Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Mar 18;10(6):1264.
doi: 10.3390/jcm10061264.

External Validation and Extension of a Clinical Score for the Discrimination of Type 2 Myocardial Infarction

Thomas Nestelberger  1   2   3 , Pedro Lopez-Ayala  1   2 , Jasper Boeddinghaus  1   2 , Ivo Strebel  1   2 , Maria Rubini Gimenez  1   2   4 , Iris Huber  1   2 , Karin Wildi  1   2   5 , Desiree Wussler  1   2 , Luca Koechlin  1   2   6 , Alexandra Prepoudis  1   2 , Danielle M Gualandro  1   2 , Christian Puelacher  1   2 , Noemi Glarner  1   2 , Philip Haaf  1 , Simon Frey  1 , Adam Bakula  1 , Rupprecht Wick  1 , Òscar Miró  2   7 , F Javier Martin-Sanchez  2   8 , Damian Kawecki  2   9 , Dagmar Keller  10 , Raphael Twerenbold  1   2 , Christian Mueller  1   2
Affiliations

External Validation and Extension of a Clinical Score for the Discrimination of Type 2 Myocardial Infarction

Thomas Nestelberger et al. J Clin Med. .

Abstract

Background: The early non-invasive discrimination of Type 2 versus Type 1 Myocardial Infarction (T2MI, T1MI) is a major unmet clinical need. We aimed to externally validate a recently derived clinical score (Neumann) combing female sex, no radiating chest pain, and high-sensitivity cardiac troponin I (hs-cTnI) concentration ≤40.8 ng/L.

Methods: Patients presenting with acute chest discomfort to the emergency department were prospectively enrolled into an international multicenter diagnostic study. The final diagnoses of T2MI and T1MI were centrally adjudicated by two independent cardiologists using all information including cardiac imaging and serial measurements of hs-cTnT/I according to the fourth universal definition of MI. Model performance for T2MI diagnosis was assessed by formal tests and graphical means of discrimination and calibration.

Results: Among 6684 enrolled patients, MI was the adjudicated final diagnosis in 1079 (19%) patients, of which 242 (22%) had T2MI. External validation of the Neumann Score showed a moderate discrimination (C-statistic 0.67 (95%CI 0.64-0.71)). Model calibration showed underestimation of the predicted probabilities of having T2MI for low point scores. Model extension by adding the binary variable heart rate >120/min significantly improved model performance (C-statistic 0.73 (95% CI 0.70-0.76, p < 0.001) and had good calibration. Patients with the highest score values of 3 (Neumann Score, 9.9%) and 5 (Extended Neumann Score, 3.3%) had a 53% and 91% predicted probability of T2MI, respectively.

Conclusion: The Neumann Score provided moderate discrimination and suboptimal calibration. Extending the Neumann Score by adding heart rate >120/min improved the model's performance.

Keywords: differentiation; external validation; risk scores; type 1 myocardial infarction; type 2 myocardial infarction.

PubMed Disclaimer

Conflict of interest statement

We disclose that Nestelberger has received research support from the Swiss National Science Foundation (P400PM_191037/1), the Swiss Heart Foundation (FF20079), the Max Cloëtta Foundation, the Margarete und Walter Lichtenstein-Stiftung (3MS1038), and the University Hospital Basel as well as speaker honoraria/consulting honoraria from B.Braun, Siemens, Beckman Coulter, Bayer, Ortho Clinical Diagnostics, and Orion Pharma, outside the submitted work. Lopez-Ayala has received research funding from the Swiss Heart Foundation (FF20079), outside the submitted work. Boeddinghaus has received research grants from the University of Basel and the Division of Internal Medicine, the Swiss Academy of Medical Sciences, the Gottfried and Julia Bangerter-Rhyner-Foundation, and speaker honoraria from Siemens, outside the submitted work. Rubini Gimenez has received research grants from the Swiss Heart Foundation and Swiss National Science Foundation (P400PM_180828) as well as speakers/consulting honoraria from Abbott, Ortho Clinical Diagnostics, Roche, and Siemens, outside the submitted work. Wildi has received research funding from the FAG Basel, and the Julia und Gottfried Bangerter-Rhyner Stiftung, the Prince Charles Hospital Foundation, the CRE Action Fund (NHMRC), the Wesley Medical Research Foundation, and a PhD n UQ scholarship from the University of Queensland, all outside the submitted work. Koechlin has received a research grant from the University of Basel, the Swiss Academy of Medical Sciences, and the Gottfried and Julia Bangerter-Rhyner Foundation, as well as the “Freiwillige Akademische Gesellschaft Basel”, outside the submitted work. Gualandro has received consulting honoraria from Roche, outside the submitted work. Martin-Sanchez has received speaker, advisory or consulting fees from Novartis, MSD, Bristol–Myers Squibb, Pfizer, The Medicine Company, Otsuka, Thermo Fisher, Cardiorentis, Sanofi, and research grants from the Spanish Ministry of Health and FEDER, Mapfre, Novartis, Bayer, MSD, Abbott, and Orion-Pharma, outside the submitted work. Twerenbold has received research support from the Swiss National Science Foundation (P300PB-167803/1) and speaker honoraria/consulting honoraria from Roche, Abbott, Brahms and Siemens, outside the submitted work. Mueller has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, the Stiftung für kardiovaskuläre Forschung Basel; Abbott, Alere, Astra Zeneca, Beckman Coulter, Biomerieux, Brahms, Roche, Siemens, Singulex, Sphingotec, and the Department of Internal Medicine, University Hospital Basel, as well as speaker honoraria/consulting honoraria from Abbott, Alere, Astra Zeneca, Biomerieux, Boehringer Ingelheim, BMS, Brahms, Cardiorentis, Novartis, Roche, Siemens, and Singulex, outside the submitted work. All other authors declare that they have no conflict of interest with this study. The investigated hs-cTn assay were donated by the manufacturer, who had no role in the design of the study, the analysis of the data, the preparation of the manuscript, or the decision to submit the manuscript for publication.

