Development of a Machine Learning and Artificial Intelligence Based Model Aimed at Forecasting the Prognostic Impact of C-Reactive Protein in Myocarditis

Year : 2024 | Volume :14 | Issue : 02 | Page : 12-24
By

indra singh,

Abdul Kareem,

  1. Professor & HOD Department of AI & ML and data Science, Moddlakatte Institute of Technology, Kundapura Karnataka India
  2. Professor, Principal & Chairman Department of AI & ML and data Science, Moddlakatte Institute of Technology, Kundapura Karnataka India

Abstract

The specific role of inflammation markers in myocarditis remains uncertain. We investigated the diagnostic and prognostic significance of C-reactive protein (CRP) levels at the initial diagnosis among myocarditis patients. Our retrospective study enrolled patients clinically suspected (CS) or biopsy-proven (BP) with myocarditis, with available CRP data at diagnosis. We collected patient information, including clinical, laboratory, and imaging findings at diagnosis and follow-up visits. We utilized machine learning methods, specifically random forest for survival data analysis, to identify factors predicting death or the need for a heart transplant (Htx). Our cohort included 409 patients, predominantly male (74%), with an average age of 37 ± 15 years and a median follow-up period of 2.9 years. Elevated CRP levels were observed in 288 patients, particularly in those with CS myocarditis (p < 0.001), recent viral infections, shorter symptom duration (p = 0.001), chest pain (p < 0.001), better functional status at diagnosis (p = 0.018), and higher troponin I levels (p < 0.001). Among the 13 patients experiencing death or requiring heart transplant, 10 had BP myocarditis, yielding an overall 10-year survival rate of 94%. However, survival rates did not significantly differ based on CRP levels (p = 0.23). The most robust predictors of survival were left ventricular ejection fraction (LVEF), presence of anti-nuclear autoantibodies (ANA), and biopsy-confirmed myocarditis. In conclusion, elevated CRP levels at diagnosis may suggest CS myocarditis and milder clinical manifestations but do not significantly contribute to predicting long-term survival. Primary predictors of adverse outcomes include reduced LVEF, biopsy-proven diagnosis, and the presence of ANA.

Keywords: Myocarditis, C-reactive protein (CRP), diagnosis, prognosis, survival analysis, random forest, machine learning, biopsy-proven myocarditis, clinically suspected myocarditis, troponin I levels, left ventricular ejection fraction (LVEF), anti-nuclear autoantibodies (ANA), chest pain, viral infections

[This article belongs to Research & Reviews: A Journal of Health Professions(rrjohp)]

How to cite this article: indra singh, Abdul Kareem. Development of a Machine Learning and Artificial Intelligence Based Model Aimed at Forecasting the Prognostic Impact of C-Reactive Protein in Myocarditis. Research & Reviews: A Journal of Health Professions. 2024; 14(02):12-24.
How to cite this URL: indra singh, Abdul Kareem. Development of a Machine Learning and Artificial Intelligence Based Model Aimed at Forecasting the Prognostic Impact of C-Reactive Protein in Myocarditis. Research & Reviews: A Journal of Health Professions. 2024; 14(02):12-24. Available from: https://journals.stmjournals.com/rrjohp/article=2024/view=167324



