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RAREMETAL Documentation

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'''Rare-Metal-Worker''' is a tool for generating summary statistics for rare variants and gene level meta analyses using Rare-Metal. It handles both related individuals and unrelated individualswiki page will on up by 2/14/2013.
If you have any questions, please contact: sfengsph at umich dot edu == Change Log ==* Version 0.0.1 was released on 11/13/2012.* Modified Rare-Metal-Worker to let it output LD matrix by a sliding window. (11/14/2012)* Uploaded to public wiki. (11/16/2012)* Enabled writing log file by defalut. (11/18/2012)* Forced sample IDs to be matched when reading in kinship from a file. Perform a sanity check before reading in kinship file. If a sample of interest is not included in kinship file, then fatal error will occur. (11/19/2012)* Added HWE pvalue and call rate in summary statistics output. (11/27/2012)* Bugs fixed to solve compiling errors on some machines (Thank you Mary Kate!). Version 0.0.2 released. (11/30/2012)* Updated output format. Version 0.0.3 released. (12/3/2012)* More messages coded into log file. (12/4/2012)* Version 0.0.4 released. (12/5/2012)* Bug fixed for empirical kinship calculation when genotypes are read from VCF file. Version 0.0.5 released. (12/6/2012)* Version 0.0.6 released. (12/6/2012)* Updated output format for monomorphic sites. (12/7/2012)* Changed executable name into bin/raremetalworker. Version 0.0.7 released. (12/10/2012)* Fixed a bug when reading genotypes from vcf file. (2/5/2013) == Key Features ==Rare-Metal-Worker has the following features:* Takes genotypes from either PED file or VCF file.* Generates summary statistics for both related and unrelated individuals.* Generates linkage disequilibrium matrices summarizing covariance between single marker statistics using an adjustable sliding window. * Optionally handles related individuals using a kinship matrix derived from either pedigree or genotype data.* Has the option of fitting shared environment.* Can handle variants on Chromosome X. == Software Download and Installation == === Where to Download === * The source package Thanks for Linux and Mac can be downloaded here: [[Media:RareMetalWorker.0.0.8.tgz|software package download]]* Save it to your local path and decompress using the following command: tar xvzf RareMetalWorker.0.0.8.tgz* For UM CSG cluster users, no installation is needed. It is available at /net/fantasia/home/sfengsph/code/Rare-Metal/RareMetalWorker/bin/raremetalworker === How to Compile === * Go to /RareMetalWorker_0.0.8/RareMetalWorker/src and use the following command: make all === How to Execute === * To execute the program, go to /RareMetalWorker_0.0.6/RareMetalWorker/bin, then the program can be executed by ./Rare-Metal-Worker.* An example command line for a related sample when you have genotype info saved in VCF file is as following: ./raremetalworker --ped your.pheno.ped --dat your.pheno.dat --vcf your.geno.vcf.gz --useCovariates --inverseNormal --prefix your.study* An example command line for a related sample when you have genotype info saved in PED/DAT file is as following: ./raremetalworker --ped your.ped --dat your.dat --useCovariates --inverseNormal --prefix your.study* An example command line for an unrelated sample when you have genotype info saved in PED/DAT file is as following: ./raremetalworker --ped your.ped --dat your.dat --useCovariates --inverseNormal --prefix your.study* An example command line for an unrelated sample when you have genotype info saved in VCF file is as following: ./raremetalworker --ped your.pheno.ped --dat your.pheno.dat --vcf your.geno.vcf.gz --useCovariates --inverseNormal --prefix your.study* An example command line to use when you have genotype info saved in VCF file and you want to adjust covariates first and then inverse normalize residuals is as following: ./raremetalworker --ped your.pheno.ped --dat your.pheno.dat --vcf your.geno.vcf.gz --makeResiduals --useCovariates --inverseNormal --prefix your.study* For more examples, please go to [[Examples]]. == Software Specifications == === Input Files ===Rare-Metal-Worker needs the following files as input: PED and DAT file in Merlin format, '''AND/OR''' a VCF file. When genotypes are stored in PED and DAT file, the VCF file is not needed. However, even if genotypes are saved in a VCF file, PED and DAT files are still needed for carrying covariate and trait information.  ==== PED and DAT Files ====* When PED file has genotypes saved, there is no need for a VCF file as input.* Rare-Metal-Worker takes PED/DAT file in Merlin format. Please refer to [[http://www.sph.umich.edu/csg/abecasis/merlin/tour/input_files.html PED/DAT format description]] for details.