# Target Trial Emulation

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researchsquare.com Oct 22, 2026
Sepsis coagulopathy screening misses its highest-risk patients: 72-hour INR and PTT trajectories recover a group with nearly double the mortality
Sepsis coagulopathy screening still rests on a single admission lab set, with platelets, INR and SOFA combined into one cross-sectional threshold. Among 3,138 sepsis patients in MIMIC-IV, clustering the joint 72-hour trajectories of platelet count, INR and PTT yielded a high-risk subphenotype with 27.8% mortality, of whom the admission SIC score flagged only 18.1%. The gradient reproduced in an independent refit of 12,828 eICU-CRD patients, where 86.3% of the high group remained SIC-negative.
Sepsis coagulopathy screening still rests on a single admission lab set, with platelets, INR and SOFA combined into one cross-sectional threshold. Among 3,138 sepsis patients in MIMIC-IV, clustering the joint 72-hour trajectories of platelet count, INR and PTT yielded a high-risk subphenotype with 27.8% mortality, of whom the admission SIC score flagged only 18.1%. The gradient reproduced in an independent refit of 12,828 eICU-CRD patients, where 86.3% of the high group remained SIC-negative.
Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University First Affiliated Hospital of Wenzhou Medical University Second Affiliated Hospital of Zhejiang University
Xueshu Yu（First author）
Sepsis-Associated Coagulopathy Gaussian Mixture Model Sepsis-Induced Coagulopathy (SIC) Score Target Trial Emulation MIMIC-IV
medRxiv Oct 14, 2026
An agent emulates an elderly clopidogrel trial: 53 of 62 SQL checks met, calibrated risk ratio point estimate rises to 1.274
TrialCalibre1 links a clinical question, study design, and executable analysis into one reviewable chain, covering reference-trial replication, direct target-trial emulation, and BenchExCal, which joins benchmarking, extension, and calibration. On synthetic PCORnet-style claims it used ASCET as benchmark and extended the clopidogrel-versus-aspirin comparison to ages 81–90: 6,069 benchmark and 1,602 extension patients, extension risk ratio 0.848 (95% CI 0.569–1.184), calibrated to a point estimate of 1.274 (0.439–3.700) with a sensitivity interval still spanning 1. Two reviewers rated 53/62 and 50/62 assessable SQL checks met and 12/13 R checks met, with protocol and proxy disagreements remaining.
TrialCalibre1 links a clinical question, study design, and executable analysis into one reviewable chain, covering reference-trial replication, direct target-trial emulation, and BenchExCal, which joins benchmarking, extension, and calibration. On synthetic PCORnet-style claims it used ASCET as benchmark and extended the clopidogrel-versus-aspirin comparison to ages 81–90: 6,069 benchmark and 1,602 extension patients, extension risk ratio 0.848 (95% CI 0.569–1.184), calibrated to a point estimate of 1.274 (0.439–3.700) with a sensitivity interval still spanning 1. Two reviewers rated 53/62 and 50/62 assessable SQL checks met and 12/13 R checks met, with protocol and proxy disagreements remaining.
University of Missouri
Amir Habibdoust（First author, Corresponding author）
TrialCalibre1 Target Trial Emulation Benchmark, Expand, and Calibration (BenchExCal)Agentic System
medRxiv Oct 11, 2026
A protective effect in observational data may be all bias: new metric attributes a 16.9% mortality drop to systematic error
Observational causal estimates gain a continuous reporting channel: the Bias Attribution Fraction (BAF) writes the share of an observed log relative risk attributable to systematic bias as a number between 0 and 1, with a 95% credible interval. Across 1,920,000 simulated repetitions, the calibrated P-value alone declared 36.02% of truly bias-dominated repetitions usable, adding the BAF point estimate cut that to 16.48%, and requiring the whole credible interval below 0.5 cut it to 10.16%. In a MIMIC IV beta-blocker target trial emulation, the 16.9% one-year mortality reduction associated with reaching target dose disappeared after calibration, with BAF 0.875 and a verdict of not usable as effect evidence.
Observational causal estimates gain a continuous reporting channel: the Bias Attribution Fraction (BAF) writes the share of an observed log relative risk attributable to systematic bias as a number between 0 and 1, with a 95% credible interval. Across 1,920,000 simulated repetitions, the calibrated P-value alone declared 36.02% of truly bias-dominated repetitions usable, adding the BAF point estimate cut that to 16.48%, and requiring the whole credible interval below 0.5 cut it to 10.16%. In a MIMIC IV beta-blocker target trial emulation, the 16.9% one-year mortality reduction associated with reaching target dose disappeared after calibration, with BAF 0.875 and a verdict of not usable as effect evidence.
