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. 2022 Jun 13;20:218. doi: 10.1186/s12916-022-02425-x

Table 3.

Plasma NfLv1 and its relation to all-cause mortality among women: mediating and interactive effects of BMI, AL, and co-morbidity index using 4-way decompositiona,b,c

Overall (N = 694), β ± SE P Women (N = 401), β ± SE P Men (N = 293), β ± SE P
X= NfLv1;M= BMI
 Total effect + 0.397 ± 0.264 0.13 + 0.877 ± 0.602 0.15 + 0.138 ± 0.345 0.69
 CDE + 0.173 ± 0.222 0.44 + 0.712 ± 0.465 0.13 − 0.073 ± 0.228 0.75
 IR + 0.083 ± 0.090 0.36 − 0.048 ± 0.191 0.80 + 0.089 ± 0.198 0.65
 IM + 0.106 ± 0.071 0.14 + 0.276 ± 0.207 0.18 + 0.031 ± 0.073 0.67
 PM + 0.035 ± 0.050 0.48 − 0.064 ± 0.094 0.50 + 0.090 ± 0.065 0.16
X= NfLv1;M= AL
 Total effect + 0.283 ± 0.220 0.20 + 0.835 ± 0.585 0.15 + 0.120 ± 0.267 0.65
 CDE + 0.282 ± 0.219 0.20 + 0.857 ± 0.586 0.14 − 0.009 ± 0.253 0.97
 IR + 0.000 ± 0.011 1.00 − 0.013 ± 0.037 0.72 + 0.079 ± 0.115 0.49
 IM + 0.004 ± 0.015 0.80 + 0.004 ± 0.018 0.84 + 0.033 ± 0.036 0.36
 PM − 0.003 ± 0.015 0.83 − 0.011 ± 0.021 0.59 + 0.017 ± 0.032 0.61
X= NfLv1;M= WHR
 Total effect + 0.540 ± 2.051 0.79 + 0.592 ± 1.976 0.76 + 0.097 ± 0.307 0.75
 CDE + 0.246 ± 0.246 0.32 + 0.609 ± 1.02 0.55 + 0.068 ± 0.293 0.82
 IR + 0.400 ± 2.391 0.87 + 0.114 ± 1.672 0.95 + 0.005 ± 0.059 0.93
 IM − 0.095 ± 0.360 0.79 − 0.051 ± 0.429 0.91 + 0.008 ± 0.041 0.84
 PM − 0.012 ± 0.099 0.91 − 0.080 ± 0.294 0.79 + 0.016 ± 0.030 0.61
X= NfLv1;M= ALB
 Total effect + 0.239 ± 0.210 0.25 + 0.728 ± 0.485 0.13 − 0.002 ± 0.242 1.00
 CDE + 0.236 ± 0.214 0.27 + 0.773 ± 0.484 0.11 − 0.007 ± 0.250 0.98
 IR − 0.003 ± 0.026 0.91 − 0.039 ± 0.069 0.58 − 0.041 ± 0.060 0.50
 IM + 0.019 ± 0.022 0.42 − 0.010 ± 0.022 0.66 + 0.046 ± 0.034 0.17
 PM − 0.011 ± 0.021 0.61 + 0.003 ± 0.015 0.85 − 0.000 ± 0.049 0.99
X= NfLv1;M= CRP
 Total effect + 0.376 ± 0.245 0.13 + 0.829 ± 0.585 0.16 + 0.132 ± 0.289 0.65
 CDE + 0.399 ± 0.244 0.10 + 1.109 ± 0.543 0.041 + 0.045 ± 0.310 0.88
 IR − 0.017 ± 0.029 0.55 − 0.274 ± 0.162 0.091 + 0.074 ± 0.110 0.50
 IM + 0.015 ± 0.022 0.49 + 0.064 ± 0.058 0.27 + 0.025 ± 0.029 0.39
 PM − 0.021 ± 0.021 0.32 − 0.071 ± 0.053 0.18 − 0.013 ± 0.022 0.57
X= NfLv1;M= HBA1C
 Total effect + 0.275 ± 0.222 0.22 + 0.884 ± 0.565 0.12 + 0.082 ± 0.277 0.77
 CDE + 0.264 ± 0.224 0.24 + 0.864 ± 0.564 0.13 + 0.084 ± 0.278 0.76
 IR − 0.001 ± 0.012 0.94 − 0.007 ± 0.022 0.74 + 0.001 ± 0.023 0.98
 IM + 0.001 ± 0.008 0.93 +0.003 ± 0.015 0.82 − 0.005 ± 0.014 0.74
 PM + 0.011 ± 0.014 0.43 + 0.023 ± 0.024 0.34 + 0.002 ± 0.016 0.89
X= NfLv1;M= CHOL
 Total effect + 0.244 ± 0.220 0.27 + 0.727 ± 0.478 0.13 − 0.002 ± 0.277 0.99
 CDE + 0.247 ± 0.219 0.26 + 0.715 ± 0.481 0.14 + 0.043 ± 0.258 0.87
 IR − 0.000 ± 0.015 0.98 + 0.017 ± 0.059 0.78 − 0.053 ± 0.071 0.46
 IM − 0.007 ± 0.012 0.59 − 0.002 ± 0.008 0.83 − 0.030 ± 0.038 0.43
 PM + 0.004 ± 0.014 0.79 − 0.003 ± 0.012 0.81 + 0.037 ± 0.041 0.36
