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1.  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 
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s00228-014-1658-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3978377  PMID: 24599513
PRR; Adverse drug reactions; ADR; Signal detection; Pharmacovigilance; Disproportionality analysis
2.  Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up 
BMC Cancer  2011;11:431.
Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se.
ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms.
In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (≤80 μg/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa.
S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue.
PMCID: PMC3199281  PMID: 21982398
3.  The metabolic syndrome and the risk of prostate cancer under competing risks of death from other causes 
Associations between Metabolic Syndrome (MetS) components and prostate cancer development have not been studied comprehensively; results have been divergent. Using the National Cholesterol Education Program Adult Treatment panel III (NCEP) and International Diabetes Federation (IDF) definitions of the MetS we investigated such associations taking competing risks of death into consideration.
In the prospective Uppsala Longitudinal Study of Adult Men (ULSAM) of 2322 Caucasian men with 34 years of follow-up baseline MetS-measurements at age 50 were used. Cumulative incidence of prostate cancer and death with/without the MetS were calculated. Competing risk of dying was taken into account by calculating the conditional probability of prostate cancer with/without the MetS.
Two-hundred-and- thirty-seven prostate cancers were identified. Prostate cancer probability by age 80 with baseline MetS compared to without the MetS was non-significantly higher, 5.2 percent-units (CI -0.8%-11.3%, (NCEP), 2.7 percent-units (CI -2.7%-8.0%) (IDF), cumulative incidence proportions of death was significantly higher, 19.3 percent-units (CI 13.4%-25.3%) (NCEP), 15.3 percent-units (CI 9.5%-21.1%) (IDF) and conditional probability of prostate cancer considering death from other causes was significantly higher, 7.3 percent-units (CI 0.2%-14.5%) odds ratio(OR) of 1.64 (CI 1.03-2.23). (NCEP), and non-significantly higher 5.0 percent-units (CI -1.6%-11.6%) OR 1.43 (CI 0.89-1.90). (IDF).
The MetS by the NCEP definition is associated with prostate cancer taking the competing risk of early death from other causes into account.
The results further highlight the public health impact of the increasing prevalence of MetS, and the importance of considering competing risks when studying risk factors for cancer.
PMCID: PMC2923431  PMID: 20647401
epidemiology; prostate cancer; metabolic syndrome; competing risk; risk factors

Results 1-3 (3)