Based on the serum TTR concentration data of the past five years, the number of cases, the mean (standard deviation, SD), median (quartile intervals), and P values (Table 1)(available in Supplement 1)for each of the 48 diseases were compared to healthy controls and summarized in Table 1.
Table 1
Serum TTR concentrations of 48 clinically defined diseases in patients and healthy controls
TTR | # of cases | Mean (SD) | Median (IQR) | p-Value |
Hepatic Encephalopathy | 91 | 114.3 (89.8) | 79.6 (57.7, 128.8) | < 0.001 |
Cirrhosis | 9,298 | 157.0 (72.2) | 151.3 (96.4, 212.4) | < 0.001 |
Sepsis | 114 | 155.6 (65.0) | 154.8 (107.2, 200.6) | < 0.001 |
Pancreatitis | 1,837 | 178.3 (67.4) | 170.6 (126.4, 222.8) | < 0.001 |
Pancreatic Cancer | 1,151 | 176.5 (72.3) | 171.9 (120.9, 229.0) | < 0.001 |
Liver Cancer | 300 | 184.6 (74.2) | 190.4 (120.0, 241.5) | < 0.001 |
Preeclampsia | 993 | 193.7 (45.4) | 196.1 (159.7, 225.0) | < 0.001 |
Gastric Cancer | 13,494 | 200.5 (63.7) | 202.0 (152.0, 247.4) | < 0.001 |
Chronic Obstructive PD | 1,644 | 207.4 (68.4) | 203.1 (156.3, 254.7) | < 0.001 |
Esophagus Cancer | 4,027 | 209.4 (68.6) | 209.7 (156.8, 260.7) | < 0.001 |
Gastric Ulcer | 306 | 218.1 (70.7) | 218.1 (160.8, 270.3) | < 0.001 |
Acute Myocardial Infarction | 2,653 | 218.4 (64.7) | 219.0 (170.6, 266.7) | < 0.001 |
Brain Trauma | 663 | 226.7 (66.5) | 225.4 (176.5, 278.9) | < 0.001 |
Colon Cancer | 6,632 | 221.9 (74.5) | 225.5 (164.1, 278.1) | < 0.001 |
Myeloproliferative Disorder | 1,288 | 226.0 (91.6) | 228.3 (156.5, 296.7) | < 0.001 |
Bone Cancer | 112 | 231.3 (64.0) | 232.7 (184.9, 281.3) | < 0.001 |
Rectum Cancer | 8,508 | 231.0 (69.8) | 233.5 (178.5, 283.2) | < 0.001 |
Hepatitis | 6,728 | 233.7 (65.0) | 236.7 (192.6, 280.0) | < 0.001 |
Intracranial Hemorrhage | 3,857 | 239.8 (68.0) | 240.8 (190.0, 290.5) | < 0.001 |
Leukemia | 5,440 | 236.7 (80.4) | 242.6 (175.1, 298.5) | < 0.001 |
Encephalitis | 560 | 240.3 (77.7) | 243.4 (180.1, 298.0) | < 0.001 |
Acute Cerebral Infarction | 9,658 | 243.5 (61.4) | 244.3 (200.5, 288.2) | < 0.001 |
Bone Fracture | 1,773 | 247.3 (67.6) | 249.0 (199.1, 297.5) | < 0.001 |
Anemia | 2,051 | 254.1 (89.4) | 249.1 (188.6, 321.0) | < 0.001 |
Lung Fibrosis | 338 | 253.8 (78.5) | 250.9 (195.1, 311.7) | < 0.001 |
Alzheimer's Disease | 108 | 235.5 (74.4) | 251.1 (193.3, 275.5) | < 0.001 |
Breast Lumps | 111 | 261.1 (51.1) | 252.2 (227.3, 293.0) | < 0.001 |
Coronary Heart Disease | 22,119 | 251.2 (64.3) | 252.4 (207.7, 297.1) | < 0.001 |
Rheumatic Arthritis | 486 | 253.2 (62.6) | 253.0 (211.3, 295.8) | < 0.001 |
Asthma | 605 | 253.1 (58.7) | 253.0 (211.1, 293.4) | < 0.001 |
Bladder Cancer | 1,071 | 249.8 (73.2) | 253.8 (196.1, 305.3) | < 0.001 |
Lymphoma | 4,555 | 247.5 (76.9) | 255.8 (196.7, 303.9) | < 0.001 |
