Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells as Novel Diagnostic Tools for Non-Alcoholic Fatty Liver Disease: Visualizing Relationships with Known and Potential Disease Biomarkers
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Participants
2.2. Measurement of Laboratory Data
2.3. Isolation of PBMCs
2.4. Extracellular Flux Analysis of PBMCs
2.5. Mitochondrial DNA Quantification
2.6. Measurement of Serum Cytokine IL-6 and TNF-α
2.7. Statistical Analysis
- Step 1: The data matrix is repeatedly perturbed, obtaining k different subsets of observations (usually k = 10,000).
- Step 2: For each perturbed subset obtained at Step 1, a single classification tree is grown.
- Step 3: Each classification tree provides predictions (classes) in correspondence to each subject.
- Step 4: Final prediction, which is stable and accurate, is obtained based on majority voting.
3. Results
3.1. Descriptive Statistics
3.1.1. Clinical, Anthropometric, and Biochemical Characteristics of the Subjects
3.1.2. Mitochondrial DNA Content and Function in PBMCs from the Study Cohort
3.1.3. Correlation
3.1.4. Random Forest and VIMrel
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variables | NAFLD | Non-NAFLD | Total | p Value |
---|---|---|---|---|
(N = 19) | (N = 18) | (N = 37) | ||
Sex | 0.330 (a) | |||
Female | 8 (42.1%) | 11 (61.1%) | 19 (51.4%) | |
Male | 11 (57.9%) | 7 (38.9%) | 18 (48.6%) | |
Age (years) | 0.068 (b) | |||
Mean (SD) | 51.84 (4.15) | 48.44 (5.74) | 50.19 (5.21) | |
Median (Q1, Q3) | 52.00 (50.00, 54.50) | 48.00 (43.25, 52.75) | 51.00 (47.00, 54.00) | |
Range | 42.00–59.00 | 40.00–59.00 | 40.00–59.00 | |
BMI (Kg/m2) | <0.001 (b) | |||
Mean (SD) | 32.62 (6.93) | 23.49 (3.64) | 28.18 (7.18) | |
Median (Q1, Q3) | 31.30 (27.85, 34.55) | 23.40 (20.50, 25.77) | 27.00 (23.50, 31.50) | |
Range | 25.20–55.00 | 17.60–31.70 | 17.60–55.00 | |
Waist Circumference (cm) | <0.001 (b) | |||
N-Miss | 0 | 2 | 2 | |
Mean (SD) | 107.34 (17.71) | 86.97 (9.42) | 98.03 (17.64) | |
Median (Q1, Q3) | 105.00 (96.50, 112.00) | 87.50 (81.00, 94.62) | 96.00 (88.00, 106.25) | |
Range | 86.00–169.00 | 70.00–99.00 | 70.00–169.00 | |
Fasting glucose (mg/dL) | 0.014 (b) | |||
Mean (SD) | 99.37 (22.30) | 86.39 (11.26) | 93.05 (18.76) | |
Median (Q1, Q3) | 91.00 (86.00, 105.00) | 81.50 (77.75, 95.25) | 88.00 (81.00, 98.00) | |
Range | 81.00–169.00 | 74.00–115.00 | 74.00–169.00 | |
Fasting insulin (µUI/mL) | <0.001 (b) | |||
Mean (SD) | 14.21 (9.76) | 4.44 (3.38) | 9.46 (8.81) | |
Median (Q1, Q3) | 12.00 (8.50, 18.00) | 4.00 (2.00, 5.00) | 8.00 (4.00, 13.00) | |
Range | 2.00–42.00 | 1.00–14.00 | 1.00–42.00 | |
HOMA index | <0.001 (b) | |||
Mean (SD) | 3.60 (2.78) | 1.02 (0.95) | 2.34 (2.45) | |
Median (Q1, Q3) | 2.86 (1.72, 4.69) | 0.81 (0.40, 1.16) | 1.60 (0.79, 3.11) | |
Range | 0.42–11.27 | 0.18–3.98 | 0.18–11.27 | |
Total cholesterol (mg/dL) | 0.027 (b) | |||
Mean (SD) | 209.37 (28.51) | 185.94 (31.09) | 197.97 (31.68) | |
