title: Accounting for multiple births in neonatal and perinatal trials: systematic review and case study.
abstract: OBJECTIVE
  To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births and to explore the sensitivity of an actual trial to several analytic approaches to multiples.
  
  
  METHODS
  A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The Nitric Oxide to Prevent Chronic Lung Disease (NO CLD) trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using nonclustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses.
  
  
  RESULTS
  In the systematic review, most studies did not describe the random assignment of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (P < .01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not.
  
  
  CONCLUSIONS
  The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue.
authors.affiliation: Department of Pediatrics, Case Western Reserve University and Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Suite 3100, Cleveland, OH 44106. annamaria.hibbs@case.edu
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Hibbs
authors.forename: Dennis
authors.initials: D
authors.lastname: Black
authors.forename: Lisa
authors.initials: L
authors.lastname: Palermo
authors.forename: Avital
authors.initials: A
authors.lastname: Cnaan
authors.forename: Xianqun
authors.initials: X
authors.lastname: Luan
authors.forename: William E
authors.initials: WE
authors.lastname: Truog
authors.forename: Michele C
authors.initials: MC
authors.lastname: Walsh
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Ballard
mesh_terms: D000328:Adult; D015982:Bias; D001993:Bronchodilator Agents / Q000627:therapeutic use; D001997:Bronchopulmonary Dysplasia / Q000517:prevention & control; D016000:Cluster Analysis; D016001:Confidence Intervals; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D019102:Infant, Very Low Birth Weight; D016015:Logistic Models; D009099:Multiple Birth Offspring / Q000706:statistics & numerical data*; D009569:Nitric Oxide / Q000627:therapeutic use; D016017:Odds Ratio; D011247:Pregnancy; D011272:Pregnancy, Multiple / Q000706:statistics & numerical data*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D012680:Sensitivity and Specificity; D016019:Survival Analysis
chemical_list: D001993:Bronchodilator Agents; D009569:Nitric Oxide