fix missing multiallelic bug

NEWS.md

@@ -3,7 +3,10 @@
 # ApplyPolygenicScore unreleased
 ## Changed
 * Fixed regression of combine.vcf.with.pgs() function that prevented it from handling multiple rsIDs on the same line.
-* added new contributor
+* Fixed bug caused by the case of a sample-specific missing variant at a multiallelic site
+
+## Added
+* Added new contributor
 
 # ApplyPolygenicScore 3.0.2
 

R/handle-multiallelic-sites.R

@@ -8,6 +8,14 @@ get.non.risk.multiallelic.site.row <- function(single.sample.multialellic.pgs.wi
         return(data.frame());
         }
 
+    # handle cases where this variant is missing in this individual sample
+    if (all(single.sample.multialellic.pgs.with.vcf.data$gt_GT_alleles == '.') | all(is.na(single.sample.multialellic.pgs.with.vcf.data$gt_GT_alleles))) { #standard importation marks missing genotypes with '.'
+        # if all alleles are missing (variant not called for this sample), the first entry of the multiallelic site
+        # is arbitrarily chosen to represent the sample (any choice would be NA regardless)
+        risk.allele.site.row.index <- 1;
+        return(single.sample.multialellic.pgs.with.vcf.data[-risk.allele.site.row.index, ]);
+        }
+
     # split genotyped alleles into separate columns
     GT.alleles <- data.table::tstrsplit(single.sample.multialellic.pgs.with.vcf.data$gt_GT_alleles, split = c('/|\\|'), keep = c(1,2));
     names(GT.alleles) <- c('called.allele.a', 'called.allele.b');

tests/testthat/generate-test-data.R

@@ -132,24 +132,26 @@ save(
 # create simple VCF data for testing multiallelic site handling
 merged.multiallelic.site.test.data <- list(
     merged.multiallelic.vcf.data = data.frame(
-        CHROM = c('chr1', 'chr1', 'chr1', 'chr2', 'chr2', 'chr2', 'chr3', 'chr3', 'chr3'),
+        CHROM = c('chr1', 'chr1', 'chr1', 'chr1', 'chr2', 'chr2', 'chr2', 'chr2', 'chr3', 'chr3', 'chr3', 'chr3'),
         # merged multiallelic site at chr2:2 with betas provided
         # merged multiallelic site at chr3:3 with no betas provided
-        POS = c(1, 1, 1, 2, 2, 2, 3, 3, 3),
-        ID = c('rs1', 'rs1', 'rs1', 'rs2', 'rs2', 'rs2', 'rs3', 'rs3', 'rs3'),
-        REF = c('T', 'T', 'T', 'T', 'T', 'T', 'T', 'T', 'T'),
+        POS = c(1, 1, 1, 1, 2, 2, 2, 2, 3, 3, 3, 3),
+        ID = c('rs1', 'rs1', 'rs1', 'rs1', 'rs2', 'rs2', 'rs2', 'rs2', 'rs3', 'rs3', 'rs3', 'rs3'),
+        REF = c('T', 'T', 'T', 'T', 'T', 'T', 'T', 'T', 'T', 'T', 'T', 'T'),
         # three possible alleles at chr2:2 (T, A, C)
-        ALT = c('A', 'A', 'A', 'A,C', 'A,C', 'A,C', 'A,G', 'A,G', 'A,G'),
-        Indiv = c('sample1', 'sample2', 'sample3', 'sample1', 'sample2', 'sample3', 'sample1', 'sample2', 'sample3'),
+        ALT = c('A', 'A', 'A', 'A', 'A,C', 'A,C', 'A,C', 'A,C', 'A,G', 'A,G', 'A,G', 'A,G'),
+        Indiv = c('sample1', 'sample2', 'sample3', 'sample4', 'sample1', 'sample2', 'sample3', 'sample4', 'sample1', 'sample2', 'sample3', 'sample4'),
         # multiallelic genotypes at chr2:2
         # sample 1 is heterozygous for alt allele A
         # sample 2 is heterozygous for alt allele C
         # sample 3 is homozygous for alt allele C
+        # sample 4 is missing this variant call
         # multiallelic genotypes at chr3:3
         # sample 1 is heterozygous for alt allele A
         # sample 2 is homozygous for alt allele G
         # sample 3 is homozygous for alt allele G
-        gt_GT_alleles = c('T/T', 'T/A', 'A/A', 'T/A', 'T/C', 'C/C', 'T/A', 'T/G', 'G/G')
+        # sample 4 is missing this variant call
+        gt_GT_alleles = c('T/T', 'T/A', 'A/A', NA, 'T/A', 'T/C', 'C/C', NA, 'T/A', 'T/G', 'G/G', NA)
         ),
     ref.as.single.risk.allele.multiallelic.pgs.weight.data = data.frame(
         CHROM = c('chr1', 'chr2', 'chr3'),

