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authorzsloan2015-04-06 10:50:59 -0500
committerzsloan2015-04-06 10:50:59 -0500
commit24fe675688467b77cb0b1e858e23f119027d08d8 (patch)
treefdc0ea6440f342f9bd2a3ed8946998859efebc9b /wqflask
parent5fb4245a3d08f7107cf885639fc275a6d73ea82d (diff)
parent67d7d982f96cfd0f3dcb9806ecc6d2f947af9dc9 (diff)
downloadgenenetwork2-24fe675688467b77cb0b1e858e23f119027d08d8.tar.gz
Merge pull request #3 from pjotrp/master
0.50-gn2-pre1
Diffstat (limited to 'wqflask')
-rw-r--r--wqflask/wqflask/my_pylmm/README.md21
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/__init__.py1
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/gwas.py173
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/input.py2
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/kinship.py22
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/lmm.py137
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/lmm2.py410
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/phenotype.py2
-rw-r--r--wqflask/wqflask/my_pylmm/pyLMM/runlmm.py75
9 files changed, 789 insertions, 54 deletions
diff --git a/wqflask/wqflask/my_pylmm/README.md b/wqflask/wqflask/my_pylmm/README.md
new file mode 100644
index 00000000..f6b0e72d
--- /dev/null
+++ b/wqflask/wqflask/my_pylmm/README.md
@@ -0,0 +1,21 @@
+# RELEASE NOTES
+
+## 0.50-gn2-pre1 release
+
+This is the first test release of multi-core pylmm into GN2. Both
+kinship calculation and GWAS have been made multi-threaded by
+introducing the Python multiprocessing module. Note that only
+run_other has been updated to use the new routines (so human is still
+handled the old way). I have taken care that we can still run both
+old-style and new-style LMM (through passing the 'new_code'
+boolean). This could be an option in the web server for users to
+select and test for any unexpected differences (of which there should
+be none, naturally ;).
+
+The current version can handle missing phenotypes, but as they are
+removed there is no way for GN2 to know what SNPs the P-values belong
+to. A future version will pass a SNP index to allow for missing
+phenotypes.
+
+
+ \ No newline at end of file
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/__init__.py b/wqflask/wqflask/my_pylmm/pyLMM/__init__.py
index e69de29b..c40c3221 100644
--- a/wqflask/wqflask/my_pylmm/pyLMM/__init__.py
+++ b/wqflask/wqflask/my_pylmm/pyLMM/__init__.py
@@ -0,0 +1 @@
+PYLMM_VERSION="0.50-gn2-pre1"
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/gwas.py b/wqflask/wqflask/my_pylmm/pyLMM/gwas.py
new file mode 100644
index 00000000..b901c0e2
--- /dev/null
+++ b/wqflask/wqflask/my_pylmm/pyLMM/gwas.py
@@ -0,0 +1,173 @@
+# pylmm-based GWAS calculation
+#
+# Copyright (C) 2013 Nicholas A. Furlotte (nick.furlotte@gmail.com)
+# Copyright (C) 2015 Pjotr Prins (pjotr.prins@thebird.nl)
+#
+# This program is free software: you can redistribute it and/or modify
+# it under the terms of the GNU Affero 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 Affero General Public License for more details.
+
+# You should have received a copy of the GNU Affero General Public License
+# along with this program. If not, see <http://www.gnu.org/licenses/>.
+#!/usr/bin/python
+
+import pdb
+import time
+import sys
+# from utility import temp_data
+import lmm2
+
+import os
+import numpy as np
+import input
+from optmatrix import matrix_initialize
+from lmm2 import LMM2
+
+import multiprocessing as mp # Multiprocessing is part of the Python stdlib
+import Queue
+
+def formatResult(id,beta,betaSD,ts,ps):
+ return "\t".join([str(x) for x in [id,beta,betaSD,ts,ps]]) + "\n"
+
+def compute_snp(j,n,snp_ids,lmm2,REML,q = None):
+ # print("COMPUTE SNP",j,snp_ids,"\n")
+ result = []
+ for snp_id in snp_ids:
+ snp,id = snp_id
+ x = snp.reshape((n,1)) # all the SNPs
+ # print "X=",x
+ # if refit:
+ # L.fit(X=snp,REML=REML)
+ ts,ps,beta,betaVar = lmm2.association(x,REML=REML,returnBeta=True)
+ # result.append(formatResult(id,beta,np.sqrt(betaVar).sum(),ts,ps))
+ result.append( (ts,ps) )
+ if not q:
+ q = compute_snp.q
+ q.put([j,result])
+ return j
+ # PS.append(ps)
+ # TS.append(ts)
+ # return len(result)
+ # compute.q.put(result)
+ # return None
+
+def f_init(q):
+ compute_snp.q = q
+
+def gwas(Y,G,K,restricted_max_likelihood=True,refit=False,verbose=True):
+ """
+ Execute a GWAS. The G matrix should be n inds (cols) x m snps (rows)
+ """
+ matrix_initialize()
+ cpu_num = mp.cpu_count()
+ numThreads = None # for now use all available threads
+ kfile2 = False
+ reml = restricted_max_likelihood
