Research Article

Novel Biomarker Candidates for Febrile Neutropenia in Hematological Patients Using Nontargeted Metabolomics

Table 1

Characteristics for the tentatively identified differential compounds in liquid chromatography-mass spectrometry analysis.

ColumnESIMWRT (min)Tentative identificationIDIdentification based on MS/MSANOVAGroupwise t-test Corrected valueGroupwise t-test noncorrected value
D0D1Fold change
Corrected valueD0D1D0D1D0D1VIP D0VIP D1

RP370.18158.957ADTS or DHTSMID355920ev: 369.1746 [M−H]−; 369.1747 (100), 96.9591 (27), 370.1794 (7), 209.6079 (7)1.08E − 078.49E − 116.80E − 040.0308645.33E − 071.94E − 04−2.37−1.932.651.74
HILIC+175.09546.357CitrullineMID16Verified with standard 10ev: 176.1043 [M+H]+; 159.0762 (100), 70.0653 (68), 113.0692 (46), 176.1043 (15)1.17E − 041.05E − 060.778890.0421030.0252012.02E − 041.3271.5721.671.69
RP767.546512.93PE(18:0/20:4)LMGP020120ev: 766.5635 [M−H]−; 766.5635 (100), 303.2348 (39), 767.5412 (34), 283.2612 (13), 59.0151 (7), 10ev: 768.5594 [M+H]+; 768.5635 (100), 627.5359 (32)1.43E − 062.25E − 090.246440.0161580.0021574.34E − 05−1.42−1.631.711.98
RP837.552511.98PC(15:0/22:6) [M+FA]LMGP010140ev: 836.546 [M+FA−H]−; 327.2326 (100), 241.2187 (42), 283.242 (39), 776.5189 (29), 168.0414 (27), 20ev: 792.5457 [M+H]+; 184.0729 (100), 792.5537 (81), 86.0693 (3)0.0074212.95E − 040.3255650.1992280.0039480.0167881.2251.2091.561.56
RP827.569712.3PC(16:0/20:4) [M+FA]LMGP010120ev: 826.5624 [M+FA−H]−; 766.5390 (100), 767.5404 (34), 826.5603 (25)0.0074213.00E − 040.3664740.1805370.0103390.007452−1.09−1.091.581.58
HILIC+763.51730.706PE(16:0/22:6)LMGP020120ev: 762.5062 [M−H]−; 327.2371 (100), 762.5071 (72), 344.5837 (55), 255.2369 (38), 764.5264 [M+H]+; 764.5264 (100), 623.4989 (50)0.0247210.0025180.6637230.1420260.0035720.007017−1.49−1.442.181.42
RP+805.563712.22PC(16:0/22:6)LMGP010120ev: 806.5696 [M+H]+; 184.0729 (100), 806.5701 (86), 524.3132 (5), 20ev: 850.5625 [M+FA−H]−; 93 (100), 850.5600 (39), 791.5447 (39), 327.2323 (18), 44.9986 (14), 851.5603 (13), 255.2322 (6)0.0278080.0010260.5990270.1876220.1163530.0043071.0991.1631.371.71
HILIC+809.59350.632PC(18:0/20:4)LMGP010120ev: 854.588 [M+FA−H]−; 794.5697 (100), 854.5934 (29), 795.5785 (21), 303.2318 (11), 283.26 (7); 10ev: 810.6012 [M+H]+; 810.6045 (100), 184.073 (17)0.096760.0285410.7849220.5047510.0479110.210616−1.1−1.061.590.99
HILIC+523.36351.08LysoPC(0:0/18:0)LMGP010540ev: 568.3607 [M+FA−H]−; 508.3418 (100), 283.2632 (30), 224.0657 (10), 44.9993 (9), 20ev: 524.3706 [M+H]+; 184.0731 (100), 524.3689 (10)0.0479610.0088560.842610.1464630.2792080.0148671.1371.3541.481.60
HILIC+521.34821.091LysoPC(0:0/18:1)LMGP010520ev: 522.3570 [M+H]+; 184.0738 (100), 522.3606 (7), 86.0964 (3)0.0403350.0058350.842610.158210.2301920.0174521.1571.3551.471.66
HILIC+495.3341.15LysoPC(0:0/16:0)LMGP010520ev: 540.3303 [M+FA−H]−; 255.2323 (100), 480.3042 (62), 242.0762 (7); 20ev: 496.3492 [M + H]+; 184.0764 (100), 496.3477 (5), 86.0974 (2)0.0470310.0078950.8870950.1420260.4360410.011111.0851.3181.471.52
HILIC+523.36531.2LysoPC(18:0/0:0)LMGP010500260.0375080.0052170.842610.1420260.2894540.0089291.1291.3651.421.54
HILIC+521.35021.215LysoPC(18:1/0:0)LMGP010540ev: 566.345 [M+FA−H]−; 281.2481 (100), 224.0735 (14), 44.999 (9)0.0247210.0027430.842610.1464630.246120.0143911.1591.3921.341.54
HILIC+519.33471.227LysoPC(18:2/0:0)LMGP010520ev: 520.3400 [M+H]+; 184.0733 (100), 520.339 (10), 104.1067 (2), 86.095 (2), 20ev: 564.3326 [M+FA−H]−; 504.3113 (100), 279.2337 (68), 44.9995 (10)0.0091864.33E − 040.8870950.1420260.453120.0069731.0931.451.291.50
