title: Methodological issues in the design and analyses of neonatal research studies: Experience of the NICHD Neonatal Research Network.
abstract: Impressive advances in neonatology have occurred over the 30 years of life of The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN). However, substantial room for improvement remains in investigating and further developing the evidence base for improving outcomes among the extremely premature. We discuss some of the specific methodological challenges in the statistical design and analysis of randomized trials and observational studies in this population. Challenges faced by the NRN include designing trials for unusual or rare outcomes, accounting for and explaining center variations, identifying other subgroup differences, and balancing safety and efficacy concerns between short-term hospital outcomes and longer-term neurodevelopmental outcomes. In conclusion, the constellation of unique patient characteristics in neonates calls for broad understanding and careful consideration of the issues identified in this article for conducting rigorous studies in this population.
authors.affiliation: Biostatistics and Epidemiology Division, RTI International, 6110 Executive Blvd, Suite 902, Rockville, MD 20852. Electronic address: adas@rti.org.
authors.forename: Abhik
authors.initials: A
authors.lastname: Das
authors.affiliation: Center for Clinical Research and Evidence-Based Medicine, University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Jon
authors.initials: J
authors.lastname: Tyson
authors.affiliation: Center for Clinical Research and Evidence-Based Medicine, University of Texas Health Science Center at Houston, Houston, TX.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pedroza
authors.affiliation: Department of Pediatrics, University of Pennsylvania, Philadelphia, PA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC.
authors.forename: Marie
authors.initials: M
authors.lastname: Gantz
authors.affiliation: Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wallace
authors.affiliation: Children's Mercy Hospitals and Clinics, University of Missouri-Kansas City School of Medicine, Kansas City, MO.
authors.forename: William E
authors.initials: WE
authors.lastname: Truog
authors.affiliation: Pregnancy and Perinatology Branch, Eunice Kennedy Shriver National Institute of Health & Human Development, National Institutes of Health, Bethesda, MD.
authors.forename: Rosemary D
authors.initials: RD
authors.lastname: Higgins
mesh_terms: D035843:Biomedical Research / Q000379:methods*; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000175:diagnosis / Q000401:mortality / Q000628:therapy; D008137:Longitudinal Studies; D054582:National Institute of Child Health and Human Development (U.S.) / Q000458:organization & administration*; D009359:Neonatology / Q000379:methods* / Q000458:organization & administration* / Q000639:trends; D064887:Observational Studies as Topic; D057216:Propensity Score; D016032:Randomized Controlled Trials as Topic; D015996:Survival Rate; D014481:United States
keywords: Causal inference; Competing outcomes; Randomization of multiples; Statistical methodology; Trial design