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Time-dependent biases in observational studies of comparative effectiveness research in rheumatology. A methodological review
  1. Michele Iudici1,
  2. Raphaël Porcher1,
  3. Carolina Riveros1,
  4. Philippe Ravaud1,2
  1. 1 Methods of Therapeutic Evaluation of Chronic Diseases (METHODS) Team, INSERM, UMR 1153, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (CRESS), Paris, France
  2. 2 Cochrane France, Paris, France
  1. Correspondence to Dr Michele Iudici, Methods of Therapeutic Evaluation of Chronic Diseases (METHODS) team, INSERM, UMR 1153, Epidemiology and Biostatistics Sorbonne Paris Cité Research Center (CRESS), Paris 75001, France; michele_iudici{at}


Objective To assess to what extent time-dependent biases (ie, immortal time bias (ITB) and time-lag bias (TLB)) occur in the latest rheumatology observational studies, describe their main mechanisms and increase the awareness on this topic.

Methods We searched PubMed for observational studies on rheumatic diseases published in leading medical journals in the last 5 years. Only studies with a time-to-event analysis exploring the association of one or more interventional strategies with an outcome were included. Each study was labelled as free from bias, at risk of TLB, at risk of misclassified ITB if the period of immortal time was incorrectly attributed to an intervention group, or at risk of excluded ITB if the immortal time was discarded from the analysis.

Results We included 78 papers. Most studies were performed in Europe or North America (46% each), were not industry funded (62%) and had a safety primary outcome (59%). In total, 13 (17%) studies were considered at risk of time-dependent biases. Among the studies at risk of ITB (n=8; 10%), in 5 (6%), waiting time to receive treatment was wrongly attributed to the treatment exposure group, which indicated misclassified ITB. Five (6%) studies were at risk of TLB: patients on conventional synthetic disease-modifying antirheumatic drugs (DMARD; first-line drugs) were compared with patients on biologic DMARDs (second or third-line drugs) without accounting for disease duration or prior medication use.

Conclusions One in six comparative effectiveness observational studies published in leading rheumatology journals is potentially flawed by time-dependent biases.

  • epidemiology
  • treatment
  • autoimmune diseases

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  • Handling editor Josef S Smolen

  • Contributors MI, RP and PR contributed to the conception and design of the work. MI and CR contributed to the acquisition of data. MI, RP, CR and PR contributed to the analysis and interpretation of data. MI, RP, CR and PR helped draft the paper and critically revised it for important intellectual content. All the authors gave final approval of the version submitted.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All the data collected are available upon request.