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        "author": "Omer Weissbrod",
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        "description": "LEAP\r\n----------------\r\n\r\nLEAP is a program for liability estimation in ascertained case-control genome-wide association studies, written in the Python language.\r\nLEAP estimates liabilities, that can then be treated as phenotypes in a GWAS context, which can greatly increase power.\r\n\r\n\r\n------------------\r\nInstallation\r\n------------------\r\nThe easiest way to install LEAP is via pip, by typing the command:\r\n```shell\r\npip install --user leap_gwas\r\n```\r\n\r\nTypically, the LEAP scripts will be installed at:\r\n```\r\n~/.local/lib/python2.7/site-packages/LEAP/\r\n```\r\n\r\nLEAP is particularly easy to install using the [Anaconda Python distribution](https://store.continuum.io/cshop/anaconda). The [numerically optimized version](http://continuum.io/blog/mkl-optimizations) of Anaconda can speed LEAP up by several orders of magnitude.\r\n\r\nAlternatively (if Anaconda can't be installed), for very fast performance it is recommended to have an optimized version of Numpy/Scipy [installed on your system](http://www.scipy.org/scipylib/building), using optimized numerical libraries such as [OpenBLAS](http://www.openblas.net) or [Intel MKL](https://software.intel.com/en-us/intel-mkl) (see [Compilation instructions for scipy with Intel MKL)](https://software.intel.com/en-us/articles/numpyscipy-with-intel-mkl). \r\n\r\nTo install LEAP manually, you need the following dependencies:\r\n* Python 2.7\r\n* [Numpy](http://www.numpy.org/) and [Scipy](http://www.scipy.org/)\r\n* [Scikits-learn](http://scikit-learn.org/stable/)\r\n* The Python [FaST-LMM package](https://github.com/MicrosoftGenomics/FaST-LMM).\r\n\r\nPlease make sure these are installed prior to using LEAP.\r\nTo verify that everything is correctly installed, please run the script test.py in the regression directory. It will run a small example analysis and print an error message if any problem is found.\r\n \r\n \r\n------------------\r\nUsage instructions\r\n----------------------\r\nThere are two ways to run LEAP.\r\nThe first is via a Python API. A detailed explanation about this option is provided in the [LEAP Ipython notebook](http://nbviewer.ipython.org/github/omerwe/LEAP/blob/master/leap/regression/Leap_example.ipynb).\r\n\r\nThe second option is to run LEAP though a series of Python scripts, as detailed below. This option is more suitable for those not familiar with Python. The script leapUtils.sh runs the full LEAP pipeline on a small example dataset, and can be used for reference.\r\n \r\nGenerally, LEAP uses the same file formats as [FaST-LMM](https://github.com/MicrosoftGenomics/FaST-LMM).\r\nNamely, input files are in [binary Plink format](http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml#bed).\r\nWhen there is a contradiction between file formats used by Plink and by FastLMM, LEAP uses the convention adopted by FastLMM.\r\nExplanations about the parameters used by all the scripts can be seen by typing\r\n```\r\npython <script_name> --help\r\n```\r\n\r\nThe command-line options for LEAP largely follow the options of the [C++ version of \r\nFaST-LMM](http://research.microsoft.com/en-us/projects/fastlmm/).\r\n \r\n \r\n### The LEAP pipeline\r\n**1) (optional): Find related individuals to be removed:**\r\n```\r\npython findRelated.py --bfilesim <Plink base file> --out <output file>\r\n```\r\n This script creates a file marking the individuals that need to be removed to eliminate relatedness.\r\n \r\n **2) Compute an eigendecomposition of the kinship matrix:**\r\n```\r\npython eigenDecompose.py --bfilesim <Plink base file> --out <output file> [--extractSim <SNPs used to estimate kinship> --pheno <phenotype file>]\r\n```\r\nThis script computes a kinship matrix and its eigendecomposition, and saves them to speed up subsequent stages. It is recommended to perform a leave-one-chromosome-out (LOCO) analysis by computing a different kinship matrix for each chromosome, each one consisting of all SNPs except those on the selected chromosome. The optional extractSim file is a text file with a list of SNP names (one SNP per line) to facilitate this. The optional phenotype file is only used to exclude individuals with an unknown phenotype.