tests/testthat/test-pgs-application.R

@@ -392,21 +392,23 @@ test_that(
         # test case with VCF multiallelic site with no extra beta, REF allele is the risk allele
         ref.as.single.risk.allele.test <- apply.polygenic.score(
             vcf.data = merged.multiallelic.site.test.data$merged.multiallelic.vcf.data,
-            pgs.weight.data = merged.multiallelic.site.test.data$ref.as.single.risk.allele.multiallelic.pgs.weight.data
+            pgs.weight.data = merged.multiallelic.site.test.data$ref.as.single.risk.allele.multiallelic.pgs.weight.data,
+            missing.genotype.method = 'none'
             );
         expect_equal(
             ref.as.single.risk.allele.test[[PGS.OUTPUT.INDEX]]$PGS,
-            c(4, 3, 0)
+            c(4, 3, 0, 0)
             );
 
         # test case with VCF multiallelic sites with no extra beta, ALT allele is the risk allele
         alt.as.single.risk.allele.test <- apply.polygenic.score(
             vcf.data = merged.multiallelic.site.test.data$merged.multiallelic.vcf.data,
-            pgs.weight.data = merged.multiallelic.site.test.data$alt.as.single.risk.allele.multiallelic.pgs.weight.data
+            pgs.weight.data = merged.multiallelic.site.test.data$alt.as.single.risk.allele.multiallelic.pgs.weight.data,
+            missing.genotype.method = 'none'
             );
         expect_equal(
             alt.as.single.risk.allele.test[[PGS.OUTPUT.INDEX]]$PGS,
-            c(2, 1, 2)
+            c(2, 1, 2, 0)
             );
         expect_no_warning(
             apply.polygenic.score(
@@ -418,11 +420,12 @@ test_that(
         # test case with a VCF multiallelic site that also has an extra beta, both ALT alleles are risk alleles
         alt.as.two.risk.alleles.test <- apply.polygenic.score(
             vcf.data = merged.multiallelic.site.test.data$merged.multiallelic.vcf.data,
-            pgs.weight.data = merged.multiallelic.site.test.data$alt.as.two.risk.alleles.multiallelic.pgs.weight.data
+            pgs.weight.data = merged.multiallelic.site.test.data$alt.as.two.risk.alleles.multiallelic.pgs.weight.data,
+            missing.genotype.method = 'none'
             );
         expect_equal(
             alt.as.two.risk.alleles.test[[PGS.OUTPUT.INDEX]]$PGS,
-            c(2, 1.5, 3)
+            c(2, 1.5, 3, 0)
             );
         expect_warning(
             apply.polygenic.score(
@@ -435,11 +438,12 @@ test_that(
         # test case with a VCF multiallelic site that also has an extra beta, one REF and one ALT allele are risk alleles
         ref.and.alt.as.two.risk.alleles.test <- apply.polygenic.score(
             vcf.data = merged.multiallelic.site.test.data$merged.multiallelic.vcf.data,
-            pgs.weight.data = merged.multiallelic.site.test.data$ref.and.alt.as.two.risk.alelles.multiallelic.pgs.weight.data
+            pgs.weight.data = merged.multiallelic.site.test.data$ref.and.alt.as.two.risk.alelles.multiallelic.pgs.weight.data,
+            missing.genotype.method = 'none'
             );
         expect_equal(
             ref.and.alt.as.two.risk.alleles.test[[PGS.OUTPUT.INDEX]]$PGS,
-            c(2, 1.5, 2)
+            c(2, 1.5, 2, 0)
             );
         expect_warning(
             apply.polygenic.score(