. 2023 Sep;112(9):1288-1301.

doi: 10.1007/s00392-023-02206-3. Epub 2023 May 2.

Personalized diagnosis in suspected myocardial infarction

Johannes Tobias Neumann^#^{1

2

3

4}, Raphael Twerenbold^#^{1

2

3

5}, Francisco Ojeda^{1

3}, Sally J Aldous⁶, Brandon R Allen⁷, Fred S Apple⁸, Hugo Babel⁹, Robert H Christenson¹⁰, Louise Cullen¹¹, Eleonora Di Carluccio⁹, Dimitrios Doudesis¹², Ulf Ekelund¹³, Evangelos Giannitsis¹⁴, Jaimi Greenslade¹¹, Kenji Inoue¹⁵, Tomas Jernberg¹⁶, Peter Kavsak¹⁷, Till Keller¹⁸, Kuan Ken Lee¹², Bertil Lindahl¹⁹, Thiess Lorenz^{1

2

3}, Simon A Mahler²⁰, Nicholas L Mills¹², Arash Mokhtari²¹, William Parsonage²², John W Pickering²³, Christopher J Pemberton²⁴, Christoph Reich¹⁴, A Mark Richards²³, Yader Sandoval²⁵, Martin P Than²³, Betül Toprak^{1

2

3

5}, Richard W Troughton²⁴, Andrew Worster²⁶, Tanja Zeller^{1

2

3

5}, Andreas Ziegler^#^{9

27}, Stefan Blankenberg^#^{28

29

30}; ARTEMIS study group

Collaborators, Affiliations

Affiliations

¹ Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
² German Center for Cardiovascular Research (DZHK), Partner SiteHamburg/Kiel/Lübeck, Hamburg, Germany.
³ Population Health Research Department, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
⁵ University Center of Cardiovascular Science, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand.
⁷ Department of Emergency Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
⁸ Departments of Laboratory Medicine and Pathology, Hennepin Healthcare/HCMC and University of Minnesota, Minneapolis, MN, USA.
⁹ Cardio-CARE, Medizincampus Davos, Davos, Switzerland.
¹⁰ Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Department of Emergency Medicine, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
¹² BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
¹³ Department of Internal and Emergency Medicine, Lund University, Skåne University Hospital, Lund, Sweden.
¹⁴ Department of Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁵ Juntendo University Nerima Hospital, Tokyo, Japan.
¹⁶ Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
¹⁸ Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany.
¹⁹ Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
²⁰ Department of Emergency Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²¹ Department of Internal Medicine and Emergency Medicine and Department of Cardiology, Lund University, Skåne University Hospital, Lund, Sweden.
²² Australian Centre for Health Service Innovation, Queensland University of Technology, Kelvin Grove, Australia.
²³ Department of Medicine, Christchurch and Emergency Department, University of Otago, Christchurch Hospital, Christchurch, New Zealand.
²⁴ Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
²⁵ Minneapolis Heart Institute, Abbott Northwestern Hospital, and Minneapolis Heart Institute Foundation, Minneapolis, MN, USA.
²⁶ Division of Emergency Medicine, McMaster University, Hamilton, ON, Canada.
²⁷ School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
²⁸ Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. s.blankenberg@uke.de.
²⁹ German Center for Cardiovascular Research (DZHK), Partner SiteHamburg/Kiel/Lübeck, Hamburg, Germany. s.blankenberg@uke.de.
³⁰ Population Health Research Department, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.blankenberg@uke.de.

^# Contributed equally.

PMID: 37131096
PMCID: PMC10449973
DOI: 10.1007/s00392-023-02206-3

Personalized diagnosis in suspected myocardial infarction

Johannes Tobias Neumann et al. Clin Res Cardiol. 2023 Sep.

. 2023 Sep;112(9):1288-1301.

doi: 10.1007/s00392-023-02206-3. Epub 2023 May 2.

Authors

Affiliations

¹ Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
² German Center for Cardiovascular Research (DZHK), Partner SiteHamburg/Kiel/Lübeck, Hamburg, Germany.
³ Population Health Research Department, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
⁵ University Center of Cardiovascular Science, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand.
⁷ Department of Emergency Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
⁸ Departments of Laboratory Medicine and Pathology, Hennepin Healthcare/HCMC and University of Minnesota, Minneapolis, MN, USA.
⁹ Cardio-CARE, Medizincampus Davos, Davos, Switzerland.
¹⁰ Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA.
¹¹ Department of Emergency Medicine, Royal Brisbane and Women's Hospital, Herston, QLD, Australia.
¹² BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.
¹³ Department of Internal and Emergency Medicine, Lund University, Skåne University Hospital, Lund, Sweden.
¹⁴ Department of Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁵ Juntendo University Nerima Hospital, Tokyo, Japan.
¹⁶ Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁷ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
¹⁸ Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany.
¹⁹ Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
²⁰ Department of Emergency Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²¹ Department of Internal Medicine and Emergency Medicine and Department of Cardiology, Lund University, Skåne University Hospital, Lund, Sweden.
²² Australian Centre for Health Service Innovation, Queensland University of Technology, Kelvin Grove, Australia.
²³ Department of Medicine, Christchurch and Emergency Department, University of Otago, Christchurch Hospital, Christchurch, New Zealand.
²⁴ Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.
²⁵ Minneapolis Heart Institute, Abbott Northwestern Hospital, and Minneapolis Heart Institute Foundation, Minneapolis, MN, USA.
²⁶ Division of Emergency Medicine, McMaster University, Hamilton, ON, Canada.
²⁷ School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa.
²⁸ Department of Cardiology, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. s.blankenberg@uke.de.
²⁹ German Center for Cardiovascular Research (DZHK), Partner SiteHamburg/Kiel/Lübeck, Hamburg, Germany. s.blankenberg@uke.de.
³⁰ Population Health Research Department, University Heart and Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. s.blankenberg@uke.de.

