Application of metabolomics to preeclampsia diagnosis

Figures & data

Figure 1. Representative workflow of metabolomics studies. ppm: parts of million (chemical shift in NMR is usually expressed in ppm), RT: retention time, MW: molecular weight, HMDB: human metabolome database, BMRB: biological magnetic resonance bank, KEGG: Kyoto Encyclopedia of Genes and Genomes.

Table 1. Summary of recent metabolomic studies in the field of PE patients.

First author (year) Country	Study population	Mean age ± SD/median age (IQR)/Age range	Gestational age	Biological specimens	Parity	Statistical analysis	Technological platform used	Metabolite identified	Change versus control	Model characteristics
Bahado-Singh et al. (2012) Canada	PC: n = 60 e-PE: n = 30	PC: 31.8 ± 5.8 e-PE: 30.6 ± 6.8	11^+0–13^+6	Plasma	Nullipara (%) PC: 41.4 e-PE: 47.5	PCA/PLS-DA/logistic regression analysis	^1H NMR (NOESY)	Citrate 3-hydroxyisovalerate Glycerol Methionine	Increased Increased Decreased Decreased	Sensitivity: 75.9% Specificity: 95.1% Accuracy: 90.4%
Kenny et al. (2005) United Kingdom	PC: n = 87 PE: n = 87	PC: 19–43 PE: 19–41	PC: 34^+3 –42^+0 PE: 26^+3 –41^+1	Plasma	Nulipara/multipara	Genetic algorithm	GC–TOF–MS	3 unidentified biomarkes	-	Sensitivity: 100% Specificity: 98% Accuracy: NA
Kenny et al. (2008) United Kingdom	PC: n = 20 PE: n = 20	PC: NA PE: NA	PC: 26^+4 –40^+2 PE: 26^+4 –38^+6	Plasma	Nulipara/multipara	Kruskal–Wallis/ANOVA	UPLC–LTQ–Orbitrap–MS	Alanine 2-Hydroxy-3-methyl-butanoic acid 2-Ethyl-3-hydroxypropionic acid 2-Oxoglutaric acid Glutamic acid Xylitol or ribitol Uric acid Creatinine	Increased Increased Increased Increased Increased Increased Increased Increased	Sensitivity: NA Specificity: NA Accuracy: NA ROC curve for each metabolite was calculated
Kenny et al. (2010) United Kingdom	PC: n = 60 PE: n = 60 New Zealand, Auckland	PC: 30.4 ± 4.7 PE: 30.2 ± 4.9	14–16	Plasma	Nuliparus women	PCA/PLS-DA/logistic regression analysis	UPLC–MS	5-Hydroxytryptophan Monosaccharide(s) Decanoylcarnitine Methylglutaric acid/or adipic acid Oleic acid Docosahexaenoic acid/or docosatriynoic Acid γ-Butyrolactone and/or oxolan-3-one 2-Oxovaleric acid/or oxo-methylbutanoic acid Acetoacetic acid Hexadecenoyleicosatetraenoyl-snglycerol Di-(octadecadienoyl)-snglycerol Sphingosine 1-phosphate Sphinganine 1-phosphate Vitamin D3 derivatives	Decreased Increased Increased Decreased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased	Sensitivity: 77% Specificity: 90% Accuracy: 94% (Model based on dicovery set)
	PC: n = 40 PE: n = 39 Australia, Adelaide	PC: 23.2 ± 5.3 PE: 22.0 ± 4.8								Sensitivity: 73% Specificity: 90% Accuracy: 92% (Model based on validation set)
Mukherjee et al. (2014) India	e-PC: n = 20 e-PE: n = 20 l-PC: n = 20 l-PE: n = 20	e-PC: 26.7 ± 4.2 e-PE: 27.8 ± 5.7 l-PC: 27.6 ± 3.9 l-PE: 28.2 ± 1.2	e-PC: 23^+3 –33^+6 e-PE: 26^+3 –31^+6 l-PC: 33^+6 –38^+2 l-PE: 32^+0 –38^+4	Serum	–	HCA/PCA	FTIR spectroscopy, ^1H NMR	e-PE vs. l-PE Glutamate Choline Alanine Lactate Arginine Citrate	Increased Increased Increased Increased Decreased Decreased	Sensitivity: NA Specificity: NA Accuracy: NA
Bahado-Singh et al. (2013) Canada	PC: n = 59 l-PE: n = 30	PC: 31.8 ± 5.8 l-PE: 30.6 ± 6.8	11^+0–13^+6	Serum	–	PCA/PLS-DA	^1H NMR	3 metabolites 14 metabolites	Decreased Increased	Sensitivity: 76.6% Specificity: 100%
