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Institute of Medical Biometry and Statistics (IMBI)

Epidemic modelling of hospital-acquired infections using individual patient data

Funding: 72 months, since 2011

Abstract

The principle aim of this project is to apply innovative statistical models and study
designs to nosocomial infections (NIs). Using a multi-center data base from the Spanish
surveillance network with 159 intensive care units (ICUs) containing 109,216 admissions,
the current project addressed the following challenges. We showed how competing events
(discharge or death) make risk estimation of NI difficult and how they can be addressed.
We showed how accounting for the time-dependency of NIs is necessary to avoid the time-
dependent bias. We showed how length bias might occur in presence of time-dependent
study entries or studying different time scales. We studied how two different time scales
(calendar time or time from admission) are related to the occurrence of NIs. Further, patients
are clustered within NIs and multilevel analyses are required to distinguish between patient-
level and ICU-specific factors. The popular case-control study design has to be adapted to
account for competing events. Finally, we provided guidance on choosing the most appropriate
study design for intervention studies.
In this follow-up application, basically three topics are planned to be investigated. The
first part is to judge and correctly interprete published prevalence, i.e., cross-sectional,
studies of NIs. This will be done by showing mathematical relationships between ratios of
incidence rates, prevalences and risks using a multistate model. The Spanish ICU data is
perfectly suitable to create artificial prevalence studies and make real-world comparisons.
Second, we aim to provide a model which accurately quantifies the association between the
duration of invasive devices and the risk of NIs. Third, we aim to study an established
multi-state model (suitable to study risk factors as well as the burden of NIs) by an extension
of the case-cohort design.
All topics are motivated from recent publications in top medical journals (such as Lancet,
Lancet Infect Dis, Lancet Resp Med, JAMA and NEJM) and studied from a mathematical
as well as a statistical point of view using simulations and real ICU data. Statistical code
will be made available to ensure transparency and reliability.

