlBa쬱9 엏1nj_}сjتjY865 -oij/4G ~v4$yFQjd^$J0QOdg'Y* g|C͑d6b/NuCx`ʎv=Vd;Dai/}s;07BJMۨŷoX v#YIe[sZ>as͉&&y{~{;@dɎiF7SzA; 0IGp1B$OdHn^Q>aY+_ĬbEUv>n7eɷg]_rRܺv7pUB\q5dZ;Y4994iz>,<2<^$z^j~^!! ofvB΋ī䀍-GEUdsM͇pRlo[gOP8@]~@NyE`snCnt[8%\@|n~nƎG%E0B~.9`4/Fa>Bf"ʒ-92W۽h(DTS k{.BGR X)'(N -uvƏrUh hGGZP i_4{۳71vW p /f INHhfNG+OH"U%"ND BFӹ%fxaTsM;;H.Λ(#~@v#{E|2&%\GR`LMWD+$[sT.O- *$; (Mǯ[`R<rAX93' -uΚ@gd!\䔳gnvyt*|B3‰9~b@.z)vNw7O_6Lw\̑R egaP24)ߕ$lm`.ۆn҅ll;IǛu+8r[9Eʋ}'H%6MnGVKu;pCx~3:|_R {?}qf ,)@*fmAAzfory5%c.wSo_C@ múI'Ld3k sK2R:k>a$CIQ+:SKhKnY5LS ^6ٹ~5H,3Ð"uV \-C5 r[Iz:ݐs;47~䴖=g uAEl8Ś,+uT!TM?hx`pUn3_~nvrD;'ZU47[y~$1ҞeUEŋ,tJ,;HH#O$3QV8>]$;U98vݿt\N7 E+d'qUޑ eLg01i2э},Vl$ xiynp$,_[r*d6ʑ&ɣ47:% ۙ"Wej\P_!Kmt@69?f)uثM_R ]נ:T~Hgp c_$S>yY;_;Ǻ}Uj2+e|tI9⏑jIJl(/nȥnh>ȑcF%Q<0$bΡM3M';:ˮ8Ht ]wȗ|mZV 5y~"0|z'~kX 6ѡ1 j{BOw="-UhDJ@{Gb:@'T-?gWr6PQ!qUё YrkIA6%2* yRW8L"gW5 Gf+%"`lVC)I/՛77@ei$QrH*Pfz\JC^~ e4 Sx*8Hzl3OE**/prlGΩD C|CGRrC>Hp!6WJ-PR'YC&ᇶtT:6rN2V# xVA\I6MowVi`و3WZqVi9ҁ ǝcjI+މea͘'>Jm7te${ WJz-6|1hKzEC &\ǵ;'B6@Ϋ%Qr%S ;hnk}H/8\ŃWB@AD%$PHKtFN }C̋J6f0 Jg\"3 1(`&ʽ?TDljQ-\Ym&)&Bv[pn;AF:&"fxwH j:t!fyst1&Z3ui-}mhIR3.NWeQŷ2=r!mU$ZD\nP ]Atˮ!<@Ur46p!y"DA>I[S lm!k*G ExCE'KD.ڪtLdIR1i j}ȠewѶ^즁#XRbímIxGMo;Np bN{ً5ҿ և(uHD-J92>@@27o#VX˹$U/r*jAvN*jN`ЀeJH /L>"Շt)A$(JI.k/P{I#i3ǑЯAL#R&7mw`;$_-G;Ζ \4P<.WENOoꪓ=s:Q}Uv!8c -:M΢J8$AAҝ+^,fDoK7"XRЄyJ+/R] IrG 3G.*e3p>AȀWȶTɈ;~gյF)}fG6iB'B#?lq1:,Hr1"MȬg8prX]zI|$yJ;ϛ5A$_OƄ) Ia!5 #)oEɞPYAJ"mr;M?KjW/%2[B9H˯ _dȊ w(6\$M.IIɐg#?>P,az;ds=)vqj{ّBESȅ(j?C_s" GN(J!&V I/].ql@㕏l $8=+˜N%I,!