title: Extending the scope of pooled analyses of individual patient biomarker data from heterogeneous laboratory platforms and cohorts using merging algorithms.
abstract: BACKGROUND
  A common challenge in medicine, exemplified in the analysis of biomarker data, is that large studies are needed for sufficient statistical power. Often, this may only be achievable by aggregating multiple cohorts. However, different studies may use disparate platforms for laboratory analysis, which can hinder merging.
  
  
  METHODS
  Using circulating placental growth factor (PlGF), a potential biomarker for hypertensive disorders of pregnancy (HDP) such as preeclampsia, as an example, we investigated how such issues can be overcome by inter-platform standardization and merging algorithms. We studied 16,462 pregnancies from 22 study cohorts. PlGF measurements (gestational age ⩾20 weeks) analyzed on one of four platforms: R&D Systems, AlereTriage, RocheElecsys or AbbottArchitect, were available for 13,429 women. Two merging algorithms, using Z-Score and Multiple of Median transformations, were applied.
  
  
  RESULTS
  Best reference curves (BRC), based on merged, transformed PlGF measurements in uncomplicated pregnancy across six gestational age groups, were estimated. Identification of HDP by these PlGF-BRCs was compared to that of platform-specific curves.
  
  
  CONCLUSIONS
  We demonstrate the feasibility of merging PlGF concentrations from different analytical platforms. Overall BRC identification of HDP performed at least as well as platform-specific curves. Our method can be extended to any set of biomarkers obtained from different laboratory platforms in any field. Merged biomarker data from multiple studies will improve statistical power and enlarge our understanding of the pathophysiology and management of medical syndromes.
authors.affiliation: Nuffield Department of Population Health, University of Oxford, Oxford, UK. Electronic address: orlaith.burke@ndph.ox.ac.uk.
authors.forename: Órlaith
authors.initials: Ó
authors.lastname: Burke
authors.affiliation: Department of Obstetrics and Gynaecology and Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Benton
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
authors.forename: Pawel
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Obstetrics and Gynaecology and Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: von Dadelszen
authors.affiliation: Yale University, New Haven, CT, USA.
authors.forename: S Catalin
authors.initials: SC
authors.lastname: Buhimschi
authors.affiliation: University of Milan, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Cetin
authors.affiliation: Women's Health Academic Centre, King's College London, London, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Chappell
authors.affiliation: Hospital Clinic, University of Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Figueras
authors.affiliation: Fetal Medicine Unit, Dept of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre and Universidad Complutense, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Galindo
authors.affiliation: Fetal Medicine Unit, Dept of Obstetrics and Gynecology, Hospital Universitario 12 de Octubre and Universidad Complutense, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Herraiz
authors.affiliation: Michigan State University, East Lansing, MI, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Holzman
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Hubel
authors.affiliation: Dept. of Obstetrics and Gynecology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Knudsen
authors.affiliation: Dept. of Oncology, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Kronborg
authors.affiliation: Medical Genetics, Obstetrics and Gynaecology and Institute for Molecular Medicine Finland, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
authors.affiliation: University of Basel, Basel, Switzerland.
authors.forename: Olav
authors.initials: O
authors.lastname: Lapaire
authors.affiliation: Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: McElrath
authors.affiliation: Interdisciplinary Centre for Gynecology, Gyneco-oncology and Feto-Maternal Medicine, Klagenfurt & Medical University, Graz, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Moertl
authors.affiliation: Maternal and Fetal Health Research Centre, St. Mary's Hospital and University of Manchester, Manchester, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Myers
authors.affiliation: University of Texas, School of Public Health, Houston, TX, USA.
authors.forename: Roberta B
authors.initials: RB
authors.lastname: Ness
authors.affiliation: Obstetrics Department, Universidade Estadual Paulista, Botucatu, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Oliveira
authors.affiliation: University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Gayle
authors.initials: G
authors.lastname: Olson
authors.affiliation: Women's Health Academic Centre, King's College London, London, UK.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Poston
authors.affiliation: Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carrie
authors.initials: C
authors.lastname: Ris-Stalpers
authors.affiliation: Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Roberts
authors.affiliation: Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Schalekamp-Timmermans
authors.affiliation: University of Jena, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schlembach
authors.affiliation: Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Steegers
authors.affiliation: University of Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stepan
authors.affiliation: Université Paris Descartes, Paris, France.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Tsatsaris
authors.affiliation: Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: van der Post
authors.affiliation: Charité University Medicine, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Verlohren
authors.affiliation: Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Pia M
authors.initials: PM
authors.lastname: Villa
authors.affiliation: Institute for Women's Health, NIHR University College London Hospitals Biomedical Research Centre, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Obstetrics and Gynecology, Medical University Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Zeisler
authors.affiliation: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
authors.forename: Christopher W G
authors.initials: CW
authors.lastname: Redman
authors.affiliation: Department of Obstetrics and Gynecology, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Anne Cathrine
authors.initials: AC
authors.lastname: Staff
mesh_terms: D000465:Algorithms; D015415:Biomarkers / Q000097:blood; D001774:Blood Chemical Analysis / Q000592:standards*; D002138:Calibration; D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods*; D016208:Databases, Factual; D005240:Feasibility Studies; D005260:Female; D005865:Gestational Age; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000097:blood* / Q000175:diagnosis; D015588:Observer Variation; D000072483:Placenta Growth Factor / Q000097:blood*; D011237:Predictive Value of Tests; D011247:Pregnancy; D012016:Reference Values; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers; C000608036:PGF protein, human; D000072483:Placenta Growth Factor
keywords: Best reference curve; Biomarker data; Individual patient data; Merging algorithms; Pooled analysis; Pre-eclampsia