References

  1. Aha, D. W., Kibler, D., and Albert, M. K. (1991). Instance-based learning algorithms. Machine learn-ing, 6(1):37–66.
  2. Anagnostis, P., Stevenson, J. C., Crook, D., Johnston, D. G.,and Godsland, I. F. (2015). Effects of menopause, gender and age on lipids and high-density lipoprotein cholesterol subfractions. Maturitas, 81(1):62–68. Breiman, L. (2001). Random forests. Machine learning, 45(1):5–32.
  3. Chen, S., Bergman, D., Miller, K., Kavanagh, A., Frown-felter, J., and Showalter, J. (2020). Using applied machine learning to predict healthcare utilization based on socioeconomic determinants of care. Am J Manag Care, 26(01):26–31.
  4. Colak C, Colak MC, Ermis N, Erdil N, Ozdemir R. Prediction of cholesterol level in patients with myocardial infarction based on medical data mining methods. Kuwait Journal of Science. 2016 Aug 8;43(3).
  5. Cortes, C. and Vapnik, V. (1995). Support-vector networks.Machine learning, 20(3):273–297.
  6. Crouse SF, O’Brien BC, Rohack JJ, Lowe RC, Green JS, Tolson HO, Reed JL. Changes in serum lipids and apolipoproteins after exercise in men with high cholesterol: influence of intensity. Journal of Applied Physiology. 1995 Jul 1;79(1):279-86.
  7. Indra VS, Maninder SS, BageSree S, Revathi R. Assessment of Output Radiation Density of Cell Phone for Epidemiological Studies: A Pilot Study in Navi Mumbai. JOURNAL OF ENVIRONMENTAL INFORMATICS LETTERS. 2024 Apr 10;11(1):21-8.
  8. Indra Vijay Singh and M.S Setia, Investigation of Power Density of Emerging Cellular Towers against the Distance and Frequency-A Case Study,. Scopus Index, IOS Press IOS Press, NieuweHemweg, 61013 BG Amsterdam, the Netherlands, ISSN online 2352-7528, Jan-2023.
  9. Singh IV, Alam MS. Inter-modulation linearity investigation of an optimally designed and optimally biased LNA for wireless LAN. Radioelectronics and Communications Systems. 2015 May;58:191-200.
  10. Avan A, Tavakoly Sany SB, Ghayour‐Mobarhan M, Rahimi HR, Tajfard M, Ferns G. Serum C‐reactive protein in the prediction of cardiovascular diseases: Overview of the latest clinical studies and public health practice. Journal of cellular physiology. 2018 Nov;233(11):8508-25.
  11. Boncler M, Wu Y, Watala C. The multiple faces of C-reactive protein—physiological and pathophysiological implications in cardiovascular disease. Molecules. 2019 May 30;24(11):2062.
  12. Osman R., L’Allier P.L., Elgharib N., Tardif J.-C. Critical appraisal of C-reactive protein throughout the spectrum of cardiovascular disease. Heal. Risk Manag. 2006;2:221–237. doi: 10.2147/vhrm.2006.2.3.221. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  13. Schwuchow-Thonke S., Göbel S., Emrich T., Schmitt V.H., Fueting F., Klank C., Escher F., Schultheiss H.P., Münzel T., Keller K., et al. Increased C reactive protein, cardiac troponin I and GLS are associated with myocardial inflammation in patients with non-ischemic heart failure. Rep. 2021;11:3008. doi: 10.1038/s41598-021-82592-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  14. Kim J.T., Cho S., III, Lee S.Y., Kim D., Lim S.H., Kang T.S., Lee M.Y. The use of machine learning algorithms for the identification of stable obstructive coronary artery disease. Am. Coll. Cardiol. 2020;75:254. doi: 10.1016/S0735-1097(20)30881-0. [CrossRef] [Google Scholar]
