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

Table 4.

Plasma δNfL and its relation to all-cause mortality, overall, and by sex: 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= δNfL;M= BMI
 Total effect + 0.201 ± 0.170 0.24 + 0.680 ± 0.386 0.079 − 0.052 ± 0.208 0.80
 CDE + 0.264 ± 0.171 0.12 + 0.750 ± 0.417 0.072 + 0.090 ± 0.173 0.60
 IR − 0.043 ± 0.044 0.33 − 0.025 ± 0.086 0.77 − 0.126 ± 0.138 0.36
 IM + 0.015 ± 0.017 0.36 + 0.016 ± 0.060 0.79 + 0.011 ± 0.017 0.52
 PM − 0.036 ± 0.024 0.14 − 0.064 ± 0.058 0.27 − 0.027 ± 0.032 0.40
X= δNfL;M= AL
 Total effect + 0.229 ± 0.179 0.20 + 0.637 ± 0.389 0.10 + 0.056 ± 0.228 0.81
 CDE + 0.230 ± 0.182 0.20 + 0.567 ± 0.405 0.15 + 0.059 ± 0.213 0.78
 IR + 0.001 ± 0.011 0.91 + 0.011 ± 0.050 0.82 + 0.015 ± 0.072 0.84
 IM − 0.002 ± 0.020 0.90 + 0.019 ± 0.052 0.71 − 0.004 ± 0.021 0.84
 PM − 0.000 ± 0.018 0.99 + 0.019 ± 0.047 0.68 − 0.014 ± 0.023 0.55
X= δNfL;M= WHR
 Total effect + 0.866 ± 2.644 0.74 + 1.33 ± 5.07 0.79 + 0.096 ± 0.249 0.70
 CDE + 0.198 ± 0.180 0.27 + 0.55 ± 0.57 0.34 + 0.090 ± 0.255 0.72
 IR + 0.798 ± 2.986 0.79 + 0.98 ± 6.12 0.87 + 0.019 ± 0.065 0.77
 IM − 0.117 ± 0.353 0.74 − 0.18 ± 0.90 0.84 − 0.003 ± 0.032 0.92
 PM − 0.012 ± 0.074 0.87 − 0.02 ± 0.17 0.91 − 0.011 ± 0.020 0.60
X= δNfL;M= ALB
 Total effect + 0.107 ± 0.167 0.52 + 0.651 ± 0.382 0.088 − 0.170 ± 0.185 0.36
 CDE + 0.090 ± 0.170 0.60 + 0.605 ± 0.383 0.11 − 0.133 ± 0.189 0.48
 IR + 0.021 ± 0.058 0.71 + 0.047 ± 0.127 0.71 − 0.026 ± 0.122 0.83
 IM − 0.005 ± 0.014 0.69 − 0.001 ± 0.011 0.94 − 0.013 ± 0.029 0.66
 PM − 0.002 ± 0.005 0.75 − 0.000 ± 0.005 0.99 + 0.002 ± 0.007 0.80
X= δNfL;M= CRP
 Total effect + 0.164 ± 0.175 0.35 + 0.578 ± 0.362 0.11 − 0.032 ± 0.217 0.88
 CDE + 0.171 ± 0.174 0.33 + 0.669 ± 0.371 0.072 − 0.036 ± 0.228 0.88
 IR − 0.008 ± 0.002 0.65 − 0.100 ± 0.107 0.35 + 0.008 ± 0.038 0.84
 IM − 0.000 ± 0.003 0.88 − 0.024 ± 0.037 0.52 + 0.003 ± 0.015 0.83
 PM + 0.001 ± 0.006 0.87 + 0.034 ± 0.037 0.35 − 0.007 ± 0.020 0.71
X= δNfL;M= HBA1C
 Total effect + 0.079 ± 0.183 0.67 + 0.393 ± 0.425 0.36 − 0.091 ± 0.222 0.68
 CDE + 0.159 ± 0.155 0.31 + 0.470 ± 0.370 0.20 + 0.011 ± 0.191 0.95
 IR − 0.077 ± 0.095 0.42 − 0.058 ± 0.135 0.67 − 0.103 ± 0.145 0.48
 IM + 0.056 ± 0.023 0.014 + 0.042 ± 0.036 0.25 + 0.061 ± 0.034 0.071
 PM − 0.059 ± 0.041 0.15 − 0.061 ± 0.080 0.44 + 0.059 ± 0.050 0.23
X= δNfL;M= CHOL
 Total effect + 0.312 ± 0.195 0.11 + 0.682 ± 0.400 0.089 + 0.116 ± 0.244 0.64
 CDE + 0.303 ± 0.194 0.12 + 0.535 ± 0.381 0.16 + 0.168 ± 0.264 0.52
 IR − 0.003 ± 0.046 0.95 + 0.101 ± 0.147 0.49 − 0.045 ± 0.064 0.48
 IM + 0.023 ± 0.018 0.20 + 0.042 ± 0.046 0.37 + 0.011 ± 0.019 0.55
 PM − 0.012 ± 0.015 0.43 + 0.004 ± 0.025 0.87 − 0.018 ± 0.022 0.42
X= δNfL;M= HDL
 Total effect + 0.230 ± 0.182 0.21 + 0.699 ± 0.411 0.089 + 0.016 ± 0.216 0.94