Median (Q1, Q3) | 212.00 (189.50, 230.00) | 185.00 (167.75, 200.25) | 195.00 (176.00, 218.00) | |
Range | 165.00–262.00 | 117.00–259.00 | 117.00–262.00 | |
HDL cholesterol (mg/dL) | 0.004 (b) | |||
Mean (SD) | 51.36 (13.93) | 67.49 (16.96) | 59.21 (17.31) | |
Median (Q1, Q3) | 47.60 (39.65, 62.80) | 69.50 (53.32, 75.33) | 55.60 (46.10, 71.80) | |
Range | 33.20–77.60 | 43.30–112.80 | 33.20–112.80 | |
LDL cholesterol (mg/dL) | 0.008 (b) | |||
Mean (SD) | 131.53 (29.39) | 102.72 (31.99) | 117.51 (33.59) | |
Median (Q1, Q3) | 127.00 (118.00, 154.50) | 95.50 (86.25, 118.75) | 119.00 (94.00, 142.00) | |
Range | 72.00–194.00 | 37.00–166.00 | 37.00–194.00 | |
Triglycerides (mg/dL) | 0.006 (b) | |||
Mean (SD) | 132.37 (73.47) | 78.78 (45.27) | 106.30 (66.37) | |
Median (Q1, Q3) | 126.00 (71.00, 155.00) | 64.00 (49.75, 91.75) | 77.00 (60.00, 131.00) | |
Range | 57.00–301.00 | 32.00–219.00 | 32.00–301.00 | |
ALT (U/L) | 0.163 (b) | |||
N-Miss | 0 | 1 | 1 | |
Mean (SD) | 33.89 (14.49) | 31.12 (23.40) | 32.58 (18.98) | |
Median (Q1, Q3) | 32.00 (22.50, 40.50) | 23.00 (18.00, 32.00) | 30.50 (19.00, 35.50) | |
Range | 13.00–64.00 | 15.00–108.00 | 13.00–108.00 | |
AST (U/L) | 0.867 (b) | |||
Mean (SD) | 16.79 (6.24) | 18.28 (10.81) | 17.51 (8.67) | |
Median (Q1, Q3) | 16.00 (11.50, 22.00) | 14.50 (10.25, 22.75) | 15.00 (11.00, 22.00) | |
Range | 8.00–27.00 | 6.00–43.00 | 6.00–43.00 | |
Total bilirubin (mg/dL) | 0.648 (b) | |||
Mean (SD) | 1.36 (3.43) | 0.66 (0.29) | 1.02 (2.46) | |
Median (Q1, Q3) | 0.55 (0.48, 0.66) | 0.56 (0.53, 0.69) | 0.56 (0.50, 0.66) | |
Range | 0.29–15.50 | 0.35–1.42 | 0.29–15.50 | |
GGT (U/L) | 0.564 (b) | |||
Mean (SD) | 33.58 (40.86) | 27.85 (34.71) | 30.79 (37.58) | |
Median (Q1, Q3) | 22.70 (11.60, 35.50) | 16.40 (12.67, 21.55) | 17.10 (12.40, 32.70) | |
Range | 0.50–178.60 | 5.30–152.40 | 0.50–178.60 | |
Haptoglobin (mg/dL) | 0.098 (b) | |||
Mean (SD) | 133.71 (57.92) | 106.71 (48.92) | 120.58 (54.73) | |
Median (Q1, Q3) | 148.00 (87.30, 170.00) | 119.00 (68.10, 134.75) | 121.00 (79.40, 165.00) | |
Range | 21.00–224.00 | 21.00–202.00 | 21.00–224.00 | |
hsCRP (mg/L) | 0.007 (b) | |||
Mean (SD) | 3.26 (3.36) | 1.32 (1.49) | 2.31 (2.77) | |
Median (Q1, Q3) | 1.43 (1.02, 4.25) | 0.61 (0.34, 1.70) | 1.13 (0.56, 2.70) | |
Range | 0.33–10.00 | 0.08–4.96 | 0.08–10.00 | |
TNF-α (pg/mL) | 0.025 (b) | |||
N-Miss | 0 | 1 | 1 | |
Mean (SD) | 3.26 (1.64) | 2.34 (1.32) | 2.83 (1.55) | |
Median (Q1, Q3) | 3.02 (2.59, 3.38) | 2.38 (1.47, 2.60) | 2.60 (2.15, 3.37) | |
Range | 1.62–9.37 | 0.00–5.68 | 0.00–9.37 | |
IL-6 (pg/mL) | 0.006 (b) | |||
Mean (SD) | 2.40 (2.11) | 1.07 (0.73) | 1.75 (1.72) | |
Median (Q1, Q3) | 1.55 (1.11, 2.70) | 0.95 (0.61, 1.30) | 1.19 (0.80, 1.58) | |
Range | 0.53–8.40 | 0.24–3.65 | 0.24–8.40 | |
Fatty Liver Index | <0.001 (b) | |||
N-Miss | 0 | 2 | 2 | |
Mean (SD) | 67.95 (29.34) | 20.13 (18.19) | 46.09 (34.44) | |
Median (Q1, Q3) | 80.59 (55.52, 89.81) | 14.53 (3.78, 33.95) | 39.57 (14.53, 80.68) | |
Range | 3.35–98.61 | 1.32–60.69 | 1.32–98.61 |