Bahado-Singh et al. (2015) Canada	PC: n = 108 e-PE: n = 50	PC: 31.7 ± 5.9 e-PE: 31 ± 7.1	11^+0–13^+6	Serum	Nullipara (%): PC: 41.7 e-PE: 46	PCA/PLS-DA/logistic regression analysis	^1H NMR	2-hydroxybutyrate 3-hydroxyisovalerate Citrate Acetone Glycerol	Increased Increased Increased Decreased Decreased	Sensitivity: 75% Specificity: 74.4% Accuracy: 83.5% (Model based on validation set)
Bahado-Singh et al. (2017b) Canada	PC: n = 115 l-PE: n = 59	PC: 31.3 ± 5.7 l-PE: 30.5 ± 6.0	11^+0–13^+6	Serum	Nullipara (%): PC: 44.4 l-PE: 57.6	PCA/PLS-DA/logistic regression analysis	^1H NMR	Carnitine Pyruvate Acetone BCAAs 2-hydroxybutyric acid Lactic acid Propan-2-ol	Increased Increased Increased Increased Increased Increased Increased	Sensitivity: 30.4% Specificity: 80.4% Accuracy: 62.9% (Model based on carnitine, pyruvate, and acetone in validation set)
Bahado-Singh et al. (2017a) USA	PC: n = 63 PE: n = 35	PC: 32.6 ± 5.8 PE: 32.3 ± 5.5	11^+0–13^+6	Serum	Nullipara (%): PC: 58 PE: 51	PCA/PLS-DA/Logistic regression analysis	^1H NMR, LC–MS/MS	Putrescine * Urea * Carnitine * Glucose PC aa C40:6 Dimethyl sulfone	Decreased Decreased Decreased Increased Increased Decreased	Sensitivity: 72.7% Specificity: 57.4% Accuracy: 70.1% (based on marked metabolites)
			32^+0–33^+6	Serum	Nullipara (%): PC: 58 PE: 51	PCA/PLS-DA/Logistic regression analysis	^1H NMR, LC–MS/MS	Methylhistidine * Serotonin * Citrate * Hexose * Propylene glycol * Hydroxyproline Acetic acid Dimethyl sulfone	Increased Decreased NA NA Increased Decreased Increased Increased	Sensitivity: 74.2% Specificity: 72.3% Accuracy: 76.1% (based on marked metabolites)
Chen et al. (2017) China	PC: n = 20 PE: n = 20	PC: 29–38 PE: 23–38	PC: 18^+4 –27^+3 PE: 21^+5 –27^+6	Serum	–	PCA/OPLS-DA	LC–Q–TOF–MS	PC(14:0/00) Proline proline Betaine	Increased Decreased Decreased	Accuracy for PC: 94% Accuracy for proline: 92.8% Accuracy for proline betaine: 93%
Koster et al. (2015) Netherlands	PC: n = 500 e-PE: n = 68	PC: 30–35 e-PE: 30–37	8^+0–13^+6	Serum	Nullipara (%): PC: 46.6 e-PE: 80.9	Student’s t-test/logistic regression analysis	UPLC–MS/MS	Hexanoylcarnitine Octenoylcarnitine Octanoylcarnitine Decenoylcarnitine Decanoylcarnitine Dodecenoylcarnitine Tetradecenoylcarnitine Linoleylcarnitine Stearoylcarnitine Isobutyrylcarnitine Lauroylcarnitine Hexadecenoylcarnitine	Increased Increased Increased Increased Increased Increased Increased Decreased Decreased Decreased Increased Increased	Sensitivity: 69% Specificity: 90% Accuracy: 78.4% Model based on: (Prior risk + PAPPA +PlGF +Stearoylcarnitine in validation set)
	PC: n = 500 l-PE: n = 99	PC: 30–35 l-PE: 30–36	8^+0–13^+6	Serum	Nullipara (%): PC: 46.6 l-PE: 72.7	Student’s t-test/logistic regression analysis	UPLC–MS/MS	Hexanoylcarnitine Octenoylcarnitine Octanoylcarnitine Decenoylcarnitine Decanoylcarnitine Dodecenoylcarnitine Tetradecenoylcarnitine Linoleylcarnitine Stearoylcarnitine Palmitoylcarnitine Oleylcarnitine	Increased Increased Increased Increased Increased Increased Increased Decreased Decreased Decreased Decreased	Sensitivity: 32% Specificity: 90% Accuracy: 70% Model based on: (Prior risk +MAP + PAPPA +PlGF +Stearoylcarnitine in validation set) Other acylcarnitines had lower accuracy and sensitivity
Kuc et al. (2014) Netherlands	PC: n = 500 e-PE: n = 68	PC: 30–35 e-PE: 30–37	8^+0–13^+6	Serum	Nullipara (%): PC: 46.6 e-PE: 80.9	Student’s t-test/logistic regression analysis	UPLC–MS/MS	Taurine Asparagine	Decreased Decreased	Sensitivity: 88% Specificity: 90 Accuracy: 93% Model based on: (Prior risk +MAP + Taurine in test set)
	PC: n = 500 l-PE: n = 99	PC: 30–35 l-PE: 30–36	8^+0–13^+6	Serum	Nullipara (%): PC: 46.6 l-PE: 72.7	Student’s t-test/logistic regression analysis	UPLC–MS/MS	Glycylglycine	Decreased	Sensitivity: 46 Specificity: 90 Accuracy: 79% Model based on: (Prior risk +MAP in test set)