  15. Nakanishi R., Dey D., Commandeur F., Slomka P., Betancur J., Gransar H., Dailing C., Osawa K., Berman D., Budoff M. Machine learning in predicting coronary heart disease and cardiovascular disease events: Results from the multi-ethnic study of atherosclerosis (mesa) Am. Coll. Cardiol. 2018;71:A1483. doi: 10.1016/S0735-1097(18)32024-2. [CrossRef] [Google Scholar]
  16. Ambale-Venkatesh B., Yang X., Wu C.O., Liu K., Hundley W.G., McClelland R., Gomes A.S., Folsom A.R., Shea S., Guallar E., et al. Cardiovascular event prediction by machine learning: The multi-ethnic study of atherosclerosis. Res. 2017;121:1092–1101. doi: 10.1161/CIRCRESAHA.117.311312. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  17. Sampedro-Gómez J., Dorado-Díaz P.I., Vicente-Palacios V., Sánchez-Puente A., Jiménez-Navarro M., Roman J.A.S., Galindo-Villardón P., Sanchez P.L., Fernández-Avilés F. Machine Learning to Predict Stent Restenosis Based on Daily Demographic, Clinical, and Angiographic Characteristics. J. Cardiol. 2020;36:1624–1632. doi: 10.1016/j.cjca.2020.01.027. [PubMed] [CrossRef] [Google Scholar]
  18. Dong P., Ye G., Kaya M., Gu L. Simulation-Driven Machine Learning for Predicting Stent Expansion in Calcified Coronary Artery. Sci. 2020;10:5820. doi: 10.3390/app10175820. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  19. Caforio A., Baritussio A., Marcolongo R., Cheng C.-Y., Pontara E., Bison E., Cattini M., Gallo N., Plebani M., Iliceto S., et al. Serum Anti-Heart and Anti-Intercalated Disk Autoantibodies: Novel Autoimmune Markers in Cardiac Sarcoidosis. Clin. Med. 2021;10:2476. doi: 10.3390/jcm10112476. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  20. Seferović P.M., Tsutsui H., McNamara D.M., Ristić A.D., Basso C., Bozkurt B., Jr L.T.C., Filippatos G., Ide T., Inomata T., et al. Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy. J. Heart Fail. 2021;23:854–871. doi: 10.1002/ejhf.2190. [PubMed] [CrossRef] [Google Scholar]
  21. Breiman L. Random Forest. Learn. 2001;45:5–32. doi: 10.1023/A:1010933404324. [CrossRef] [Google Scholar]
  22. Ishwaran H., Kogalur U.B., Blackstone E.H., Lauer M.S. Random survival forests. App. Stat. 2008;2:841–860. doi: 10.1214/08-AOAS169. [CrossRef] [Google Scholar]
  23. Ishwaran H., Kogalur U.B., Gorodeski E.Z., Minn A.J., Lauer M.S. High-Dimensional Variable Selection for Survival Data. Am. Stat. Assoc. 2010;105:205–217. doi: 10.1198/jasa.2009.tm08622. [CrossRef] [Google Scholar]
  24. Harrell F.E., Jr., Lee K.L., Mark D.B. Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Med. 1996;15:361–387. doi: 10.1002/(SICI)1097-0258(19960229)15:43.0.CO;2-4. [PubMed] [CrossRef] [Google Scholar]
  25. Shaikhina T., Lowe D., Daga S., Briggs D., Higgins R., Khovanova N. Decision tree and random forest models for outcome prediction in antibody incompatible kidney transplantation. Signal Process. Control. 2019;52:456–462. doi: 10.1016/j.bspc.2017.01.012. [CrossRef] [Google Scholar]
  26. R Development Core Team . 0.1. A Language and Environment for Statistical Computing. Volume 2. R Foundation for Statistical Computing; Vienna, Austria: 2019. [(accessed on 1 June 2020)]. Available online: http://www.R-project.org [Google Scholar]
  27. Harrell F.E., Jr. Package ‘rms’: Regression Modeling Strategies. R Foundation for Statistical Computing; Vienna, Austria: 2019. [(accessed on 1 June 2020)]. pp. 1–246. Available online: https://cran.rorg/web/packages/rms/rms.pdf [Google Scholar]
  28. Therneau T., Grambsch P. Modeling Survival Data: Extending the Cox Model. Springer; New York, NY, USA: 2000. [Google Scholar]
