TABLE 1.
Association between TMAO concentrations and health outcomes and evidence class for meta-analyses1
| Outcomes | Population | Study design | Comparison | Studies, n | Cases, n | Participants, n | Metric | Random-effects RR/HR/OR/WMD (95% CI) | P value | 95% PI | Egger's P2 | I 2,3 % | P value for excess significance test4 | Evidence class5 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cardiovascular outcomes | ||||||||||||||
| CVD | CVD/non-CVD | CC/CS | High vs. low | 12 | 5276 | 22,945 | OR | 1.50 (1.26, 1.79) | 8.00E−06 | 0.92, 2.44 | 0.000 | 63.97 | 0.16 | III |
| Hypertension | Healthy/hypertension | CO/CC/CS | High vs. low | 15 | 10,293 | 18,854 | RR | 1.39 (1.22, 1.57) | 3.47E−07 | 0.97, 1.99 | 0.201 | 70.99 | NP | II |
| MACE | CKD/CVD/DM | CO/CC/CS | High vs. low | 36 | >7070 | 39,314 | HR | 1.74 (1.55, 1.95) | 1.13E−22 | 1.07, 2.82 | 0.011 | 65.59 | 0.00 | II |
| Stroke | Stroke/CVD/DM | CO/CC/CS | High vs. low | 9 | 2546 | 9393 | OR | 2.88 (1.54, 5.39) | 9.35E−04 | 0.44, 18.81 | 0.439 | 91.54 | NP | III |
| Mortality | ||||||||||||||
| All-cause mortality | General/CVD/CKD/DM | CO | High vs. low | 37 | >10,510 | 44,480 | HR | 1.60 (1.43, 1.79) | 8.33E−16 | 0.91, 2.82 | 0.000 | 83.63 | 0.10 | II |
| CVD mortality | CVD/non-CVD | CO/CC | High vs. low | 8 | >1002 | 11,296 | HR | 2.02 (1.74, 2.34) | 6.01E−21 | 1.74, 2.34 | 0.480 | 0.00 | 0.24 | II |
| Blood pressure and cardiometabolic biomarkers | ||||||||||||||
| SBP | General/DM/CVD/stroke | CO/CC/CS | High vs. low | 16 | NA | 17,369 | WMD | 1.92 (1.33, 2.51) | 1.70E−10 | 0.74, 3.10 | 0.530 | 32.42 | 0.45 | IV |
| DBP | General/DM/CVD/stroke | CO/CC/CS | High vs. low | 14 | NA | 10,085 | WMD | −0.25 (−0.95, 0.46) | 0.495 | −2.07, 1.57 | 0.338 | 79.15 | 0.85 | NS |
| BMI | General/DM/CVD/stroke | CO/CC/CS | High vs. low | 19 | NA | 20,851 | WMD | 0.54 (0.12, 0.97) | 0.012 | −1.11, 2.20 | 0.954 | 96.13 | 0.18 | IV |
| HDL cholesterol | General/DM/CVD/stroke | CO/CC/CS | High vs. low | 15 | NA | 21,481 | WMD | −0.44 (−1.59, 0.71) | 0.453 | −4.42, 3.54 | 0.151 | 94.91 | NP | NS |
| LDL cholesterol | General/DM/CVD/stroke | CO/CC/CS | High vs. low | 15 | NA | 20,504 | WMD | −1.09 (−2.62, 0.44) | 0.164 | −5.31, 3.14 | 0.286 | 87.44 | 0.70 | NS |
| TC | General/DM/CVD/stroke | CO/CC/CS | High vs. low | 15 | NA | 16,523 | WMD | −0.57 (−1.14, −0.01) | 0.047 | −2.16, 1.02 | 0.513 | 88.65 | 0.65 | IV |
| CRP | General/DM/CVD/stroke | CO/CS | High vs. low | 11 | NA | 12,233 | WMD | 0.27 (0.06, 0.48) | 0.012 | −0.27, 0.81 | 0.112 | 86.11 | NP | IV |
| Triglycerides | General/DM/CVD | CO/CC/CS | High vs. low | 14 | NA | 16,219 | WMD | 0.15 (−0.36, 0.65) | 0.566 | −0.83, 1.13 | 0.000 | 60.02 | 0.76 | NS |
| Diabetes mellitus | ||||||||||||||
| Diabetes | CVD/diabetes/renal disease | CO/CC/CS | High vs. low | 18 | >5554 | 22,999 | OR | 1.75 (1.42, 2.16) | 1.50E−07 | 0.83, 3.70 | 0.886 | 82.05 | 0.10 | II |
| GDM | GDM/non-GDM | CC | High vs. low | 3 | 952 | 2180 | OR | 2.24 (1.72, 2.93) | 3.08E−09 | 1.71, 2.94 | 0.240 | 0.94 | 0.78 | IV |
| Renal outcomes | ||||||||||||||
| GFR | CKD/general | CO/CC/CS | High vs. low | 20 | NA | 29,497 | WMD | −13.30 (−16.73, −9.86) | 3.14E−14 | −28.65, 2.05 | 0.724 | 97.92 | 0.76 | II |
| Cancer | ||||||||||||||
| CRC | CRC/non-CRC | CC | High vs. low | 3 | 1058 | 2291 | OR | 1.49 (1.19, 1.88) | 5.93E−04 | 1.11, 2.00 | 0.194 | 21.72 | 0.65 | III |
CC, case–control study; CKD, chronic kidney disease; CO, cohort study; CRC, colorectal cancer; CRP, C-reactive protein; CS, cross-sectional study; CVD, cardiovascular disease; DBP, diastolic blood pressure; DM, diabetes mellitus; GDM, gestational diabetes mellitus; GFR, glomerular filtration rate; MACE, major adverse cardiovascular events; NA, not available; NP, not pertinent (because the number of expected significant studies was larger than the number of observed significant studies); NS, not significant; PI, prediction interval; SBP, systolic blood pressure; TC, total cholesterol; WMD, weighted mean difference.
Egger's regression test was used to evaluate the small-study effects.
Interstudy heterogeneity was tested using the Cochran Q statistic (t2) at a significance level of P < 0.10 and quantified by the I2 statistic. An I2 value ≥50% is considered to indicate substantial heterogeneity. All results are presented as RR/OR/HR/WMD with 95% CIs, using the Mantel–Haenszel method with a random-effects model.
Excess significance test was conducted to investigate whether the observed number of studies with significant results differed from the expected number of significant studies using the χ2 test.
Evidence class criteria: class I (convincing): statistical significance with P < 10−6, >1000 cases (or >20,000 participants for continuous outcomes), the largest component study reported a statistically significant effect (P < 0.05), 95% PI excluded the null, no large heterogeneity (I2 < 50%), no evidence of small-study effects (P > 0.10) or excess significance bias (P > 0.10); class II (highly suggestive): statistical significance with P < 10−6, >1000 cases (or >20,000 participants for continuous outcomes), the largest component study reported a statistically significant effect (P < 0.05); class III (suggestive): statistical significance with P < 10−3, >1000 cases (or >20,000 participants for continuous outcomes); class IV (weak): the remaining statistically significant associations with P < 0.05.