Table 1.

Selection of Major NRN Studies Conducted in the Last 10 Years

Study Title*	Statistical Design Features	Statistical Analysis Features
Active Randomized Clinical Trials
Hydrocortisone for BPD	Powered for joint evaluation of efficacy conditional on safety	Two-stage sequential evaluation of efficacy conditional on safety
Late Hypothermia	RCT stratified by age of enrollment and level of encephalopathy	Bayesian interim monitoring for safety, futility, and efficacy Bayesian analysis of final outcomes for treatment benefit
MILK Trial	RCT stratified by birth weight (BW), center and feeding group eligibility Simulations for operating characteristics	Linear regression to estimate the adjusted mean difference in cognitive scaled scores between the two treatment groups
NEC Surgery Trial (NEST)	Comprehensive cohort design Randomization stratified by predicted baseline risk	Meta-analysis of randomized and preference cohorts after propensity modeling/adjustment in the latter
Optimizing Cooling	2×2 factorial design with stratified randomization	Marginal and within-table adjusted analyses
Transfusion of Prematures (TOP)	Pragmatic RCT with stratified randomization and pilot study of blood bank variations	Survival analyses of death Longitudinal modeling of growth Economic evaluation
Hydrocortisone for Cardiovascular Insufficiency	Randomized, multicenter, double- blind, placebo-controlled trial Patients are enrolled and randomized in a variable block design, 1:1 ratio of hydrocortisone or placebo	Planned sample size reanalysis after 1 year of enrollment based on overall outcome rate
Preemie Hypothermia	RCT stratified by age of enrollment and level of encephalopathy	Bayesian interim monitoring for safety, futility, and efficacy Bayesian analysis of final outcomes for treatment benefit
Incubator Weaning	RCT stratified by center and gestational age	Median regression adjusting for the trial stratification factors
Inositol RCT	RCT stratified by center and gestational age	Separate analyses plans for publication and FDA submission
Completed Randomized Clinical Trials
Early BP Pilot	Time-limited feasibility pilot study with 2×2 factorial design	Feasibility analyses
Vitamin E Pilot	Pilot, double-blind placebo- controlled RCT	Analyses of Vitamin E levels over time
SUPPORT	2×2 factorial design, randomization stratified by site and GA groups	Marginal outcomes analyses Interim group sequential monitoring in factorial setup Familial clustering
Inositol Multidose Trial	Double-blind phase II trial conducted under IND from FDA in three treatment groups stratified by GA	PK modeling allowing for endogenous Inositol synthesis and change from IV to oral administration during the intervention Used to establish dosage for pivotal phase III trial
Phototherapy	RCT stratified by site and BW groups	Primary outcome at 18 months (used surrogate markers for interim safety/efficacy monitoring)
Registry Studies
Generic Data Base (GDB)	Registry of all NRN very low BW births	Varied analytic approaches, including multiple regression, Classification and Regression Trees, longitudinal analyses, multilevel hierarchical generalized linear models, prediction modeling, and genetic epidemiology analyses
22–26 Month Follow-Up	Registry of all NRN extremely low BW outcomes at 18 months
Moderate Preterm Registry	Registry of moderate preterm births
Term Control Registry
Active Observational Studies
ALPS aEEG	Prospective, cohort study
Early Onset Sepsis II	Surveillance study	Incidence/prevalence rates
Completed Observational Studies
Term Hypotension	Observational, time-limited study	Linear and logistic regression
Early Blood Pressure	Observational, time-limited study	BP profiles analyses
Early Onset Sepsis	Surveillance study	Incidence/prevalence rates
Preemie aEEG	Prospective cohort study Sample size based on false- negative rate	Interobserver reliability modeling Prediction modeling
Candida	Prospective cohort study	Likelihood ratio–based risk stratification, latent class analyses for diagnostic tests
PCV-7	Vaccine efficacy study	Multiple linear/logistic regression for geometric mean titers