Publications

  • F. P. Paling, D. P. R. Troeman, M. Wolkewitz, R. Kalyani, D. R. Prins, S. Weber, C. Lammens, L. Timbermont, H. Goossens, S. Malhotra-Kumar, F. Sifakis, M. J. M. Bonten, and J. A. J. W. Kluytmans, "Rationale and design of ASPIRE-ICU: a prospective cohort study on the incidence and predictors of Staphylococcus aureus and Pseudomonas aeruginosa pneumonia in the ICU", BMC Infect. Dis., vol. 17, no. 1, Sep. 2017.
  • M. Wolkewitz, M. Zortel, M. Palomar-Martinez, F. Alvarez-Lerma, P. Olaechea-Astigarraga, and M. Schumacher, "Landmark prediction of nosocomial infection risk to disentangle short- and long-stay patients", J. Hosp. Infect., vol. 96, no. 1, pp. 81-84, May 2017.
  • M. Wolkewitz, M. von Cube, and M. Schumacher, "Multistate Modeling to Analyze Nosocomial Infection Data: An Introduction and Demonstration", Infection Control and Hospital Epidemiology, pp. 1-7, June 2017.
  • J. F. Timsit, M. E. A. de Kraker, H. Sommer, E. Weiss, E. Bettiol, M. Wolkewitz, S. Nikolakopoulos, D. Wilson, and S. Harbarth, "Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE's STAT-Net", Intensive Care Med, vol. 43, no. 7, pp. 1002-1012, July 2017.
  • H. Sommer, M. Wolkewitz, and M. Schumacher, "The time-dependent "cure-death" model investigating two equally important endpoints simultaneously in trials treating high-risk patients with resistant pathogens", Pharmaceutical Statistics, vol. 16, no. 4, pp. 267-279, July 2017.
  • M. von Cube, M. Schumacher, and M. Wolkewitz, "Basic parametric analysis for a multi-state model in hospital epidemiology", Bmc Medical Research Methodology, vol. 17, no. 1, July 2017.
  • F. P. Paling, M. Wolkewitz, L. G. Bode, P. M. Klein Klouwenberg, D. S. Ong, P. Depuydt, L. de Bus, F. Sifakis, M. J. Bonten, and J. A. Kluytmans, "Staphylococcus aureus colonization at ICU admission as a risk factor for developing S. aureus ICU pneumonia", Clin. Microbiol. Infect., vol. 23, no. 1, pp. 9-49, Jan. 2017.
  • T. Heister, K. Kaier, and M. Wolkewitz, "Estimating the burden of nosocomial infections: Time dependency and cost clustering should be taken into account", Am J Infect Control, vol. 45, no. 1, pp. 94-95, Jan. 2017.
  • M. von Cube, M. Schumacher, M. Palomar-Martinez, P. Olaechea-Astigarraga, F. Alvarez-Lerma, and M. Wolkewitz, "A case-cohort approach for multi-state models in hospital epidemiology", Statistics in Medicine, vol. 36, no. 3, pp. 481-495, Feb. 2017.
  • M. von Cube, M. Schumacher, M. Palomar-Martinez, P. Olaechea-Astigarraga, F. Alvarez-Lerma, and M. Wolkewitz, "A case-cohort approach for multi-state models in hospital epidemiology", Stat Med, vol. 36, no. 3, pp. 481-495, Feb. 2017.
  • Martin Wolkewitz, Gerta Rücker, and Martin Schumacher, "Changes in Rates of Ventilator-Associated Pneumonia", Jama-journal of the American Medical Association, vol. 317, no. 15, pp. 1580-1581, Apr. 2017.
  • M. Wolkewitz and M. Schumacher, "Survival biases lead to flawed conclusions in observational treatment studies of influenza patients", Journal of Clinical Epidemiology, vol. 84, pp. 121-129, Apr. 2017.
  • H. Sommer, J. F. Timsit, and M. Wolkewitz, "Bezlotoxumab and Recurrent Clostridium difficile Infection", New England Journal of Medicine, vol. 376, no. 16, 04 2017.
  • F. P. Paling, M. Wolkewitz, P. Depuydt, L. de Bus, F. Sifakis, M. J. M. Bonten, and J. A. J. W. Kluytmans, "P. aeruginosa colonization at ICU admission as a risk factor for developing P. aeruginosa ICU pneumonia", Antimicrob Resist Infect Control, vol. 6, 2017.
  • M. Wolkewitz, "Accounting for Competing Events in Multivariate Analyses of Hospital-Acquired Infection Risk Factors", Infect Control Hosp Epidemiol, vol. 37, no. 9, pp. 1122-1124, Sep. 2016.
  • M. Wolkewitz, B. S. Cooper, M. Palomar-Martinez, F. Alvarez-Lerma, P. Olaechea-Astigarraga, A. G. Barnett, and M. Schumacher, "Multiple time scales in modeling the incidence of infections acquired in intensive care units", Bmc Medical Research Methodology, vol. 16, no. 1, Sep. 2016.
  • M. Wolkewitz, B. S. Cooper, M. Palomar-Martinez, F. Alvarez-Lerma, P. Olaechea-Astigarraga, A. G. Barnett, and M. Schumacher, "Multiple time scales in modeling the incidence of infections acquired in intensive care units", BMC Med Res Methodol, vol. 16, no. 1, Sep. 2016.
  • Maja von Cube, Martin Schumacher, Mercedes Palomar-Martinez, Pedro Olaechea-Astigarraga, Francisco Alvarez-Lerma, and Martin Wolkewitz, "A case-cohort approach for multi-state models in hospital epidemiology", Statistics in Medicine, Oct. 2016.
  • S. Weber, M. von Cube, H. Sommer, and M. Wolkewitz, "Necessity of a Competing Risk Approach in Risk Factor Analysis of Central Line-Associated Bloodstream Infection", Infect Control Hosp Epidemiol, vol. 37, no. 10, pp. 1255-1257, Oct. 2016.
  • M. Wolkewitz, M. Palomar-Martinez, P. Olaechea-Astigarraga, F. Alvarez-Lerma, and M. Schumacher, "A full competing risk analysis of hospital-acquired infections can easily be performed by a case-cohort approach", Journal of Clinical Epidemiology, vol. 74, pp. 187-193, June 2016.
  • M. Dettenkofer, H. Humphreys, H. Saenz, J. Carlet, H. Hanberger, C. Ruef, A. Widmer, M. Wolkewitz, and B. Cookson, "Key priorities in the prevention and control of healthcare-associated infection: a survey of European and other international infection prevention experts", Infection, vol. 44, no. 6, pp. 719-724, Dec. 2016.
