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Reducing the noise in signal detection of adverse drug reactions by standardizing the background: a pilot study on analyses of proportional reporting ratios-by-therapeutic area
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
2014 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 5, 627-635 p.Article in journal (Refereed) Published
Abstract [en]

Disproportionality screening analysis is acknowledged as a tool for performing signal detection in databases of adverse drug reactions (ADRs), e.g., in the European Union (EU) Drug Authority setting. The purpose of this study was to explore the possibility of decreasing false-positive signals of disproportionate reporting (SDR) by calculating the proportional reporting ratio (PRR)-by-therapeutic area (TA), while still maintaining the ability to detect relevant SDRs. In the EudraVigilance (EV) Database, output from PRR calculated with a restricted TA comparator background was compared in detail to output from conventional authority-setting PRR calculations for four drugs: bicalutamide, abiraterone, metformin, and vildagliptin, within the TAs of prostate gland disease and type 2 diabetes mellitus. ADR reports per investigated drug ranged from 2,400 to 50,000. The PRR-TA's ability to detect true-positive SDRs (as acknowledged in approved labeling) was increased compared to the conventional PRR, and performed 8-31 % better than a recently proposed stricter EU-SDR definition. The PRR-TA removed false SDRs confounded by disease or disease spill-over by up to 63 %, while retaining/increasing the number of unclassified SDRs relevant for manual validation, and thereby improving the ratio between confounded SDRs (i.e., noise) and unclassified SDRs for all investigated drugs (possible signals). The performance of the PRR was improved by background restriction with the PRR-TA method; the number of false-positive SDRs decreased, and the ability to detect true-positive SDRs increased, improving the signal-to-noise ratio. Further development and validation of the method is needed within other TAs and databases, and for disproportionality analysis methods.

Place, publisher, year, edition, pages
2014. Vol. 70, no 5, 627-635 p.
Keyword [en]
Signal detection, disproportionality analysis, PRR, proportional reporting ratio, prostate cancer, type 2 diabetes mellitus, PRR-TA, adverse drig reactions, ADR, SDR, signals of disproportionate reporting, signal, noise
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology
Identifiers
URN: urn:nbn:se:uu:diva-195805DOI: 10.1007/s00228-014-1658-1ISI: 000334422700015OAI: oai:DiVA.org:uu-195805DiVA: diva2:608346
Available from: 2013-02-27 Created: 2013-02-27 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Prostate Cancer; Metabolic Risk Factors, Drug Utilisation, Adverse Drug Reactions
Open this publication in new window or tab >>Prostate Cancer; Metabolic Risk Factors, Drug Utilisation, Adverse Drug Reactions
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Increased possibilities during the last decades for early detection of prostate cancer have sparked research on preventable or treatable risk factors and on improvements in therapy. Treatments of the disease still entail significant side effects potentially affecting men during the rest of their lives. The studies of the present thesis concern different aspects of prostate cancer from etiological risk factors and factors influencing treatment to an improved methodology for the detection of treatment side effects.

Papers I, II, both based in the population based cohort ULSAM (Uppsala Longitudinal Study of Adult Men), investigate possible risk factors of prostate cancer with options for intervention: selenium levels and the metabolic syndrome. The phenomenon of competing risk of death from other causes than prostate cancer and its impact on and importance for choice of statistical methods is also exemplified and discussed for the first time in prostate cancer research.

-Smokers with low selenium status have an increased future risk of later development of prostate cancer. Influence of genetic variability appears plausible.

-The metabolic syndrome and especially its increased waist circumference component are associated with later development of prostate cancer – taking competing risks of death from other causes into account.

Papers III and IV using pharmacoepidemiological methods investigate aspects of drug utilisation in prostate cancer using nationwide and international databases. In Paper III factors influencing anti-androgen use in prostate cancer are investigated, both from a prescriber- and patient perspective.  The age and disease risk group of the patient, unsupported scientifically, influence both the prescribers’ choice of dose and the patients’ adherence to treatment.

-Adherence, not previously investigated in male cancer patients, was considerably higher than reported for adjuvant breast cancer treatment. Subgroups of men suitable for intervention to increase adherence were identified.

Paper IV, investigates the feasibility of improving an established method for screening large adverse drug reactions databases, the proportional reporting ratio (PRR), this by using restricted sub-databases according to treatment area (TA), introducing the concept of PRR-TA.

-The PRR-TA method increases the signal-noise relationship of analyses; a finding highly relevant for possibly conserving manual resources in Pharmacovigilance work in a drug-authority setting.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 115 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 870
Keyword
Prostate cancer, Epidemiology, Pharmacoepidemiology, Metabolic Syndrome, Selenium, Smoking, hOGG1, MnSOD, Competing Risk, Adherence, Persistance, Medical Possession Ratio, MPR, Signal Detection, PRR, proportional reporting ratio, ULSAM, PcBaSE, EudraVigilance, SPDR, Swedish Prescribe Drug Registry, NPCR, National Prostate Cancer Registry, SDR, Signal, disproportionality analysis, PRR-TA, EudraVigilance
National Category
Surgery
Research subject
Epidemiology; Urology; Oncology; Geriatrics
Identifiers
urn:nbn:se:uu:diva-194297 (URN)978-91-554-8609-9 (ISBN)
Public defence
2013-04-25, Universitetshuset, Biskopsgatan 3, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-03-26 Created: 2013-02-12 Last updated: 2013-06-27

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Grundmark, BirgittaHolmberg, LarsZethelius, Björn

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