  29. Alboukadel K., Marcin K., Przemyslaw B., Scheipl F. Drawing Survival Curves Using ‘ggplot2’ [R package Survminer Version 0.4.3] R Foundation for Statistical Computing; Vienna, Austria: 2018. R Package Version 0.4.3. [Google Scholar]
  30. Harrell F.E., Jr., Lee K.L., Matchar D.B., Reichert T.A. Regression models for prognostic prediction: Advantages, problems, and suggested solutions. Cancer Treat. Rep. 1985;69:1071– 1077. [PubMed] [Google Scholar]
  31. Peduzzi P., Concato J., Feinstein A.R., Holford T.R. Importance of events per independent variable in proportional hazards regression analysis II. Accuracy and precision of regression estimates. Clin. Epidemiol. 1995;48:1503–1510. doi: 10.1016/0895-4356(95)00048-8. [PubMed] [CrossRef] [Google Scholar]
  32. Concato J., Peduzzi P., Holford T.R., Feinstein A.R. Importance of events per independent variable in proportional hazards analysis I. Background, goals, and general strategy. Clin. Epidemiol. 1995;48:1495–1501. doi: 10.1016/0895-4356(95)00510-2. [PubMed] [CrossRef] [Google Scholar]
  33. Ogundimu E.O., Altman D.G., Collins G.S. Adequate sample size for developing prediction models is not simply related to events per variable. Clin. Epidemiol. 2016;76:175–182. doi: 10.1016/j.jclinepi.2016.02.031. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  34. Salkind N.J. Encyclopedia of Research Design. Volume 1 SAGE; Newbury Park, CA, USA: 2010. [Google Scholar]
  35. Steele A.J., Denaxas S.C., Shah A.D., Hemingway H., Luscombe N.M. Machine learning models in electronic health records can outperform conventional survival models for predicting patient mortality in coronary artery disease. PLoS ONE. 2018;13:e0202344. doi: 10.1371/journal.pone.0202344. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  36. Ammirati E., Cipriani M., Moro C., Raineri C., Pini D., Sormani P., Mantovani R., Varrenti M., Pedrotti P., Conca C., et al. Clinical Presentation and Outcome in a Contemporary Cohort of Patients with Acute Myocarditis: Multicenter Lombardy Registry. 2018;138:1088–1099. doi: 10.1161/CIRCULATIONAHA.118.035319. [PubMed] [CrossRef] [Google Scholar]
  37. Verdonschot J.A.J., Merlo M., Dominguez F., Wang P., Henkens M.T.H.M., Adriaens M.E., Hazebroek M.R., Masè M., Escobar L.E., Cobas-Paz R., et al. Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences. Heart J. 2021;42:162–174. doi: 10.1093/eurheartj/ehaa841. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  38. Caforio A.L.P., De Luca G., Baritussio A., Seguso M., Gallo N., Bison E., Cattini M.G., Pontara E., Gargani L., Pepe A., et al. Serum Organ-Specific Anti-Heart and Anti-Intercalated Disk Autoantibodies as New Autoimmune Markers of Cardiac Involvement in Systemic Sclerosis: Frequency, Clinical and Prognostic Correlates. 2021;11:2165. doi: 10.3390/diagnostics11112165. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  39. Baritussio A., Schiavo A., Basso C., Giordani A.S., Cheng C., Pontara E., Cattini M.G., Bison E., Gallo N., De Gaspari M., et al. Predictors of relapse, death or heart transplantation in myocarditis before the introduction of immunosuppression: Negative prognostic impact of female gender, fulminant onset, lower ejection fraction and serum autoantibodies. J. Heart Fail. 2022;24:1033–1044. doi: 10.1002/ejhf.2496. [PubMed] [CrossRef] [Google Scholar]