Capital Medical University Beijing Anzhen Hospital
Zhechun ZENG（First author, Corresponding author）
Bias Attribution Fraction Reliability calibration Target Trial Emulation Targeted Maximum Likelihood Estimation MIMIC-IV
发表出处待核验 Sep 27, 2026
Doctoral thesis pooling homecare data from six countries links moderate-to-higher physical activity to better function, health outcomes and mortality in older homecare recipients
This doctoral thesis, conducted within the EU-funded I-CARE4OLD project, first maps the definition and use of non-pharmacological interventions (NPIs)—a systematic review shows highly heterogeneous and predominantly negatively framed definitions, and data from six countries show underuse of interventions with proven benefits (physical therapy, occupational therapy, psychosocial interventions, social participation) alongside relatively frequent use of physical restraints in some countries—and second, using longitudinal real-world data from the Netherlands and Ontario, Canada, with propensity-based methods, generalized estimating equations, and target trial emulation with causal machine learning, finds that moderate and higher levels of physical activity are associated with beneficial effect
This doctoral thesis, conducted within the EU-funded I-CARE4OLD project, first maps the definition and use of non-pharmacological interventions (NPIs)—a systematic review shows highly heterogeneous and predominantly negatively framed definitions, and data from six countries show underuse of interventions with proven benefits (physical therapy, occupational therapy, psychosocial interventions, social participation) alongside relatively frequent use of physical restraints in some countries—and second, using longitudinal real-world data from the Netherlands and Ontario, Canada, with propensity-based methods, generalized estimating equations, and target trial emulation with causal machine learning, finds that moderate and higher levels of physical activity are associated with beneficial effect
Elizabeth Cornelia Maria Kooijmans（First author, Corresponding author）
Non-pharmacological interventions Physical activity Homecare for older adults Target Trial Emulation Systematic Review
medRxiv Sep 21, 2026
MES: A Multi-Agent Evidence Synthesis System for Medical Decision-Making
This work presents MES, a multi-agent framework of six specialized agents (Supervisor, LiteratureMiner, RWD-Analyst, KG-Specialist, Statistician, SafeChecker) that integrates published literature and trial evidence, generates question-specific real-world evidence from real-world clinical data, and queries biomedical knowledge graphs while preserving source traceability; evaluated in two clinical use cases (an Alzheimer disease medication question with no matching literature and a septic shock beta-blocker question with inconsistent randomized evidence) and across 144 clinical queries spanning six evidence-based medicine categories, it produced structured reports that preserved source traceability, identified cross-source disagreement and communicated uncertainty, and its SafeChecker improv
This work presents MES, a multi-agent framework of six specialized agents (Supervisor, LiteratureMiner, RWD-Analyst, KG-Specialist, Statistician, SafeChecker) that integrates published literature and trial evidence, generates question-specific real-world evidence from real-world clinical data, and queries biomedical knowledge graphs while preserving source traceability; evaluated in two clinical use cases (an Alzheimer disease medication question with no matching literature and a septic shock beta-blocker question with inconsistent randomized evidence) and across 144 clinical queries spanning six evidence-based medicine categories, it produced structured reports that preserved source traceability, identified cross-source disagreement and communicated uncertainty, and its SafeChecker improv
Weill Cornell Medicine Cornell University
Haoyang Li（First author）Fei Wang（Corresponding author）
MES SafeChecker Multi-Agent Workflow Medical Evidence Synthesis Target Trial Emulation

You’re all caught up

Sepsis coagulopathy screening misses its highest-risk patients: 72-hour INR and PTT trajectories recover a group with nearly double the mortality

An agent emulates an elderly clopidogrel trial: 53 of 62 SQL checks met, calibrated risk ratio point estimate rises to 1.274

A protective effect in observational data may be all bias: new metric attributes a 16.9% mortality drop to systematic error

Doctoral thesis pooling homecare data from six countries links moderate-to-higher physical activity to better function, health outcomes and mortality in older homecare recipients

MES: A Multi-Agent Evidence Synthesis System for Medical Decision-Making