+
+ sys.stderr.write(str(G.shape)+"\n")
+ n = G.shape[1] # inds
+ inds = n
+ m = G.shape[0] # snps
+ snps = m
+ sys.stderr.write(str(m)+" SNPs\n")
+ # print "***** GWAS: G",G.shape,G
+ assert snps>inds, "snps should be larger than inds (snps=%d,inds=%d)" % (snps,inds)
+
+ # CREATE LMM object for association
+ # if not kfile2: L = LMM(Y,K,Kva,Kve,X0,verbose=verbose)
+ # else: L = LMM_withK2(Y,K,Kva,Kve,X0,verbose=verbose,K2=K2)
+
+ lmm2 = LMM2(Y,K) # ,Kva,Kve,X0,verbose=verbose)
+ if not refit:
+ if verbose: sys.stderr.write("Computing fit for null model\n")
+ lmm2.fit() # follow GN model in run_other
+ if verbose: sys.stderr.write("\t heritability=%0.3f, sigma=%0.3f\n" % (lmm2.optH,lmm2.optSigma))
+
+ # outFile = "test.out"
+ # out = open(outFile,'w')
+ out = sys.stderr
+
+ def outputResult(id,beta,betaSD,ts,ps):
+ out.write(formatResult(id,beta,betaSD,ts,ps))
+ def printOutHead(): out.write("\t".join(["SNP_ID","BETA","BETA_SD","F_STAT","P_VALUE"]) + "\n")
+
+ # printOutHead()
+ res = []
+
+ # Set up the pool
+ # mp.set_start_method('spawn')
+ q = mp.Queue()
+ p = mp.Pool(numThreads, f_init, [q])
+ collect = []
+
+ # Buffers for pvalues and t-stats
+ # PS = []
+ # TS = []
+ count = 0
+ job = 0
+ jobs_running = 0
+ for snp in G:
+ snp_id = (snp,'SNPID')
+ count += 1
+ if count % 1000 == 0:
+ job += 1
+ if verbose:
+ sys.stderr.write("Job %d At SNP %d\n" % (job,count))
+ if numThreads == 1:
+ print "Running on 1 THREAD"
+ compute_snp(job,n,collect,lmm2,reml,q)
+ collect = []
+ j,lst = q.get()
+ if verbose:
+ sys.stderr.write("Job "+str(j)+" finished\n")
+ res.append((j,lst))
+ else:
+ p.apply_async(compute_snp,(job,n,collect,lmm2,reml))
+ jobs_running += 1
+ collect = []
+ while jobs_running > cpu_num:
+ try:
+ j,lst = q.get_nowait()
+ if verbose:
+ sys.stderr.write("Job "+str(j)+" finished\n")
+ res.append((j,lst))
+ jobs_running -= 1
+ except Queue.Empty:
+ time.sleep(0.1)
+ pass
+ if jobs_running > cpu_num*2:
+ time.sleep(1.0)
+ else:
+ break
+
+ collect.append(snp_id)
+
+ if numThreads==1 or count<1000 or len(collect)>0:
+ job += 1
+ print "Collect final batch size %i job %i @%i: " % (len(collect), job, count)
+ compute_snp(job,n,collect,lmm2,reml,q)
+ collect = []
+ j,lst = q.get()
+ res.append((j,lst))
+ print "count=",count," running=",jobs_running," collect=",len(collect)
+ for job in range(jobs_running):
+ j,lst = q.get(True,15) # time out
+ if verbose:
+ sys.stderr.write("Job "+str(j)+" finished\n")
+ res.append((j,lst))
+
+ print "Before sort",[res1[0] for res1 in res]
+ res = sorted(res,key=lambda x: x[0])
+ # if verbose:
+ # print "res=",res[0][0:10]
+ print "After sort",[res1[0] for res1 in res]
+ print [len(res1[1]) for res1 in res]
+ ts = [item[0] for j,res1 in res for item in res1]
+ ps = [item[1] for j,res1 in res for item in res1]
+ return ts,ps
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/input.py b/wqflask/wqflask/my_pylmm/pyLMM/input.py
index f7b556a5..7063fedf 100644
--- a/wqflask/wqflask/my_pylmm/pyLMM/input.py
+++ b/wqflask/wqflask/my_pylmm/pyLMM/input.py
@@ -135,6 +135,8 @@ class plink:
def normalizeGenotype(self,G):
# print "Before",G
# print G.shape
+ print "call input.normalizeGenotype"
+ raise "This should not be used"
x = True - np.isnan(G)
m = G[x].mean()
s = np.sqrt(G[x].var())
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/kinship.py b/wqflask/wqflask/my_pylmm/pyLMM/kinship.py
index 28f2042d..0c43587e 100644
--- a/wqflask/wqflask/my_pylmm/pyLMM/kinship.py
+++ b/wqflask/wqflask/my_pylmm/pyLMM/kinship.py
@@ -21,6 +21,7 @@
import sys
import os
import numpy as np
+from scipy import linalg
import multiprocessing as mp # Multiprocessing is part of the Python stdlib
import Queue
import time
@@ -85,12 +86,13 @@ def kinship(G,computeSize=1000,numThreads=None,useBLAS=False,verbose=True):
m = G.shape[0] # snps
snps = m
sys.stderr.write(str(m)+" SNPs\n")
- assert m>n, "n should be larger than m (snps>inds)"
+ assert snps>inds, "snps should be larger than inds (%i snps, %i inds)" % (snps,inds)
q = mp.Queue()
p = mp.Pool(numThreads, f_init, [q])
cpu_num = mp.cpu_count()
print "CPU cores:",cpu_num
+ print snps,computeSize
iterations = snps/computeSize+1
# if testing:
# iterations = 8
@@ -153,5 +155,23 @@ def kinship(G,computeSize=1000,numThreads=None,useBLAS=False,verbose=True):
# np.savetxt(outFile+".kve",Kve)
return K
+def kvakve(K, verbose=True):
+ """
+ Obtain eigendecomposition for K and return Kva,Kve where Kva is cleaned
+ of small values < 1e-6 (notably smaller than zero)
+ """
+ if verbose: sys.stderr.write("Obtaining eigendecomposition for %dx%d matrix\n" % (K.shape[0],K.shape[1]) )
