Ancestry inference in Hail

Hi Hail team,

After running PCA in Hail, I see clearly four major groups when plotting the first few PCs. Is there available some tutorial/material describing how to assign ancestry using PCA in Hail? I have really few samples with ancestry annotations.

How can I predict the unknown ones? Do I need train a classifier (i.e. RF) using external data to do it?

Thanks

There are only four major groups. What you will get with more data is a smearing of ethnicity based on the variants groups that you are looking at. Hapmap data is a good reference/classifier to use depending on the variants that you are using.

Smearing comes with Admix groups like Brazilans. My buddy Gui can talk for days on the subject. :slight_smile:

https://www.ncbi.nlm.nih.gov/pubmed/?term=Suarez-Kurtz%20G[Author]&cauthor=true&cauthor_uid=26265036

A kmeans / RF classifier would be a great addition. We don’t have anything like this right now, unfortunately, though I imagine it would be possible to take a samples table to pandas / spark, use their tools, and annotate back.

Hi @klong and @tpoterba,

Many thanks for your replies. Are you planning to include this feature in the next Hail’s release (@tpoterba )?

I was wondering if it is possible to ‘interpolate’ the data with the HapMap (used as reference) (both in the format: sample, PC1, PC2, …). Does it make sense? Any suggestion?

Thanks in advance,

We plan to develop on the 0.2 version for a while, so while we definitely won’t have this at the beginning, it’s totally possible we’ll have something like this at some point during the life of 0.2.

I don’t see it being easy to impute ancestry from HapMap / 1KG PCs. You’d need the exact same set of variants used for your samples and the external samples and the same MAF – this doesn’t seem possible.

My guess is that the easiest thing would be to add 1kg samples to your dataset, run PCA on everything, and use the reference samples to define ancestry clusters for kmeans.

Hi @tpoterba,

Many thanks for your reply and suggestions…I did it and I am getting good results now. In the last step, rather than run k-means I have trained a RF classifier using the first PCs to define/predict ancestry. But I guess kmeans might work equally nice!

Thanks again

excellent! If you’re willing to share that code, I’m sure others would appreciate seeing it as well!

Hi,

Yes sure. Below the code that I’m using to do this analysis. It can break down into two main part: i) PCA in Hail and ii) training RF model and prediction in R. Here I’m using a previous approach that we have already developed for a previous work (https://doi.org/10.1371/journal.pone.0189875) which combine recursive feature elimination (here PCs) and RF. Ideally, it should be possible to have everything done in python for easier integration, but it requires extra work that I’m planning to do in the near future.

i) PCA in Hail


# read VDS 1kgenome-phase 3
vds_1kg = hc.read('/path/1000G_phase3/vds/vds_1kg_v3.vds')

# Preparing 1000genome data for PCA
# filtering
vds_filtered_1kg = vds_1kg.filter_multi() # filter out multi-allelic variants.
vds_filtered_1kg = vds_filtered_1kg.filter_variants_expr('v.altAllele().isSNP()', keep=True) # keep only SNPs

# read interval table (Purcell 5k)
purcell5k = KeyTable.import_bed('/path/1000G_phase3/purcell5k_intervals.bed')
vds_filtered_1kg = vds_filtered_1kg.\
                   filter_variants_table(purcell5k.key_by('interval'), keep=True) # keep overlapping variant

# Read target VDS 
vds = hc.read('/path/wes_vcf_merged.vds')

# Filtering
vds = vds.filter_multi() # filter out multi-allelic variants.
vds = vds.filter_variants_expr('v.altAllele().isSNP()', keep=True) # keep only SNPs

# Merge dataset in overlapping SNPs (inner join)
vds_merged = vds.join(vds_filtered_1kg)

# computing variant QC on merged VDS
vds_merged = vds_merged.variant_qc().cache()

# Basic variant filtering before PCA
# Keep common SNPs (AF > 1%)
# LD pruning
common_vds = (vds_merged
              .filter_variants_expr('va.qc.AF > 0.01')
              .ld_prune(memory_per_core=512, num_cores=16))

# Perform PCA on merged VDS (getting 10 first PCs)
vds_pca = common_vds.pca('sa.pca', k=10, eigenvalues='global.eigen')

# Getting sample annotations as Pandas dataframe
pca_table = vds_pca.samples_table().to_pandas()

ii) Training/testing RF classifier and prediction


library(caret)

