Hypothesis-free screening of large administrative databases for unsuspected drug-outcome associations

Abstract

Active surveillance for unknown or unsuspected adverse drug effects may be carried out by applying epidemiological techniques to large administrative databases. Self-controlled designs, like the symmetry design, have the advantage over conventional design of adjusting for confounders that are stable over time. The aim of this paper was to describe the output of a comprehensive open-ended symmetry analysis of a large dataset. All drug dispensings and all secondary care contacts in Denmark during the period 1995–2012 for persons born before 1950 were analyzed by a symmetry design. We analyzed all drug–drug sequences and all drug–disease sequences occurring during the study period. The identified associations were ranked according to the number of outcomes that potentially could be attributed to the exposure. In the main analysis, 29,891,212 incident drug therapies, and 21,300,000 incident diagnoses were included. Out of 186,758 associations tested in the main analysis, 43,575 (23.3%) showed meaningful effect size. For the top 200 drug–drug associations, 47% represented unknown associations, 24% represented known adverse drug reactions, 30% were explained by mutual indication or reverse causation. For the top 200 drug–disease associations the proportions were 31, 15, and 55%, respectively. Screening by symmetry analysis can be a useful starting point for systematic pharmacovigilance activities if coupled with a systematic post-hoc review of signals.

Appendices

Appendix 1

Drug and disease main groups suggestive of confounding by indication. See text for explanation

Drug main group (ATC)	Drug group, plain text	Disease main group (ICD10)	Disease group, plain text
C	Cardiovascular system	I	Diseases of circulatory system
D	Dermatologicals	L	Skin diseases
G	Genito urinary system and sex hormones	N	Genitourinari and renal diseases
H	Systemic hormonal preparations, excl. sex hormones and insulins	E	Endocrine, nutritional and metabolic diseases
J	Antiinfectives for systemic use	B	Bacterial and certain viral infections
J	Antiinfectives for systemic use	A	Viral, fungal and parasitic infections
L	Antineoplastic and immunomodulating agents	C	Malignant neoplasms
L	Antineoplastic and immunomodulating agents	D	Benign neoplasms and hematological diseases
L	Antineoplastic and immunomodulating agents	M	Diseases of the musculoskeletal system and connective tissue
M	Musculo-skeletal system	M	Diseases of the musculoskeletal system and connective tissue
P	Antiparasitic products, insecticides and repellents	B	Viral, fungal and parasitic infections
P	Antiparasitic products, insecticides and repellents	A	Bacterial and certain viral infections
R	Respiratory system	J	Diseases of respiratory system
S	Sensory organs	H	Diseases of ear and eye

1. ATC Anatomical Therapeutic Chemical classification, ICD10 International classification of diseases version 10

Appendix 2

Short description of the data sources included in the study.

The Danish National Prescription Registry contains data on all prescription drugs dispensed to Danish citizens from community pharmacies since 1995. Among other variables, the data include the dispensed substance, the date of dispensing, and quantity dispensed. Dosing information and indication for prescribing are not systematically recorded and were not used for this study. Drugs are categorized according to the Anatomic Therapeutic Chemical (ATC) index, a hierarchical classification system developed by the WHO, and the quantity dispensed for each prescription is given by the number of units and strength of the pharmaceutical product, as well as quantity expressed in the defined daily doses (DDD). The Danish National Prescription Registry does not include medications dispensed during hospitalization.

The Danish National Patient Register contains nationwide data on all non-psychiatric hospital admissions since 1977 and both psychiatric and non-psychiatric outpatient encounters since 1995. Discharge/contact diagnoses have been coded according to ICD-10 since 1994. Diagnoses established in primary care alone, i.e. without any involvement of hospital care, are not captured by the Danish National Patient Register.

The Danish Civil Registration System contains data on date of death and migrations to and from Denmark since 1968, which allowed us to keep track of all subjects during the study period.