title: Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms.
abstract: OBJECTIVE
  We sought to use an innovative tool that is based on common biologic pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB) to enhance investigators' ability to identify and to highlight common mechanisms and underlying genetic factors that are responsible for SPTB.
  
  
  METHODS
  We performed a secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB ≤34.0 weeks' gestation. Each woman was assessed for the presence of underlying SPTB causes. A hierarchic cluster analysis was used to identify groups of women with homogeneous phenotypic profiles. One of the phenotypic clusters was selected for candidate gene association analysis with the use of VEGAS software.
  
  
  RESULTS
  One thousand twenty-eight women with SPTB were assigned phenotypes. Hierarchic clustering of the phenotypes revealed 5 major clusters. Cluster 1 (n = 445) was characterized by maternal stress; cluster 2 (n = 294) was characterized by premature membrane rupture; cluster 3 (n = 120) was characterized by familial factors, and cluster 4 (n = 63) was characterized by maternal comorbidities. Cluster 5 (n = 106) was multifactorial and characterized by infection (INF), decidual hemorrhage (DH), and placental dysfunction (PD). These 3 phenotypes were correlated highly by χ(2) analysis (PD and DH, P < 2.2e-6; PD and INF, P = 6.2e-10; INF and DH, (P = .0036). Gene-based testing identified the INS (insulin) gene as significantly associated with cluster 3 of SPTB.
  
  
  CONCLUSIONS
  We identified 5 major clusters of SPTB based on a phenotype tool and hierarch clustering. There was significant correlation between several of the phenotypes. The INS gene was associated with familial factors that were underlying SPTB.
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, and Department of Maternal-Fetal Medicine, Intermountain Healthcare, Salt Lake City, UT. Electronic address: sean.esplin@imail.org.
authors.forename: M Sean
authors.initials: MS
authors.lastname: Esplin
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, and Department of Maternal-Fetal Medicine, Intermountain Healthcare, Salt Lake City, UT.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Manuck
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Utah School of Medicine, and Department of Maternal-Fetal Medicine, Intermountain Healthcare, Salt Lake City, UT.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Varner
authors.affiliation: Golden Helix, Bozeman, MT.
authors.forename: Bryce
authors.initials: B
authors.lastname: Christensen
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham School of Medicine, Birmingham, AL.
authors.forename: Joseph
authors.initials: J
authors.lastname: Biggio
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: Radek
authors.initials: R
authors.lastname: Bukowski
authors.affiliation: Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Parry
authors.affiliation: Department of Biostatistics, Yale University School of Public Health, New Haven, CT.
authors.forename: Heping
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, Yale University School of Public Health, New Haven, CT.
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham School of Medicine, Birmingham, AL.
authors.forename: William
authors.initials: W
authors.lastname: Andrews
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
authors.forename: George
authors.initials: G
authors.lastname: Saade
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Yoel
authors.initials: Y
authors.lastname: Sadovsky
authors.affiliation: Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Reddy
authors.affiliation: Pregnancy and Perinatology Branch, Center for Developmental Biology and Perinatal Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
authors.forename: John
authors.initials: J
authors.lastname: Ilekis
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics; D016015:Logistic Models; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth / Q000209:etiology* / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D005819:Genetic Markers; D007328:Insulin
keywords: cluster analysis; gene-based analysis; phenotype; spontaneous preterm birth