* An example PED file is in the following: 1 1 0 0 1 1.5 1 23 A A A A A A A A A A 2 1 0 0 1 1.0 1 34 A C A C A C A C A C 3 1 0 0 2 0.4 1 43 A A A A A A A A A A 4 1 0 0 2 0.9 1 13 A C A C A C A C A C* The matching DAT file is in the following: T YourTraitName C SEX C AGE M 1:123456 M 1:234567 M 2:111111 M 2:222222 M X:12345* DAT file must have variant names in the following format "M chr:pos". * Orders of labels in DAT file have to match the order of fields in PED file. * '''Markers in PED and DAT file must be sorted by chromosome and position.''' * Covariate and trait values are saved in PED file. Covariate and trait descriptions are saved in DAT file. ==== VCF File ====* Another option is to use VCF as input. Please refer to the following link for VCF file specification: [[http://www.1000genomes.org/wiki/Analysis/Variant%20Call%20Format/vcf-variant-call-format-version-41 1000 genome wiki VCF specs]] * VCF file should be compressed by bgzip and indexed by tabix, using the following command: bgzip input.vcf ## this command will produce input.vcf.gz tabix -pvcf -f input.vcf.gz ## this command will produce input.vcf.gz.tbi* Even with the presence of VCF file, PED/DAT files are still needed for covariates and phenotypes. === Software Options ===The following options are currently available in Rare-Metal-Worker:  Options: Input Files : --ped [Exomechip.pheno.ped], --dat [Exomechip.pheno.dat], --vcf [] Output Files : --prefix [], --LDwindow [1000000] VC Options : --vcShared, --vcX, --useCovariates [ON] Trait Options : --makeResiduals, --inverseNormal [ON], --traitName [] Kinship Source : --kinPedigree [ON], --kinGeno, --kinFile [], --kinSave Kinship Options : --kinMaf [0.05], --kinMiss [0.05] Chromosome X : --xLabel [X], --xStart [2699520], --xEnd [154931044]  ==== Input Files ====* When genotypes are saved in a VCF file, PED and DAT files are used for specifying pedigree structure, covariate and trait information. An example command line might look like this: --ped input.ped --dat input.dat --vcf input.vcf.gz* When genotypes are saved in the PED file, the VCF file is not needed. An example command line might look like this: --ped input.ped --dat input.dat ==== Output Files ====* --prefix is optional. * If --prefix is not specified, the output file names will be: traitname.singlevar.score.txt traitname.singlevar.cov.txt* If --prefix prefix is specified, then the output file names are: prefix.traitname.singlevar.score.txt prefix.traitname.singlevar.cov.txt* --LDwindow specifies the length of the window that LD Matrix should be generated upon each variant. The default is 1MB. ==== VC Options ====* When --vcShared and --vcX are specified, Rare-Metal-Worker knows that you want to fit shared environment and/or chromosome X variance component together with genetic component and non-shared environment.* When --useCovariates is specified, Rare-Metal-Worker understands covariates should be read from PED file. Covariates are modeled as fixed effects.==== Trait Options ====* --makeResiduals can be combined with --useCovariates to generate residuals from a simple linear regressions before analysis. If the --inverseNormal option is also used, then the residuals will be quantile normalized before fitting variance component model. ** An example Command line requesting pre-adjustment for covariates before fitting a variance component follows: --useCovariates --makeResiduals --inverseNormal** An example command line requesting joint modeling of fixed effects and variance components follows: --useCovariates --inverseNormal * If --inverseNormal is used WITHOUT --makeResiduals, then trait values are inverse normalized before any model fitting.* --traitName is created for situations when you have many traits saved in your PED and DAT file, but you are interested in one or a few of them. It can read a file ending with .txt with each trait of interest in a separate line, or trait names separated with "/". An example to handle one trait or multiple traits is in the following: --traitName LDL --traitName LDL/HDL/TG --traitName traitsOfInterest.txt* If --traitName is not used, all traits in PED/DAT file will be analyzed. ==== Kinship Source ====* --kinPedigree allows Rare-Metal-Worker to generate kinship matrix from pedigree, when pedigree information is available. This option is on by default. * --kinGeno informs Rare-Metal-Worker to generate kinship matrix from all available variants that pass the criteria, specified in --kinMaf and --kinMiss options. The default will take variants with MAF>0.05 and genotype missing rate <0.05.* --kinFile let Rare-Metal-Worker read in a kinship matrix from a file. The first row of the kinship file has to be the sample IDs included in the kinship file. If a sample of interest is not included in the kinship file, fatal error will occur and the program will be terminated. A sample of interest is a sample that is phenotyped and has all covariates measured when --useCovariates is specified.* --kinSave allows you to save the kinship matrix. ==== Kinship Options ====* --kinMiss and --kinMaf should be used with --kinGeno together. * --kinMiss specifies the maximum genotype missing rate when calculating kinship from genotypes. The default is 0.05.* --kinMaf specifies the minimum minor allele frequency used when calculating kinship from genotypes. The default is 0.05. ==== Chromosome X ====* --xLabel should have a value of a string which specifies how variants on chromosome X are coded. The default is "X".* --xStart and --xEnd specifies the start and end of non-pseudo-autosomal regions on chromosome X. These options should be specified when --vcX is used.