Odibo et al. (2011) USA	PC: n = 41 PE: n = 41	PC: 32.9 ± 5.5 PE: 30.5 ± 6.2	11–14	Serum	Nullipara (%): PC: 29.3 PE: 48.8	Univariate analysis/logistic regression analysis	LC–MS/MS	Hydroxyhexanoylcarnitine Phenylalanine Glutamate Alanine	Increased Increased Increased Increased	Sensitivity: 50 Specificity: 80% Accuracy: 82.3%
Senyavina et al. (2013) Russia.	PC: n = 25 PE: n = 6	29.2 ± 3.9	34–35	Serum	–	Univariate analysis	reverse phase HPLC	Hypoxanthine Xanthine uric acid	Decreased Increased Increased	Sensitivity: NA Specificity: NA Accuracy: NA
Austdal M. (2015a) Norwey	PC (n = 552) GH (n = 21) PE (n = 26)	PC: 28 (5) GH: 28 (6) PE: 26 (7)	11^+0–13^+6	Serum	Nulipara/multipara	PCA/PLS-DA	^1H NMR (CPMG)	Triglycerides 3-hydroxybutyrate Pyruvate Lactate Phosphatidylcholine	Increased Increased Decreased Decreased Decreased	Sensitivity: 63.8% Specificity: 65.4% Accuracy: 64.6%
				Urine	Nulipara/multipara	PCA/PLS-DA	^1H NMR (CPMG)	Creatinine Glycine 4-deoxythreonic acid α-hydroxyisobutyrate Histidine Dimethylamine Hippurate Lactate/Threonine Proline betaine	Increased Increased Increased Increased Increased Increased Decreased Decreased Decreased	Sensitivity: 67.5% Specificity: 74.2% Accuracy: 70.8%
Austdal et al. (2014) Norwey	NP (n = 10) PC (n = 10) PE (n = 10)	NP: 24–39 PC: 28–39 PE: 22–39	PC: 21^+5 –37^+6 PE: 18^+4 –37^+3	Serum	–	PCA/PLS-DA	^1H NMR (CPMG)	Histidine VLDL LDL HDL	Decreased Increased Increased Decreased	Sensitivity: 90% Specificity: 100% Accuracy: 95%
				Urine	–	PCA/PLS-DA	^1H NMR (NOESY)	Glycine p-Cresol Sulfate Hippurate Histidine Asparagine Isobutyrate Dimethylamine Trigonelline Glucose	Increased Increased Increased Increased Increased Decreased Decreased Increased Increased	Sensitivity: 80% Specificity: 100% Accuracy: 90%
Diaz et al. (2013) Portugal	PC: n = 84 PE: n = 9	PC: 21–42 PE: 24–41	PC: 15–26 PE: 16–17	Urine	–	PCA/PLS-DA	^1H NMR, 2D NMR (TOCSY, HSQC, J-resolved)	Acetate Formate Fumarate succinate, 2-Oxoglutarate Isoleucine	Decreased Decreased Decreased Decreased Decreased Decreased	Sensitivity: 75% Specificity: 94% Accuracy: 94%
Austdal M. (2015b) Norwey	PC: n = 15 PE: n = 19	PC: 34 (5) PE: 28 (9)	PC: 38^+2 –40^+0 PE: 25^+4 –39^+1	Placenta	Primipara, (%) PC: 13.3 PE: 47.4	PCA/PLS-DA	HR-MAS MRS	Glycerophosphocholine Phosphocholine Aspartate Ethanolamine Glutamate Glycine Taurine Ascorbate	Increased Increased Increased Decreased Decreased Decreased Decreased Decreased	Sensitivity: 87% Specificity: 98.4% Accuracy: 92.7%
Dunn et al. (2012) UK	PC: n = 11 PE: n = 6	PC: 27–35 PE: 30–39	PC: 37^+6 –41^+0 PE: 35^+2 –39^+3	Placenta	–	PCA/Univariate analysis	GC–TOF–MS, UPLC–LTQ-MS	422 metabolites	The most of them decreased in PE	Sensitivity: NA Specificity: NA Accuracy: NA
Zhou et al. (2017) China	PC: n = 11 PE: n = 11	PC: 31.0 ± 4.3 PE: 30.0 ± 3.9	PC: 37^+1 –38^+2 PE: 35^+5 –38^+3	Placenta (mitochondria)	–	PLS-DA	GC–MS	γ-linoleate * Bihomo-γ-lineolate * Arachidonate * Docosapentaenoate * Myristate * 2-phosphoenolpyruvate Β-citrylglutamate Threonine Glutamine Aspargine Oxalate	Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased	Sensitivity>80% Specificity> 80% Accuracy> 90% (based on marked metabolites)
Jain et al. (2004) Ohio	PC: n = 5 PE: n = 3	–	After delivery	Placenta	–	–	ESI-MS	Fatty acids (mainly arachidonate) Plasmenyl phosphatidylethanolamine	Increased Decreased	Sensitivity: NA Specificity: NA Accuracy: NA

