Target Trial Emulation for Transparent and Robust Estimation of Treatment Effects for Health Technology Assessment Using Real-World Data: Opportunities and Challenges

Gomes, Manuel; Latimer, Nicholas; Soares, Marta; Dias, Sofia; Baio, Gianluca; Freemantle, Nick; Dawoud, Dalia; Wailoo, Allan; Grieve, Richard

doi:10.1007/s40273-022-01141-x

Cited by 13 publications

(6 citation statements)

References 47 publications

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“…Interest in the target trial emulation framework is gaining momentum in human epidemiology [ 76 ], with the current study being one of the pioneering applications of target trial emulation in the veterinary field. The framework aims to make the ‘target trial’ explicit, which helps avoid common design flaws and methodological pitfalls in the analysis of non-randomised studies, keeping each step transparent and accessible [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

Target trial emulation: Do antimicrobials or gastrointestinal nutraceuticals prescribed at first presentation for acute diarrhoea cause a better clinical outcome in dogs under primary veterinary care in the UK?

Pegram,

Diaz-Ordaz,

Brodbelt

et al. 2023

PLoS ONE

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Target trial emulation applies design principles from randomised controlled trials to the analysis of observational data for causal inference and is increasingly used within human epidemiology. Veterinary electronic clinical records represent a potentially valuable source of information to estimate real-world causal effects for companion animal species. This study employed the target trial framework to evaluate the usefulness on veterinary observational data. Acute diarrhoea in dogs was used as a clinical exemplar. Inclusion required dogs aged ≥ 3 months and < 10 years, presenting for veterinary primary care with acute diarrhoea during 2019. Treatment strategies were: 1. antimicrobial prescription compared to no antimicrobial prescription and 2. gastrointestinal nutraceutical prescription compared to no gastrointestinal nutraceutical prescription. The primary outcome was clinical resolution (defined as no revisit with ongoing diarrhoea within 30 days from the date of first presentation). Informed from a directed acyclic graph, data on the following covariates were collected: age, breed, bodyweight, insurance status, comorbidities, vomiting, reduced appetite, haematochezia, pyrexia, duration, additional treatment prescription and veterinary group. Inverse probability of treatment weighting was used to balance covariates between the treatment groups for each of the two target trials. The risk difference (RD) of 0.4% (95% CI -4.5% to 5.3%) was non-significant for clinical resolution in dogs treated with antimicrobials compared with dogs not treated with antimicrobials. The risk difference (RD) of 0.3% (95% CI -4.5% to 5.0%) was non-significant for clinical resolution in dogs treated with gastrointestinal nutraceuticals compared with dogs not treated with gastrointestinal nutraceuticals. This study successfully applied the target trial framework to veterinary observational data. The findings show that antimicrobial or gastrointestinal prescription at first presentation of acute diarrhoea in dogs causes no difference in clinical resolution. The findings support the recommendation for veterinary professionals to limit antimicrobial use for acute diarrhoea in dogs.

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Section: Discussionmentioning

confidence: 99%

Target trial emulation: Do antimicrobials or gastrointestinal nutraceuticals prescribed at first presentation for acute diarrhoea cause a better clinical outcome in dogs under primary veterinary care in the UK?

Pegram,

Diaz-Ordaz,

Brodbelt

et al. 2023

PLoS ONE

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“…Every attempt is made to emulate the features of the targeted RCT, except that randomization is not conducted. 57,58 Early emulation studies have shown that discrepancies in effect estimates between RCTs and NRSIs that address a similar question are to a lesser extent the result of unmeasured confounding and can be largely explained by differences in study design and analytic methods, such as time since disease onset and duration of followup. [59][60][61][62] However, unmeasured confounding and other issues are still important and may not be adequately addressed in some trial emulation studies.…”

Section: Advanced Analytic Approaches: Trial Emulation Effortsmentioning

confidence: 99%

Inclusion of Nonrandomized Studies of Interventions in Systematic Reviews of Intervention Effectiveness: An Update

