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Impact of intermediate events in multi-state models

  • Principal investigator

Prof. Dr. Martin Schumacher
Institute for Medical Biometry and Medical Informatics
University Hospital Freiburg
Stefan-Meier-Str. 26, 79104 Freiburg, Germany
Phone: ++49 (0)761 203 6661
Fax: ++49 (0)761 203 6688

  • Researchers
Prof. Dr. Martin Schumacher ms@imbi.uni-freiburg.de ++49 (0)761 203 6661
Arthur Allignol, M.Sc. arthur@imbi.uni-freiburg.de ++49 (0)761 203 7708
Dr. Jan Beyersmann jan@imbi.uni-freiburg.de ++49 (0)761 203 7702
Dr. Martin Wolkewitz wolke@imbi.uni-freiburg.de ++49 (0)761 203 770

  • Summary
Multi-state and competing risks methodology have remained a highly complex, but also practically very relevant field in biomedical research and application. Analysis of single transition hazards is feasible, but interpretationally difficult. Also, multi-state models are usually assumed to be Markovian, buth this assumption may be questioned in practice. In this project, we will study direct regression of transition probabilities, use the relationship of multi-state models and multiple time scales to relax the nonparametric Markov assumption, and further promote multistate methodology, in particular our results from the first three years, in applications. The methodology shall be made available to the statistical community and beyond through openly available R-packages. Cooperation with statistical computing will consequently be intensive. Hospital infection data will continue to be a focus for application of our methodology. This field has recently shown an increasing interest in so-called `mathematical modeling'; our project will also work in this area, relating epidemic models from `mathematical modeling' to the actual data. The aim is to establish nonparametric data analysis based on counting processes for transmission models of hospital infection.

