Extreme p-values in SAIGE conditional analysis

[zrayw]

Dear Wei,

I encountered an issue with extreme p-values when running SAIGE Step 2 for conditional analysis, which appears similar to the previously mentioned issue.

To investigate further, I conducted additional checks on these extreme cases:

1. I ran COJO conditional analysis using the unconditioned SAIGE summary statistics and the same genotype data as a reference. The results between COJO (p_COJO) and SAIGE (p.value_c) were highly consistent (Spearman’s ρ ~ 0.99), except for the extreme cases. For these, COJO estimated the conditional p-value at ~0.04, whereas SAIGE reported p-values < 1e-20.

2. I examined the LD between the SNP I conditioned on and the extreme cases (R2 column). These SNPs are located far apart and are in complete LD.

3. The extreme cases are common variants with allele frequency >0.01.

4. Indeed some of the extreme case have large var_c, but it is not always the case (e.g. some of the var_c is ~4).

Could you please provide insights or suggestions for addressing this issue? Your guidance would be greatly appreciated.

Best,
Ruiwen

Below are the version and scripts I use for saige:

Loading required package: RhpcBLASctl
R version 3.6.3 (2020-02-29)
Platform: x86_64-pc-linux-gnu (64-bit)
Running under: Ubuntu 20.04.4 LTS
Matrix products: default
BLAS: /usr/lib/x86_64-linux-gnu/openblas-pthread/libblas.so.3
LAPACK: /usr/lib/x86_64-linux-gnu/openblas-pthread/liblapack.so.3
locale:
[1] C
attached base packages:
[1] stats graphics grDevices utils datasets methods base
other attached packages:
[1] data.table_1.12.8 optparse_1.7.3 RhpcBLASctl_0.21-247.1
[4] SAIGE_1.1.6.2
loaded via a namespace (and not attached):
[1] compiler_3.6.3 Matrix_1.5-1 Rcpp_1.0.7 getopt_1.20.3
[5] grid_3.6.3 RcppParallel_5.1.5 lattice_0.20-40
step2_SPAtests.R --bgenFile="$saige_pfile_dir"/chr"$chr""$race".bgen
--bgenFileIndex="$saige_pfile_dir"/chr"$chr""$race".bgen.bgi
--sampleFile="$saige_pfile_dir"/chr"$chr""$race".sample
--AlleleOrder=ref-first --chrom=$chr --minMAF=0 --minMAC=20
--is_Firth_beta=TRUE --pCutoffforFirth=0.01 --is_output_moreDetails=TRUE --LOCO=TRUE
--GMMATmodelFile="$saige_dir"/saige_step1"$race".rda
--varianceRatioFile="$saige_dir"/saige_step1_"$race".varianceRatio.txt
--SAIGEOutputFile="$cond_dir"/cond_chr"$chr"_"$race".txt
--condition="chr5:132703440:C:A;rs2285700"