+
+ Kva,Kve = linalg.eigh(K)
+ if verbose:
+ print("Kva is: ", Kva.shape, Kva)
+ print("Kve is: ", Kve.shape, Kve)
+
+ if sum(Kva < 1e-6):
+ if verbose: sys.stderr.write("Cleaning %d eigen values (Kva<0)\n" % (sum(Kva < 0)))
+ Kva[Kva < 1e-6] = 1e-6
+ return Kva,Kve
+
+
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/lmm.py b/wqflask/wqflask/my_pylmm/pyLMM/lmm.py
index 937d3340..58ff809b 100644
--- a/wqflask/wqflask/my_pylmm/pyLMM/lmm.py
+++ b/wqflask/wqflask/my_pylmm/pyLMM/lmm.py
@@ -50,8 +50,10 @@ has_gn2=True
from utility.benchmark import Bench
from utility import temp_data
-from kinship import kinship, kinship_full
+from kinship import kinship, kinship_full, kvakve
import genotype
+import phenotype
+import gwas
try:
from wqflask.my_pylmm.pyLMM import chunks
@@ -254,7 +256,7 @@ def human_association(snp,
# refit=False,
# temp_data=None):
-def run_other(pheno_vector,
+def run_other_old(pheno_vector,
genotype_matrix,
restricted_max_likelihood=True,
refit=False,
@@ -270,7 +272,7 @@ def run_other(pheno_vector,
"""
- print("In run_other")
+ print("Running the original LMM engine in run_other (old)")
print("REML=",restricted_max_likelihood," REFIT=",refit)
with Bench("Calculate Kinship"):
kinship_matrix,genotype_matrix = calculate_kinship(genotype_matrix, tempdata)
@@ -278,25 +280,79 @@ def run_other(pheno_vector,
print("kinship_matrix: ", pf(kinship_matrix))
print("kinship_matrix.shape: ", pf(kinship_matrix.shape))
- with Bench("Create LMM object"):
- lmm_ob = LMM(pheno_vector, kinship_matrix)
+ # with Bench("Create LMM object"):
+ # lmm_ob = LMM(pheno_vector, kinship_matrix)
- with Bench("LMM_ob fitting"):
- lmm_ob.fit()
+ # with Bench("LMM_ob fitting"):
+ # lmm_ob.fit()
- print("genotype_matrix: ", genotype_matrix.shape)
+ print("run_other_old genotype_matrix: ", genotype_matrix.shape)
print(genotype_matrix)
with Bench("Doing GWAS"):
t_stats, p_values = GWAS(pheno_vector,
- genotype_matrix,
- kinship_matrix,
- restricted_max_likelihood=True,
- refit=False,
- temp_data=tempdata)
+ genotype_matrix,
+ kinship_matrix,
+ restricted_max_likelihood=True,
+ refit=False,
+ temp_data=tempdata)
Bench().report()
return p_values, t_stats
+def run_other_new(pheno_vector,
+ genotype_matrix,
+ restricted_max_likelihood=True,
+ refit=False,
+ tempdata=None # <---- can not be None
+ ):
+
+ """Takes the phenotype vector and genotype matrix and returns a set of p-values and t-statistics
+
+ restricted_max_likelihood -- whether to use restricted max likelihood; True or False
+ refit -- whether to refit the variance component for each marker
+ temp_data -- TempData object that stores the progress for each major step of the
+ calculations ("calculate_kinship" and "GWAS" take the majority of time)
+
+ """
+
+ print("Running the new LMM2 engine in run_other_new")
+ print("REML=",restricted_max_likelihood," REFIT=",refit)
+
+ # Adjust phenotypes
+ Y,G,keep = phenotype.remove_missing(pheno_vector,genotype_matrix,verbose=True)
+ print("Removed missing phenotypes",Y.shape)
+
+ # if options.maf_normalization:
+ # G = np.apply_along_axis( genotype.replace_missing_with_MAF, axis=0, arr=g )
+ # print "MAF replacements: \n",G
+ # if not options.skip_genotype_normalization:
+ # G = np.apply_along_axis( genotype.normalize, axis=1, arr=G)
+
+ with Bench("Calculate Kinship"):
+ K,G = calculate_kinship(G, tempdata)
+
+ print("kinship_matrix: ", pf(K))
+ print("kinship_matrix.shape: ", pf(K.shape))
+
+ # with Bench("Create LMM object"):
+ # lmm_ob = lmm2.LMM2(Y,K)
+ # with Bench("LMM_ob fitting"):
+ # lmm_ob.fit()
+
+ print("run_other_new genotype_matrix: ", G.shape)
+ print(G)
+
+ with Bench("Doing GWAS"):
+ t_stats, p_values = gwas.gwas(Y,
+ G.T,
+ K,
+ restricted_max_likelihood=True,
+ refit=False,verbose=True)
+ Bench().report()
+ return p_values, t_stats
+
+# def matrixMult(A,B):
+# return np.dot(A,B)
def matrixMult(A,B):
@@ -334,8 +390,10 @@ def calculate_kinship_new(genotype_matrix, temp_data=None):
Call the new kinship calculation where genotype_matrix contains
inds (columns) by snps (rows).
"""
+ print("call genotype.normalize")
G = np.apply_along_axis( genotype.normalize, axis=0, arr=genotype_matrix)
- return kinship(G.T),G
+ print("call calculate_kinship_new")
+ return kinship(G.T),G # G gets transposed, we'll turn this into an iterator (FIXME)
def calculate_kinship_old(genotype_matrix, temp_data=None):
"""
@@ -345,6 +403,7 @@ def calculate_kinship_old(genotype_matrix, temp_data=None):
normalizes the resulting vectors and returns the RRM matrix.