#up$} SB!3]48Hbņ={\% M<dk]kY(o2!mF]RRFHݿEMdrO͑XT>Ӥ!xH@؎G.g$a]9%~Ğ͢VYXQ #nn~ei\bx{`nZ`H=n7w'CY(` 3f_so:9љxvblMHE.M |l'DOHw`|ȽHw@`87I( JWf< ɩGȮk vGpE܏@QSڔ_Z I|{MOq @]Ɂ̶oy^uCZ`cFrt ~-X9%D(1GX,4WzƢJ "HQKIVz%YItJO O"M6xhzѽ=(M;NڑCÈޏC>!%TCx d(;*)>` dP[KDV"A4nvUvqi&.U:J[Ƨ-OzXjrWf?ݥНSſ0eK(g3"\sAH>x bga>l7?qu˹O*FH ːhQڇ=٠OH*Bډpg\WS B2 Cv 'ovN[ERq/3497[_EyBui,DL2#Q˃){ҭ#"m(`ibr;-Zr ̗Z^mR3~3ưȫ+HX >\PMF3ɄETY ebk@*\!s?4V4^$9)%`u:wp(|Gk>'t`X.ZÀA@n֖EV1z:s$}\* NtqO"\GHoh4Z]䘡rܪӦ3AXlHfGhֹ`K<sF#L^;@"vD96gd5 ,)ݪ *.Hcj 0HcwfCU[' RyIS#]I@FB/TDׯ验~l#$UQ t< 눊FbѺgm}AB~";Uѱ/5l \Qp'@TW#Zot2P>À$DHȉ㳍H(:kV-Br zktMJM1J"$V };p$K90`PsM C!W\B@q_FW I bT\$ZA"["#$$( 9H2LHA_g|#㼺8x7fr *2REi$C̗"3VU?O=&0;yVeDA@@EV7σ/$ѓ,4΋$=._#I@܅" Uesk:*Цqqul5Dʈ H poJ7_YEv~KSQ<ƇYctuW?it,* 5ݗUE@m\J5$FTlA$nJdi;yKԈ )-yPTBNt֛Ke ܃%OC ΢O"9/@o(Pqf$-5&œJ[?PtɡS*BU-F'€AY6^I" = M2Q?!P~A;%%~;Y A 7zUt J` 2qูFT3{ E dkqM}[JU't;XWaF$:ل:vԗA[P38 Fwŭp(/;HJH#(ךxUn(eQ0;A8ʞ&˪[|Ix ru!Ȗ).=}*NDvC{9uRp SWdz6~S$), '8zB\C}G~_+yqP;o%$is (U_B_ :tzsU8,CB5 e5N 5+V]; k,Q28J!A$'DK%vX=$82 fUhj GMiRH: RVuS@r/CH4⫇oy fV;7B?+I6Y0xIqv| RЇÔ7P5 8nZfoڻ*BDFG'WT'VaўvOLHXXgV2IYZSIWǯ#VNRoXćg؛y%\DS #yeM}>~1Ɯ9p M}dJ6\ E$'$ͷH5@Bh.>42U=~ɮk l+3И>⫉OE2إR=1 2jש#5k)?H|?^2v'#b Q"wFS:zECp&4}b~eo6~5H_Sݠf'L]ܧf*Kל^\;DƆ&?2 \:', 81$a4[`Ztc4*njQ_P"kK-0=5 YBtƣ K5ׄ dY 닙@3 Sbvo-Ŋ|%@v$m]L75>SE3B,L|FK&&7q8a7 rL]EIEAVsdO>fj(j.&Āh,#I5xaMA8WMLFOb Cro$δX""Hrb#͐ALۓtPq R#ed+!zAZ9&oVIY׍>I:$1Yb!z ݐ=g^ɒhHL^VFgPi_ɤObjQ'd3P:[c`piLTp$lp!?緈g5#L*DA@Q,ɪ2ݻMCJ#}rE!Q֐YdLZ$om:@>7 Cgo(4 D@ȶ|uAD(ߨ q@c*hɑE 3H+pm益-9%LLo>|T冄uvCۆPU׷xKKy$*@u7 5`D4?[\KR"|B(}7G @RvI ^#qN&fo;Ć,hzBrp B i(uŃ|n=9EFvQ6R8? 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