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Case finding of early pregnancies at risk of preeclampsia using maternal blood leptin/ceramide ratio: multi-omics discovery and validation from a longitudinal study
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  • Qianyang Huang,
  • Shiying Hao,
  • Jin You,
  • Xiaoming Yao,
  • Zhen Li,
  • James Schilling,
  • Zhen Li,
  • Sheeno Thyparambil,
  • Wei-Li Liao,
  • Xin Zhou,
  • Lihong Mo,
  • Subhashini Ladella,
  • David Fan,
  • John Whitin,
  • Harvey Cohen,
  • Doff McElhinney,
  • Ronald Wong,
  • Gary Shaw,
  • David Stevenson,
  • Karl Sylvester,
  • Xuefeng Ling
Qianyang Huang
mProbe, Inc.
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Shiying Hao
Stanford University School of Medicine
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Jin You
University of California Riverside
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Xiaoming Yao
mProbe, Inc.
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Zhen Li
Stanford University School of Medicine
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James Schilling
mProbe, Inc.
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Zhen Li
Southeast University
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Sheeno Thyparambil
mProbe, Inc.
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Wei-Li Liao
mProbe, Inc.
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Xin Zhou
Pingjin Hospital Heart Center
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Lihong Mo
University of California San Francisco Fresno Center for Medical Education and Research
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Subhashini Ladella
University of California San Francisco Fresno Center for Medical Education and Research
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David Fan
University of California Santa Barbara
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John Whitin
Stanford University School of Medicine
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Harvey Cohen
Stanford University School of Medicine
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Doff McElhinney
Stanford University School of Medicine
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Ronald Wong
Stanford University School of Medicine
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Gary Shaw
Stanford University School of Medicine
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David Stevenson
Lucile Salter Packard Children's Hospital at Stanford
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Karl Sylvester
Stanford University School of Medicine
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Xuefeng Ling
Stanford University School of Medicine
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Abstract

Objective To evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation. Design Retrospective multi-omics discovery and longitudinal validation. Setting Maternity units in two US hospitals. Methods A multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent and liquid chromatography-tandem mass spectrometric assays. Main outcome measures Interval from positive prediction to confirmative diagnosis. Results Genomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation. Conclusions Non-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test. Tweetable abstract Non-invasive longitudinal assessment by serological evaluation of Lep and Cer ratio can predict preeclampsia early in gestation.