Personalized diagnosis in suspected myocardial infarction
Authors: Neumann Johannes Tobias , Twerenbold Raphael , Ojeda Francisco , Aldous Sally J. , Allen Brandon R. , Apple Fred S. , Babel Hugo , Christenson Robert H. , Cullen Louise , Di Carluccio Eleonora , Doudesis Dimitrios , Ekelund Ulf , Giannitsis Evangelos , Greenslade Jaimi , Inoue Kenji , Jernberg Tomas , Kavsak Peter , Keller Till , Lee Kuan Ken , Lindahl Bertil , Lorenz Thiess , Mahler Simon A. , Mills Nicholas L. , Mokhtari Arash , Parsonage William , Pickering John W. , Pemberton Christopher J. , Reich Christoph , Richards A. Mark , Sandoval Yader , Than Martin P. , Toprak Betül , Troughton Richard W. , Worster Andrew , Zeller Tanja , Ziegler Andreas , Blankenberg Stefan ,   the ARTEMIS study group, Brownlee Emily , Eggers Kai M. , Fincher Gavin , Frey Norbert , Gaikwad Niranjan , Gangathimmaiah Vinay , Hall Emma , Haller Paul M. , Hamilton-Craig Christian , Hancock Rebecca , Hobbins-King Andrew , Keijzers Gerben , Bayat Maryam Khorramshahi , Koliopanos Georgios , Lehmacher Jonas , Ljung Lina , Madsen Troy , Mahmoodi Ehsan , McCormick Ellyse , Mumma Bryn , Nowak Richard , Blazquez Vanessa , Perez Siegfried , Qaderi Vazhma , Ranasinghe Isuru , Schock Alina , Sörensen Nils A. , Staib Andrew , Stephensen Laura , Weaver Michael , Wilkerson R. Gentry , Zournazi Anna 
Published: May 2023

Abstract
Background
In suspected myocardial infarction (MI), guidelines recommend using high-sensitivity cardiac troponin (hs-cTn)-based approaches. These require fixed assay-specific thresholds and timepoints, without directly integrating clinical information. Using machine-learning techniques including hs-cTn and clinical routine variables, we aimed to build a digital tool to directly estimate the individual probability of MI, allowing for numerous hs-cTn assays.

Methods
In 2,575 patients presenting to the emergency department with suspected MI, two ensembles of machine-learning models using single or serial concentrations of six different hs-cTn assays were derived to estimate the individual MI probability (ARTEMIS model). Discriminative performance of the models was assessed using area under the receiver operating characteristic curve (AUC) and logLoss. Model performance was validated in an external cohort with 1688 patients and tested for global generalizability in 13 international cohorts with 23,411 patients.

Results
Eleven routinely available variables including age, sex, cardiovascular risk factors, electrocardiography, and hs-cTn were included in the ARTEMIS models. In the validation and generalization cohorts, excellent discriminative performance was confirmed, superior to hs-cTn only. For the serial hs-cTn measurement model, AUC ranged from 0.92 to 0.98. Good calibration was observed. Using a single hs-cTn measurement, the ARTEMIS model allowed direct rule-out of MI with very high and similar safety but up to tripled efficiency compared to the guideline-recommended strategy.

Conclusion
We developed and validated diagnostic models to accurately estimate the individual probability of MI, which allow for variable hs-cTn use and flexible timing of resampling. Their digital application may provide rapid, safe and efficient personalized patient care.

Trial Registration numbers
Data of following cohorts were used for this project: BACC (www.clinicaltrials.gov; NCT02355457), stenoCardia (www.clinicaltrials.gov; NCT03227159), ADAPT-BSN (www.australianclinicaltrials.gov.au; ACTRN12611001069943), IMPACT (www.australianclinicaltrials.gov.au, ACTRN12611000206921), ADAPT-RCT (www.anzctr.org.au; ANZCTR12610000766011), EDACS-RCT (www.anzctr.org.au; ANZCTR12613000745741); DROP-ACS (https://www.umin.ac.jp, UMIN000030668); High-STEACS (www.clinicaltrials.gov; NCT01852123), LUND (www.clinicaltrials.gov; NCT05484544), RAPID-CPU (www.clinicaltrials.gov; NCT03111862), ROMI (www.clinicaltrials.gov; NCT01994577), SAMIE (https://anzctr.org.au; ACTRN12621000053820), SEIGE and SAFETY (www.clinicaltrials.gov; NCT04772157), STOP-CP (www.clinicaltrials.gov; NCT02984436),
UTROPIA (www.clinicaltrials.gov; NCT02060760).

Graphical Abstract