Osteoporosis | 278 | 256.8 (56.9) | 255.9 (218.1, 296.7) | < 0.001 |
Lung Cancer | 10,932 | 257.0 (65.2) | 259.9 (213.6, 305.4) | < 0.001 |
Cerebrovascular Disease | 4,771 | 258.9 (59.7) | 260.2 (219.9, 300.7) | < 0.001 |
Cerebral Ischemia | 2,279 | 261.6 (55.0) | 260.3 (224.5, 301.0) | < 0.001 |
Multiple Myeloma | 2,329 | 256.3 (72.0) | 260.4 (209.7, 305.6) | < 0.001 |
Knee-Joint Degenerative Diseases | 445 | 260.5 (50.2) | 262.6 (224.4, 297.6) | < 0.001 |
Bladder Stone | 162 | 262.1 (54.8) | 264.7 (225.3, 294.3) | < 0.001 |
Ovarian Cancer | 2,359 | 261.2 (62.6) | 267.0 (224.5, 306.3) | < 0.001 |
Type 2 Diabetes Mellitus | 11,561 | 266.4 (61.5) | 267.8 (225.0, 309.6) | < 0.001 |
Diabetic Nephropathy | 599 | 268.3 (70.6) | 271.0 (219.1, 318.5) | < 0.001 |
Cerebral Arteriosclerosis | 821 | 269.2 (56.2) | 271.4 (232.9, 305.2) | < 0.001 |
Endometrial Cancer | 1,222 | 272.7 (51.8) | 272.4 (238.4, 312.2) | < 0.001 |
Cervical Cancer | 2,274 | 275.6 (51.8) | 276.9 (238.6, 312.7) | < 0.001 |
Gastritis | 3,407 | 277.1 (58.8) | 277.7 (238.1, 318.4) | < 0.001 |
Psoriasis | 145 | 277.9 (63.5) | 277.9 (235.0, 317.9) | < 0.001 |
Renal Cyst | 525 | 280.5 (52.6) | 278.3 (244.5, 317.4) | < 0.001 |
Necrosis of Femoral Head | 173 | 276.8 (52.4) | 278.6 (240.3, 313.5) | < 0.001 |
Breast Cancer | 5,491 | 281.9 (44.4) | 280.0 (250.1, 311.7) | < 0.001 |
Lupus Erythematosus | 1,310 | 284.6 (78.0) | 280.9 (228.0, 334.0) | < 0.001 |
Ankylosing Spondylitis | 102 | 278.5 (67.5) | 285.6 (220.1, 330.7) | < 0.001 |
Healthy Controls > 65 years old | 808 | 299.5 (50.6) | 291.9 (263.1, 331.9) | - |
Gout | 1,475 | 296.3 (69.0) | 299.4 (248.5, 344.6) | < 0.001 |
Nephrotic Syndrome | 3,838 | 300.4 (81.6) | 299.4 (244.4, 357.8) | < 0.001 |
Nephritis | 2,147 | 299.9 (69.4) | 301.1 (253.5, 348.6) | < 0.001 |
Kidney Cancer | 1,553 | 309.0 (66.4) | 312.6 (269.6, 355.7) | < 0.001 |
Healthy Controls | 9,473 | 325.1 (55.8) | 322.3 (283.3, 364.3) | - |
Uremia | 6,533 | 337.0 (84.8) | 337.2 (277.0, 395.7) | < 0.001 |
Healthy control is bolded to make an easy comparison. SD: standard deviation, |
IQR: interquartile range. Chronic Obstructive PD: Chronic Obstructive Pulmonary Disease. |
Uremia was the only disease in which the median value of TTR concentrations was higher than that in healthy controls. The median values of TTR concentrations in the rest of 47 different diseases were significantly decreased compared to that in the healthy controls (p < 0.001, Table 1). Among the 47 diseases, patients diagnosed with hepatic encephalopathy had the lowest median value of TTR concentrations, followed by patients suffering cirrhosis, sepsis, pancreatitis, pancreatic cancer, liver cancer, preeclampsia, and gastric cancer, respectively. (Table 1).