 CDE + 0.222 ± 0.171 0.20 + 0.736 ± 0.402 0.067 − 0.000 ± 0.230 1.00
 IR + 0.002 ± 0.037 0.95 − 0.024 ± 0.180 0.89 + 0.014 ± 0.050 0.77
 IM + 0.001 ± 0.004 0.85 − 0.001 ± 0.012 0.97 − 0.004 ± 0.011 0.72
 PM + 0.005 ± 0.010 0.65 − 0.013 ± 0.029 0.66 + 0.006 ± 0.012 0.64
X= δNfL;M= RHR
 Total effect + 0.223 ± 0.171 0.20 + 0.599 ± 0.382 0.12 + 0.032 ± 0.191 0.87
 CDE + 0.220 ± 0.172 0.20 + 0.425 ± 0.385 0.27 + 0.062 ± 0.189 0.74
 IR − 0.022 ± 0.032 0.50 + 0.085 ± 0.124 0.50 − 0.031 ± 0.070 0.66
 IM − 0.012 ± 0.021 0.58 + 0.051 ± 0.056 0.36 − 0.031 ± 0.029 0.29
 PM + 0.036 ± 0.025 0.16 + 0.037 ± 0.049 0.45 + 0.032 ± 0.033 0.33
X= δNfL;M= SBP
 Total effect + 0.211 ± 0.176 0.23 + 0.654 ± 0.389 0.093 + 0.009 ± 0.208 0.97
 CDE + 0.190 ± 0.181 0.29 + 0.639 ± 0.385 0.097 − 0.0236 ± 0.221 0.92
 IR + 0.006 ± 0.019 0.76 + 0.005 ± 0.039 0.89 + 0.010 ± 0.039 0.80
 IM + 0.010 ± 0.018 0.58 + 0.001 ± 0.041 0.83 + 0.020 ± 0.030 0.52
 PM + 0.005 ± 0.019 0.79 + 0.001 ± 0.025 0.98 + 0.003 ± 0.038 0.94
X= δNfL;M= DBP
 Total effect + 0.248 ± 0.180 0.17 + 0.678 ± 0.404 0.094 + 0.043 ± 0.207 0.84
 CDE + 0.248 ± 0.184 0.18 + 0.682 ± 0.398 0.087 − 0.020 ± 0.230 0.93
 IR − 0.010 ± 0.024 0.68 − 0.014 ± 0.042 0.74 + 0.031 ± 0.086 0.72
 IM − 0.005 ± 0.014 0.74 − 0.002 ± 0.018 0.93 + 0.015 ± 0.036 0.68
 PM + 0.015 ± 0.017 0.36 + 0.011 ± 0.020 0.58 + 0.017 ± 0.036 0.63
X= δNfL;M= HYPERT
 Total effect + 0.248 ± 0.185 0.18 + 0.666 ± 0.392 0.089 + 0.138 ± 0.259 0.59
 CDE + 0.322 ± 0.261 0.22 + 0.252 ± 0.369 0.50 + 0.377 ± 0.416 0.37
 IR − 0.089 ± 0.140 0.53 + 0.296 ± 0.338 0.38 − 0.181 ± 0.172 0.30
 IM − 0.016 ± 0.025 0.53 + 0.047 ± 0.059 0.43 + 0.043 ± 0.045 0.33
 PM + 0.031 ± 0.028 0.28 + 0.071 ± 0.051 0.16 − 0.015 ± 0.042 0.73
X= δNfL;M= DIAB
 Total effect + 0.153 ± 0.178 0.39 + 0.644 ± 0.395 0.10 − 0.072 ± 0.222 0.75
 CDE + 0.037 ± 0.237 0.88 + 0.206 ± 0.396 0.60 − 0.190 ± 0.336 0.57
 IR + 0.098 ± 0.096 0.31 + 0.321 ± 0.258 0.22 + 0.123 ± 0.134 0.36
 IM + 0.021 ± 0.021 0.33 + 0.093 ± 0.084 0.27 + 0.022 ± 0.026 0.41
 PM − 0.002 ± 0.023 0.94 + 0.023 ± 0.057 0.69 − 0.026 ± 0.028 0.37
X= δNfL;M= HYPERCHOL
 Total effect + 0.207 ± 0.178 0.25 + 0.552 ± 0.380 0.15 + 0.023 ± 0.209 0.91
 CDE + 0.128 ± 0.207 0.54 + 0.407 ± 0.440 0.36 + 0.003 ± 0.252 0.99
 IR + 0.081 ± 0.078 0.30 + 0.136 ± 0.163 0.41 + 0.023 ± 0.083 0.79
 IM + 0.006 ± 0.011 0.56 + 0.023 ± 0.033 0.49 + 0.001 ± 0.006 0.92
 PM − 0.008 ± 0.012 0.49 − 0.014 ± 0.023 0.55 − 0.004 ± 0.021 0.86
X= δNfL;M= CVD
 Total effect + 0.203 ± 0.172 0.24 + 0.542 ± 0.385 0.16 + 0.047 ± 0.211 0.82
 CDE + 0.146 ± 0.184 0.43 + 0.485 ± 0.434 0.26 + 0.054 ± 0.228 0.81
 IR + 0.057 ± 0.048 0.23 + 0.060 ± 0.109 0.58 + 0.002 ± 0.036 0.96
 IM + 0.011 ± 0.012 0.34 + 0.004 ± 0.013 0.75 + 0.001 ± 0.019 0.95
 PM − 0.010 ± 0.012 0.38 − 0.009 ± 0.017 0.64 − 0.009 ± 0.023 0.68

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)]