"""
+ print("call calculate_kinship_old")
n = genotype_matrix.shape[0]
m = genotype_matrix.shape[1]
print("genotype 2D matrix n (inds) is:", n)
@@ -375,7 +434,7 @@ def calculate_kinship_old(genotype_matrix, temp_data=None):
temp_data.store("percent_complete", percent_complete)
genotype_matrix = genotype_matrix[:,keep]
- print("genotype_matrix: ", pf(genotype_matrix))
+ print("After kinship (old) genotype_matrix: ", pf(genotype_matrix))
kinship_matrix = np.dot(genotype_matrix, genotype_matrix.T) * 1.0/float(m)
return kinship_matrix,genotype_matrix
@@ -533,11 +592,13 @@ class LMM:
print("this K is:", K.shape, pf(K))
if len(Kva) == 0 or len(Kve) == 0:
- if self.verbose: sys.stderr.write("Obtaining eigendecomposition for %dx%d matrix\n" % (K.shape[0],K.shape[1]) )
+ # if self.verbose: sys.stderr.write("Obtaining eigendecomposition for %dx%d matrix\n" % (K.shape[0],K.shape[1]) )
begin = time.time()
- Kva,Kve = linalg.eigh(K)
+ # Kva,Kve = linalg.eigh(K)
+ Kva,Kve = kvakve(K)
end = time.time()
if self.verbose: sys.stderr.write("Total time: %0.3f\n" % (end - begin))
+ print("sum(Kva),sum(Kve)=",sum(Kva),sum(Kve))
self.K = K
self.Kva = Kva
@@ -547,10 +608,11 @@ class LMM:
self.Y = Y
self.X0 = X0
self.N = self.K.shape[0]
-
- if sum(self.Kva < 1e-6):
- if self.verbose: sys.stderr.write("Cleaning %d eigen values\n" % (sum(self.Kva < 0)))
- self.Kva[self.Kva < 1e-6] = 1e-6
+
+ # ----> Below moved to kinship.kvakve(K)
+ # if sum(self.Kva < 1e-6):
+ # if self.verbose: sys.stderr.write("Cleaning %d eigen values\n" % (sum(self.Kva < 0)))
+ # self.Kva[self.Kva < 1e-6] = 1e-6
self.transform()
@@ -713,7 +775,10 @@ class LMM:
ts = beta / np.sqrt(var * sigma)
ps = 2.0*(1.0 - stats.t.cdf(np.abs(ts), self.N-q))
- if not len(ts) == 1 or not len(ps) == 1: raise Exception("Something bad happened :(")
+ if not len(ts) == 1 or not len(ps) == 1:
+ print("ts=",ts)
+ print("ps=",ps)
+ raise Exception("Something bad happened :(")
return ts.sum(),ps.sum()
def plotFit(self,color='b-',title=''):
@@ -739,7 +804,11 @@ class LMM:
pl.title(title)
-def gn2_redis(key,species):
+def gn2_redis(key,species,new_code=True):
+ """
+ Invoke pylmm using Redis as a container. new_code runs the new
+ version
+ """
json_params = Redis.get(key)
params = json.loads(json_params)
@@ -761,11 +830,18 @@ def gn2_redis(key,species):
geno = np.array(params['genotype_matrix'])
print('geno', geno.shape, geno)
- ps, ts = run_other(pheno_vector = np.array(params['pheno_vector']),
- genotype_matrix = geno,
- restricted_max_likelihood = params['restricted_max_likelihood'],
- refit = params['refit'],
- tempdata = tempdata)
+ if new_code:
+ ps, ts = run_other_new(pheno_vector = np.array(params['pheno_vector']),
+ genotype_matrix = geno,
+ restricted_max_likelihood = params['restricted_max_likelihood'],
+ refit = params['refit'],
+ tempdata = tempdata)
+ else:
+ ps, ts = run_other_old(pheno_vector = np.array(params['pheno_vector']),
+ genotype_matrix = geno,
+ restricted_max_likelihood = params['restricted_max_likelihood'],
+ refit = params['refit'],
+ tempdata = tempdata)
results_key = "pylmm:results:" + params['temp_uuid']
@@ -790,7 +866,7 @@ def gn2_main():
gn2_redis(key,species)
-def gn2_load_redis(key,species,kinship,pheno,geno):
+def gn2_load_redis(key,species,kinship,pheno,geno,new_code=True):
print("Loading Redis from parsed data")
if kinship == None:
k = None
@@ -811,7 +887,7 @@ def gn2_load_redis(key,species,kinship,pheno,geno):
Redis.set(key, json_params)
Redis.expire(key, 60*60)
- return gn2_redis(key,species)
+ return gn2_redis(key,species,new_code)
if __name__ == '__main__':
print("WARNING: Calling pylmm from lmm.py will become OBSOLETE, use runlmm.py instead!")
@@ -821,4 +897,3 @@ if __name__ == '__main__':
print("Run from runlmm.py instead")
-
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/lmm2.py b/wqflask/wqflask/my_pylmm/pyLMM/lmm2.py
new file mode 100644
index 00000000..d4b3ac82
--- /dev/null
+++ b/wqflask/wqflask/my_pylmm/pyLMM/lmm2.py
@@ -0,0 +1,410 @@
+# pylmm is a python-based linear mixed-model solver with applications to GWAS
+
+# Copyright (C) 2013,2014 Nicholas A. Furlotte (nick.furlotte@gmail.com)
+#
+# This program is free software: you can redistribute it and/or modify
+# it under the terms of the GNU Affero 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 Affero General Public License for more details.
+
+# You should have received a copy of the GNU Affero General Public License
+# along with this program. If not, see <http://www.gnu.org/licenses/>.