X= NfLv1;M= HDL
 Total effect + 0.436 ± 0.280 0.12 + 1.166 ± 0.714 0.10 + 0.106 ± 0.332 0.75
 CDE + 0.298 ± 0.239 0.21 + 0.672 ± 0.484 0.17 + 0.083 ± 0.330 0.80
 IR + 0.072 ± 0.072 0.32 + 0.365 ± 0.311 0.24 − 0.007 ± 0.036 0.85
 IM + 0.050 ± 0.038 0.20 + 0.104 ± 0.098 0.29 + 0.010 ± 0.060 0.87
 PM + 0.016 ± 0.024 0.50 + 0.026 ± 0.036 0.47 − 0.020 ± 0.041 0.63
X= NfLv1;M= RHR
 Total effect + 0.310 ± 0.229 0.18 + 0.725 ± 0.515 0.16 + 0.215 ± 0.327 0.51
 CDE + 0.348 ± 0.239 0.15 + 0.757 ± 0.530 0.15 + 0.228 ± 0.324 0.48
 IR − 0.029 ± 0.040 0.47 + 0.020 ± 0.085 0.81 − 0.013 ± 0.113 0.91
 IM + 0.004 ± 0.009 0.66 − 0.015 ± 0.025 0.55 + 0.005 ± 0.029 0.87
 PM − 0.014 ± 0.016 0.39 − 0.037 ± 0.037 0.32 − 0.004 ± 0.020 0.84
X= NfLv1;M= SBP
 Total effect + 0.247 ± 0.225 0.27 + 0.759 ± 0.495 0.13 + 0.046 ± 0.278 0.87
 CDE + 0.257 ± 0.227 0.26 + 0.769 ± 0.495 0.12 + 0.044 ± 0.284 0.88
 IR + 0.003 ± 0.012 0.83 − 0.000 ± 0.008 0.97 + 0.015 ± 0.058 0.79
 IM − 0.006 ± 0.017 0.71 + 0.001 ± 0.037 0.99 − 0.009 ± 0.021 0.67
 PM − 0.007 ± 0.021 0.76 − 0.010 ± 0.049 0.84 − 0.003 ± 0.019 0.88
X= NfLv1;M= DBP
 Total effect + 0.268 ± 0.218 0.22 + 0.812 ± 0.529 0.13 + 0.093 ± 0.280 0.74
 CDE + 0.291 ± 0.221 0.19 + 0.912 ± 0.558 0.10 + 0.111 ± 0.290 0.70
 IR − 0.002 ± 0.030 0.95 + 0.029 ± 0.090 0.75 − 0.015 ± 0.072 0.83
 IM − 0.001 ± 0.021 0.97 − 0.090 ± 0.096 0.34 + 0.001 ± 0.008 0.88
 PM − 0.020 ± 0.021 0.33 − 0.038 ± 0.057 0.51 − 0.004 ± 0.013 0.76
X= NfLv1;M= HYPERT
 Total effect + 0.288 ± 0.217 0.19 + 0.729 ± 0.489 0.14 + 0.077 ± 0.271 0.78
 CDE + 0.080 ± 0.232 0.73 + 0.096 ± 0.347 0.78 + 0.174 ± 0.354 0.62
 IR + 0.199 ± 0.159 0.21 + 0.600 ± 0.379 0.11 − 0.092 ± 0.167 0.58
 IM + 0.006 ± 0.013 0.64 + 0.020 ± 0.053 0.71 − 0.003 ± 0.010 0.76
 PM + 0.003 ± 0.008 0.69 + 0.013 ± 0.034 0.71 − 0.002 ± 0.008 0.81
X= NfLv1;M= DIAB
 Total effect + 0.370 ± 0.244 0.13 + 0.714 ± 0.485 0.14 + 0.158 ± 0.314 0.62
 CDE + 0.484 ± 0.295 0.10 + 0.760 ± 0.501 0.13 + 0.314 ± 0.431 0.47
 IR − 0.117 ± 0.120 0.32 + 0.032 ± 0.225 0.89 − 0.174 ± 0.175 0.32
 IM + 0.016 ± 0.019 0.38 − 0.007 ± 0.051 0.89 + 0.012 ± 0.020 0.56
 PM − 0.014 ± 0.019 0.46 − 0.070 ± 0.057 0.21 + 0.006 ± 0.014 0.68
X= NfLv1;M= HYPERCHOL
 Total effect + 0.279 ± 0.244 0.25 + 0.637 ± 0.481 0.19 + 0.137 ± 0.338 0.69
 CDE + 0.270 ± 0.300 0.37 + 0.566 ± 0.528 0.28 + 0.182 ± 0.414 0.66
 IR + 0.006 ± 0.089 0.95 + 0.078 ± 0.141 0.58 − 0.047 ± 0.091 0.61
 IM − 0.001 ± 0.006 0.83 − 0.010 ± 0.021 0.64 + 0.000 ± 0.007 0.99
 PM + 0.004 ± 0.009 0.67 + 0.003 ± 0.018 0.87 + 0.002 ± 0.020 0.94
X= NfLv1;M= CVD
 Total effect + 0.158 ± 0.213 0.46 + 0.362 ± 0.414 0.38 + 0.055 ± 0.282 0.85
 CDE + 0.078 ± 0.230 0.73 + 0.260 ± 0.446 0.56 + 0.007 ± 0.285 0.98
 IR + 0.080 ± 0.053 0.13 + 0.102 ± 0.122 0.41 + 0.049 ± 0.057 0.40
 IM + 0.002 ± 0.011 0.87 + 0.002 ± 0.019 0.90 + 0.000 ± 0.011 1.00
 PM − 0.002 ± 0.012 0.84 − 0.003 ± 0.024 0.90 − 0.000 ± 0.009 0.99

