Send to

Choose Destination
Pharmacoepidemiol Drug Saf. 2015 Aug;24(8):858-64. doi: 10.1002/pds.3780. Epub 2015 Apr 22.

Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries.

Author information

Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, The University of Hong Kong, Pok Fu Lam, Hong Kong.
Medical Research Collaborating Centre, Seoul National University College of Medicine/Seoul National University Hospital, Seoul, South Korea.
Department of Medical Informatics, Hamamatsu University School of Medicine, Shizuoka, Japan.
Department of Pharmacoepidemiology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Institute of Clinical Pharmacy and Pharmaceutical Sciences, Health Outcome Research Centre, National Cheng Kung University, Tainan City, Taiwan.
Department of Preventative Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Korea Institute of Drug Safety and Risk Management, Seoul, South Korea.



Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings.


Using a distributed network model, we analyzed prescription dispensing data using PSSA in Australia, Hong Kong, Japan, Korea, and Taiwan. Positive control was amiodarone and thyroxine, as a marker of amiodarone-induced hypothyroidism, a known adverse event with a clear temporal relationship to amiodarone initiation. Negative controls were amiodarone and allopurinol, as a marker of amiodarone-induced gout and thyroxine and allopurinol, as a marker of thyroxine-induced gout. Gout is not recorded as an adverse event in product information for either medicine. Adjusted sequence ratios (ASR) were calculated for each country. Pooled estimates were obtained by using the generic inverse variance method.


A positive association was identified between amiodarone and thyroxine in all settings with a pooled ASR 2.63 (95% confidence interval (CI) 1.47-4.72). Temporal analysis showed the effect occurred within the first few weeks of treatment. No significant associations were found for the negative controls in any setting; pooled ASR were 0.76 (95%CI 0.62-0.93) and 0.98 (95%CI 0.85-1.12) for amiodarone-allopurinol and thyroxine-allopurinol, respectively.


Despite different health settings, different populations, and different patterns of medicine utilization, PSSA gave consistent estimates across countries for a well-known positive association and two negative control adverse events.


amiodarone; hyperthyroidism; pharmacoepidemiology; pharmacovigilance; prescription symmetry analysis

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center