+
+import sys
+import time
+import numpy as np
+from scipy.linalg import eigh, inv, det
+import scipy.stats as stats # t-tests
+from scipy import optimize
+from optmatrix import matrixMult
+import kinship
+
+def calculateKinship(W,center=False):
+ """
+ W is an n x m matrix encoding SNP minor alleles.
+
+ This function takes a matrix oF SNPs, imputes missing values with the maf,
+ normalizes the resulting vectors and returns the RRM matrix.
+ """
+ n = W.shape[0]
+ m = W.shape[1]
+ keep = []
+ for i in range(m):
+ mn = W[True - np.isnan(W[:,i]),i].mean()
+ W[np.isnan(W[:,i]),i] = mn
+ vr = W[:,i].var()
+ if vr == 0: continue
+
+ keep.append(i)
+ W[:,i] = (W[:,i] - mn) / np.sqrt(vr)
+
+ W = W[:,keep]
+ K = matrixMult(W,W.T) * 1.0/float(m)
+ if center:
+ P = np.diag(np.repeat(1,n)) - 1/float(n) * np.ones((n,n))
+ S = np.trace(matrixMult(matrixMult(P,K),P))
+ K_n = (n - 1)*K / S
+ return K_n
+ return K
+
+def GWAS(Y, X, K, Kva=[], Kve=[], X0=None, REML=True, refit=False):
+ """
+
+ Performs a basic GWAS scan using the LMM. This function
+ uses the LMM module to assess association at each SNP and
+ does some simple cleanup, such as removing missing individuals
+ per SNP and re-computing the eigen-decomp
+
+ Y - n x 1 phenotype vector
+ X - n x m SNP matrix (genotype matrix)
+ K - n x n kinship matrix
+ Kva,Kve = linalg.eigh(K) - or the eigen vectors and values for K
+ X0 - n x q covariate matrix
+ REML - use restricted maximum likelihood
+ refit - refit the variance component for each SNP
+
+ """
+ n = X.shape[0]
+ m = X.shape[1]
+ prins("Initialize GWAS")
+ print("genotype matrix n is:", n)
+ print("genotype matrix m is:", m)
+
+ if X0 == None:
+ X0 = np.ones((n,1))
+
+ # Remove missing values in Y and adjust associated parameters
+ v = np.isnan(Y)
+ if v.sum():
+ keep = True - v
+ keep = keep.reshape((-1,))
+ Y = Y[keep]
+ X = X[keep,:]
+ X0 = X0[keep,:]
+ K = K[keep,:][:,keep]
+ Kva = []
+ Kve = []
+
+ if len(Y) == 0:
+ return np.ones(m)*np.nan,np.ones(m)*np.nan
+
+ L = LMM(Y,K,Kva,Kve,X0)
+ if not refit: L.fit()
+
+ PS = []
+ TS = []
+
+ n = X.shape[0]
+ m = X.shape[1]
+
+ for i in range(m):
+ x = X[:,i].reshape((n,1))
+ v = np.isnan(x).reshape((-1,))
+ if v.sum():
+ keep = True - v
+ xs = x[keep,:]
+ if xs.var() == 0:
+ PS.append(np.nan)
+ TS.append(np.nan)
+ continue
+
+ Ys = Y[keep]
+ X0s = X0[keep,:]
+ Ks = K[keep,:][:,keep]
+ Ls = LMM(Ys,Ks,X0=X0s)
+ if refit:
+ Ls.fit(X=xs)
+ else:
+ Ls.fit()
+ ts,ps = Ls.association(xs,REML=REML)
+ else:
+ if x.var() == 0:
+ PS.append(np.nan)
+ TS.append(np.nan)
+ continue
+
+ if refit:
+ L.fit(X=x)
+ ts,ps = L.association(x,REML=REML)
+
+ PS.append(ps)
+ TS.append(ts)
+
+ return TS,PS
+
+class LMM2:
+
+ """
+ This is a simple version of EMMA/fastLMM.
+ The main purpose of this module is to take a phenotype vector (Y), a set of covariates (X) and a kinship matrix (K)
+ and to optimize this model by finding the maximum-likelihood estimates for the model parameters.
+ There are three model parameters: heritability (h), covariate coefficients (beta) and the total
+ phenotypic variance (sigma).
+ Heritability as defined here is the proportion of the total variance (sigma) that is attributed to
+ the kinship matrix.
+
+ For simplicity, we assume that everything being input is a numpy array.
+ If this is not the case, the module may throw an error as conversion from list to numpy array
+ is not done consistently.
+
+ """
+ def __init__(self,Y,K,Kva=[],Kve=[],X0=None,verbose=False):
+
+ """
+ The constructor takes a phenotype vector or array Y of size n.
+ It takes a kinship matrix K of size n x n. Kva and Kve can be computed as Kva,Kve = linalg.eigh(K) and cached.
+ If they are not provided, the constructor will calculate them.
+ X0 is an optional covariate matrix of size n x q, where there are q covariates.
+ When this parameter is not provided, the constructor will set X0 to an n x 1 matrix of all ones to represent a mean effect.
