title: Development and validation of a spontaneous preterm delivery predictor in asymptomatic women.
abstract: BACKGROUND
  Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries.
  
  
  OBJECTIVE
  To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women.
  
  
  METHODS
  A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed.
  
  
  RESULTS
  The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects.
  
  
  CONCLUSIONS
  A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.
authors.affiliation: Department of Obstetrics & Gynecology, The University of Texas Medical Branch, Galveston, Texas. Electronic address: gsaade@utmb.edu.
authors.forename: George R
authors.initials: GR
authors.lastname: Saade
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Boggess
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Sullivan
authors.affiliation: Maternal Fetal Medicine, Baystate Medical Center, Springfield, Massachusetts.
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Markenson
authors.affiliation: Department of Obstetrics & Gynecology, The Ohio State University, Columbus, Ohio.
authors.forename: Jay D
authors.initials: JD
authors.lastname: Iams
authors.affiliation: Department of Obstetrics and Gynecology, Maricopa Integrated Health System/District Medical Group, Phoenix, Arizona.
authors.forename: Dean V
authors.initials: DV
authors.lastname: Coonrod
authors.affiliation: Division of Maternal-Fetal Medicine, Oregon Health & Science University, Portland, Oregon.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Pereira
authors.affiliation: Division of Maternal Fetal Medicine, Intermountain Healthcare, Murray, Utah.
authors.forename: M Sean
authors.initials: MS
authors.lastname: Esplin
authors.affiliation: San Diego Perinatal Center, Maternal Fetal Medicine Division, Rady Children's Specialists of San Diego, San Diego, California.
authors.forename: Larry M
authors.initials: LM
authors.lastname: Cousins
authors.affiliation: Regional Obstetrical Consultants, Chattanooga, Tennessee.
authors.forename: Garrett K
authors.initials: GK
authors.lastname: Lam
authors.affiliation: Department of Obstetrics & Gynecology, Christiana Care Health System, Newark, Delaware.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Hoffman
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Severinsen
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Trina
authors.initials: T
authors.lastname: Pugmire
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Flick
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Fox
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Amir J
authors.initials: AJ
authors.lastname: Lueth
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Rust
authors.affiliation: Dana Farber Cancer Institute, Department of Biostatistics and Computational Biology, Boston, Massachusetts.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Mazzola
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: ChienTing
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Max T
authors.initials: MT
authors.lastname: Dufford
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Chad L
authors.initials: CL
authors.lastname: Bradford
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Ilia E
authors.initials: IE
authors.lastname: Ichetovkin
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Tracey C
authors.initials: TC
authors.lastname: Fleischer
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Ashoka D
authors.initials: AD
authors.lastname: Polpitiya
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Critchfield
authors.affiliation: Integrated Diagnostics, Inc, Seattle, Washington.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Kearney
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: J Jay
authors.initials: JJ
authors.lastname: Boniface
authors.affiliation: Sera Prognostics, Inc, Salt Lake City, Utah.
authors.forename: Durlin E
authors.initials: DE
authors.lastname: Hickok
mesh_terms: D015415:Biomarkers / Q000097:blood; D005260:Female; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000097:blood*; D013058:Mass Spectrometry; D011247:Pregnancy; D011262:Pregnancy Trimester, Second / Q000097:blood; D047928:Premature Birth / Q000097:blood*; D011446:Prospective Studies; D012372:ROC Curve; D012680:Sensitivity and Specificity; D012738:Sex Hormone-Binding Globulin / Q000032:analysis*
chemical_list: D015415:Biomarkers; D018974:Insulin-Like Growth Factor Binding Protein 4; D012738:Sex Hormone-Binding Globulin
keywords: IBP4; IGFBP4; SHBG; biomarker; pregnancy; preterm birth; proteomics