Table 1.

Gene-wide empirical type 1 error rates by coding definition 1 in simulation studies at =0.001

	Continuous Traits	Binary Traits (prevalence=20%)
Burden	0.88 (0.64, 1.18)	0.94 (0.69, 1.25)
A-Burden	1.22 (0.93, 1.57)	0.66 (0.45, 0.93)
Burden-S	1.06 (0.79, 1.39)	0.80 (0.57, 1.09)
Burden-V1	1.24 (0.95, 1.59)	0.32 (0.18, 0.52)
Burden-V2	1.56 (1.23, 1.95)	0.32 (0.18, 0.52)
SKAT	0.64 (0.44, 0.9)	1.20 (0.92, 1.54)
SKAT-O	0.64 (0.44, 0.9)	1.14 (0.86, 1.48)
ACAT	0.72 (0.50, 1.00)	1.18 (0.90, 1.52)

The number in each cell represents the ratio of type I error and expected significance level of 0.001. Burden, original burden test; Burden-A, adaptive burden test; Burden-S, z-score weighting burden test; Burden-V1, variable threshold burden test with minimum p value; Burden-V2, variable threshold burden test with ACAT p value combination method; SKAT, sequence kernel association test; SKAT-O, sequence kernel association test-optimal test; ACAT, aggregated Cauchy association test combining burden and SKAT. We simulated 50,000 replicates for evaluating type I error rate. We simulated a continuous variable and a binary variable in response to heteroplasmies located in the mitochondrial cytochrome b (MT-CYB) gene in European American participants (N=3,415) of Atherosclerosis Risk in Communities (ARIC) Study.