^# Contributed equally.

PMID: 37131096
PMCID: PMC10449973
DOI: 10.1007/s00392-023-02206-3

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).

Keywords: Acute myocardial infarction; Biomarker; Machine learning; Probability; Super learner; Troponin; Validation.

PubMed Disclaimer

Conflict of interest statement

SB receives fundings from Abbott Diagnostics, Bayer, SIEMENS, Amgen and NOVARTIS as well as honoraria for lectures and/or chairs from Abbott, Abbott Diagnostics,, AMGEN, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS (Bristol Meyer Squib), Daiichi Sankyo, LumiraDx, NOVARTIS and Thermo Fisher. SB is a member of advisory boards and consultant of Thermo Fisher. JTN, RT, FO, TZ, AZ and SB are co-founders and shareholders of the ART-EMIS Hamburg GmbH, which holds an international patent application on the use of a computing device to estimate the probability of myocardial infarction (Publication Numbers WO2022043229A1, TW202219980A). JTN reports speaker honoraria/consulting honoraria from PHC, Roche and Siemens. RT reports research support from the Kühne Foundation, the Swiss National Science Foundation (Grant No P300PB_167803), the Swiss Heart Foundation, the Swiss Society of Cardiology and speaker honoraria/consulting honoraria from Abbott, Amgen, Astra Zeneca, Roche, Siemens, and Singulex. BRA receives research funding/support from Roche Diagnostics, Siemens, and Beckman Coulter. BRA is a consultant for Roche Diagnostics. FSA is a consultant for HyTest Ltd and an associate Editor for Clinical Chemistry. FSA is part of the advisory boards of Werfen, Siemens Healthineers, Qorvo and AWE Medical Group. FSA receives honorarium for speaking at industry conferences of Siemens Healthineers and Beckman Coulter. FSA is PI on Industry Funded Grants (non-salaried) on cardiac biomarkers through Hennepin Healthcare Research Institute for Abbott Diagnostics, Abbott POC, BD, Beckman Coulter, Ortho-Clinical Diagnostics, Roche Diagnostics, Siemens Healthcare, ET Healthcare and Qorvo. RHC is a consultant for and receives funding/support from Roche Diagnostics, Siemens Healthineers, Beckman Coulter Diagnostics, Becton Dickinson and Co, Quidel Corp, and Sphingotec GMBH. LC reports research funding from Siemens, Abbott, and Beckman. EG reports personal fees from Bayer Vital, personal fees from Astra Zeneca, personal fees from Roche Diagnostics, personal fees from Brahms Germany, personal fees from Daiichi Sankyo, personal fees from Lilly Deutschland, outside the submitted work. EG reports participation on a Data Safety. Monitoring Board or Advisory Board at Boehringer Ingelheim and Roche Diagnostics. JG receives grants from Siemen´s Point of Care and Beckman Coulter. KI receives grants from Japanese KAKENHI (grant number JP18K09554). KI reported payment for honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche Diagnostics to Fujirebio Inc. PK reports support for this manuscript to his institution from Canadian Institutes of Health Research, Abbott Diagnostics and Roche Diagnostics. PK reports grants for his institution from Abbott Diagnostics, Roche Diagnostics, Randox laboratories, Beckman Coulter, Ortho Clinical Diagnostics and Siemens Healthcare Diagnostics. PK receives consulting fees from Abbott, Beckman Coulter, Roche Diagnostics, Quidel and Siemens Healthcare. PK receives reports honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Beckman Coulter, Roche Diagnostics, Siemens Healthcare and Thermo Fisher Scientific. PK receives support for attending meetings and/or travel from Randox Laboratories ans Roche Diagnostics. McMaster University has filed a patent with PK listed as an inventor in the acute cardiovascular biomarker field, in particular, a patent has been awarded in Europe (EP 3 341 723 B1) on a Method of determining risk of an adverse cardiac event. McMaster University has also filed patents with PK listed as an inventor on Quality Control Materials for Cardiac Troponin Testing and Identifying pregnant women at increased risk for hypertension and future cardiovascular disease. PK reports participation on a Data Safety Monitoring Board or Advisory Board for Roche Diagnostics, Siemens Healthcare Diagnostics, Beckman Coulter and Quidel. BL is a member (unpaid) of Study Group on Biomarkers of the ESC Association for Acute CardioVascular Care. SAM receives research funding/support from Roche Diagnostics, Abbott Laboratories, Ortho Clinical Diagnostics, Creavo Medical Technologies, Siemens, Pathfast, Grifols, Rigel Pharmaceuticals, the Agency for Healthcare Research and Quality, the Patient-Centered Outcomes Research Institute, the National Heart, Lung, and Blood Institute (1 R01 HL118263-01), and the Health Resources and Services Administration (1 H2ARH399760100). Dr Mahler is a consultant for Roche Diagnostics and Amgen and is the chief medical officer for Impathiq Inc. NLM reported grants from British Heart Foundation to his institution (CH/F/21/90010, RG/20/10/34966, RE/18/5/34216). NLM has received honoraria or consultancy from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. NLM reports participation on an Advisory Board of LumiraDx, Roche Diagnostics and Siemens Healthineers. NLM is supported by a Chair Award, Programme Grant, Research Excellence Award (CH/F/21/90010, RG/20/10/34966, RE/18/5/34216) from the British Heart Foundation. JWP has received non-directed funds from Abbott Diagnostics, Roche, Siemens within the last 5 years and consulted for Abbott. CJP receives Project grants from the Health Research Council of New Zealand and from the Heart Foundation of New Zealand. He is PI on grants hosted by University of Otago. CJP received project grant from the Ministry of Business, Innovation and Employment, New Zealand. CJP is inventor on patents (granted and filed) for the diagnosis of acute coronary syndromes. CJP is CSO at Upstream Medical Technologies. CJP reported research support from Upstream Medical Technologies and from Biovendor R&D. AMR reports speaker honoraria/advisory board fees and research grants in kind and/or cash funding from Roche Diagnostics, Astra Zeneca, Abbott Laboratories, Novartis, NovoNordisk, Thermo Fisher, Critical Diagnostics, Sphingotec, Medtronic and Boston Scientific. AMR reports grants from National Medical Council of Singapore and NovoNordisk research grants. He has received publicly contestable funding from the New Zealand Health Research Council, NZ Heart Foundation and the National Medical research Council of Singapore. AMR reports personal fees from Roche Diagnostics, Novartis and Roche Diagnostics. AMR reports participation on a Data Safety Monitoring Board or Advisory Board in the Pontiac 2 trial and STAREE Trial. YS has previously served on Advisory Boards for Roche Diagnostics and Abbott Diagnostics. YS has also been a speaker for Abbott Diagnostics. WP reported research grants and consulting fees to his institution from Siemens Healthineers. MPT received Funding for clinical research from Abbott, Alere, Beckman, Radiometer and Roche (to his institution). MPT received payment for speaking from Abbott, Alere, and Roche as well as Consulting fees from Abbott, Roche and Siemens. MPT received payment for participation in advisory boards from Abbott, Radiometer, Roche and Siemens as well as funding for education from Abbott, Alere and Beckman (to his institution). BT receives a project-related grant from German Heart foundation and from the Ernst und Berta Grimmke-Stiftung. RWT received payments to his institution from Health Research Council of NZ, Heart Foundation of NZ, American Regent, Merck and Bayer. RWT receives consulting fees from American Regent, Merck, Bayer and Roche Diagnostics.AW is having a patent on the Clinical Chemistry Score. TZ is supported by the German Centre for Cardiovascular Research (DZHK e.V.) grant numbers 81Z1710101 and 81Z0710102.TZ is supported by EU Horizon 2020 programme and EU ERANet and ERAPreMed Programmes.

