Table 4.
Prognostic markers of functional decline
| Prognostic Marker (in quartiles or binary) | Unadjusted Analysis * | Adjusted Analysis * | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| ALSFRS-R slope (points/month): Estimate (SE) 1 | p-value | ALSFRS-R slope (points/month): Estimate (SE) 1 | p-value | |||||||
| Q1 /No | Q2 | Q3 | Q4 / Yes | Q1 /No | Q2 | Q3 | Q4/ Yes | |||
| Sex, male | −0.90 (−1.1, −0.74) | -- | -- | −0.88 (−1.0, −0.73) | 0.80 | −0.90 (−1.1, −0.75) | -- | -- | −0.88 (−1.0, −0.74) | 0.83 |
| Age at onset | −0.74 (−.95, −0.53) | −0.90 (−1.1, −0.70) | −1.00 (−1.2, −0.79) | −0.91 (−1.1, −0.67) | 0.38 | −0.87 (−1.1, −0.66) | −0.91 (−1.10, −0.72) | −0.95 (−1.1, −0.75) | −0.79 (−1.0, −0.56) | 0.77 |
| Bulbar symptoms at onset | −0.82 (−.94, −0.70) | -- | -- | −1.07 (−1.3, −0.87) | 0.036 | −0.84 (−0.96, −0.72) | -- | -- | −1.02 (−1.2, −0.82) | 0.14 |
| Diagnostic delay | −1.10 (−1.3, −.090) | −0.99 (−1.2, −0.79) | −0.70 (−.92, −0.48) | −0.73 (−.93, −0.52) | 0.016 | −0.99 (−1.2, −0.78) | −0.93 (−1.10, −0.73) | −0.73 (−0.94, −0.51) | −0.89 (−1.1, −0.66) | 0.38 |
| Baseline ΔFRS | −0.72 (−0.91, −0.54) | −0.83 (−1.0, −0.62) | −0.69 (−.89, −0.48) | −1.37 (−1.6, −1.1) | <0.0001 10 | −0.87 (−1.1, −0.66) | −0.83 (−1.00, −0.62) | −0.66 (−0.86, −0.45) | −1.22 (−1.5, −0.98) | 0.0036 |
| Baseline age | −0.76 (−0.97, −0.55) | −0.99 (−1.2, −0.79) | −0.91 (−1.1, −0.69) | −0.89 (−1.1, −0.66) | 0.47 | −0.88 (−1.1, −0.68) | −0.99 (−1.20, −0.79) | −0.87 (−1.1, −0.66) | −0.80 (−1.0, −0.58) | 0.63 |
| Baseline ALSFRS-R | −0.96 (−1.2, −0.75) | −0.92 (−1.1, −0.70) | −0.68 (−.92, −0.45) | −0.93 (−1.1, −0.73) | 0.31 | −0.88 (−1.1, −0.67) | −0.93 (−1.10, −0.72) | −0.70 (−0.92, −0.47) | −1.00 (−1.2, −0.80) | 0.24 |
| Baseline SVC %predicted | −1.08 (−1.3, −0.86) | −0.90 (−1.1, −0.70) | −0.85 (−1.1, −0.64) | −0.70 (−.92, −0.48) | 0.12 | −0.96 (−1.2, −0.74) | −0.92 (−1.10, −0.72) | −0.91 (−1.1, −0.71) | −0.73 (−0.94, −0.52) | 0.44 |
| Baseline ECAS total 2 | −0.99 (−1.2, −0.76) | −0.77 (−1.0, −0.53) | −0.79 (−1.0, −0.55) | −0.84 (−1.1, −0.60) | 0.54 | −0.98 (−1.2, −0.76) | −0.72 (−0.95, −0.49) | −0.80 (−1.0, −0.57) | −0.92 (−1.1, −0.68) | 0.38 |
| Baseline ECAS ALS-specific 2 | −0.83 (−1.1, −0.60) | −0.84 (−1.1, −0.62) | −0.92 (−1.2, −0.68) | −0.81 (−1.1, −0.55) | 0.92 | −0.84 (−1.1, −0.61) | −0.81 (−1.00, −0.59) | −0.93 (−1.2, −0.70) | −0.85 (−1.1, −0.60) | 0.89 |