+ """
+
+ if X0 == None:
+ X0 = np.ones(len(Y)).reshape(len(Y),1)
+ self.verbose = verbose
+
+ x = True - np.isnan(Y)
+ x = x.reshape(-1,)
+ if not x.sum() == len(Y):
+ if self.verbose: sys.stderr.write("Removing %d missing values from Y\n" % ((True - x).sum()))
+ Y = Y[x]
+ K = K[x,:][:,x]
+ X0 = X0[x,:]
+ Kva = []
+ Kve = []
+ self.nonmissing = x
+
+ print("this K is:", K.shape, K)
+
+ if len(Kva) == 0 or len(Kve) == 0:
+ # if self.verbose: sys.stderr.write("Obtaining eigendecomposition for %dx%d matrix\n" % (K.shape[0],K.shape[1]) )
+ begin = time.time()
+ # Kva,Kve = linalg.eigh(K)
+ Kva,Kve = kinship.kvakve(K)
+ end = time.time()
+ if self.verbose: sys.stderr.write("Total time: %0.3f\n" % (end - begin))
+ print("sum(Kva),sum(Kve)=",sum(Kva),sum(Kve))
+
+ self.K = K
+ self.Kva = Kva
+ self.Kve = Kve
+ self.N = self.K.shape[0]
+ self.Y = Y.reshape((self.N,1))
+ self.X0 = X0
+
+ if sum(self.Kva < 1e-6):
+ if self.verbose: sys.stderr.write("Cleaning %d eigen values\n" % (sum(self.Kva < 0)))
+ self.Kva[self.Kva < 1e-6] = 1e-6
+
+ self.transform()
+
+ def transform(self):
+
+ """
+ Computes a transformation on the phenotype vector and the covariate matrix.
+ The transformation is obtained by left multiplying each parameter by the transpose of the
+ eigenvector matrix of K (the kinship).
+ """
+
+ self.Yt = matrixMult(self.Kve.T, self.Y)
+ self.X0t = matrixMult(self.Kve.T, self.X0)
+ self.X0t_stack = np.hstack([self.X0t, np.ones((self.N,1))])
+ self.q = self.X0t.shape[1]
+
+ def getMLSoln(self,h,X):
+
+ """
+ Obtains the maximum-likelihood estimates for the covariate coefficients (beta),
+ the total variance of the trait (sigma) and also passes intermediates that can
+ be utilized in other functions. The input parameter h is a value between 0 and 1 and represents
+ the heritability or the proportion of the total variance attributed to genetics. The X is the
+ covariate matrix.
+ """
+
+ S = 1.0/(h*self.Kva + (1.0 - h))
+ Xt = X.T*S
+ XX = matrixMult(Xt,X)
+ XX_i = inv(XX)
+ beta = matrixMult(matrixMult(XX_i,Xt),self.Yt)
+ Yt = self.Yt - matrixMult(X,beta)
+ Q = np.dot(Yt.T*S,Yt)
+ sigma = Q * 1.0 / (float(self.N) - float(X.shape[1]))
+ return beta,sigma,Q,XX_i,XX
+
+ def LL_brent(self,h,X=None,REML=False):
+ #brent will not be bounded by the specified bracket.
+ # I return a large number if we encounter h < 0 to avoid errors in LL computation during the search.
+ if h < 0: return 1e6
+ return -self.LL(h,X,stack=False,REML=REML)[0]
+
+ def LL(self,h,X=None,stack=True,REML=False):
+
+ """
+ Computes the log-likelihood for a given heritability (h). If X==None, then the
+ default X0t will be used. If X is set and stack=True, then X0t will be matrix concatenated with
+ the input X. If stack is false, then X is used in place of X0t in the LL calculation.
+ REML is computed by adding additional terms to the standard LL and can be computed by setting REML=True.
+ """
+
+ if X == None: X = self.X0t
+ elif stack:
+ self.X0t_stack[:,(self.q)] = matrixMult(self.Kve.T,X)[:,0]
+ X = self.X0t_stack
+
+ n = float(self.N)
+ q = float(X.shape[1])
+ beta,sigma,Q,XX_i,XX = self.getMLSoln(h,X)
+ LL = n*np.log(2*np.pi) + np.log(h*self.Kva + (1.0-h)).sum() + n + n*np.log(1.0/n * Q)
+ LL = -0.5 * LL
+
+ if REML:
+ LL_REML_part = q*np.log(2.0*np.pi*sigma) + np.log(det(matrixMult(X.T,X))) - np.log(det(XX))
+ LL = LL + 0.5*LL_REML_part
+
+
+ LL = LL.sum()
+ return LL,beta,sigma,XX_i
+
+ def getMax(self,H, X=None,REML=False):
+
+ """
+ Helper functions for .fit(...).
+ This function takes a set of LLs computed over a grid and finds possible regions
+ containing a maximum. Within these regions, a Brent search is performed to find the
+ optimum.
+
+ """
+ n = len(self.LLs)
+ HOpt = []
+ for i in range(1,n-2):
+ if self.LLs[i-1] < self.LLs[i] and self.LLs[i] > self.LLs[i+1]:
+ HOpt.append(optimize.brent(self.LL_brent,args=(X,REML),brack=(H[i-1],H[i+1])))
+ if np.isnan(HOpt[-1]): HOpt[-1] = H[i-1]
+ #if np.isnan(HOpt[-1]): HOpt[-1] = self.LLs[i-1]
+ #if np.isnan(HOpt[-1][0]): HOpt[-1][0] = [self.LLs[i-1]]
+
+ if len(HOpt) > 1:
+ if self.verbose: sys.stderr.write("NOTE: Found multiple optima. Returning first...\n")
+ return HOpt[0]
+ elif len(HOpt) == 1: return HOpt[0]
+ elif self.LLs[0] > self.LLs[n-1]: return H[0]
+ else: return H[n-1]
+
+
+ def fit(self,X=None,ngrids=100,REML=True):
+
+ """
+ Finds the maximum-likelihood solution for the heritability (h) given the current parameters.
+ X can be passed and will transformed and concatenated to X0t. Otherwise, X0t is used as
+ the covariate matrix.
+
+ This function calculates the LLs over a grid and then uses .getMax(...) to find the optimum.
+ Given this optimum, the function computes the LL and associated ML solutions.
