Generalizability Analyses with a Partially Nested Trial Design: The Necrotizing Enterocolitis Surgery Trial

Abstract

We discuss generalizability analyses under a partially nested trial design, where part of the trial is nested within a cohort of trial-eligible individuals, while the rest of the trial is not nested. This design arises, for example, when only some centers participating in a trial are able to collect data on nonrandomized individuals, or when data on nonrandomized individuals cannot be collected for the full duration of the trial. Our work is motivated by the Necrotizing Enterocolitis Surgery Trial, which compared initial laparotomy versus peritoneal drain for infants with necrotizing enterocolitis or spontaneous intestinal perforation. During the first phase of the study, data were collected from randomized individuals as well as consenting nonrandomized individuals; during the second phase of the study, however, data were only collected from randomized individuals, resulting in a partially nested trial design. We propose methods for generalizability analyses with partially nested trial designs. We describe identification conditions and propose estimators for causal estimands in the target population of all trial-eligible individuals, both randomized and nonrandomized, in the part of the data where the trial is nested while using trial information spanning both parts. We evaluate the estimators in a simulation study and provide an illustration using the Necrotizing Enterocolitis Surgery Trial study.

Keywords: Adherence; Causal inference; Generalizability; Intention-to-treat effect; Noncompliance; Per-protocol effect; Transportability.