Development and internal validation of a gradient-boosted trees model for prediction of delirium after surgery and anesthesia (the BioCog study)

medRxiv

Abstract

Abstract IMPORTANCE Postoperative delirium (POD) is a multietiological condition and affects 20% of older surgical patients. It is associated with poor clinical outcome and increased mortality. OBJECTIVE We aimed to develop and validate a risk prediction algorithm for POD based on a multimodal biomarker database exploiting preoperative data (predisposing factors) and procedural factors as well as perioperative molecular changes associated with POD (precipitating factors). DESIGN BioCog is a prospective cohort study conducted from November 2014 to April 2017. Patients were followed up for seven postoperative days after surgery for POD. Gradient-boosted trees (GBT) with nested cross-validation was used for POD prediction. SETTING Patients aged ≥65 years were enrolled at the anesthesiologic departments of two tertiary care centers. EXPOSURE All patients underwent surgery with an expected duration of at least 60min. Clinical, neuropsychological, neuroimaging data and blood were collected and clinically well established as well as non-established biomarkers (e.g., gene expression profiling) were measured pre- and postoperatively. MAIN OUTCOME POD according to DSM 5 until the seventh postoperative day RESULTS 184 of 929 (20%) patients experienced POD. A GBT algorithm using both preoperative data, characteristics of the intervention and postoperative changes in laboratory parameters achieved the highest area under the curve (0.83, [0.79; 0.86]) with a Brier score of 0.12 (0.12; 0.13). CONCLUSIONS AND RELEVANCE Models combining predisposing factors with precipitating factors predict POD best. Non-routine laboratory data provide useful information for POD risk prediction, providing relevant results for future studies on the molecular factors of POD. In addition, possibly relevant molecular mechanisms contributing to the development of POD were identified, mostly indicating a dysregulated postoperative immune response. This study constitutes the basis for future hypothesis-driven analyses or implementation of prediction expert system for clinical practice.

Authors 57

1. Florian Lammers‐Lietz corresponding

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

   Pharmaimage Biomarker Solutions GmbH, Berlin, Germany

2. Levent Akyuez

   Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Berlin Institute of Health at Charité –Universitätsmedizin Berlin, BIH Center for Regenerative therapies (BCRT), and Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, CVK, Augustenburger Platz 1, 13353 Berlin, Germany

   CheckImmune GmbH, Berlin, Germany

3. Diana Boraschi

   Institute of Protein Biochemistry · National Research Council

   Affiliation as printed

   Institute of Protein Biochemistry, Consiglio Nazionale delle Ricerche (CNR) di Pisa, Pisa, Italy

4. Friedrich Borchers

   Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

   Affiliation as printed

   Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

5. Jeroen de Bresser Aachen Department of Radiology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Radiology, Leiden University Medical Center, Leiden, Netherlands

6. Marta Correia

   MRC Cognition and Brain Sciences Unit · University of Cambridge

   Affiliation as printed

   MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, United Kingdom

7. Nikola M. de Lange

   University of Luxembourg · Luxembourg Centre for Systems Biomedicine

   Affiliation as printed

   Bioinformatics Core, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg

8. Thomas Bernd Dschietzig

   Immundiagnostik (Germany)

   Affiliation as printed

   Immundiagnostik AG, Bensheim, Germany

9. Soumyabrata Ghosh

   University of Luxembourg · Luxembourg Centre for Systems Biomedicine

   Affiliation as printed

   Bioinformatics Core, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg

10. Insa Feinkohl

    Witten/Herdecke University · Max Delbrück Center

    Affiliation as printed

    Faculty of Health at Department of Medicine, Witten/Herdecke University

    Molecular Epidemiology Research Group, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

11. Izabela Ferreira da Silva

    University of Luxembourg · Luxembourg Centre for Systems Biomedicine

    Affiliation as printed

    Bioinformatics Core, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg

12. Marinus Fislage

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

13. Anna Fournier

    University of Luxembourg · ETH Zurich · Swiss Data Science Center · Luxembourg Centre for Systems Biomedicine

