Table 4.
Elaborate example Multiplicative and Additive interactions of two SNPs in the CaSR gene and CRC outcomes
| ALL-CAUSE MORTALITY | COLORECTAL CANCER SPECIFIC MORTALITY | ||||||
|---|---|---|---|---|---|---|---|
| SUPPLEMENTAL CALCIUM INTAKE*3:121936453_G/A (rs11713280) | SUPPLEMENTAL CALCIUM INTAKE**3:121936453_G/A (rs11713280) | ||||||
| <1 pill | ≥1 pill | Effect of supplement intake within the strata of ‘3:121936453_G/A‘ | <1 pill | ≥1 pill | Effect of supplement intake within the strata of ‘3:121936453_G/A‘ | ||
| 3:121936453_G/A |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
3:121936453_G/A |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
| GG |
6493/2276 Ref |
1436/496 0.93 (0.84–1.04) |
7929/2772 0.93 (0.84–1.04) |
GG |
6493/1410 Ref |
1436/316 0.97 (0.85–1.11) |
7929/1726 0.97 (0.85–1.11) |
| GA |
1003/326 0.86 (0.76–0.96) |
237/98 1.15 (0.93–1.41) |
1240/424 1.35 (1.07–1.70) |
GA |
1003/196 0.88 (0.76–1.02) |
237/68 1.31 (1.02–1.69) |
1240/264 1.50 (1.13–1.99) |
| AA |
31/9 0.64 (0.33–1.24) |
7/5 2.13 (0.88–5.13) |
38/14 3.83 (1.23–11.96) |
AA |
31/5 0.67 (0.28–1.62) |
7/4 2.57 (0.96–6.89) |
38/9 3.92 (1.05–14.72) |
| Effect of ‘3:121936453_G/A‘ within the strata of supplement intake |
7527/2611 0.85 (0.76–0.95) |
1680/599 1.27 (1.04–1.55) |
Effect of ‘3:121936453_G/A‘ within the strata of supplement intake |
7527/1611 0.87 (0.76–1.00) |
1680/388 1.39 (1.09–1.77) |
||
| Multiplicative scale | 1.49 (1.19–1.87) P = 0.0006 | Multiplicative scale |
1.60 (1.21–2.11) P = 0.0009 |
||||
| RERI |
0.40 (0.15–0.64) P = 0.0009 |
RERI |
0.51 (0.18–0.84) P = 0.002 |
||||
| SUPPLEMENTAL CALCIUM INTAKE*3:121932422_C/T (rs62269066) | SUPPLEMENTAL CALCIUM INTAKE*3:121932422_C/T (rs62269066) | ||||||
|---|---|---|---|---|---|---|---|
| <1 pill | ≥1 pill | Effect of supplement intake within the strata of ‘3:121932422_C/T‘ | <1 pill | ≥1 pill | Effect of supplement intake within the strata of ‘3:121932422_C/T ‘ | ||
| 3:121932422_C/T |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
3:121932422_C/T |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
Number/events HR [95% CI] |
| CC |
3113/1130 Ref |
706/223 0.81 (0.69–0.94) |
3819/1353 0.80 (0.69–0.93) |
CC |
3113/707 Ref |
706/145 0.85 (0.71–1.03) |
3819/852 0.85 (0.71–1.03) |
| CT |
3476/1193 0.90 (0.83–0.98) |
747/296 1.01 (0.88–1.16) |
4223/1486 1.12 (0.98–1.28) |
CT |
3476/724 0.90 (0.81–0.99) |
747/190 1.08 (0.91–1.28) |
4223/911 1.20 (1.02–1.43) |
| TT |
938/288 0.78 (0.68–0.89) |
227/80 0.93 (0.74–1.17) |
1165/368 1.19 (0.92–1.53) |
TT |
938/180 0.81 (0.69–0.96) |
227/53 0.99 (0.75–1.32) |
1165/233 1.23 (0.90–1.67) |
| Effect of ‘3:121932422_C/T‘ within the strata of supplement intake |
7527/2611 0.89 (0.84–0.94) |
1680/599 1.11 (0.99–1.25) |
Effect of ‘3:121932422_C/T ‘ within the strata of supplement intake |
7527/1611 0.90 (0.84–0.97) |
1680/388 1.11 (0.97–1.29) |
||
| Multiplicative scale | 1.25 (1.10–1.43) P = 0.0006 | Multiplicative scale |
1.24 (1.06–1.46) P = 0.008 |
||||
| RERI |
0.21 (0.10–0.32) P = 0.0006 |
RERI |
0.21 (0.06–0.35) p = 0.004 |
||||
Models were adjusted for age at diagnosis, sex, cohort, and the first three principal components of genetic ancestry and for the interaction models also for the main effects of calcium intake (dietary, supplemental or total) and SNP.
The estimated effective number of independent tests among 325 SNPS was 35 based on the simple M approach. Therefore, p < 0.001 were considered statistically significant (n = 35; 0.05/35 = 0.001).
A RERI of zero should be interpret as no additive interaction, a RERI < 0 a negative additive interaction and a RERI > 0 a positive additive interaction.
Total calcium intake is not included in this table because of the small sample sizes in the subgroups (n = 4646 for total population with total calcium intake available).
*Median split sex- and cohort-specific dietary calcium intake.