Figures

Figure 1
Figure 1
Patient flow. AMI, acute myocardial infarction, hs-cTnI, high-sensitivity cardiac Troponin I.
Figure 2
Figure 2
Neumann risk score distribution and relationship with the observed probability of T2MI for each score. (A) Distribution of the calculated Neumann risk score and its relationship with the observed probability of T2MI in all 1079 patients. (B) Total number of AMI patients for each score and patient stratification for T1MI and T2MI. Percentages show the number of patients in each group with respect to the total number of T1MI or T2MI patients (left Y-axis). For calculating the observed probability of T2MI in the validation cohort, the reader only needs to divide the number of T2MI/all patients for the desired score (e.g., for a 3-point score, the observed probability of T2MI would be 24/45 = 53.3%). The observed probability for each point score appears in the right Y-axis.
Figure 3
Figure 3
Calibration plot of the original and recalibrated Neumann Score tested in the validation cohort. Assessment of goodness of fit. (A) Calibration plot of the Neumann Score tested in the validation cohort. The highest predicted probability (0.53) is obtained with a score of 3. An intercept >0 indicates that the score’s predicted probabilities in the validation cohort are systematically too high. (B) Calibration plot of the recalibrated Neumann Score tested in the validation cohort. The highest predicted probability (0.64) is obtained with a score of 3. The agreement between predicted and observed probability appears improved for low risk Scores. An overestimation of the predicted probability can now be observed for the highest score (3). Perfect calibration is represented by the dotted line through the origin. Whiskers indicate 95% CI’s.
Figure 4
Figure 4
Extended Neumann Score, its distribution, and its relationship with the observed probability of T2MI for each Score. (A) Extended Neumann risk score. (B) Distribution of the calculated Extended Neumann risk score and its relationship with the observed probability of T2MI for all 1079 patients. (C) Total number of AMI patients for each score and stratification for T1 and T2MI. Percentages show the number of patients in each group with respect to the total number of T1 or T2MI patients (left Y-axis). For calculating the observed probability of T2MI in the validation cohort, the reader only needs to divide the number of T2MI/all patients for the desired score (e.g., for a 3-point score, the observed probability of T2MI would be 38/67 = 56.7%). The observed probability for each point score appears in the right Y-axis of (B).
Figure 5
Figure 5
Receiver operating characteristic curve to diagnose type 2 MI for the Neumann and Extended Neumann risk Scores.
Figure 6
Figure 6
Calibration plot of the extended Neumann Score tested in the validation cohort. Assessment of goodness of fit. Calibration plot of the prediction Score with the extended Neumann risk groups. The highest predicted probability (1.0) is obtained with a score of 5. A nearly optimal calibration slope was achieved. The calibration plot shows good agreement overall, assessed by the proximity of the six scores (0 to 5). Confidence interval increases as sample size reduces in the score groups. Perfect calibration is represented by the dotted line through the origin. Whiskers indicate 95% CIs.
Figure 7
Figure 7
Classification performance for ruling in T2MI. Positive predictive value (PPV) and true positive rate (TPR) for each point of the Neumann (left) and Extended Neumann Scores (right). (A) The maximum reached PPV with the Neuman Score is 53%, meaning that 53% of patients scoring 3 points are correctly diagnosed with T2MI. For a Score of 3, the TPR is 10%, meaning that 10% of all T2MI patients have a score of 3. (B) The maximum PPV reached with the Extended Neumann Score is 100%, meaning that all patients scoring 5 points are correctly diagnosed with T2MI. For a score of 5, the TPR is 3.3%, meaning that 3.3% of all T2MI patients have a score of 5.
See this image and copyright information in PMC

References

    1. Collet J.-P., Thiele H., Barbato E., Barthélémy O., Bauersachs J., Bhatt D.L., Dendale P., Dorobantu M., Edvardsen T., Folliguet T., et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur. Hear. J. 2020 doi: 10.1093/eurheartj/ehaa624. - DOI - PubMed
    1. Thygesen K., Alpert J.S., Jaffe A.S., Chaitman B.R., Bax J.J., Morrow D.A., White H.D., Mickley H., Crea F., Van de Werf F., et al. Fourth Universal Definition of Myocardial Infarction. J. Am. Coll. Cardiol. 2018;72:2231–2264. doi: 10.1016/j.jacc.2018.08.1038. - DOI - PubMed
    1. Sandoval Y., Jaffe A.S. Type 2 Myocardial Infarction. J. Am. Coll. Cardiol. 2019;73:1846–1860. doi: 10.1016/j.jacc.2019.02.018. - DOI - PubMed
    1. McCarthy C.P., Vaduganathan M., Januzzi J.L. Type 2 Myocardial Infarction—Diagnosis, Prognosis, and Treatment. JAMA. 2018;320:433. doi: 10.1001/jama.2018.7125. - DOI - PubMed
    1. Nestelberger T., Boeddinghaus J., Badertscher P., Twerenbold R., Wildi K., Breitenbücher D., Sabti Z., Puelacher C., Giménez M.R., Kozhuharov N., et al. Effect of Definition on Incidence and Prognosis of Type 2 Myocardial Infarction. J. Am. Coll. Cardiol. 2017;70:1558–1568. doi: 10.1016/j.jacc.2017.07.774. - DOI - PubMed

LinkOut - more resources