Table 2.
Analysis of Area Under the Curve (AUC)1 of biomarkers across interventions
| Measures | Immediate vs. Gradual | Immediate vs. Control | Gradual vs. Control | |||
|---|---|---|---|---|---|---|
| Mean Difference/Ratio of Geometric Means2 (95% CI) |
P Value3 | Mean Difference/Ratio of Geometric Means2 (95% CI) |
P Value3 | Mean Difference/Ratio of Geometric Means2 (95% CI) |
P Value3 | |
| Linear Regression of AUC, Adjusted For Baseline4 | ||||||
| 8-iso-PGF2α (pmol/mg creatinine) | 0.99 (0.95, 1.04) | 0.69 | 0.96 (0.92, 1.01) | 0.14 | 0.97 (0.92, 1.02) | 0.28 |
| hs-CRP (mg/L) | 0.98 (0.91, 1.06) | 0.61 | 1.06 (0.97, 1.17) | 0.17 | 1.09 (0.99, 1.19) | 0.078 |
| hs-CRP (mg/L), ≤10 values only6 | 0.97 (0.91, 1.03) | 0.27 | 1.04 (0.96, 1.13) | 0.29 | 1.08 (1.00, 1.16) | 0.045 |
| WBC (103/μL) | −0.26 (−0.40, −0.12) | 0.0004 | −0.10 (−0.26, 0.07) | 0.27 | 0.17 (0.00, 0.33) | 0.056 |
| WBC (103/μL), ≤14 values only6 | −0.19 (−0.34, −0.05) | 0.008 | −0.13 (−0.29, 0.03) | 0.10 | 0.06 (−0.10, 0.22) | 0.45 |
| PGEM (pmol/mg creatinine) | 0.99 (0.92, 1.06) | 0.73 | 0.94 (0.86, 1.02) | 0.14 | 0.95 (0.87, 1.03) | 0.23 |
| Red cell count (106/μL) | −0.01 (−0.04, 0.01) | 0.28 | −0.01 (−0.04, 0.02) | 0.52 | 0.00 (−0.02, 0.03) | 0.78 |
| Hemoglobin (g/dL) | −0.04 (−0.11, 0.04) | 0.32 | −0.06 (−0.15, 0.02) | 0.14 | −0.03 (−0.11, 0.06) | 0.51 |
| Hematocrit (%) | −0.12 (−0.34, 0.10) | 0.27 | −0.20 (−0.46, 0.06) | 0.13 | −0.08 (−0.33, 0.17) | 0.54 |
| MCV (fL) | −0.07 (−0.28, 0.14) | 0.52 | −0.23 (−0.48, 0.01) | 0.061 | −0.17 (−0.40, 0.07) | 0.17 |
| MCH (pg) | −0.01 (−0.09, 0.07) | 0.79 | −0.07 (−0.16, 0.02) | 0.13 | −0.06 (−0.15, 0.03) | 0.21 |
| MCHC (g/dL) | 0.04 (−0.04, 0.11) | 0.32 | 0.02 (−0.06, 0.10) | 0.62 | −0.02 (−0.10, 0.07) | 0.71 |
| RDW (%) | −0.11 (−0.18, −0.04) | 0.004 | −0.15 (−0.23, −0.06) | 0.001 | −0.04 (−0.12, 0.05) | 0.43 |
| Platelet count (103/μL) | −1.58 (−5.06, 1.89) | 0.37 | 3.03 (−1.08, 7.14) | 0.15 | 4.61 (0.61, 8.61) | 0.024 |
| MPV (fL) | 0.07 (−0.08, 0.21) | 0.36 | 0.02 (−0.09, 0.13) | 0.74 | −0.05 (−0.18, 0.09) | 0.50 |
| Linear Regression of AUC, Adjusted For Baseline and Other Covariates5 | ||||||
| 8-iso-PGF2α (pmol/mg creatinine) | 0.99 (0.95, 1.03) | 0.60 | 0.96 (0.92, 1.01) | 0.13 | 0.97 (0.93, 1.03) | 0.32 |
| hs-CRP (mg/L) | 0.98 (0.91, 1.06) | 0.66 | 1.07 (0.97, 1.17) | 0.16 | 1.08 (0.99, 1.19) | 0.083 |
| hs-CRP (mg/L), ≤10 values only6 | 0.97 (0.91, 1.03) | 0.31 | 1.04 (0.97, 1.13) | 0.28 | 1.08 (1.00, 1.16) | 0.050 |
| WBC (103/μL) | −0.27 (−0.41, −0.13) | 0.0002 | −0.10 (−0.27, 0.07) | 0.24 | 0.17 (0.00, 0.34) | 0.049 |
| WBC (103/μL), ≤14 values only6 | −0.21 (−0.35, −0.06) | 0.005 | −0.14 (−0.30, 0.02) | 0.089 | 0.07 (−0.09, 0.23) | 0.40 |
| PGEM (pmol/mg creatinine) | 0.98 (0.92, 1.05) | 0.65 | 0.94 (0.86, 1.02) | 0.16 | 0.96 (0.88, 1.04) | 0.29 |