PC: pregnant control; NP: non-pregnant control; GH: gestational hypertension; PE: preeclampsia; e-PE: early onset PE; l-PE: late onset PE; PCA: principal component analysis; PLS-DA: partial least squares-discriminant analysis; ANOVA: analysis of variance; ¹H NMR: proton nuclear magnetic resonance spectroscopy; NOESY: The nuclear overhauser effect spectroscopy; CPMG: The Carr–Purcell–Meiboom–Gill sequence; HR-MAS MRS: high-resolution magic angle spinning magnetic resonance spectroscopy; LC–HRMS: liquid chromatography coupled with accurate mass high-resolution mass-spectrometry; UPLC–MS: ultra performance liquid chromatography-mass spectrometer; UPLC–QTOF–MS: ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry; GC–MS: gas chromatography-mass spectrometer; BCAAs: branch chain amino acids; phosphatidylcholine: PC; Fourier transform infrared (FTIR) spectroscopy; hierarchical cluster analysis (HCA); total correlation spectroscopy, TOCSY; heteronuclear single quantum coherence, HSQC; ESI-MS: electrospray ionization mass spectrometry; NA: not available.

Figure 2. Flowchart illustrating selection of articles included in the review.

Bahado-Singh RO, Akolekar R, Mandal R, Dong E, Xia J, Kruger M, Wishart DS, Nicolaides K. 2012. Metabolomics and first-trimester prediction of early-onset preeclampsia. J Matern Fetal Neonatal Med. 25(10):1840–1847. eng.

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