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. 2024 Nov 12;14(11):e086595.
doi: 10.1136/bmjopen-2024-086595.

Conducting observational analyses with the target trial emulation approach: a methodological systematic review

Noémie Simon-Tillaux  1   2 , Guillaume L Martin  2 , David Hajage  2 , Carole Scheifer  2 , Maxime Beydon  2 , Agnes Dechartres #  2 , Florence Tubach #  2
Affiliations

Conducting observational analyses with the target trial emulation approach: a methodological systematic review

Noémie Simon-Tillaux et al. BMJ Open. .

Abstract

Objectives: Target trial emulation is an approach that is increasingly used to improve transparency in observational studies and help mitigate biases. For studies declaring that they emulated a target trial, we aimed to evaluate the specification of the target trial, examine its consistency with the observational emulation and assess the risk of bias in the observational analysis.

Design: Methodological systematic review reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.

Data sources: The database MEDLINE (Medical Literature Analysis and Retrieval System Online) was interrogated for all studies published from 1 January 2021 to 3 July 2022. We performed an additional manual search of 20 general medical and specialised journals that spanned the same period.

Eligibility criteria: All studies that declared emulating a hypothetical or real randomised trial were eligible.

Data extraction and synthesis: Two independent reviewers performed the whole systematic review process (screening and selection of studies, data extraction and risk of bias assessment). The main outcomes were the definition of the key protocol components of the target trial and its emulation, consistency between the target trial and its emulation and risk of bias according to the ROBINS-I (Risk Of Bias In Non-randomised Studies - of Interventions) tool.

Results: Among the selected sample of 100 studies, 24 (24%) did not specify the target trial. Only 40 studies (40%) provided detailed information on all components of the target trial protocol. Eligibility criteria, intervention strategies and outcomes were consistent between the target trial and its emulation in 35 studies (46% of those specifying the target trial). Overall, 28 studies (28%) exhibited serious risk of bias and 41 (41%) had misalignments in the timing of eligibility assessment, treatment assignment and the start of follow-up (time-zero). As compared with studies that did not specify the target trial, those that did specify the trial less frequently seemed to have both time-zero issues (39% vs 52%) and serious risk of bias (26% vs 33%).

Conclusions: One-quarter of studies declaring that they emulated a target trial did not specify the trial. Target trials and their emulations were particularly inconsistent for studies emulating a real randomised trial. Risk of methodological issues seemed lower in observational analyses that specified versus did not specify the target trial.

Keywords: EPIDEMIOLOGY; Observational Study; STATISTICS & RESEARCH METHODS.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare that they have no competing interest related to the study. GLM declares consulting fees from Synapse Medicine, unrelated to the study.

Figures

Figure 1
Figure 1. Summary plot of the specification of the target trial protocol components (n=100). Each bar represents the specification of the key protocol components of the target trial. The full research question was deemed specified if eligibility criteria, treatment strategies and outcome protocol components were specified for the target trial.
Figure 2
Figure 2. Summary plot of the consistency of the target trial and its emulation for studies that emulated a real or a hypothetical target trial (n=76). Bars in light colours represent the consistency of studies that emulated a real target trial and bars in dark colours represent the consistency of studies that emulated a hypothetical target trial. Consistency was assessed only if both the target trial and its emulation specified the considered protocol component, and deemed not evaluable otherwise.
Figure 3
Figure 3. Summary plot of ROBINS-I assessment of risk of bias according to specification of the target trial. Bars in light colours represent the risk of bias of studies that specified the target trial and bars in dark colours represent the risk of bias of studies that did not specify the target trial. The target trial was deemed specified if at least one protocol component was documented. The risk of bias in the selection of the reported result was assessed only when a protocol was available for the observational study (n=12). For a given study, the overall risk of bias was the highest risk of bias observed in one of the individual risk of bias domains.
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