HILIC+495.33451.284LysoPC(16:0/0:0)LMGP010500180.1030870.0311160.9097640.1850130.6097420.025291.0551.2761.481.59
HILIC222.021.302Unknown10ev: 221.0126; 221.012 (100), 148.9898 (35), 130.9797 (12), 94.9242 (5), 92.9242 (3)0.0161069.59E − 040.5853290.333960.0138590.057424−1.16−1.131.641.14
RP+231.14662.065Butyryl-L-carnitineMID964Verified with standard. 10ev: 232.1545 [M+H]+; 232.1549 (100), 85.0276 (95), 173.0738 (16), 60.0784 (3)0.496390.2187450.464690.7825170.0472310.482634−1.39−1.141.570.81
RP173.99872.408Unknown20ev: 172.9929 [M−H]−?; 93.0348 (100), 34.9705 (6)0.4046750.1166030.8614340.2732290.5947680.030835−1.19−2.011.361.82
RP+250.17855.666Unknown10ev: 251.1860; 59.05 (100), 117.0906 (19), 41.0397 (7), 251.1881 (6)0.0091471.34E − 040.8242110.2169780.3806350.008023−1.021.270.861.55
HILIC+155.06956.772L-HistidineMID21Verified with standard 10ev: 156.0765 [M+H]+; 110.0712 (100), 156.0758 (30), 95.0609 (11), 83.0602 (5)0.0168220.0013020.6700330.8263550.0080340.6146351.2071.0351.760.86
RP396.19738.611Pregnenolone sulfateMID574020ev: 395.1903 [M−H]−; 395.1903 (100), 96.9607 (23), 248.8949 (7), 305.7866 (6)0.0827240.0108270.3840930.3987820.0150510.079233−1.5−1.381.711.12
RP+567.333310.12LysoPC(22:6/0:0) (RP a)LMGP010520ev: 612.3301 [M+FA−H]−; 552.3112 (100), 327.2352 (25), 283.243 (8), 44.9985 (4), 20ev: 568.3392 [M+H]+; 104.1063 (100), 184.0726 (98), 568.3392 (86), 86.096 (14)0.0089331.03E − 040.4572690.1056660.0414135.08E − 041.2911.4981.231.51
RP+505.413311.69Unknown10ev: 506.4203; 60.0816 (100), 61.083 (4)0.1593820.0291540.3144580.7997410.011880.5058121.3071.0711.790.87
RP849.552611.87PC(16:1/22:6) [M+FA]LMGP010140ev: 848.5490 [M+FA−H]−; 327.2322 (100), 253.2164 (52), 283.2444 (49), 478.2944 (31), 44.9987 (30), 20ev: 804.5531 [M+H]+; 184.0718 (100), 804.5512 (67)0.033110.0026480.3664740.3095250.0086460.0417231.3091.2351.561.32
RP801.553312.02PC(16:1/18:2) [M+FA]LMGP010120ev: 756.5562 [M+H]+; 184.0737 (100), 756.5533 (78), 20ev: 800.5511 [M+FA−H]−; 740.5234 (100), 800.545 (53), 279.2312 (15), 253.2161 (11), 44.9988 (6)0.0353140.0029090.3727590.3127870.012270.043172−1.5−1.441.761.19
RP+415.357212.15Unknown10ev: 416.3633; 416.3617 (100), 164.1129 (4), 191.1039 (3)0.0672830.0060090.5136590.3338930.0706420.049803−1.2−1.21.331.60
RP+831.578112.33PC(18:1/22:6)LMGP010120ev: 832.5857 [M+H]+; 184.0738 (100), 832.585 (97), 40ev: 876.5774 [M+FA−H]−; 327.2333 (100), 281.2478 (67), 283.243 (32), 816.5537 (18), 44.9985 (18)0.0091471.40E − 040.5348830.1056660.079693.23E − 041.1631.3331.441.66
RP+771.577512.58Unknown PC20ev: 772.5868 [M+H]+; 772.587 (100), 184.0736 (94), 86.0975 (5), double peak, no MS/MS from the first one0.3566620.113370.3144580.8489460.0119440.591385−1.241.0461.980.98
RP+759.578412.8PC(16:0/18:1)LMGP010120ev: 804.5795 [M+FA−H]−; 745.5581 (28), 804.5754 (26), 281.2484 (14), 255.2315 (6), 44.9982 (3), 20ev: 760.5859 [M+H]+; 184.0732 (100), 760.5862 (82)0.0156024.25E − 040.2980090.5965210.0084910.213038−1.15−1.061.581.24
RP+833.594312.81PC(18:0/22:6)LMGP010120ev:834.6028 [M+H]+; 834.5985 (100), 184.0727 (91), 86.0979 (2), 40ev: 878.5934 [M+FA−H]; 327.2332 (100), 283.2625 (48), 283.2436 (36), 818.5716 (20), 508.3402 (20), 44.9983 (10)0.0455890.0028760.6538250.2169780.1659910.0073181.1251.2511.231.51
RP+837.624513.57Unknown PC20ev: 838.6312 [M+H]+; 838.6324 (100), 184.0728 (56), 185.0744 (6)0.0770380.0076880.2859430.6609690.0075430.291104−1.42−1.131.571.11
RP+787.608713.61PC(18:0/18:1)LMGP010120ev: 788.6156 [M+H]+; 184.0728 (100), 788.6134 (100), 84.0787 (2); 40ev:832.6118 [M+FA−H]−; 281.2489 (100), 283.2635 (46), 772.5866 (14), 44.9979 (11)0.0916920.0106570.3018150.8393440.0089490.568381−1.32−1.061.600.84