  40. Abbate A., Toldo S., Marchetti C., Kron J., Van Tassell B.W., Dinarello C.A. Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease. Res. 2020;126:1260–1280. doi: 10.1161/CIRCRESAHA.120.315937. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  41. Ridker P.M., Everett B.M., Thuren T., MacFadyen J.G., Chang W.H., Ballantyne C., Fonseca F., Nicolau J., Koenig W., Anker S.D., et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. Engl. J. Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914. [PubMed] [CrossRef] [Google Scholar]
  42. Abbate A., Van Tassell B.W., Biondi-Zoccai G., Kontos M.C., Grizzard J.D., Spillman D.W., Oddi C., Roberts C.S., Melchior R.D., Mueller G.H., et al. Effects of Interleukin-1 Blockade with Anakinra on Adverse Cardiac Remodeling and Heart Failure After Acute Myocardial Infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) Pilot Study] J. Cardiol. 2013;111:1394–1400. doi: 10.1016/j.amjcard.2013.01.287. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  43. Buckley L.F., Viscusi M.M., Van Tassell B.W., Abbate A. Interleukin-1 blockade for the treatment of pericarditis. Heart J. Cardiovasc. Pharmacother. 2018;4:46–53. doi: 10.1093/ehjcvp/pvx018. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  44. Brucato A., Imazio M., Gattorno M., Lazaros G., Maestroni S., Carraro M., Finetti M., Cumetti D., Carobbio A., Ruperto N., et al. Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: The AIRTRIP Randomized Clinical Trial. 2016;316:1906–1912. doi: 10.1001/jama.2016.15826. [PubMed] [CrossRef] [Google Scholar]
  45. Blanco-Domínguez R., Sánchez-Díaz R., de la Fuente H., Jiménez-Borreguero L.J., Matesanz-Marín A., Relaño M., Jiménez-Alejandre R., Linillos-Pradillo B., Tsilingiri K., Martín-Mariscal M.L., et al. A Novel Circulating Noncoding Small RNA for the Detection of Acute Myocarditis. Engl. J. Med. 2021;384:2014–2027. doi: 10.1056/NEJMoa2003608. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  46. Caforio A.L., Calabrese F., Angelini A., Tona F., Vinci A., Bottaro S., Ramondo A., Carturan E., Iliceto S., Thiene G., et al. A prospective study of biopsy-proven myocarditis: Prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Heart J. 2007;28:1326–1333. doi: 10.1093/eurheartj/ehm076. [PubMed] [CrossRef] [Google Scholar]
  47. Anzulovic-Mirosevic D., Razzolini R., Zaninotto M., Plebani M., Mion M.M., Rozga A., Dalla-Volta S. The C-Reactive Protein Levels in Left Ventricular Dysfunction of Different Etiology. Allergy Frug Targets. 2009;8:247–251. doi: 10.2174/187152809789352212. [PubMed] [CrossRef] [Google Scholar]
  48. Lee S.-S., Singh S., Link K., Petri M. High-Sensitivity C-Reactive Protein as an Associate of Clinical Subsets and Organ Damage in Systemic Lupus Erythematosus. Arthritis Rheum. 2008;38:41–54. doi: 10.1016/j.semarthrit.2007.09.005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  49. Oikonomou E., Marwan M., Desai M.Y., Mancio J., Alashi A., Centeno E.H., Thomas S., Herdman L., Kotanidis C., Thomas K.E., et al. Non-invasive detection of coronary inflammation using computed tomography and prediction of residual cardiovascular risk (the CRISP CT study): A post-hoc analysis of prospective outcome data. 2018;392:929–939. doi: 10.1016/S0140-6736(18)31114-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  50. Baritussio A., Vacirca F., Ocagli H., Tona F., Pergola V., Motta R., Marcolongo R., Lorenzoni G., Gregori D., Iliceto S., et al. Assessment of Coronary Inflammation by Pericoronary Fat Attenuation Index in Clinically Suspected Myocarditis with Infarct-Like Presentation. Clin. Med. 2021;10:4200. doi: 10.3390/jcm10184200. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  51. Goeller M., Achenbach S., Herrmann N., Bittner D.O., Kilian T., Dey D., Raaz-Schrauder D., Marwan M. Pericoronary adipose tissue CT attenuation and its association with serum levels of atherosclerosisrelevant inflammatory mediators, coronary calcification and major adverse cardiac events. Cardiovasc. Comput. Tomogr. 2021;15:449–454. doi: 10.1016/j.jcct.2021.03.005. [PubMed] [CrossRef] [Google Scholar]
  52. Baritussio A., Williams M.C. Gaining evidence on coronary inflammation. Cardiovasc. Comput. Tomogr. 2021;15:455–456. doi: 10.1016/j.jcct.2021.04.004. [PubMed] [CrossRef] [Google Scholar]
  53. Imazio M., Brucato A., Maestroni S., Cumetti D., Dominelli A., Natale G., Trinchero R. Prevalence of C-Reactive Protein Elevation and Time Course of Normalization in Acute Pericarditis. 2011;123:1092–1097. doi: 10.1161/CIRCULATIONAHA.110.986372. [PubMed] [CrossRef] [Google Scholar]
  54. Kaneko K., Kanda T., Hasegawa A., Suzuki T., Kobayashi I., Nagai R. C-reactive Protein as a Prognostic Marker in Lymphocytic Myocarditis. Heart J. 2000;41:41–47. doi: 10.1536/jhj.41.41. [PubMed] [CrossRef] [Google Scholar]
  55. Ammirati E., Veronese G., Brambatti M., Merlo M., Cipriani M., Potena L., Sormani P., Aoki T., Sugimura K., Sawamura A., et al. Fulminant Versus Acute Nonfulminant Myocarditis in Patients with Left Ventricular Systolic Dysfunction. Am. Coll. Cardiol. 2019;74:299–311. doi: 10.1016/j.jacc.2019.04.063. [PubMed] [CrossRef] [Google Scholar]
  56. Anzini M., Merlo M., Sabbadini G., Barbati G., Finocchiaro G., Pinamonti B., Salvi A., Perkan A., Di Lenarda A., Bussani R., et al. Long-Term Evolution and Prognostic Stratification of Biopsy-Proven Active Myocarditis. 2013;128:2384–2394. doi: 10.1161/CIRCULATIONAHA.113.003092. [PubMed] [CrossRef] [Google Scholar]
  57. Ammirati E., Cipriani M., Lilliu M., Sormani P., Varrenti M., Raineri C., Petrella D., Garascia A., Pedrotti P., Roghi A., et al. Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis. 2017;136:529–545. doi: 10.1161/CIRCULATIONAHA.117.026386. [PubMed] [CrossRef] [Google Scholar]
  58. Mason J.W., O’Connell J.B., Herskowitz A., Rose N.R., McManus B.M., Billingham M.E., Moon T.E. A Clinical Trial of Immunosuppressive Therapy for Myocarditis. Engl. J. Med. 1995;333:269–275. doi: 10.1056/NEJM199508033330501. [PubMed] [CrossRef] [Google Scholar]
  59. Frustaci A., Russo M.A., Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: The TIMIC study. Heart J. 2009;30:1995–2002. doi: 10.1093/eurheartj/ehp249. [PubMed] [CrossRef] [Google Scholar]
  60. Kandolin R., Lehtonen J., Salmenkivi K., Räisänen-Sokolowski A., Lommi J., Kupari M. Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression. Heart Fail. 2013;6:15–22. doi: 10.1161/CIRCHEARTFAILURE.112.969261. [PubMed] [CrossRef] [Google Scholar].
  61. Tymińska A, Ozierański K, Caforio AL, Marcolongo R, Marchel M, Kapłon-Cieślicka A, Baritussio A, Filipiak KJ, Opolski G, Grabowski M. Myocarditis and inflammatory cardiomyopathy in 2021: An update. Pol. Arch. Intern. Med. 2021 May 24;131(6):594-606.

Regular Issue Subscription Review Article
Volume 14
Issue 02
Received June 24, 2024
Accepted July 2, 2024
Published August 16, 2024

Check Our other Platform for Workshops in the field of AI, Biotechnology & Nanotechnology.
Check Out Platform for Webinars in the field of AI, Biotech. & Nanotech.