| Baseline ECAS ALS non-specific 2 | −0.91 (−1.1, −0.67) | −0.70 (−.92, −0.48) | −0.98 (−1.2, −0.75) | −0.80 (−1.1, −0.54) | 0.36 | −0.87 (−1.1, −0.65) | −0.73 (−0.95, −0.52) | −0.99 (−1.2, −0.77) | −0.82 (−1.1, −0.56) | 0.42 |
| Baseline cognitive impairment 2 | −0.83 (−0.96, −0.70) | -- | -- | −0.89 (−1.2, −0.54) | 0.73 | −0.83 (−0.95, −0.70) | -- | -- | −0.89 (−1.2, −0.54) | 0.75 |
| Baseline behavioural impairment 2 | −0.78 (−0.93, −0.63) | -- | -- | −1.04 (−1.4, −0.66) | 0.21 | −0.76 (−0.90, −0.61) | -- | -- | −0.97 (−1.3, −0.61) | 0.29 |
| Baseline ENCALS predictor score | −0.57 (−0.76, −0.37) | −0.70 (−.89, −0.51) | −1.02 (−1.2, −0.81) | −1.27 (−1.5, −1.1) | <0.0001 10 | −0.62 (−0.90, −0.34) | −0.71 (−0.90, −0.51) | −1.00 (−1.2, −0.79) | −1.23 (−1.5, −0.96) | 0.021 |
| Baseline serum NfL | −0.41 (−0.58, −0.24) | −0.67 (−.84, −0.50) | −1.10 (−1.3, −0.92) | −1.49 (−1.7, −1.3) | <0.0001 10 | −0.44 (−0.60, −0.27) | −0.71 (−0.88, −0.54) | −1.08 (−1.3, −0.90) | −1.44 (−1.6, −1.2) | <0.0001 10 |
| Baseline serum pNfH | −0.68 (−0.88, −0.48) | −0.96 (−1.2, −0.74) | −0.82 (−1.0, −0.61) | −1.13 (−1.4, −0.91) | 0.024 | −0.70 (−0.89, −0.51) | −0.91 (−1.10, −0.71) | −0.86 (−1.1, −0.65) | −1.12 (−1.3, −0.91) | 0.041 |
| Baseline urinary p75ECD | −0.93 (−1.2, −0.70) | −0.75 (−1.0, −0.50) | −1.03 (−1.3, −0.79) | −0.97 (−1.2, −0.73) | 0.44 | −0.99 (−1.2, −0.77) | −0.76 (−1.00, −0.52) | −0.96 (−1.2, −0.73) | −0.96 (−1.2, −0.73) | 0.50 |
| Baseline serum uric acid | −0.96 (−1.2, −0.75) | −0.85 (−1.1, −0.63) | −0.91 (−1.1, −0.70) | −0.82 (−1.0, −0.60) | 0.82 | −0.98 (−1.2, −0.78) | −0.82 (−1.00, −0.61) | −0.93 (−1.1, −0.73) | −0.81 (−1.0, −0.60) | 0.61 |
| Baseline serum creatinine | −0.90 (−1.1, −0.69) | −0.89 (−1.1, −0.67) | −0.80 (−1.0, −0.57) | −0.95 (−1.2, −0.74) | 0.81 | −0.91 (−1.1, −0.71) | −0.94 (−1.20, −0.73) | −0.76 (−0.98, −0.54) | −0.93 (−1.1, −0.74) | 0.61 |
| Baseline serum albumin | −0.82 (−1.0, −0.61) | −0.87 (−1.1, −0.64) | −1.03 (−1.2, −0.85) | −0.71 (−.98, −0.45) | 0.23 | −0.74 (−0.95, −0.54) | −0.83 (−1.00, −0.62) | −1.09 (−1.3, −0.92) | −0.76 (−1.0, −0.50) | 0.039 |
| Baseline serum CRP 3 | −0.85 (−0.97, −0.72) | −1.12 (−1.6, −0.66) | −0.97 (−1.2, −0.74) | 0.38 | −0.84 (−0.96, −0.72) | −1.08 (−1.5, −0.64) | −0.98 (−1.2, −0.77) | 0.37 | ||
| Baseline plasma miR-181ab | −0.71 (−0.92, −0.50) | −0.82 (−1.0, −0.61) | −0.92 (−1.1, −0.70) | −1.11 (−1.3, −0.89) | 0.061 | −0.71 (−0.91, −0.51) | −0.83 (−1.00, −0.63) | −0.95 (−1.2, −0.74) | −1.07 (−1.3, −0.86) | 0.085 |
