European Journal of Epidemiology

, Volume 32, Issue 7, pp 567–582 | Cite as

Sequence symmetry analysis in pharmacovigilance and pharmacoepidemiologic studies

  • Edward Chia-Cheng Lai
  • Nicole Pratt
  • Cheng-Yang Hsieh
  • Swu-Jane Lin
  • Anton Pottegård
  • Elizabeth E. RougheadEmail author
  • Yea-Huei Kao YangEmail author
  • Jesper HallasEmail author


Sequence symmetry analysis (SSA) is a method for detecting adverse drug events by utilizing computerized claims data. The method has been increasingly used to investigate safety concerns of medications and as a pharmacovigilance tool to identify unsuspected side effects. Validation studies have indicated that SSA has moderate sensitivity and high specificity and has robust performance. In this review we present the conceptual framework of SSA and discuss advantages and potential pitfalls of the method in practice. SSA is based on analyzing the sequences of medications; if one medication (drug B) is more often initiated after another medication (drug A) than before, it may be an indication of an adverse effect of drug A. The main advantage of the method is that it requires a minimal dataset and is computationally efficient. By design, SSA controls time-constant confounders. However, the validity of SSA may be affected by time-varying confounders, as well as by time trends in the occurrence of exposure or outcome events. Trend effects may be adjusted by modeling the expected sequence ratio in the absence of a true association. There is a potential for false positive or negative results and careful consideration should be given to potential sources of bias when interpreting the results of SSA studies.


Sequence symmetry analysis Self-control method Case-based design Signal detection Pharmacoepidemiology Pharmacovigilance 



This study was supported by a grant from the Ministry of Science and Technology of Taiwan (ID: NSC 102-2628-B-006-003-MY).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Springer Science+Business Media B.V. 2017

Authors and Affiliations

  • Edward Chia-Cheng Lai
    • 1
    • 2
    • 3
  • Nicole Pratt
    • 4
  • Cheng-Yang Hsieh
    • 1
    • 5
  • Swu-Jane Lin
    • 6
  • Anton Pottegård
    • 7
  • Elizabeth E. Roughead
    • 4
    Email author
  • Yea-Huei Kao Yang
    • 1
    • 2
    Email author
  • Jesper Hallas
    • 7
    Email author
  1. 1.School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  2. 2.Health Outcome Research CenterNational Cheng Kung UniversityTainanTaiwan
  3. 3.Department of PharmacyNational Cheng Kung University HospitalTainanTaiwan
  4. 4.Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health ResearchUniversity of South AustraliaAdelaideAustralia
  5. 5.Department of NeurologyTainan Sin-Lau HospitalTainanTaiwan
  6. 6.Department of Pharmacy Systems, Outcomes and Policy, College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  7. 7.Clinical Pharmacology and Pharmacy, Department of Public HealthUniversity of Southern DenmarkOdense CDenmark

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