title: Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth.
abstract: BACKGROUND
  It is of critical importance to evaluate the role of environmental chemical exposures in premature birth. While a number of studies investigate this relationship, most utilize single exposure measurements during pregnancy in association with the outcome. The studies with repeated measures of exposure during pregnancy employ primarily cross-sectional analyses that may not be fully leveraging the power and additional information that the data provide.
  
  
  METHODS
  We examine 9 statistical methods that may be utilized to estimate the relationship between a longitudinal exposure and a binary, non-time-varying outcome. To exemplify these methods we utilized data from a nested case-control study examining repeated measures of urinary phthalate metabolites during pregnancy in association with preterm birth.
  
  
  RESULTS
  The methods summarized may be useful for: 1) Examining sensitive windows of exposure in association with an outcome; 2) Summarizing repeated measures to estimate the relationship between average exposure and an outcome; 3) Identifying acute exposures that may be relevant to the outcome; and 4) Understanding the contribution of temporal patterns in exposure levels to the outcome of interest. In the study of phthalates, changes in urinary metabolites over pregnancy did not appear to contribute significantly to preterm birth, making summary of average exposure across gestation optimal given the current design.
  
  
  CONCLUSIONS
  The methods exemplified may be of great use in future epidemiologic research projects intended to: 1) Elucidate the complex relationships between environmental chemical exposures and preterm birth; 2) Investigate biological mechanisms in prematurity using repeated measures of maternal factors throughout pregnancy; and 3) More generally, address the relationship between a longitudinal predictor and a binary, non-time-varying outcome.
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Ferguson
authors.affiliation: Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Meeker
authors.affiliation: Division of Maternal-Fetal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: McElrath
authors.affiliation: Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA. bhramar@umich.edu.
authors.forename: Bhramar
authors.initials: B
authors.lastname: Mukherjee
mesh_terms: D000328:Adult; D000367:Age Factors; D015415:Biomarkers / Q000652:urine; D001900:Boston; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003627:Data Interpretation, Statistical; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D015386:Hazardous Substances / Q000009:adverse effects*; D006801:Humans; D007231:Infant, Newborn; D018811:Maternal Exposure / Q000009:adverse effects; D008875:Middle Aged; D015233:Models, Statistical; D010795:Phthalic Acids / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced* / Q000652:urine*; D012959:Socioeconomic Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D015386:Hazardous Substances; D010795:Phthalic Acids