| Baseline miR-181ab > 39,300 UMI 4 | −0.80 (−0.93, −0.68) | -- | -- | −1.09 (−1.3, −0.89) | 0.017 | −0.82 (−0.94, −0.70) | -- | -- | −1.06 (−1.3, −0.87) | 0.037 |
| Baseline miR-181ab > 24,590 UMI 5 | −0.76 (−0.91, −0.61) | -- | -- | −1.01 (−1.2, −0.86) | 0.023 | −0.77 (−0.91, −0.63) | -- | -- | −1.01 (−1.2, −0.86) | 0.022 |
| Baseline NfL+miR181ab poor Px 6 | −0.69 (−0.80, −0.57) | -- | -- | −1.39 (−1.6, −1.2) | <0.0001 10 | −0.71 (−0.82, −0.60) | -- | -- | −1.34 (−1.5, −1.1) | <0.0001 10 |
| Baseline NfL+miR181ab poor Px 7 | −0.56 (−0.68, −0.43) | -- | -- | −1.28 (−1.4, −1.1) | <0.0001 10 | −0.59 (−0.72, −0.47) | -- | -- | −1.24 (−1.4, −1.1) | <0.0001 10 |
| Baseline NfL median split 8 | −0.54 (−0.66, −0.41) | -- | -- | −1.28 (−1.4, −1.1) | <0.0001 10 | −0.58 (−0.70, −0.45) | -- | -- | −1.24 (−1.4, −1.1) | <0.0001 10 |
| Baseline NfL 4-level split 9 | −0.44 (−0.59, −0.30) | −0.73 (−.94, −0.52) | −1.05 (0.11) | −1.41 (−1.6, −1.2) | <0.0001 10 | −0.48 (−0.63, −0.34) | −0.74 (−0.95, −0.53) | −1.05 (−1.3, −0.83) | −1.36 (−1.5, −1.2) | <0.0001 10 |
Random slopes model. ENCALS predictor score included in adjusted analysis. Q1-Q4 indicate quartiles of continuous predictors, with higher quartiles representing higher values. Yes/No in column headings captures the presence/absence of binary predictors.
Without inclusion of covariate or prognostic marker in the model, ALSFRS-R slope (SE) = −0.89 (0.05) points/month.
Among English speakers (n=171)
More than 50% of observations were below the lower limit of quantification and were imputed at 0.1 mg/dL
Threshold of 39,300 UMI in plasma as defined by Magen et al 11
Median of 24,590 UMI in plasma in the current dataset
Poor prognosis based on published optimal combination of NfL and miR-181ab, in which a poor prognostic factor is defined as either (NfL > 109.8 pg/mL) or (NfL > 59.0 pg/mL and miR-181ab > 39,300 UMI) 11.
Poor prognosis based on recalculated combination of NfL and mIR-181ab using thresholds obtained from the current dataset; a poor prognostic factor is defined as either (NfL > 80.8 pg/mL) or (NfL > 44.8 pg/mL and mIR-181ab > 24,590 UMI).
Median serum NfL = 67.9 pg/mL
Serum NfL 4-level split is at the 33rd, 50th, and 67th percentiles (44.8 pg/mL, 67.9 pg/mL, and 80.8 pg/mL, respectively), i.e., tertiles and median, rather than quartiles, to mimic construction of the NfL+miR18ab measure 11.
p-value remains statistically significant after adjustment for multiplicity. Holm-Bonferroni adjusted p-values are reported in eTable 7.