Figures

**Fig. 1**
Study concept and diagnostic model development. This figure displays the overall study design including study populations, development of the diagnostic model, model validation and generalization, as well as comparison to the current standard of care

**Fig. 2**
Discrimination measures using the diagnostic model based on a single and on a serial hs-cTn measurement per assay summarized across the validation and generalization cohorts. This figure summarizes the discrimination measures AUC and LogLoss with 95% CI for each hs-cTn assay using the diagnostic model with single and serial hs-cTn measurements. The displayed measured represent the summarized values from the validation and generalization cohorts. Detailed results from each cohort are displayed in Figure S5. Abbreviations: *AUC* area under the curve, CI confidence interval, *hs-cTn* high-sensitivity troponin

**Fig. 3**
Diagnostic pathway in patients with suspected myocardial infarction—the machine-learning supported clinical application. This figure displays the clinical workflow to estimate the individual MI probability using the ARTEMIS diagnostic model. Abbreviations: *CAD* coronary artery disease, *ECG* electrocardiogram, MI myocardial infarction, *hs-cTn* high-sensitivity cardiac troponin

See this image and copyright information in PMC

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Personalized diagnosis in suspected myocardial infarction

Collaborators

Affiliations

Personalized diagnosis in suspected myocardial infarction

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

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MeSH terms

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Grants and funding

LinkOut - more resources

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