Analysis of neonatal clinical trials with twin births.
BACKGROUND
In neonatal trials of pre-term or low-birth-weight infants, twins may represent 10-20% of the study sample. Mixed-effects models and generalized estimating equations are common approaches for handling correlated continuous or binary data. However, the operating characteristics of these methods for mixes of correlated and independent data are not well established.


METHODS
Simulation studies were conducted to compare mixed-effects models and generalized estimating equations to linear regression for continuous outcomes. Similarly, mixed-effects models and generalized estimating equations were compared to ordinary logistic regression for binary outcomes. The parameter of interest is the treatment effect in two-armed clinical trials. Data from the National Institute of Child Health & Human Development Neonatal Research Network are used for illustration.


RESULTS
For continuous outcomes, while the coverage never fell below 0.93, and the type I error rate never exceeded 0.07 for any method, overall linear mixed-effects models performed well with respect to median bias, mean squared error, coverage, and median width. For binary outcomes, the coverage never fell below 0.90, and the type I error rate never exceeded 0.07 for any method. In these analyses, when randomization of twins was to the same treatment group or done independently, ordinary logistic regression performed best. When randomization of twins was to opposite treatment arms, a rare method of randomization in this setting, ordinary logistic regression still performed adequately. Overall, generalized linear mixed models showed the poorest coverage values.


CONCLUSIONS
For continuous outcomes, using linear mixed-effects models for analysis is preferred. For binary outcomes, in this setting where the amount of related data is small, but non-negligible, ordinary logistic regression is recommended.
Shaffer
Michele L
ML
Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA. mshaffer@hes.hmc.psu.edu
Kunselman
Allen R
AR
Watterberg
Kristi L
KL
D000465:Algorithms; D000704:Analysis of Variance; D001699:Biometry / Q000379:methods*; D001724:Birth Weight; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007231:Infant, Newborn; D016015:Logistic Models; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D014427:Twins
D016756:Immunoglobulins, Intravenous