| 1. |
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| 2. |
- Caster, Ola, et al.
(författare)
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Computing limits on medicine risks based on collections of individual case reports
- 2014
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Ingår i: Theoretical Biology and Medical Modelling. - : Springer Science and Business Media LLC. - 1742-4682. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Quantifying a medicine's risks for adverse effects is crucial in assessing its value as a therapeutic agent. Rare adverse effects are often not detected until after the medicine is marketed and used in large and heterogeneous patient populations, and risk quantification is even more difficult. While individual case reports of suspected harm from medicines are instrumental in the detection of previously unknown adverse effects, they are currently not used for risk quantification. The aim of this article is to demonstrate how and when limits on medicine risks can be computed from collections of individual case reports. Methods: We propose a model where drug exposures in the real world may be followed by adverse episodes, each containing one or several adverse effects. Any adverse episode can be reported at most once, and each report corresponds to a single adverse episode. Based on this model, we derive upper and lower limits for the per-exposure risk of an adverse effect for a given drug. Results: An upper limit for the per-exposure risk of the adverse effect Y for a given drug X is provided by the reporting ratio of X together with Y relative to all reports on X, under two assumptions: (i) the average number of adverse episodes following exposure to X is one or less; and (ii) adverse episodes that follow X and contain Y are more frequently reported than adverse episodes in general that follow X. Further, a lower risk limit is provided by dividing the number of reports on X together with Y by the total number of exposures to X, under the assumption that exposures to X that are followed by Y generate on average at most one report on X together with Y. Using real data, limits for the narcolepsy risk following Pandemrix vaccination and the risk of coeliac disease following antihypertensive treatment were computed and found to conform to reference risk values from epidemiological studies. Conclusions: Our framework enables quantification of medicine risks in situations where this is otherwise difficult or impossible. It has wide applicability, but should be particularly useful in structured benefit-risk assessments that include rare adverse effects.
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| 3. |
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| 4. |
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| 5. |
- Caster, Ola, et al.
(författare)
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Quantitative benefit-risk assessment of methylprednisolone in multiple sclerosis relapses
- 2015
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Ingår i: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: High-dose short-term methylprednisolone is the recommended treatment in the management of multiple sclerosis relapses, although it has been suggested that lower doses may be equally effective. Also, glucocorticoids are associated with multiple and often dose-dependent adverse effects. This quantitative benefit-risk assessment compares high-and low-dose methylprednisolone (at least 2000 mg and less than 1000 mg, respectively, during at most 31 days) and a no treatment alternative, with the aim of determining which regimen, if any, is preferable in multiple sclerosis relapses. Methods: An overall framework of probabilistic decision analysis was applied, combining data from different sources. Effectiveness as well as risk of non-serious adverse effects were estimated from published clinical trials. However, as these trials recorded very few serious adverse effects, risk intervals for the latter were derived from individual case reports together with a range of plausible distributions. Probabilistic modelling driven by logically implied or clinically well motivated qualitative relations was used to derive utility distributions. Results: Low-dose methylprednisolone was not a supported option in this assessment; there was, however, only limited data available for this treatment alternative. High-dose methylprednisolone and the no treatment alternative interchanged as most preferred, contingent on the risk distributions applied for serious adverse effects, the assumed level of risk aversiveness in the patient population, and the relapse severity. Conclusions: The data presently available do not support a change of current treatment recommendations. There are strong incentives for further clinical research to reduce the uncertainty surrounding the effectiveness and the risks associated with methylprednisolone in multiple sclerosis relapses; this would enable better informed and more precise treatment recommendations in the future.
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| 6. |
- Caster, Ola, et al.
