Difference between revisions of "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 individuals.
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'''Rare Metal''' wiki page will on up by 2/14/2013.
  
If you have any questions, please contact: sfengsph at umich dot edu
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Thanks for your patience!
 
 
== 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 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 ==
 

Revision as of 17:31, 13 February 2013

Rare Metal wiki page will on up by 2/14/2013.

Thanks for your patience!