Biometrical Journal

Analyzing self‐controlled case series data when case confirmation rates are estimated from an internal validation sample

Early View

  • Author(s): Stanley Xu, Christina L. Clarke, Sophia R. Newcomer, Matthew F. Daley, Jason M. Glanz
  • Article first published online: 16 May 2018
  • DOI: 10.1002/bimj.201700088
  • Read on Online Library
  • Subscribe to Journal


Vaccine safety studies are often electronic health record (EHR)‐based observational studies. These studies often face significant methodological challenges, including confounding and misclassification of adverse event. Vaccine safety researchers use self‐controlled case series (SCCS) study design to handle confounding effect and employ medical chart review to ascertain cases that are identified using EHR data. However, for common adverse events, limited resources often make it impossible to adjudicate all adverse events observed in electronic data. In this paper, we considered four approaches for analyzing SCCS data with confirmation rates estimated from an internal validation sample: (1) observed cases, (2) confirmed cases only, (3) known confirmation rate, and (4) multiple imputation (MI). We conducted a simulation study to evaluate these four approaches using type I error rates, percent bias, and empirical power. Our simulation results suggest that when misclassification of adverse events is present, approaches such as observed cases, confirmed case only, and known confirmation rate may inflate the type I error, yield biased point estimates, and affect statistical power. The multiple imputation approach considers the uncertainty of estimated confirmation rates from an internal validation sample, yields a proper type I error rate, largely unbiased point estimate, proper variance estimate, and statistical power.

Related Topics

Related Publications

Related Content

Site Footer


This website is provided by John Wiley & Sons Limited, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ (Company No: 00641132, VAT No: 376766987)

Published features on are checked for statistical accuracy by a panel from the European Network for Business and Industrial Statistics (ENBIS)   to whom Wiley and express their gratitude. This panel are: Ron Kenett, David Steinberg, Shirley Coleman, Irena Ograjenšek, Fabrizio Ruggeri, Rainer Göb, Philippe Castagliola, Xavier Tort-Martorell, Bart De Ketelaere, Antonio Pievatolo, Martina Vandebroek, Lance Mitchell, Gilbert Saporta, Helmut Waldl and Stelios Psarakis.