| Red cell count (106/μL) | −0.01 (−0.04, 0.01) | 0.32 | −0.01 (−0.04, 0.02) | 0.47 | 0.00 (−0.02, 0.03) | 0.89 |
| Hemoglobin (g/dL) | −0.04 (−0.11, 0.04) | 0.32 | −0.07 (−0.16, 0.01) | 0.10 | −0.04 (−0.12, 0.05) | 0.41 |
| Hematocrit (%) | −0.12 (−0.34, 0.10) | 0.27 | −0.22 (−0.47, 0.04) | 0.097 | −0.09 (−0.34, 0.16) | 0.46 |
| MCV (fL) | −0.08 (−0.29, 0.12) | 0.43 | −0.24 (−0.49, 0.00) | 0.049 | −0.16 (−0.40, 0.08) | 0.18 |
| MCH (pg) | −0.01 (−0.10, 0.07) | 0.73 | −0.08 (−0.17, 0.02) | 0.11 | −0.06 (−0.16, 0.03) | 0.20 |
| MCHC (g/dL) | 0.04 (−0.03, 0.11) | 0.29 | 0.01 (−0.07, 0.09) | 0.78 | −0.03 (−0.11, 0.05) | 0.52 |
| RDW (%) | −0.11 (−0.18, −0.04) | 0.003 | −0.14 (−0.23, −0.06) | 0.001 | −0.03 (−0.12, 0.05) | 0.45 |
| Platelet count (103/μL) | −1.15 (−4.64, 2.33) | 0.52 | 3.24 (−0.87, 7.36) | 0.12 | 4.39 (0.37, 8.41) | 0.032 |
| MPV (fL) | 0.06 (−0.08, 0.21) | 0.37 | 0.02 (−0.09, 0.14) | 0.67 | −0.04 (−0.18, 0.10) | 0.57 |
Area under the curve (AUC) scaled by time (i.e., time-weighted average); the unit is the same as its original variable.
Mean difference for WBC, red cell count, hemoglobin, hematocrit, MCV, MCH, MCHC, RDW, platelet count, and MPV; ratio of geometric means for 8-iso-PGF2α, PGEM, and hs-CRP.
P < 0.00057 were considered statistically significant for secondary endpoints (8-iso-PGF2α, hs-CRP, and WBC); hs-CRP (≤ 10 values only) and WBC (≤ 14 values only) were analyzed as a sensitivity analysis for their respective non-restricted counterparts, hence the same P-value cutoff points were applied; P < 0.0167 were considered statistically significant for all the other biomarkers which are exploratory endpoints.
Linear regression of the AUC adjusted for the corresponding baseline measure of the biomarker; log-transformation was used for the AUC of 8-iso-PGF2α, PGEM, and hs-CRP and their baseline measure.
Linear regression of the AUC adjusted for the corresponding baseline measure of the biomarker, study site, together with any baseline variables which were different between treatment arms at P<0.20 (employment, Fagerström Test for Nicotine Dependence, and serum nicotine metabolic ratio); log-transformation was used for the AUC of 8-iso-PGF2α, PGEM, and hs-CRP.
Analysis conducted excluding out-of-range values.
Abbreviation: 8isoPGF2α (pmol/mg), (Z)-7-[1R,2R,3R,5S]-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid) or 8-iso-prostaglandin F2α; hs-CRP, high sensitivity C Reactive Protein; WBC (103/μL), white cell count; PGEM (pmol/ml), Prostaglandin E Metabolite; MCV (fL), mean corpuscular volume (measure of size of red blood cells); MCH (pg), mean corpuscular hemoglobin (quantity of hemoglobin in red blood cell), MCHC (g/dL), mean corpuscular hemoglobin concentration (concentration of hemoglobin in red blood cells); RDW (%), red blood cell distribution, (variation in size and volume of red blood cells); MPV (fL), mean platelet volume (size of platelet)