Near real-time vaccine safety surveillance using electronic health records-a systematic review of the application of statistical methods

Abstract

Purpose: Pre-licensure studies have limited ability to detect rare adverse events (AEs) to vaccines, requiring timely post-licensure studies. With the increasing availability of electronic health records (EHR) near real-time vaccine safety surveillance using these data has emerged as an option. We reviewed methods currently used to inform development of similar systems for countries considering their introduction.

Methods: Medline, EMBASE and Web of Science were searched, with additional searches of conference abstract books. Questionnaires were sent to organizations worldwide to ascertain unpublished studies. Eligible studies used EHR and regularly assessed pre-specified AE to vaccine(s). Key features of studies were compared descriptively.

Results: From 2779 studies, 31 were included from the USA (23), UK (6), and Taiwan and New Zealand (1 each). These were published/conducted between May 2005 and April 2015. Thirty-eight different vaccines were studied, focusing mainly on influenza (47.4%), especially 2009 H1N1 vaccines. Forty-six analytic approaches were used, reflecting frequency of EHR updates and the AE studied. Poisson-based maximized sequential probability ratio test was the most common (43.5%), followed by its binomial (23.9%) and conditional versions (10.9%). Thirty-seven of 49 analyses (75.5%) mentioned control for confounding, using an adjusted expected rate (51.4% of those adjusting), stratification (16.2%) or a combination of a self-controlled design and stratification (13.5%). Guillain-Barré syndrome (11.9%), meningitis/encephalitis/myelitis (11.9%) and seizures (10.8%) were studied most often.

Conclusions: Near real-time vaccine safety surveillance using EHR has developed over the past decade but is not yet widely used. As more countries have access to EHR, it will be important that appropriate methods are selected, considering the data available and AE of interest.

Keywords: electronic health records; pharmacoepidemiology; safety; sequential tests; statistical process control; vaccines.

Figure 1

Flowchart of included studies. Studies were excluded for (i) not considering vaccines (nonvaccine), (ii) not analysing the safety of a vaccine (not safety), (iii) considering safety issues but not applying the methods of interest (other safety), (iv) only developing new methods (methods only) and (v) having no abstract available (not available)

Figure 2

Studies included in the review, ordered by the year of publication. Continuous sequential test are displayed in blue, group sequential in orange and statistical process control in green. Grey background indicates non‐published studies. *Results with previous published results. MaxSPRT, maximized sequential. Probability ratio test: P, Poisson version (^†use of the conditional version); B, binomial version (^‡use of self‐controlled case series or extensions of the test). DMSS, Defense Medical Surveillance System; DTaP, acellular diphtheria‐tetanus‐pertussis vaccine; DTwP, whole cell diphtheria‐tetanus‐pertussis vaccine; GBMV, group B meningococcal vaccine; HPS, Health Protection Scotland; HPV2, bivalent human papillomavirus vaccine; HPV4, quadrivalent human papillomavirus vaccine; IHS, (US) Indian Health. Service: IPV, inactivated poliovirus vaccine; MCV, meningococcal conjugate vaccine; MHRA, Medicines and Healthcare products Regulatory Agency; MMRV, measles‐mumps‐rubella‐varicella combination vaccine; PCV13, 13‐valent pneumococcal conjugate vaccine; PRISM, Post‐Licensure Rapid Immunization Safety. Monitoring: RRV, rhesus‐rotavirus vaccine; RV5, pentavalent rotavirus vaccine; VA, Veterans Affairs; VSD, Vaccine Safety Datalink