######################################################################################
# This script could be used for training a Random Forest classifier and predict
# Population ancestry using PCs as features. It has been tested after run PCA on ~5,000
# polymorphic SNPs (Purcell interval) on two 'merged' dataset: 1) 1000Genomes
# (used as reference since it contains sample population annotations) and 2)
# target dataset (actually the dataset which sample population are unknown). Both dataset 
# were merged before running the PCA, thus, PCs will be used as features for training and predicting.
######################################################################################


# dataframe with samples, population and PCs (i.e. 10 first PC) from Hail workflow
pca_wes10k <- pca_table

# getting subset with known population info
training <- subset(pca_wes10k, sa.SuperPopulation %in% c("AFR","AMR","EAS","EUR","SAS"))

# Getting subset with unknown population information
# we are going to predict ancestry on this subset...
discovery <- subset(pca_wes10k, !sa.SuperPopulation %in% c("AFR","AMR","EAS","EUR","SAS"))

# Extract training features (Prinipal components)
features <- as.matrix(training[,c(6:15)])

# Extract response variable (Population info)
class <- as.vector(training$sa.SuperPopulation)

# Warning: if you are going to scale your data,
# do it before split it, otherwise, it will 
# introduce a bias in the prediction phase, since
# you are using 'different' features for training the model
# and predicting new instances!

# Scale data features
# features <- scale(features, center=TRUE, scale=TRUE)

# define some workflow metrics
n <- 10 # folds to repit the entire workflow (on randomized test data)
nVars <- vector() # number of features in the final model
accv <- vector() # prediction accuracy per run

for(i in seq(1,n,1)){
  
  # Divide the dataset in train and test sets
  inTrain <- createDataPartition(as.factor(class), p = 2/3, list = FALSE)
  
  # Create the training dataset
  trainDescr <- features[inTrain,]
  
  # Create the testing dataset
  testDescr <- features[-inTrain,]
  
  # create the training class subset
  trainClass <- class[inTrain]
  
  # create the testing class subset
  testClass <- class[-inTrain]
  
  #### recursive feature elimination plus random forest
  rfProfile <- rfe(x = trainDescr, 
                   y = as.factor(trainClass),
                   maximize = TRUE,
                   metric = 'Accuracy',
                   sizes = c(1:10), 
                   rfeControl = rfeControl(functions = rfFuncs, 
                                           method = "cv",
                                           number = 10,
                                           verbose = TRUE))
  
  
  ## predict variable response (class) for all sammples with the new model
  predictedClass <- predict(rfProfile, newdata = testDescr)
  
  ## compute prediction accuracy
  accTable <- postResample(predictedClass, as.factor(testClass))
  accv[i] <- accTable[['Accuracy']] 
  
  ## keep best model
  if (accv[length(accv)] >= max(accv)){
    bestModel <- rfProfile
  }
  
  ## retrive number of variable used
  nVar <- rfProfile$optsize
  nVars[i] <- nVar
}

## summary metrics
nVar_mean <- mean(nVars)
acc_mean <- mean(accv)
acc_sd <- sd(accv)

# Dataframe with variables metric (i.e. Accuracy) information
results <- bestModel$results

# plotting/saving RFE object
png("performance_vs_variables_RFE_RF.png", width = 800, height = 800)
plot.rfe(x = bestModel, xlab='Number of variables')
dev.off()

# Predict ancestry/population from discovery subset using the 'best classifier'

# Extract features (PCs) from discovery subset
unknown <- as.matrix(discovery[,c(6:15)])

# predict new Populations for unknown instances/samples
predicted.ancestry <- predict(bestModel, newdata = unknown)

# rename columns
names(predicted.ancestry) <- c('predictedPopulation', 
                               'probability_AFR', 
                               'probability_AMR', 
                               'probability_EAS',
                               'probability_EUR',
                               'probability_SAS')

# add predicted Population to original data
# merge here by row index since it remains unchanged.
merged <- merge(discovery, predicted.ancestry, by=0, all = T)

# save file with sample population predicted
write.table(merged, file = 'population_predicted_random_forest.txt', row.names = FALSE, sep = '\t')


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