\r\n \r\n**3) Compute heritability using the method of [Golan et al.](http://www.pnas.org/content/111/49/E5272.long):**\r\n```\r\npython calc_h2.py --bfilesim <Plink base file> --prev <prevalence> --pheno <phenotype file> --h2coeff 1.0 [--eigen <eigen file> --extractSim <SNPs used for heritability estimation>  --related <relatedness file> --h2coeff <heritability coefficient>]\r\n```\r\nThis script outputs the heritability estimate. The optional eigen file is the one created in stage 2. The optional extractSim file is a text file with a list of SNP names (one SNP per line) that will be used for heritability estimation. It is recommended to perform a different heritability and liability estimation for every excluded chromosome, and then testing the SNPs on the excluded chromosome for association with the estimated liabilities. The bfilesim and extractSim parameters must be the same as the ones used in stage 2. The optional relatedness file should be the output of stage 1, and is used to exclude related individuals from the analysis, which improves analysis results.\r\n\r\n**4) Estimate liabilities:**\r\n```\r\npython probit.py --bfilesim <Plink base file> --pheno <phenotype file> --prev <prevalence> --out <output base file> --h2 <heritability> [--eigen <eigen file> --extractSim <SNPs used in the liability estimation> --related <relatedness file>]\r\n```\r\nThis script creates a file called \\<output base file\\>.liabs, with estimated liabilities for every individual. The estimated liabilities can be used directly for GWAS by using them as a standard phenotype file. The eigen file is the one computes in stage 2, and the h2 parameter should be the heritability estimate from stage 3. The extractSim and relatedness file parameters should be the same as in stage 3.\r\n\r\n**5) Test for Associations:**\r\n```\r\npython leap_gwas.py --bfilesim <Plink base file for kinship estimation> --bfile <Plink file with tested SNPs> --pheno <estimated liabilities file> --out <output file> --h2 <heritability> [--eigen <eigen file> --extractSim <SNPs used in the LMM kinship matrix>  --extract <SNPs to test>]\r\n```\r\nThis script performs GWAS with a prespecified heritability level (as computed in stage 2). The eigen file is the one from stage 2, and the pheno parameter is the liabilities file computed in stage 4. The syntax largely follows that of the [C++ version of FaST-LMM](http://research.microsoft.com/en-us/projects/fastlmm/).\r\nThe bfile and bfilesim parameters can both point to the same file. In this case, the extract and extractSim parameters should be used to guarantee that kinship estimation doesn't use SNPs on the excluded chromosome, and that all tested SNPs are on the excluded chromosome.\r\n \r\n \r\n-----------------\r\nGeneral comments and tips\r\n-------------------------\r\n**1)** Fixed effects can be included in stages 2-4 by adding the flag --covar.\r\nPlease type\r\n```\r\npython probit.py --help\r\n```\r\nand\r\n```\r\npython leap_gwas.py --help\r\n```\r\nfor instructions. However, we note that under extreme ascertainment, it is recommded to use covariates only in stages 2-3 (see the paper for details).\r\n \r\n**2)** As described in the main text, it is recommended to perform a different liability estimation for every excluded chromosome, and then testing the SNPs on the excluded chromosome for association with the estimated liabilities. The -extractSim flag is useful for this. Please see the example file leap_pipeline.sh for a usage example.\r\n \r\n**3)** A complete end-to-end usage example is provided with the LEAP source files, and can be invoked via the script leap_pipeline.sh.\r\nThis example estimates liabilities for a small balanced case-control dataset.\r\nThe dataset was simulated with 50% heritability and  0.1% prevalence. It included 500 cases, 500 controls, 499 causal SNPs and 10000 SNPs differentiated with FST=0.01. Causal SNPs are called csnp\\<i\\>.  The original liabilities for this file are available in the file dataset1.phe.liab (but this file is not used by LEAP).\r\n \r\n\r\n-----------------\r\nContact\r\n---------\r\nFor questions and comments, please contact Omer Weissbrod at omerw[at]cs.technion.ac.il",
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