Saldanha¹,

Skelly²,

Ley³

et al. 2022

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Introduction: Nonrandomized studies of interventions (NRSIs) are observational or experimental studies of the effectiveness and/or harms of interventions, in which participants are not randomized to intervention groups. There is increasingly widespread recognition that advancements in the design and analysis of NRSIs allow NRSI evidence to have a much more prominent role in decision making, and not just as ancillary evidence to randomized controlled trials (RCTs). Objective: To guide decisions about inclusion of NRSIs for addressing the effects of interventions in systematic reviews (SRs), this chapter updates the 2010 guidance on inclusion of NRSIs in Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) SRs. The chapter focuses on considerations for decisions to include or exclude NRSIs in SRs. Methods: In November 2020, AHRQ convened a 20-member workgroup that comprised 13 members representing 8 of 9 AHRQ-appointed EPCs, 3 AHRQ representatives, 1 independent consultant with expertise in SRs, and 3 representatives of the AHRQ-appointed Scientific Resource Center. The workgroup received input from the full EPC Program regarding the process and specific issues through discussions at a virtual meeting and two online surveys regarding challenges with NRSI inclusion in SRs. One survey focused on current practices by EPCs regarding NRSI inclusion in ongoing and recently completed SRs. The other survey focused on the appropriateness, completeness, and usefulness of existing EPC Program methods guidance. The workgroup considered the virtual meeting and survey input when identifying aspects of the guidance that needed updating. The workgroup used an informal method for generating consensus about guidance. Disagreements were resolved through discussion. Results: We outline considerations for the inclusion of NRSIs in SRs of intervention effectiveness. We describe the strengths and limitations of RCTs, study design features and types of NRSIs, and key considerations for making decisions about inclusion of NRSIs (during the stages of topic scoping and refinement, SR team formation, protocol development, SR conduct, and SR reporting). We discuss how NRSIs may be applicable for the decisional dilemma being addressed in the SR, threats to the internal validity of NRSIs, as well as various data sources and advanced analytic methods that may be used in NRSIs. Finally, we outline an approach to incorporating NRSIs within an SR and key considerations for reporting. Conclusion: The main change from the previous guidance is the overall approach to decisions about inclusion of NRSIs in EPC SRs. Instead of recommending NRSI inclusion only if RCTs are insufficient to address the Key Question, this updated guidance handles NRSI evidence as a valuable source of information and lays out important considerations for decisions about the inclusion of NRSIs in SRs of intervention effectiveness. Different topics may require different decisions regarding NRSI inclusion. This guidance is intended to improve the utility of the final product to end-users. Inclusion of NRSIs will increase the scope, time, and resources needed to complete SRs, and NRSIs pose potential threats to validity, such as selection bias, confounding, and misclassification of interventions. Careful consideration must be given to both concerns.

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“…The framework outlines items to be reported in the protocol of a target trial and its emulation, including: eligibility criteria, treatment strategies, assignment procedures, follow-up period, outcome(s), causal contrast(s), and analysis plan. Since the introduction of the framework, several articles have been published to assist researchers in conducting these studies and educating clinicians and other end users to interpret their findings . However, there is limited understanding of how researchers have implemented the target trial framework when reporting observational analyses with the explicit aim to emulate a target trial.…”

Section: Introductionmentioning

confidence: 99%

“…Since the introduction of the framework, several articles have been published to assist researchers in conducting these studies and educating clinicians and other end users to interpret their findings. 3 , 5 , 11 , 12 , 13 , 14 However, there is limited understanding of how researchers have implemented the target trial framework when reporting observational analyses with the explicit aim to emulate a target trial.…”

Section: Introductionmentioning

confidence: 99%

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials

Hansford,

Cashin,

Jones

et al. 2023

JAMA Netw Open

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ImportanceObservational (nonexperimental) studies that aim to emulate a randomized trial (ie, the target trial) are increasingly informing medical and policy decision-making, but it is unclear how these studies are reported in the literature. Consistent reporting is essential for quality appraisal, evidence synthesis, and translation of evidence to policy and practice.ObjectiveTo assess the reporting of observational studies that explicitly aimed to emulate a target trial.Evidence ReviewWe searched Medline, Embase, PsycINFO, and Web of Science for observational studies published between March 2012 and October 2022 that explicitly aimed to emulate a target trial of a health or medical intervention. Two reviewers double-screened and -extracted data on study characteristics, key predefined components of the target trial protocol and its emulation (eligibility criteria, treatment strategies, treatment assignment, outcome[s], follow-up, causal contrast[s], and analysis plan), and other items related to the target trial emulation.FindingsA total of 200 studies that explicitly aimed to emulate a target trial were included. These studies included 26 subfields of medicine, and 168 (84%) were published from January 2020 to October 2022. The aim to emulate a target trial was explicit in 70 study titles (35%). Forty-three studies (22%) reported use of a published reporting guideline (eg, Strengthening the Reporting of Observational Studies in Epidemiology). Eighty-five studies (43%) did not describe all key items of how the target trial was emulated and 113 (57%) did not describe the protocol of the target trial and its emulation.Conclusion and RelevanceIn this systematic review of 200 studies that explicitly aimed to emulate a target trial, reporting of how the target trial was emulated was inconsistent. A reporting guideline for studies explicitly aiming to emulate a target trial may improve the reporting of the target trial protocols and other aspects of these emulation attempts.

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Target Trial Emulation for Transparent and Robust Estimation of Treatment Effects for Health Technology Assessment Using Real-World Data: Opportunities and Challenges

Cited by 13 publications

References 47 publications

Target trial emulation: Do antimicrobials or gastrointestinal nutraceuticals prescribed at first presentation for acute diarrhoea cause a better clinical outcome in dogs under primary veterinary care in the UK?

Target trial emulation: Do antimicrobials or gastrointestinal nutraceuticals prescribed at first presentation for acute diarrhoea cause a better clinical outcome in dogs under primary veterinary care in the UK?

Inclusion of Nonrandomized Studies of Interventions in Systematic Reviews of Intervention Effectiveness: An Update

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials

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