* The default for --xStart is 2699520 and default for --xEnd is 154931044, according to NCBI genome build 37. === Handling Unrelated Individuals ===* To let Rare-Metal-Worker handle unrelated individuals, we just have to code the individuals as unrelated in PED file, or each individual belongs to a unique family. Then Rare-Metal-Worker will take care of the rest.* However, when --kinGenotype is also used, Rare-Metal-Worker will consider them as related and generate kinship matrix from genotypes.* An example is shown as following (header is included for illustration purpose, not in real PED file):  famid pid fid mid sex age trait 1 1.1 0 0 1 10 -0.3 2 2.1 0 0 1 56 0.0 3 3.1 0 0 2 31 0.4 4 4.1 0 0 2 23 0.008 5 5.1 0 0 2 34 2.35 == Output Formats == * There are three files generated automatically by default:  prefix.traitName.singlevar.score.txt prefix.traitName.singlevar.cov.txt prefix.singlevar.log * prefix.traitName.singlevar.score.txt contains summary statistics that are needed by Rare-Metal. An example is shown in below:  LDL mean= -0.00, variance= 1.00, heritability= 34.30 CHR POS REF_ALLELE ALT_ALLELE INFORMATIVE_N FOUNDER_AF ALL_AF INFORMATIVE_AC HWE_PVALUE STAT ALT_ALLELE_EFFSIZE PVALUE 10 45410002 G A 6103 0.0341589 0.0341589 410 0.165893 126.205 0.309798 4.03074e-10 19 45412079 G A 6103 0.0368124 0.0368124 434 0.714645 -265.84 -0.587356 7.87851e-36 19 45414451 G A 6103 0.444989 0.444989 5312 0.0759271 -26.1212 -0.00837122 0.640058 * pvalues from the above output are from the family-based single variant score test. * prefix.traitName.singlevar.cov.txt contains the LD matrix among a variant and the adjacent markers within a prefixed-sized window. The default window size is 1MB. It has the following format: CHR POS VAR_POS_IN_WINDOW LD_MATRIX 1 762320 762320,865628,865665,878744,879381,1560000 0.0359084,-0.000242112,-0.00125797,-0.000993422,-0.000344509,-0.00017077, 1 865628 865628,865665,878744,879381,1560000,1864659 0.419804,-0.0103663,-0.00635265,0.0594056,0.0534505,-0.00462183, 1 878744 878744,879381,1560000,1864659,1877659 0.000404537,-0.000235215,-1.4455e-05,-8.69137e-06,-3.1027e-05, * An example log file is in the following: Summary statistics for trait LDL have been saved in LDL.singlevar.score.txt. LD matrices for trait LDL have been saved in LDL.singlevar.cov.txt. Rare-Metal-Worker handled all individuals as related. The following parameters are in effect: Input Files: ============================ --ped [APOE.ped] --dat [APOE.dat] --vcf [] Output Files: ============================ --prefix [] --LDwindow [1000000] VC Options: ============================ --vcShared [false] --vcX [false] --useCovariates [false] Trait Options: ============================ --makeResiduals [true] --inverseNormal [true] --traitName [LDL] Kinship Source: ============================ --kinPedigree [true] --kinGeno [false] --kinFile [] --kinSave [false] Kinship Options: ============================ --kinMaf [0.05] --kinMiss [0.05] Chromosome X: ============================ xLabel [X] xStart [2699520] xEnd [154931044] == Examples == === Related individuals ===* When you have genotype stored in ped file and dat file, and want to use pedigree kinship and inverse normalize trait values before adjusting any covariates and doing analysis:  /bin/raremetalworker --ped yourInput.ped --dat yourInput.dat --traitName LDL --inverseNormal --useCovariates * When you have genotype stored in ped file and dat file, and want to use pedigree kinship and adjust covariates before inverse normalizing the residuals and doing further analysis:  /bin/raremetalworker --ped yourInput.ped --dat yourInput.dat --traitName LDL --useCovariates --makeResiduals --inverseNormal  * When you have genotype stored in ped file and dat file, and want to use kinship generated from genotypes: /bin/raremetalworker --ped yourInput.ped --dat yourInput.dat --kinGeno --kinSave --traitName LDL (--kinSave allows you to save kinship matrix for future use; it is optional.) * When you have genotype stored in vcf file and want to use pedigree kinship:   /bin/raremetalworker --ped yourInput.ped --dat yourInput.dat --vcf yourInput.vcf.gz * When you have genotype stored in vcf file and want to use kinship generated from genotype:   /bin/raremetalworker --ped yourInput.ped --dat yourInput.dat --vcf yourInput.vcf.gz --kinGeno --kinSave (--kinSave allows you to save kinship matrix for future use.) === Unrelated individuals === * Commands are the same as in above example, except each individual has to have a distinct family ID in PED file, and their father and mother ids should be "0".* When you have genotypes from ped and marker information from dat file, and assuming no relatedness in the sample:  ./raremetalworker --ped yours.ped --dat yours.dat * When you have genotypes from vcf and covariates and trait information saved in ped and dat file, assuming there is no relatedness in the sample, you should use the following:  ./raremetalworker --ped yours.ped --dat yours.dat --vcf yours.vcf.gz * When you have genotypes from vcf and covariates and trait information saved in ped and dat file, assuming there is cryptic relatedness in the sample, you should use the following:  ./raremetalworker --ped yours.ped --dat yours.dat --vcf yours.vcf.gz --kinGeno (# this will handle individuals as related, and generate kinship matrix from genotype.) == Q & A ==patience!
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