Working Group GePaRD & Target Trials for Causal Inference (GeTTCausal)

Many research questions in epidemiology can only be answered using observational data because randomized controlled trials would be practically or ethically infeasible, e.g. when investigating long-term effects or vulnerable subpopulations. However, analyses of observational data can yield highly misleading results if conducted in a way that violates basic principles of study design, as illustrated by the so-called HRT story (Hernán et al 2008 Epidemiology 19:766).

To overcome these issues and sensitize to these avoidable biases, the powerful general principle of target trial emulation (TTE) has been developed (Hernán & Robins 2016 Am J Epidemiol 183:758). It ensures the practical interpretability and meaningfulness of any analysis, and achieves a high protection against avoidable biases. The principle of target trial emulation is increasingly being adopted in the field of causal analyses of electronic health records, claims data or other observational data (Caniglia et al 2020 Neurology 95:e1322).

The overall goal of the GeTTCausal working group is to apply and further develop the TTE approach to advance our knowledge on effects and side-effects of medical treatments or interventions. We will also explore and develop methods for tailored sensitivity analyses to address unavoidable biases, e.g. by using negative controls, sequential eligibility restrictions, or quantitative bias modelling.

The working group GeTTCausal capitalises on and combines BIPS' expertise in causal analysis, clinical epidemiology and claims data analysis. With BIPS' access to the German pharmacoepidemiological research database (GePaRD) we are uniquely placed to carry out cutting-edge robust analyses that will be of direct relevance to patients, doctors and public health decision makers.

Using GePaRD for TTE provides the following opportunities:

  • the database covers ~20% of the German population (~16 million per year, total number of persons in the database: 25 million); all regions and age groups in Germany are represented.
  • it covers a time span of over 15 years (data beginning in 2004)
  • there is no volunteer nor recall bias
  • vulnerable subgroups such as pregnant women are well-represented and identifiable
  • all levels of care are covered (in- and outpatient care, including specialists).

Completed, ongoing or planned projects address, for example,

  • the effectiveness of mammography screening in reducing breast cancer mortality in Germany
  • the effectiveness of screening colonoscopy in reducing incidence of colorectal cancer in the distal vs. the proximal colon
  • the effect of antidiabetic drugs on pancreatic cancer incidence (Börnhorst et al. 2021 Clin Epi 13:1027)
  • a head-to-head comparison of different direct oral anticoagulants in atrial fibrillation (effectiveness and safety)
  • the effect of combined use of tamoxifen and antidepressants on breast cancer recurrence.

Vice versa, using TTE on GePaRD provides the following opportunities:

  • the analysis is guided by an explicit research question so as to inform decision makers (Didelez 2016 IJE 45:2049)
  • various self-inflicted (usually time-related) sources of bias are avoided, e.g. immortal time or prevalent user bias
  • potential sources of bias, e.g. protopathic bias, are more easily detectable and can explicitly be addressed or assessed in sensitivity analyses
  • TTE provides a framework that can be combined with a wide variety of statistical methods.

Regarding statistical approaches, the working group aims at developing a systematic procedure for choosing suitable methods e.g. to adjust for confounding and for sensitivity / bias analyses. Hence, we will compare existing, and develop novel methods for TTE with GePaRD, such as double-machine learning to adjust for high-dimensional cofounding or separable effects approaches in competing risks settings (Didelez 2019 LIDA 25:593; Stensrud et al 2020 JASA 117:175). Moreover, we will exploit opportunities to empirically illustrate the superiority of TTE over common but biased approaches, thus contributing to improved research with observational data (Pigeot et al 2021 Gesundheitswesen 2021 83:S69).

Selected Publications

    Guidelines and reports

  • The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), in collaboration with Schink T, Ehrenstein V, Hall G, Klungel O, Hallas J, Kurz X. The target trial approach. Amsterdam, The Netherlands 2021.
  • Articles with peer review

  • Braitmaier M, Didelez V. Emulierung von Target Trials mit Real World Daten - Ein allgemeines Prinzip, um den Herausforderungen von Beobachtungsdaten zu begegnen. Prävention und Gesundheitsförderung. 2024; (Epub 2022 Jul 29).
  • Braitmaier M, Kollhorst B, Heinig M, Langner I, Czwikla J, Heinze F, Buschmann L, Minnerup H, García-Albéniz X, Hense H-W, Karch A, Zeeb H, Haug U, Didelez V. Effectiveness of mammography screening on breast cancer mortality - A study protocol for emulation of target trials using German health claims data. Clinical Epidemiology. 2022;14:1293-1303.
  • Stensrud MJ, Young JG, Didelez V, Robins JM, Hernán MA. Separable effects for causal inference in the presence of competing events. Journal of the American Statistical Association. 2022;117(537):175-183.
  • Braitmaier M, Schwarz S, Kollhorst B, Senore C, Didelez V, Haug U. Screening colonoscopy similarly prevented distal and proximal colorectal cancer: A prospective study among 55-69-year-olds. Journal of Clinical Epidemiology. 2022;149:118-126.
  • Börnhorst C, Reinders T, Rathmann W, Bongaerts B, Haug U, Didelez V, Kollhorst B. Avoiding time-related biases: A feasibility study on antidiabetic drugs and pancreatic cancer applying the parametric g-formula to a large German healthcare database. Clinical Epidemiology. 2021;(13):1027-1038.
  • Pigeot I, Kollhorst B, Didelez V. Nutzung von Sekundärdaten für die pharmakoepidemiologische Forschung - Machen wir das Beste draus! Das Gesundheitswesen. 2021;83(S 02):S69-S76.
  • Didelez V. Defining causal mediation with a longitudinal mediator and a survival outcome. Lifetime Data Analysis. 2019;25(4):593-610. (This paper was one of 2020’s top downloaded and one of 2021's top cited Lifetime Data Analysis research articles).
  • Book chapters

  • Haug U, Schink T. German Pharmacoepidemiological Research Database (GePaRD). In: Sturkenboom MCJM, Schink T, editors. Databases for pharmacoepidemiological research. Cham: Springer. 2021. S. 119-124.
  • Presentations at scientific meetings/conferences

  • Braitmaier M, Schwarz S, Kollhorst B, Didelez V, Haug U. Effectiveness of screening colonoscopy in reducing colorectal cancer incidence - Emulated target trials from German claims data. 42nd Conference of the International Society for Clinical Biostatistics (ISCB), 18-22 July 2021, online presentation.
  • Presentations at scientific meetings/conferences (invited)

  • Braitmaier M. Emulating target trials from health claims data to evaluate cancer screening programs. Fortbildungsveranstaltung des Instituts für Medizinische Informatik, Biometrie und Epidemiologie (IMIBE) am Universitätsklinikum Essen, 8. Februar 2022, Online-Vortrag.
  • Braitmaier M. Emulating target trials from health claims data to evaluate cancer screening programs. 16. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi), 20.-22. September 2021, Online-Vortrag.

Vanessa Didelez
Deputy Head of Department (Head of Research Group)

Prof. Dr. Vanessa Didelez
Tel: +49 (0)421 218-56939
Fax: +49 (0)421 218-56941