Annals of the American Thoracic Society · 2026
Sequential likelihood ratios and e-processes in the analysis of the RENOVATE trial.
СтатьяРандомизированное исследованиеНазвание и аннотация: Перевод в очереди
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Zampieri Fernando G, Cavalcanti Alexandre B, Cahusac Peter M B, Kawano-Dourado Leticia, Harhay Michael O, Maia Israel S
Аннотация
RATIONALE: Adaptive platform trials enrolling heterogeneous populations face a critical challenge: when treatment effects differ across subgroups and enrollment is non-concurrent, pooled analyses can produce misleading results due to shifting patient composition over time.
OBJECTIVES: To quantify treatment effect heterogeneity in the RENOVATE trial using evidential methods and e-processes, and to demonstrate how temporal shifts in enrollment composition can create statistical artifacts in sequential monitoring.
METHODS: Secondary analysis of the RENOVATE trial, which randomized 1766 adults with acute respiratory failure to high-flow nasal oxygen (HFNO) versus noninvasive ventilation (NIV) across five populations: non-immunocompromised hypoxemia (n = 485), immunocompromised hypoxemia (n = 50), COPD exacerbation (n = 77), cardiogenic pulmonary edema (n = 272), and COVID-19 (n = 882). We computed sequential likelihood ratio (SLR) processes within each group for the primary outcome (death or intubation at 7 days), testing a 5% absolute risk reduction hypothesis. We compared group-specific trajectories with pooled analysis to visualize how enrollment composition influenced evidence accumulation. Sensitivity analyses used conditional e-processes (which eliminate the baseline rate parameter) and randomization-based e-processes (assumption-free).
RESULTS: Treatment effects varied substantially across populations. Cardiogenic edema showed strong evidence of HFNO benefit (absolute risk difference -11.0%; S-3 interval -15.8% to -3.8%; final support S = 3.36). COVID-19 showed a point estimate suggesting harm (+4.3%; S-3 interval -1.3% to + 9.8%; S = -3.23). The pooled SLR displayed a V-shaped artifact, with support dropping to S = -5.5 during the COVID-dominated enrollment period, then reversing to S = +5.6 as lower-risk patients entered. Alternative analyses were aligned with SLR but did not suffer from artifact interpretation due to baseline risk change.
CONCLUSIONS: Sequential evidential analysis reveals substantial treatment effect heterogeneity, which is masked by pooled analysis, with enrollment composition mechanistically driving the evidence trajectories. E-processes provide a diagnostic tool for platform trials, making visible the interaction between enrollment dynamics and treatment heterogeneity that conventional pooled estimates cannot reveal.
CLINICAL TRIAL REGISTRATION: NCT03643939.
PRIMARY SOURCE OF FUNDING: Brazilian Ministry of Health.
OBJECTIVES: To quantify treatment effect heterogeneity in the RENOVATE trial using evidential methods and e-processes, and to demonstrate how temporal shifts in enrollment composition can create statistical artifacts in sequential monitoring.
METHODS: Secondary analysis of the RENOVATE trial, which randomized 1766 adults with acute respiratory failure to high-flow nasal oxygen (HFNO) versus noninvasive ventilation (NIV) across five populations: non-immunocompromised hypoxemia (n = 485), immunocompromised hypoxemia (n = 50), COPD exacerbation (n = 77), cardiogenic pulmonary edema (n = 272), and COVID-19 (n = 882). We computed sequential likelihood ratio (SLR) processes within each group for the primary outcome (death or intubation at 7 days), testing a 5% absolute risk reduction hypothesis. We compared group-specific trajectories with pooled analysis to visualize how enrollment composition influenced evidence accumulation. Sensitivity analyses used conditional e-processes (which eliminate the baseline rate parameter) and randomization-based e-processes (assumption-free).
RESULTS: Treatment effects varied substantially across populations. Cardiogenic edema showed strong evidence of HFNO benefit (absolute risk difference -11.0%; S-3 interval -15.8% to -3.8%; final support S = 3.36). COVID-19 showed a point estimate suggesting harm (+4.3%; S-3 interval -1.3% to + 9.8%; S = -3.23). The pooled SLR displayed a V-shaped artifact, with support dropping to S = -5.5 during the COVID-dominated enrollment period, then reversing to S = +5.6 as lower-risk patients entered. Alternative analyses were aligned with SLR but did not suffer from artifact interpretation due to baseline risk change.
CONCLUSIONS: Sequential evidential analysis reveals substantial treatment effect heterogeneity, which is masked by pooled analysis, with enrollment composition mechanistically driving the evidence trajectories. E-processes provide a diagnostic tool for platform trials, making visible the interaction between enrollment dynamics and treatment heterogeneity that conventional pooled estimates cannot reveal.
CLINICAL TRIAL REGISTRATION: NCT03643939.
PRIMARY SOURCE OF FUNDING: Brazilian Ministry of Health.