    Affiliation as printed

    Bioinformatics Core, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg

    Swiss Data Science Center (SDSC), ETH Zurich, Zurich, Switzerland

14. Jürgen Gallinat

    University Medical Center Hamburg-Eppendorf

    Affiliation as printed

    Department of Psychiatry, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany

15. Daniel A. Hadzidiakos

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

16. Fatima Yürek

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

17. Stefanie Heilmann‐Heimbach

    University of Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Bonn, Germany

18. Maria Heinrich

    Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BIH Academy, (Digital) Clinician Scientist Program, Berlin, Germany

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

19. Jeroen Hendrikse

    University Medical Center Utrecht

    Affiliation as printed

    Department of Radiology and Brain Center Rudolf Magnus, University Medical Center Utrecht (UMC), Utrecht, Netherlands

20. Per Hoffmann

    University of Bonn · University of Basel · University Hospital of Basel

    Affiliation as printed

    Division of Medical Genetics, University Hospital, Basel, Switzerland

    Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland

    Institute of Human Genetics, University of Bonn, Bonn, Germany

21. Ilse M.J. Kant

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Intensive Care Medicine and Brain Center, University Medical Center Utrecht (UMC), Utrecht University, Utrecht, the Netherlands

22. Angelie Kraft
    Affiliation as printed

    AdaLab UG, Hamburg, Germany

    Pharmaimage Biomarker Solutions Inc., Cambridge, USA

23. Roland Krause

    University of Luxembourg · Luxembourg Centre for Systems Biomedicine

    Affiliation as printed

    Bioinformatics Core, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg

24. Jochen Kruppa

    Humboldt-Universität zu Berlin · Hochschule Osnabrück · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Charitéplatz 10117 Berlin

    Hochschule Osnabrück, University of Applied Sciences, Osnabrück, Germany

25. Simone Kühn

    Humboldt-Universität zu Berlin · University Medical Center Hamburg-Eppendorf · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

    Department of Psychiatry, University Medical-Center Hamburg-Eppendorf, Hamburg, Germany

26. Gunnar Lachmann

    Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BIH Academy, (Digital) Clinician Scientist Program, Berlin, Germany

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

27. Markus Laubach

    LMU Klinikum · Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

    Department of Orthopaedics and Trauma Surgery, Musculoskeletal University Center Munich (MUM), LMU University Hospital, LMU Munich, Munich, Germany

    Pharmaimage Biomarker Solutions Inc., Cambridge, USA

28. Christoph Lippert

    Hasso Plattner Institute · University of Potsdam

    Affiliation as printed

    Hasso-Plattner Institute, University of Potsdam, Potsdam, Germany

29. David Krishna Menon

    University of Cambridge · Cambridge University Hospitals NHS Foundation Trust

    Affiliation as printed

    Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom

    Neurosciences/Trauma Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom

30. Rudolf Mörgeli

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

31. Anika Mueller

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

32. Henk J. M. M. Mutsaerts

    Amsterdam UMC Location University of Amsterdam · Amsterdam Neuroscience · Amsterdam University Medical Centers

    Affiliation as printed

    Amsterdam Neuroscience, Amsterdam, The Netherlands

    Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

33. Markus Maria Nöthen

    University of Bonn

    Affiliation as printed

    Institute of Human Genetics, University of Bonn, Bonn, Germany

34. Peter Nürnberg

    University of Cologne · Atlas Biolabs (Germany) · University Hospital Cologne

    Affiliation as printed

    Atlas Biolabs GmbH, Berlin, Germany

    Cologne Center for Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

    Institute for Genetics of the University of Cologne, Cologne, Germany

35. Kwaku Ofosu

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

36. Malte Pietzsch
    Affiliation as printed

    Cellogic GmbH (Cellogic), Berlin, Germany

37. Sophie K. Piper

    University of Cambridge · Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Charitéplatz 10117 Berlin

    Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom

38. Tobias Pischon

    Max Delbrück Center · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Core Facility Biobank, Berlin, Germany

    Biobank Technology Platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

    Molecular Epidemiology Research Group, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany

39. Jacobus Preller

    University of Cambridge · Cambridge University Hospitals NHS Foundation Trust

    Affiliation as printed

    Department of Medicine, University of Cambridge

    Neurosciences/Trauma Critical Care Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom

40. Konstanze Scheurer

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

41. Reinhard Schneider

    University of Luxembourg · Luxembourg Centre for Systems Biomedicine

    Affiliation as printed

    Bioinformatics Core, Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg

42. Kathrin Scholtz

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

43. Peter H. Schreier

    University of Cologne

    Affiliation as printed

    Institute for Genetics of the University of Cologne, Cologne, Germany

    Pharmaimage Biomarker Solutions Inc., Cambridge, USA

44. Arjen J. C. Slooter

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Intensive Care Medicine and Brain Center, University Medical Center Utrecht (UMC), Utrecht University, Utrecht, the Netherlands

45. Emmanuel Andreas Stamatakis

    University of Cambridge

    Affiliation as printed

    Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom

    Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, United Kingdom

46. Clarissa von Haefen

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

47. Simone J.T. van Montfort

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Intensive Care Medicine and Brain Center, University Medical Center Utrecht (UMC), Utrecht University, Utrecht, the Netherlands

48. Edwin van Dellen

    Utrecht University · University Medical Center Utrecht

    Affiliation as printed

    Department of Intensive Care Medicine and Brain Center, University Medical Center Utrecht (UMC), Utrecht University, Utrecht, the Netherlands

    Department of Psychiatry and UMC Utrecht Brain Center, University Medical Center Utrecht (UMC), Utrecht, Netherlands

49. Hans‐Dieter Volk

    Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Berlin Institute of Health at Charité –Universitätsmedizin Berlin, BIH Center for Regenerative therapies (BCRT), and Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Medical Immunology, CVK, Augustenburger Platz 1, 13353 Berlin, Germany

    CheckImmune GmbH, Berlin, Germany

50. Simon A. Weber
    Affiliation as printed

    Cellogic GmbH (Cellogic), Berlin, Germany

51. Janine Wiebach

    Humboldt-Universität zu Berlin · Berlin Institute of Health at Charité - Universitätsmedizin Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    BIH Berlin Institute of Health at Charité–Universitätsmedizin Berlin, 10117 Berlin, Germany, Core Unit Metabolomics

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Biometry and Clinical Epidemiology, Charitéplatz 10117 Berlin

52. Anton Wiehe
    Affiliation as printed

    AdaLab UG, Hamburg, Germany

    Pharmaimage Biomarker Solutions Inc., Cambridge, USA

53. Jeanne M. Winterer

    Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Psychiatry |CCM, Charitéplatz 1, 10117 Berlin, Berlin, Germany

    Department of Education and Psychology, Freie Universität Berlin, Berlin, Germany

    Pharmaimage Biomarker Solutions GmbH, Berlin, Germany

54. Alissa Wolf

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

55. Norman Zacharias

    Humboldt-Universität zu Berlin · Freie Universität Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

    Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany

    Pharmaimage Biomarker Solutions Inc., Cambridge, USA

56. Claudia Spies

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

57. Georg Winterer

    Humboldt-Universität zu Berlin · Charité - Universitätsmedizin Berlin

    Affiliation as printed

    Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine | CCM | CVK, Augustenburger Platz 1, 13353 Berlin, Germany

    Pharmaimage Biomarker Solutions GmbH, Berlin, Germany

    Pharmaimage Biomarker Solutions Inc., Cambridge, USA