Rare variant burden assessed by RVTT in quality-filtered European PF cases (N = 24) and sepsis controls (N = 87)
| Type . | RVTT-fixed test statistic (gnomAD cutoff = 0.05) . | RVTT-fixed Perm P value (gnomAD cutoff = 0.05) . | RVTT-variable selected MAF threshold (no cutoff) . | RVTT-variable test statistic (no cutoff) . | RVTT-variable Perm P value (no cutoff) . | RVTT-variable selected MAF threshold (cutoff = 0.05) . | RVTT-variable test statistic (cutoff = 0.05) . | RVTT-variable Perm P value (cutoff = 0.05) . |
|---|---|---|---|---|---|---|---|---|
| Complement system pathway (N = 27) | ||||||||
| ΔP variants | 2.4951 | .0168 | 0.0833 | 2.7229 | .0278 | 0.0463 | 2.6236 | .0134 |
| Synonymous | 1.5071 | .1368 | 0.25 | 1.1308 | .8166 | 0.0463 | 1.0267 | .4438 |
| Neutral missense | 1.0195 | .323 | 0.3704 | 1.0636 | .8954 | 0.0463 | 0.7881 | .7237 |
| Procoagulant genes (N = 27) | ||||||||
| ΔP variants | 0.9582 | .3075 | 0.0157 | 2.0983 | .1054 | 0.0157 | 2.0983 | .0934 |
| Synonymous | 1.5327 | .1326 | 0.0119 | 2.4547 | .0584 | 0.0119 | 2.4547 | .0575 |
| Neutral missense | 0.5990 | .6026 | 0.3228 | 1.6853 | .3315 | 0.0433 | 0.5990 | .9198 |
| Anticoagulant genes (N = 19) | ||||||||
| ΔP variants | 1.9988 | .0595 | 0.0354 | 1.9988 | .1680 | 0.0354 | 1.9988 | .1140 |
| Synonymous | 1.9414 | .1818 | 0.0354 | 2.0340 | .1359 | 0.0354 | 2.0340 | .0993 |
| Neutral missense | 1.2307 | .1931 | 0.0714 | 1.3959 | .4013 | 0.0354 | 1.2307 | .4541 |
| Glycolysis pathway (N = 68) | ||||||||
| ΔP variants | 0.0536 | .9563 | 0.035 | 1.0827 | .5804 | 0.0315 | 1.0827 | .5265 |
| Synonymous | 0.1035 | .9256 | 0.185 | 1.4843 | .309 | 0.0079 | 0.8554 | .7307 |
| Neutral missense | 0.3942 | .7607 | 0.169 | 1.8254 | .2089 | 0.0118 | 0.6315 | .7491 |
| Type . | RVTT-fixed test statistic (gnomAD cutoff = 0.05) . | RVTT-fixed Perm P value (gnomAD cutoff = 0.05) . | RVTT-variable selected MAF threshold (no cutoff) . | RVTT-variable test statistic (no cutoff) . | RVTT-variable Perm P value (no cutoff) . | RVTT-variable selected MAF threshold (cutoff = 0.05) . | RVTT-variable test statistic (cutoff = 0.05) . | RVTT-variable Perm P value (cutoff = 0.05) . |
|---|---|---|---|---|---|---|---|---|
| Complement system pathway (N = 27) | ||||||||
| ΔP variants | 2.4951 | .0168 | 0.0833 | 2.7229 | .0278 | 0.0463 | 2.6236 | .0134 |
| Synonymous | 1.5071 | .1368 | 0.25 | 1.1308 | .8166 | 0.0463 | 1.0267 | .4438 |
| Neutral missense | 1.0195 | .323 | 0.3704 | 1.0636 | .8954 | 0.0463 | 0.7881 | .7237 |
| Procoagulant genes (N = 27) | ||||||||
| ΔP variants | 0.9582 | .3075 | 0.0157 | 2.0983 | .1054 | 0.0157 | 2.0983 | .0934 |
| Synonymous | 1.5327 | .1326 | 0.0119 | 2.4547 | .0584 | 0.0119 | 2.4547 | .0575 |
| Neutral missense | 0.5990 | .6026 | 0.3228 | 1.6853 | .3315 | 0.0433 | 0.5990 | .9198 |
| Anticoagulant genes (N = 19) | ||||||||
| ΔP variants | 1.9988 | .0595 | 0.0354 | 1.9988 | .1680 | 0.0354 | 1.9988 | .1140 |
| Synonymous | 1.9414 | .1818 | 0.0354 | 2.0340 | .1359 | 0.0354 | 2.0340 | .0993 |
| Neutral missense | 1.2307 | .1931 | 0.0714 | 1.3959 | .4013 | 0.0354 | 1.2307 | .4541 |
| Glycolysis pathway (N = 68) | ||||||||
| ΔP variants | 0.0536 | .9563 | 0.035 | 1.0827 | .5804 | 0.0315 | 1.0827 | .5265 |
| Synonymous | 0.1035 | .9256 | 0.185 | 1.4843 | .309 | 0.0079 | 0.8554 | .7307 |
| Neutral missense | 0.3942 | .7607 | 0.169 | 1.8254 | .2089 | 0.0118 | 0.6315 | .7491 |
RVTT was applied to 3 gene sets: the complement system, the coagulation system, and the glycolysis pathway. For each gene set, ΔP, synonymous, and neutral missense variants were tested. Qualifying low-frequency variants were selected using 3 settings: (1) fixed threshold gnomAD MAF <0.05, (2) variable threshold with no cutoff, and (3) variable threshold with MAF cutoff = 0.05. Significant enrichment of low-frequency ΔP complement variants in PF patients when compared with control patients was observed under all 3 settings.
P values <.05 are in bold type.