The characteristics include both uncorrected and FDR- (Benjamini-Hochberg false discovery rate-) corrected values on d0 and d1, fold changes, variable influence on projection (VIP) values, and identification references, together with parameters for the LC-MS analysis, including chromatography (column), ionization mode in mass spectrometry (Ioni), molecular weight (MW), retention time (RT), and fragment ions in tandem mass spectrometry (MS/MS fragments). (20 patients with complicated course of febrile neutropenia (complicated) and 65 patients without complicated course of febrile neutropenia (noncomplicated). ADTS: androsterone sulfate; DHTS: dihydrotestosterone sulfate; PC: phosphatidylcholine; PE: phosphatidylethanolamine; LysoPC: lysophosphatidylcholine. ANOVA (analysis of variance) and groupwise t-test (unpaired t-test) comparing the fold changes between complicated versus noncomplicated patients. values < 0.05. Fold changes = average fold changes when comparing complicated group against noncomplicated group, with values. Fold changes ≥ ± 1.2 were considered significant. Positive values indicate increased plasma levels in complicated versus noncomplicated patients, whereas negative values indicate decreased plasma levels in complicated versus noncomplicated patients. ID identification of metabolites is based on references: MID refers to METLIN database https://metlin.scripps.edu/index.php, LMGP refers to LIPID MAPS database http://lipidmaps.org/data/structure/index.html, and HMDB refers to Human Metabolome Database http://www.hmdb.ca/.