+ """
+
+ if X == None: X = self.X0t
+ else:
+ #X = np.hstack([self.X0t,matrixMult(self.Kve.T, X)])
+ self.X0t_stack[:,(self.q)] = matrixMult(self.Kve.T,X)[:,0]
+ X = self.X0t_stack
+
+ H = np.array(range(ngrids)) / float(ngrids)
+ L = np.array([self.LL(h,X,stack=False,REML=REML)[0] for h in H])
+ self.LLs = L
+
+ hmax = self.getMax(H,X,REML)
+ L,beta,sigma,betaSTDERR = self.LL(hmax,X,stack=False,REML=REML)
+
+ self.H = H
+ self.optH = hmax.sum()
+ self.optLL = L
+ self.optBeta = beta
+ self.optSigma = sigma.sum()
+
+ return hmax,beta,sigma,L
+
+ def association(self,X,h=None,stack=True,REML=True,returnBeta=False):
+ """
+ Calculates association statitics for the SNPs encoded in the vector X of size n.
+ If h == None, the optimal h stored in optH is used.
+
+ """
+ if False:
+ print "X=",X
+ print "h=",h
+ print "q=",self.q
+ print "self.Kve=",self.Kve
+ print "X0t_stack=",self.X0t_stack.shape,self.X0t_stack
+
+ if stack:
+ # X = np.hstack([self.X0t,matrixMult(self.Kve.T, X)])
+ m = matrixMult(self.Kve.T,X)
+ # print "m=",m
+ m = m[:,0]
+ self.X0t_stack[:,(self.q)] = m
+ X = self.X0t_stack
+
+ if h == None: h = self.optH
+
+ L,beta,sigma,betaVAR = self.LL(h,X,stack=False,REML=REML)
+ q = len(beta)
+ ts,ps = self.tstat(beta[q-1],betaVAR[q-1,q-1],sigma,q)
+
+ if returnBeta: return ts,ps,beta[q-1].sum(),betaVAR[q-1,q-1].sum()*sigma
+ return ts,ps
+
+ def tstat(self,beta,var,sigma,q,log=False):
+
+ """
+ Calculates a t-statistic and associated p-value given the estimate of beta and its standard error.
+ This is actually an F-test, but when only one hypothesis is being performed, it reduces to a t-test.
+ """
+
+ ts = beta / np.sqrt(var * sigma)
+ #ps = 2.0*(1.0 - stats.t.cdf(np.abs(ts), self.N-q))
+ # sf == survival function - this is more accurate -- could also use logsf if the precision is not good enough
+ if log:
+ ps = 2.0 + (stats.t.logsf(np.abs(ts), self.N-q))
+ else:
+ ps = 2.0*(stats.t.sf(np.abs(ts), self.N-q))
+ if not len(ts) == 1 or not len(ps) == 1:
+ raise Exception("Something bad happened :(")
+ return ts.sum(),ps.sum()
+
+ def plotFit(self,color='b-',title=''):
+
+ """
+ Simple function to visualize the likelihood space. It takes the LLs
+ calcualted over a grid and normalizes them by subtracting off the mean and exponentiating.
+ The resulting "probabilities" are normalized to one and plotted against heritability.
+ This can be seen as an approximation to the posterior distribuiton of heritability.
+
+ For diagnostic purposes this lets you see if there is one distinct maximum or multiple
+ and what the variance of the parameter looks like.
+ """
+ import matplotlib.pyplot as pl
+
+ mx = self.LLs.max()
+ p = np.exp(self.LLs - mx)
+ p = p/p.sum()
+
+ pl.plot(self.H,p,color)
+ pl.xlabel("Heritability")
+ pl.ylabel("Probability of data")
+ pl.title(title)
+
+ def meanAndVar(self):
+
+ mx = self.LLs.max()
+ p = np.exp(self.LLs - mx)
+ p = p/p.sum()
+
+ mn = (self.H * p).sum()
+ vx = ((self.H - mn)**2 * p).sum()
+
+ return mn,vx
+
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/phenotype.py b/wqflask/wqflask/my_pylmm/pyLMM/phenotype.py
index bb620052..682ba371 100644
--- a/wqflask/wqflask/my_pylmm/pyLMM/phenotype.py
+++ b/wqflask/wqflask/my_pylmm/pyLMM/phenotype.py
@@ -36,5 +36,5 @@ def remove_missing(y,g,verbose=False):
sys.stderr.write("runlmm.py: Cleaning the phenotype vector and genotype matrix by removing %d individuals...\n" % (v.sum()))
y1 = y[keep]
g1 = g[keep,:]
- return y1,g1
+ return y1,g1,keep
diff --git a/wqflask/wqflask/my_pylmm/pyLMM/runlmm.py b/wqflask/wqflask/my_pylmm/pyLMM/runlmm.py
index 6bb79856..324c4f2c 100644
--- a/wqflask/wqflask/my_pylmm/pyLMM/runlmm.py
+++ b/wqflask/wqflask/my_pylmm/pyLMM/runlmm.py
@@ -21,7 +21,7 @@ from optparse import OptionParser
import sys
import tsvreader
import numpy as np
-from lmm import gn2_load_redis, calculate_kinship
+from lmm import gn2_load_redis, calculate_kinship_old
from kinship import kinship, kinship_full
import genotype
import phenotype
@@ -54,9 +54,12 @@ parser.add_option("--geno",dest="geno",
parser.add_option("--maf-normalization",
action="store_true", dest="maf_normalization", default=False,
help="Apply MAF genotype normalization")
-parser.add_option("--skip-genotype-normalization",
- action="store_true", dest="skip_genotype_normalization", default=False,
- help="Skip genotype normalization")