Variables | NAFLD | Non-NAFLD | Total | p Value |
---|---|---|---|---|
(N = 19) | (N = 18) | (N = 37) | ||
mtDNAcn | 0.318 (a) | |||
N-Miss | 0 | 1 | 1 | |
Mean (SD) | 3.32 (0.43) | 3.46 (0.37) | 3.39 (0.40) | |
Median (Q1, Q3) | 3.32 (2.91, 3.76) | 3.54 (3.15, 3.80) | 3.39 (3.02, 3.80) | |
Range | 2.78–3.97 | 2.89–3.94 | 2.78–3.97 | |
Basal respiration | 0.023 (a) | |||
Mean (SD) | −0.37 (0.74) | 0.45 (1.17) | 0.03 (1.05) | |
Median (Q1, Q3) | −0.52 (−0.84, 0.09) | 0.37 (−0.39, 1.34) | −0.24 (−0.73, 0.63) | |
Range | −1.74–1.22 | −1.54–2.45 | −1.74–2.45 | |
ATP production | 0.021 (a) | |||
Mean (SD) | −0.37 (0.71) | 0.46 (1.17) | 0.04 (1.04) | |
Median (Q1, Q3) | −0.39 (−0.83, 0.10) | 0.43 (−0.40, 1.12) | −0.11 (−0.63, 0.77) | |
Range | −1.77–1.17 | −1.64–2.41 | −1.77–2.41 | |
Proton leak | 0.191 (a) | |||
Mean (SD) | −0.19 (0.80) | 0.22 (1.08) | 0.01 (0.96) | |
Median (Q1, Q3) | −0.39 (−0.81, 0.11) | −0.15 (−0.64, 0.79) | −0.27 (−0.75, 0.30) | |
Range | −0.97–2.41 | −0.87–2.62 | −0.97–2.62 | |
Maximal respiration | 0.045 (a) | |||
Mean (SD) | −0.30 (0.81) | 0.38 (1.01) | 0.03 (0.96) | |
Median (Q1, Q3) | −0.31 (−0.93, 0.28) | 0.16 (−0.39, 1.08) | 0.02 (−0.73, 0.57) | |
Range | −1.60–1.52 | −1.00–2.33 | −1.6–2.33 | |
Spare respiratory capacity | 0.045 (a) | |||
Mean (SD) | −0.26 (0.81) | 0.33 (0.98) | 0.02 (0.93) | |
Median (Q1, Q3) | −0.18 (−0.94, 0.20) | 0.16 (−0.63, 1.09) | −0.06 (−0.69, 0.55) | |
Range | −1.46–1.63 | −0.93–2.27 | −1.46–2.27 | |
Non-mitochondrial respiration | 0.715 (a) | |||
Mean (SD) | −0.06 (0.82) | 0.08 (1.04) | 0.01 (0.92) | |
Median (Q1, Q3) | 0.07 (−0.79, 0.60) | 0.17 (−0.58, 0.86) | 0.17 (−0.72, 0.64) | |
Range | −1.37–1.26 | −1.75–1.76 | −1.75–1.76 |
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Garrafa, E.; Segala, A.; Vezzoli, M.; Bottani, E.; Zanini, B.; Vetturi, A.; Bracale, R.; Ricci, C.; Valerio, A. Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells as Novel Diagnostic Tools for Non-Alcoholic Fatty Liver Disease: Visualizing Relationships with Known and Potential Disease Biomarkers. Diagnostics 2023, 13, 2363. https://doi.org/10.3390/diagnostics13142363
Garrafa E, Segala A, Vezzoli M, Bottani E, Zanini B, Vetturi A, Bracale R, Ricci C, Valerio A. Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells as Novel Diagnostic Tools for Non-Alcoholic Fatty Liver Disease: Visualizing Relationships with Known and Potential Disease Biomarkers. Diagnostics. 2023; 13(14):2363. https://doi.org/10.3390/diagnostics13142363
Chicago/Turabian StyleGarrafa, Emirena, Agnese Segala, Marika Vezzoli, Emanuela Bottani, Barbara Zanini, Alice Vetturi, Renata Bracale, Chiara Ricci, and Alessandra Valerio. 2023. "Mitochondrial Dysfunction in Peripheral Blood Mononuclear Cells as Novel Diagnostic Tools for Non-Alcoholic Fatty Liver Disease: Visualizing Relationships with Known and Potential Disease Biomarkers" Diagnostics 13, no. 14: 2363. https://doi.org/10.3390/diagnostics13142363