Interaction analysis of subgroup effects in randomized trials: the essential methodological points

Abstract

Subgroup analysis aims to identify subgroups (usually defined by baseline/demographic characteristics), who would (or not) benefit from an intervention under specific conditions. Often performed post hoc (not pre-specified in the protocol), subgroup analyses are prone to elevated type I error due to multiple testing, inadequate power, and inappropriate statistical interpretation. Aside from the well-known Bonferroni correction, subgroup treatment interaction tests can provide useful information to support the hypothesis. Using data from a previously published randomized trial where a p value of 0.015 was found for the comparison between standard and Hemopatch® groups in (the subgroup of) 135 patients who had hand-sewn pancreatic stump closure we first sought to determine whether there was interaction between the number and proportion of the dependent event of interest (POPF) among the subgroup population (patients with hand-sewn stump closure and use of Hemopatch®), Next, we calculated the relative excess risk due to interaction (RERI) and the "attributable proportion" (AP). The p value of the interaction was p = 0.034, the RERI was - 0.77 (p = 0.0204) (the probability of POPF was 0.77 because of the interaction), the RERI was 13% (patients are 13% less likely to sustain POPF because of the interaction), and the AP was - 0.616 (61.6% of patients who did not develop POPF did so because of the interaction). Although no causality can be implied, Hemopatch® may potentially decrease the POPF after distal pancreatectomy when the stump is closed hand-sewn. The hypothesis generated by our subgroup analysis requires confirmation by a specific, randomized trial, including only patients undergoing hand-sewn closure of the pancreatic stump after distal pancreatectomy.Trial registration: INS-621000-0760.

Keywords: Attributable proportion; Distal pancreatectomy; Hemopatch®; Interaction analysis; Post-operative pancreatic fistula; Randomized trial; Relative excess risk due to interaction; Secondary analysis; Subgroup analysis.

Figure 1

Flow chart of the total population included in the original pancreatic stump trial*. *List of Research sites: Department of Surgery, Medical University of Graz, Graz, Austria; Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Minimally Invasive Surgery Center, Shanghai, P. R. China; Klinik für Allgemein- und Viszeralchirurgie St. Josef-Hospital, Bochum, Germany; Pancreatic Surgery Unit, Humanitas Clinical and Research Center-IRCCS, Rozzano (MI), Italy Humanitas University, Pieve Emanuele (MI), Italy; Division of General and Transplant Surgery, University of Pisa, Pisa, Italy; Department of General and Visceral Surgery, Raphaelsklinik Münster, Münster, Germany; Klinik und Poliklinik für Chirurgie, Klinikum Rechts der Isar, Technische Universität München, München, Germany; Department of General and Pancreatic Surgery—Pancreas Institute, University of Verona, Verona Hospital Trust, Verona, Italy; Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria; Department of Surgery, Salzkammergut-Klinikum,Vöcklabruck, Austria; Clinical Division of General, Visceral and Transplantation Surgery, Medical University of Graz, Austria; Department of Surgery, Campus Bio-Medico University of Rome, Rome, Italy; 2nd Department of Surgery Aretaieio Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece; ##Department of Surgery, Instituto de Investigación Sanitaria Aragón, Miguel Servet University Hospital, Zaragoza, Spain; Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University Goztepe Training & Research Hospital, Istanbul, Turkey; General Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; and Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.