+parser.add_option("--genotype-normalization",
+ action="store_true", dest="genotype_normalization", default=False,
+ help="Force genotype normalization")
+parser.add_option("--remove-missing-phenotypes",
+ action="store_true", dest="remove_missing_phenotypes", default=False,
+ help="Remove missing phenotypes")
parser.add_option("-q", "--quiet",
action="store_false", dest="verbose", default=True,
help="don't print status messages to stdout")
@@ -99,28 +102,58 @@ if options.geno:
g = tsvreader.geno(options.geno)
print g.shape
-if cmd == 'redis':
+if cmd == 'redis_new':
+ # The main difference between redis_new and redis is that missing
+ # phenotypes are handled by the first
+ Y = y
+ G = g
+ print "Original G",G.shape, "\n", G
+
+ gt = G.T
+ G = None
+ ps, ts = gn2_load_redis('testrun','other',k,Y,gt,new_code=True)
+ print np.array(ps)
+ print len(ps),sum(ps)
+ # Test results
+ p1 = round(ps[0],4)
+ p2 = round(ps[-1],4)
+ sys.stderr.write(options.geno+"\n")
+ if options.geno == 'data/small.geno':
+ assert p1==0.0708, "p1=%f" % p1
+ assert p2==0.1417, "p2=%f" % p2
+ if options.geno == 'data/small_na.geno':
+ assert p1==0.0897, "p1=%f" % p1
+ assert p2==0.0405, "p2=%f" % p2
+ if options.geno == 'data/test8000.geno':
+ # assert p1==0.8984, "p1=%f" % p1
+ # assert p2==0.9621, "p2=%f" % p2
+ assert round(sum(ps)) == 4070
+ assert len(ps) == 8000
+elif cmd == 'redis':
# Emulating the redis setup of GN2
G = g
print "Original G",G.shape, "\n", G
- if y != None:
+ if y != None and options.remove_missing_phenotypes:
gnt = np.array(g).T
- Y,g = phenotype.remove_missing(y,g.T,options.verbose)
+ Y,g,keep = phenotype.remove_missing(y,g.T,options.verbose)
G = g.T
print "Removed missing phenotypes",G.shape, "\n", G
+ else:
+ Y = y
if options.maf_normalization:
G = np.apply_along_axis( genotype.replace_missing_with_MAF, axis=0, arr=g )
print "MAF replacements: \n",G
- if not options.skip_genotype_normalization:
+ if options.genotype_normalization:
G = np.apply_along_axis( genotype.normalize, axis=1, arr=G)
g = None
gnt = None
gt = G.T
G = None
- ps, ts = gn2_load_redis('testrun','other',k,Y,gt)
+ ps, ts = gn2_load_redis('testrun','other',k,Y,gt, new_code=False)
print np.array(ps)
- # Test results
+ print len(ps),sum(ps)
+ # Test results 4070.02346579
p1 = round(ps[0],4)
p2 = round(ps[-1],4)
sys.stderr.write(options.geno+"\n")
@@ -128,15 +161,15 @@ if cmd == 'redis':
assert p1==0.0708, "p1=%f" % p1
assert p2==0.1417, "p2=%f" % p2
if options.geno == 'data/small_na.geno':
- assert p1==0.0958, "p1=%f" % p1
- assert p2==0.0435, "p2=%f" % p2
+ assert p1==0.0897, "p1=%f" % p1
+ assert p2==0.0405, "p2=%f" % p2
if options.geno == 'data/test8000.geno':
- assert p1==0.8984, "p1=%f" % p1
- assert p2==0.9623, "p2=%f" % p2
+ assert round(sum(ps)) == 4070
+ assert len(ps) == 8000
elif cmd == 'kinship':
G = g
print "Original G",G.shape, "\n", G
- if y != None:
+ if y != None and options.remove_missing_phenotypes:
gnt = np.array(g).T
Y,g = phenotype.remove_missing(y,g.T,options.verbose)
G = g.T
@@ -144,32 +177,32 @@ elif cmd == 'kinship':
if options.maf_normalization:
G = np.apply_along_axis( genotype.replace_missing_with_MAF, axis=0, arr=g )
print "MAF replacements: \n",G
- if not options.skip_genotype_normalization:
+ if options.genotype_normalization:
G = np.apply_along_axis( genotype.normalize, axis=1, arr=G)
g = None
gnt = None
if options.test_kinship:
- K = kinship_full(G)
+ K = kinship_full(np.copy(G))
print "Genotype",G.shape, "\n", G
print "first Kinship method",K.shape,"\n",K
k1 = round(K[0][0],4)
- K2 = calculate_kinship(np.copy(G.T),temp_data=None)
+ K2,G = calculate_kinship_old(np.copy(G).T,temp_data=None)
print "Genotype",G.shape, "\n", G
print "GN2 Kinship method",K2.shape,"\n",K2
k2 = round(K2[0][0],4)
print "Genotype",G.shape, "\n", G
- K3 = kinship(np.copy(G),options)
+ K3 = kinship(G.T)
print "third Kinship method",K3.shape,"\n",K3
sys.stderr.write(options.geno+"\n")
k3 = round(K3[0][0],4)
if options.geno == 'data/small.geno':
- assert k1==0.7939, "k1=%f" % k1
+ assert k1==0.8, "k1=%f" % k1
assert k2==0.7939, "k2=%f" % k2
assert k3==0.7939, "k3=%f" % k3
if options.geno == 'data/small_na.geno':
- assert k1==0.7172, "k1=%f" % k1
+ assert k1==0.8333, "k1=%f" % k1
assert k2==0.7172, "k2=%f" % k2
assert k3==0.7172, "k3=%f" % k3
if options.geno == 'data/test8000.geno':