  • M. Wolkewitz, J. Beyersmann, K. Ohneberg, and M. Schumacher, "RE: "COMPARISON OF STATISTICAL APPROACHES FOR DEALING WITH IMMORTAL TIME BIAS IN DRUG EFFECTIVENESS STUDIES"", Am. J. Epidemiol., vol. 184, no. 11, pp. 856-858, 12 2016.
  • M. Wolkewitz and M. Schumacher, "Neuraminidase Inhibitors and Hospital Mortality in British Patients with H1N1 Influenza A: A Re-Analysis of Observational Data", PLoS ONE, vol. 11, no. 9, 2016.
  • M. Wolkewitz, "Estimating the Risk of Ventilator-associated Pneumonia as a Function of Time", Am. J. Respir. Crit. Care Med., vol. 192, no. 5, pp. 640-641, Sep. 2015.
  • N. Green, A. P. Johnson, K. L. Henderson, B. Muller-Pebody, S. Thelwall, J. V. Robotham, M. Sharland, M. Wolkewitz, and S. R. Deeny, "Quantifying the Burden of Hospital-Acquired Bloodstream Infection in Children in England by Estimating Excess Length of Hospital Stay and Mortality Using a Multistate Analysis of Linked, Routinely Collected Data", J Pediatric Infect Dis Soc, vol. 4, no. 4, pp. 305-312, Dec. 2015.
  • M. Wolkewitz and M. Schumacher, "Statistical and methodological concerns about the beneficial effect of neuraminidase inhibitors on mortality", Lancet Respir Med, vol. 2, no. 7, pp. 8-9, July 2014.
  • M. Wolkewitz, B. S. Cooper, M. Palomar-Martinez, P. Olaechea-Astigarraga, F. Alvarez-Lerma, and M. Schumacher, "Nested case-control studies in cohorts with competing events", Epidemiology, vol. 25, no. 1, pp. 122-125, Jan. 2014.
  • M. Wolkewitz, "Avoidable statistical pitfalls in analyzing length of stay in intensive care units or hospitals", Crit Care, vol. 18, no. 1, Feb. 2014.
  • M. Wolkewitz, A. G. Barnett, M. Palomar Martinez, U. Frank, and M. Schumacher, "Interventions to control nosocomial infections: study designs and statistical issues", J. Hosp. Infect., vol. 86, no. 2, pp. 77-82, Feb. 2014.
  • K Kaier, ML Lambert, UK Frank, W Vach W, M Wolkewitz, E Tacconelli, J Rello, U Theuretzbacher, and M Martin, "Impact of availability of guidelines and active surveillance in reducing the incidence of ventilator-associated pneumonia in Europe and worldwide", Bmc Infectious Diseases, vol. 14:199, Apr. 2014.
  • K. Kaier, M. L. Lambert, U. K. Frank, W. Vach, M. Wolkewitz, E. Tacconelli, J. Rello, U. Theuretzbacher, and M. Martin, "Impact of availability of guidelines and active surveillance in reducing the incidence of ventilator-associated pneumonia in Europe and worldwide", BMC Infect. Dis., vol. 14, Apr. 2014.
  • M. Wolkewitz, B. S. Cooper, M. Palomar-Martinez, F. Alvarez-Lerma, P. Olaechea-Astigarraga, A. G. Barnett, S. Harbarth, and M. Schumacher, "Multilevel competing risk models to evaluate the risk of nosocomial infection", Crit Care, vol. 18, no. 2, Apr. 2014.
  • M. Wolkewitz, B.S. Cooper, M. Palomar-Martinez, F. Alvarez-Lerma, P. Olaechea-Astigarraga, A.G. Barnett, S. Harbarth, and M. Schumacher, "Multilevel competing risk models to evaluate the risk of nosocomial infection", Critical Care, vol. 18, 2:R64, 2014.
  • M. Wolkewitz and H. Sommer, "Evaluating mortality in an intensive care unit requires extended survival models", Critical Care, vol. 18:415, 2014.
  • Martin Wolkewitz, "Avoidable statistical pitfalls in analyzing length of stay in intensive care units or hospitals", Critical Care, vol. 18, 1:408, 2014.
  • M. Wolkewitz, A.G. Barnett, M. Palomar Martinez, U. Frank, and M. Schumacher, "Interventions to control nosocomial infections: study designs and statistical issues", Journal of Hospital Infection, vol. 86, 2:77-82, 2014.
  • M. Wolkewitz, B.S. Cooper, M. Palomar-Martinez, P. Olaechea-Astigarraga, F. Alvarez-Lerma, and M. Schumacher, "Nested case-control studies in cohorts with competing events", Critical Care, vol. 1:122-5, 2014.
  • Martin Wolkewitz, Ben S Cooper, Marc JM Bonten, Adrian G Barnett, Martin Schumacher, and others, "Interpreting and comparing risks in the presence of competing events", BMJ, vol. 349, BMJ Publishing Group Ltd, 2014.
  • Martin Schumacher, Arthur Allignol, Jan Beyersmann, Nadine Binder, and Martin Wolkewitz, "Hospital-acquired infections-appropriate statistical treatment is urgently needed!", International Journal of Epidemiology, vol. 42, no. 5, pp. 1502-1508, Oct. 2013.
  • M. Wolkewitz, E. Tacconelli, and M. Schumacher, "Aggressive versus conservative initiation of antibiotics", Lancet Infectious Diseases, vol. 13, no. 5, pp. 387-388, May 2013.
  • M. Wolkewitz, S. Harbarth, and J. Beyersmann, "Daily chlorhexidine bathing and hospital-acquired infection", N. Engl. J. Med., vol. 368, 24:2330, 2013.
  • M. Wolkewitz, S. Di Termini, B. Cooper, J. Meerpohl, and M. Schumacher, "Paediatric hospital-acquired bacteraemia in developing countries", Lancet, vol. 379, no. 9825, pp. 1484-1485, Apr. 2012.
  • M. Wolkewitz, A. Allignol, S. Harbarth, G. de Angelis, M. Schumacher, and J. Beyersmann, "Time-dependent study entries and exposures in cohort studies can easily be sources of different and avoidable types of bias", Journal of Clinical Epidemiology, vol. 65, no. 11, pp. 1171 - 1180, 2012.
  • M. Wolkewitz, B. Cooper, A. G. Barnett, N. Binder, and M. Schumacher, "Treatment of hospital-acquired pneumonia", Lancet Infect Dis, vol. 11, no. 10, pp. 731-732, Oct. 2011.