  • Publications

  1. Beyersmann J, Schumacher M: Time-dependent categorical covariates in the Fine and Gray regression model for competing risks, 2006. Manuscript, submitted.
  2. Beyersmann J, Schumacher M, Wangler M: Change in length of stay due to an intermediate event revisited, 2006. Manuscript, submitted.
  3. Beyersmann J: A random time interval approach for analysing the impact of a possible intermediate event on a terminal event, 2006. Manuscript, submitted.
  4. Beyersmann J, Gastmeier P, Grundmann H, Bärwolff S, Geffers C, Behnke M, Rüden H, Schumacher M: Use of multistate models to assess prolongation of intensive care unit stay due to nosocomial infection. Infection Control and Hospital Epidemiology, 2006; 27: 493-499.
  5. Beyersmann J, Schumacher M: Letter to the editor: comment on `A Latouche and V Boisson and R Porcher and S Chevret: Misspecified regression model for the subdistribution hazard of a competing risk, Statistics in Medicine, 2006, DOI: 10.2002/sim.2600'. Statistics in Medicine, 2006; online.
  6. Beyersmann J, Gerds T, Schumacher M: Letter to the editor: comment on `Illustrating the impact of a time-varying covariate with an extended Kaplan-Meier estimator' by Steven Snapinn, Qi Jiang, and Boris Iglewicz in the November 2005 issue of The American Statistician. The American Statistician, 2006; 60: 295-296.
  7. Beyersmann J, Dettenkofer M, Bertz H, Schumacher M: A competing risks analysis of bloodstream infection after stem-cell transplantation using subdistribution hazards and cause-specific hazards, 2006. Manuscript, submitted.
  8. Graw F: Regressionsmodelle für kumulative Inzidenzfunktionen bei konkurrierenden Risiken über Pseudowerte. Diploma thesis, Albert-Ludwigs-University Freiburg, Germany, 2006.
  9. Latouche A, Beyersmann J, Fine J: Letter to the editor: comment on `M Pintilie: Analysing and interpreting competing risk data, Statistics in Medicine, 2006, DOI: 10.1002/sim.2655', 2006; Accepted for Statistics in Medicine.
  10. Meyer E, Beyersmann J, Bertz H, Wenzler-Röttele S, Babikir R, Schumacher M, Daschner F, Rüden H, Dettenkofer M, the ONKO-KISS study group: Risk factor analysis of blood stream infection and pneumonia in neutropenic patients after peripheral blood stem-cell transplantation. Accepted for Bone Marrow Transplant, 2006.
  11. Schumacher M, Wangler M, Wolkewitz M, Beyersmann J: Attributable mortality due to nosocomial infections: a simple and useful application of multistate models, 2006. Manuscript, submitted.
  12. Wangler M, Beyersmann J, Schumacher M: changeLOS: An R-package for change in length of hospital stay based on the Aalen-Johansen estimator. R News, 2006; 6: 31-35. http:///cran.r-project.org/doc/Rnews/Rnews_2006-2.pdf.
  13. Wolkewitz M, Dettenkofer M, Huebner J, Schumacher M: Modelling the transmission dynamics of nosocomial pathogens with data of a recent VRE-outbreak at a university hospital. In H Reinauer (ed.) GMDS, 11-14, September 2006, Leipzig, Meeting Abstract. GMS German Medical Science - an Interdisciplinary Journal. Oral presentation, online.
  14. Beyersmann J: Book review: Handbook of statistics 23: advances in survival analysis. N. Balakrishnan and C.R. Rao (eds), Elsevier, Amsterdam, 2004. Statistics in Medicine, 2005; 24: 2581.
  15. Beyersmann J: On change in length of stay associated with an intermediate event: estimation within multi-state models and large sample properties. Ph.D. thesis, Albert-Ludwigs-Universität Freiburg im Breisgau, Germany, 2005.
  16. Schulgen G, Olschewski M, Krane V, Wanner C, Ruf G, Schumacher M: Sample sizes for clinical trials with time-to-event endpoints and competing risks. Contemporary Clinical Trials, 2005; 26: 386-395.
  17. Beyersmann J, Schumacher M: SIR 3: Estimation of prolongation of hospital stay due to nosocomial infection. Technical Report, Institute of Medical Biometrics and Medical Informatics, University Hospital, Freiburg, February 2003.
  18. de Haes H, Olschewski M, Kaufmann M, Schumacher M, Jonat W, Sauerbrei W: Quality of life in goserelin-treated versus cyclophosphamide + methotrexate + fluorouracil-treated premenopausal and perimenopausal patients with node-positive, early breast cancer: The Zoladex Early Breast Cancer Research Association Trialists Group. Journal of Clinical Oncology, 2003; 21: 4510-4516.
  19. Kaufmann M, Jonat W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes J, Schumacher M, Sauerbrei W, on~behalf of the Zoladex Early Breast Cancer Research Association (ZEBRA) Trialists' Group: Survival analyses from the ZEBRA study: goserelin (zoladex tm) versus CMF in premenopausal women with node-positive breast cancer. European Journal of Cancer, 2003; 39: 1711-1717.
  20. Dietrich ES, Demmler M, Schulgen G, Fekec K, Mast O, Pelz K, Daschner FD: Nosocomial pneumonia: A cost-of-illness analysis. Infect, 2002; 30: 61-67.
  21. Meier-Hirmer C: Multistate models for the long-term prognosis of breast cancer. Diploma thesis, University of Freiburg, 2002.
  22. Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B: Goserelin versus Cyclophosphamide, Methotrexate, and Fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study. J Clin Oncol, 2002; 20(24): 4628-4635.
  23. Gerds TA, Schumacher M: On functional misspecification of covariates in the Cox regression model. Biometrika, 2001; 88: 572-580.
  24. Schmoor C, Sauerbrei W, Bastert G, Bojar H, Schumacher M for the German Breast Cancer Study Group: Long-term prognosis of breast cancer patients with 10 or more positive lymph nodes treated with CMF. Eur J Cancer, 2001; 37: 1123-1131.
  25. Maurer TB, Ochsner PE, Schwarzer G, Schumacher M: Increased loosening of cemented straight stem prostheses made from titanium alloys. An analysis and comparison with prostheses made of cobalt-chromium-nickel alloy. Int Orthop, 2001; 25: 77-80.
  26. Schwarzer G, Schumacher M, Maurer TB, Ochsner PE: Statistical analysis of failure times in total joint replacement. J Clin Epidemiol, 2001; 54: 997-1003.
  27. Schmoor C, Sauerbrei W, Bastert G, Schumacher M for the German, Breast Cancer Study Group, (GBSG): Role of isolated locoregional recurrence of breast cancer: results of four prospective studies. J Clin Oncol, 2000; 18: 1696-1708.
  28. Schmoor C, Bastert G, Dunst J, Bojar H, Christmann D, Unbehaun V, Tümmers G, Bauer W, Sauerbrei W, Schumacher M for the German Breast Cancer Study Group: Randomized trial on the effect of radiotherapy in addition to 6 cycles of CMF in node positive breast cancer patients. Int J Cancer, 2000; 86: 408-415.
  29. Schulgen G, Kropec A, Kappstein I, Daschner F, Schumacher M: Estimation of extra hospital stay attributable to nosocomial infections: heterogeneity and timing of events. J Clin Epidemiol, 2000; 53: 409-417.
  30. Frank U, Daschner FD, Schulgen G, Mills J: Incidence and epidemiology of nosocomial infections in patients infected with human immunodeficiency virus. Clin Infect Dis, 1997; 25: 318-320.
  31. Schulgen G, Schumacher M: Estimation of prolongation of hospital stay attributable to nosocomial infections: New approaches based on multistate models. Lifetime Data Anal, 1996; 2: 219-240.
  32. Kropec A, Schulgen G, Just H, Geiger K, Schumacher M: Scoring system for nosocomial pneumonia in ICUs. Intensive Care Med, 1996; 22: 1155-1161.
  33. Kappstein I, Schulgen G, Fraedrich G, Schlosser V, Schumacher M, Daschner FD: Added hospital stay due to wound infections following cardiac surgery. Thorac CardiovasC Surg, 1992, 40. 148-151.
  34. Kappstein I, Schulgen G, Beyer U, Schumacher M, Daschner FD: Prolongation of hospital stay and extra costs due to ventilator-associated pneumonia in an intensive care unit. European J Clin Microbiol Infect Dis, 1991; 11: 504-508.
  35. Grüger J, Kay R and Schumacher M: The validity of inferences based on incomplete observations in disease state models. Biometrics, 1991; 47: 595-605.
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