Abbreviations: AL allostatic load, ALB albumin, BMI body mass index, CDE controlled direct effect, CES-D Center for Epidemiological Studies-Depression, CHOL total cholesterol, CRP C-reactive protein (high sensitivity), Loge transformed, CVD cardiovascular disease, DBP diastolic blood pressure, DIAB diabetes, HBA1C glycated hemoglobin, HDL high-density lipoprotein cholesterol, HEI-2010 Healthy Eating Index-2010 version, HYPERT hypertension, HYPERCHOL hypercholesterolemia, IM interaction, mediated, IR interaction, reference, M mediators/effect modifier, NfL plasma neurofilament light chain, Loge transformed, PM pure mediation, RHR resting heart rate, SBP systolic blood pressure, WHR waist-hip ratio, X exposure

aSee the “Methods” section and Table 1 for the definition of each NfL exposure (i.e., NfLv1 and δNfL). All exposures (X) and potential mediators/effect modifiers (M) were z-scored for ease of interpretation, with the exception of binary M (coded as 0/1), namely DIAB, HYPERT, HYPERCHOL, and CVD. Control variables were set at their means

bCox models for which 4-way decomposition was conducted are equivalent to model 2 (Table 2), for continuous exposures, to which M was added and considered as a potential mediator/effect modifier. Control variables included age at v1, sex, race, poverty status, education, HEI-2010 total score, mean energy intake (kcal/day), current tobacco use, current illicit drug use, the CES-D total score, and the inverse mills ratio

cTotal effects are beta = Loge(HR) ± SE with associated p-values from Cox PH hazards models associated with each NfL exposure of interest. Hazard ratio (HR) point estimates the exponent of beta. 95% CI for HR can be calculated as follows: lower confidence limit (LCL): exp[LogeHR − 1.96×SE(LogeHR)]; upper confidence limit (UCL): exp[LogeHR + 1.96×SE(LogeHR)]