Receiver operating characteristic curve (ROC) analysis was then performed for all 48 different types of diseases. Based on the ROC analysis (Fig. 1), the area under the curve (AUC), accuracy, sensitivity, and specificity for all diseases were summarized in Fig. 2. Among the 48 diseases, 40 of them had AUCs above 0.60, ranging from 0.60 to 0.97. TTR served as the best biomarker for sepsis with the AUC, sensitivity, specificity of 0.97,0.93, and 0.89, respectively, followed by cirrhosis, pancreatitis, live cancer hepatic encephalopathy based on AUC values (Fig. 2). Interestingly, TTR had the lowest AUCs for all female-related cancers, which included ovarian cancer (0.66), endometrial cancer (0.63), cervical cancer (0.60), and breast cancer (0.59), compared to that in other types of cancers except for kidney cancer. The AUC values were below 0.60 for the following diseases, i.e., uremia, nephrotic syndrome, lupus erythematosus, nephritis, kidney cancer, azotemia, and aplastic anemia. However, all the diseases with lower AUC values were associated with the abnormal shape of the ROC curves, as shown in Fig. 1B and 1C.
We noticed that certain diseases had high specificity (0.90-1.00) but low sensitivity (0.08–0.55) when TTR was served as a biomarker (Fig. 2). Such diseases were kidney-related diseases including diabetic nephropathy, kidney cancer, nephritis, nephrotic syndrome, and azotemia; female-associated cancers including cervical cancer and ovarian cancer; and blood-related cancer and diseases including leukemia, myeloproliferative disorder, and anemia; and autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus. Most of these diseases had either S- or reversed S-shaped ROC curves (Fig. 1B and 1C).
The serum TTR concentration distributions of 48 diseases were plotted to show the relationships between different ROC curves and the AUC values among different diseases (Fig. 3). Our data analysis contained 95% of the data collected during the past five years by excluding 2.5% of the patients with the highest and lowest serum TTR values, respectively, to eliminate potential human and instrumental errors. The lowest value (2.5 percentile), the first quartile (25 percentile), the median quartile (50 percentile), the third quartile (75 percentile), and the maximum value (97.5 percentile) were shown for each of the 48 diseases.
Among all diseases, the serum TTR concentrations in patients suffering hepatic encephalopathy had the lowest median level (50 percentile) and the lowest serum TTR 2.5%, 25%, 75%, and 97.5% values (Fig. 3). The median value of TTR concentrations in patients suffering hepatic encephalopathy was about four times lower than that in the healthy controls (322.3 mg/L vs. 79.6 mg/L), which was followed by a 2-fold decrease in liver cirrhosis (322.3 mg/L vs. 151.3mg/L) and a 2-fold decrease in sepsis (322.3 mg/L vs. 154.8 mg/L), a 1.9-fold decrease in pancreatitis (322.3mg/L vs. 170.6 mg/L) and pancreatic cancer, and 1.7-fold decrease (322.3 mg/L vs. 190.6 mg/L) in liver cancer compared to that in healthy controls (322.3 mg/L). In contrast, all kidney-related diseases had relatively higher median values of TTR concentrations compared to other diseases. Moreover, kidney- and blood-related diseases had the broadest TTR concentration ranges. The above data suggested that the liver, pancreas, kidney, and blood were the major sites that caused up- and down-regulations of circulating TTR concentrations.
TTR concentration distributions in 6 categories of diseases and healthy controls were plotted in Fig. 4. Among the six categories of diseases, liver-related diseases had the lowest, whereas kidney-related diseases had the highest median TTR values. Notably, the two aging-related fetal diseases, cancers and vascular diseases, had lower TTR median values than those in autoimmune and kidney-related diseases. Moreover, blood-, autoimmune-, and kidney-related diseases had one common characteristic: almost doubled lowest to highest TTR concentration ranges compared to that in the healthy controls. Furthermore, the 97.5 percentile TTR values for blood-, autoimmune-, and kidney-related diseases were exceeded that in the healthy controls, which indicated that TTR concentrations were over up-regulated in blood-, autoimmune-, and kidney-related diseases.
We further analyzed six statistical characteristics of serum TTR concentrations, including mean, standard deviation, 2.5, 25, 50, 75, 97.5 percentiles. The 48 diseases were divided into six main categories: cancers, autoimmune diseases, vascular diseases, blood-related diseases, and kidney diseases. The color-coded results of the major component analysis for 48 diseases were shown in Fig. 5.
Indeed, clustering of the same category of diseases was observed. Kidney diseases, i.e., nephritis, diabetic nephropathy, azotemia, nephrotic syndrome, and uremia, were located at the lower-left part of Fig. 5. Cancers and vascular diseases were around the center of Fig. 5. The autoimmune diseases were at the downside of Fig. 5. Interestingly, liver cancer, pancreas cancer, liver- and pancreas-related diseases, and other critical illnesses with the lowest TTR median values were scattered at the far-right side of Fig. 5.