(författare)
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Quantitative Benefit-Risk Assessment Using Only Qualitative Information on Utilities
- 2012
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Ingår i: Medical decision making. - 0272-989X .- 1552-681X. ; 32:6, s. E1-E15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Utilities of pertinent clinical outcomes are crucial variables for assessing the benefits and risks of drugs, but numerical data on utilities may be unreliable or altogether missing. We propose a method to incorporate qualitative information into a probabilistic decision analysis framework for quantitative benefit-risk assessment. Objective: To investigate whether conclusive results can be obtained when the only source of discriminating information on utilities is widely agreed upon qualitative relations, for example, ''sepsis is worse than transient headache'' or ''alleviation of disease is better without than with complications.'' Method: We used the structure and probabilities of 3 published models that were originally evaluated based on the standard metric of quality-adjusted life years (QALYs): terfenadine versus chlorpheniramine for the treatment of allergic rhinitis, MCV4 vaccination against meningococcal disease, and alosetron for irritable bowel syndrome. For each model, we identified clinically straightforward qualitative relations among the outcomes. Using Monte Carlo simulations, the resulting utility distributions were then combined with the previously specified probabilities, and the rate of preference in terms of expected utility was determined for each alternative. Results: Our approach conclusively favored MCV4 vaccination, and it was concordant with the QALY assessments for the MCV4 and terfenadine versus chlorpheniramine case studies. For alosetron, we found a possible unfavorable benefit-risk balance for highly risk-averse patients not identified in the original analysis. Conclusion: Incorporation of widely agreed upon qualitative information into quantitative benefit-risk assessment can provide for conclusive results. The methods presented should prove useful in both population and individual-level assessments, especially when numerical utility data are missing or unreliable, and constraints on time or money preclude its collection.
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| 7. |
- Caster, Ola, 1982-
(författare)
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Quantitative methods to support drug benefit-risk assessment
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Joint evaluation of drugs’ beneficial and adverse effects is required in many situations, in particular to inform decisions on initial or sustained marketing of drugs, or to guide the treatment of individual patients. This synthesis, known as benefit-risk assessment, is without doubt important: timely decisions supported by transparent and sound assessments can reduce mortality and morbidity in potentially large groups of patients. At the same time, it can be hugely complex: drug effects are generally disparate in nature and likelihood, and the information that needs to be processed is diverse, uncertain, deficient, or even unavailable. Hence there is a clear need for methods that can reliably and efficiently support the benefit-risk assessment process. For already marketed drugs, this process often starts with the detection of previously unknown risks that are subsequently integrated with all other relevant information for joint analysis.In this thesis, quantitative methods are devised to support different aspects of drug benefit-risk assessment, and the practical usefulness of these methods is demonstrated in clinically relevant case studies. Shrinkage regression is adapted and implemented for large-scale screening in collections of individual case reports, leading to the discovery of a link between methylprednisolone and hepatotoxicity. This adverse effect is then considered as part of a complete benefit-risk assessment of methylprednisolone in multiple sclerosis relapses, set in a general framework of probabilistic decision analysis. Two methods devised in the thesis substantively contribute to this assessment: one for efficient generation of utility distributions for the considered clinical outcomes, driven by modelling of qualitative information; and one for computing risk limits for rare and otherwise non-quantifiable adverse effects, based on collections of individual case reports.
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| 8. |
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| 9. |
- Chandler, Rebecca E., et al.
(författare)
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Current Safety Concerns with Human Papillomavirus Vaccine : A Cluster Analysis of Reports in VigiBase®
- 2017
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Ingår i: Drug Safety. - : Springer Science and Business Media LLC. - 0114-5916 .- 1179-1942. ; 40:1, s. 81-90
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A number of safety signals-complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), and chronic fatigue syndrome (CFS)-have emerged with human papillomavirus (HPV) vaccines, which share a similar pattern of symptomatology. Previous signal evaluations and epidemiological studies have largely relied on traditional methodologies and signals have been considered individually.OBJECTIVE: The aim of this study was to explore global reporting patterns for HPV vaccine for subgroups of reports with similar adverse event (AE) profiles.METHODS: All individual case safety reports (reports) for HPV vaccines in VigiBase(®) until 1 January 2015 were identified. A statistical cluster analysis algorithm was used to identify natural groupings based on AE profiles in a data-driven exploratory analysis. Clinical assessment of the clusters was performed to identify clusters relevant to current safety concerns.RESULTS: Overall, 54 clusters containing at least five reports were identified. The four largest clusters included 71 % of the analysed HPV reports and described AEs included in the product label. Four smaller clusters were identified to include case reports relevant to ongoing safety concerns (total of 694 cases). In all four of these clusters, the most commonly reported AE terms were headache and dizziness and fatigue or syncope; three of these four AE terms were reported in >50 % of the reports included in the clusters. These clusters had a higher proportion of serious cases compared with HPV reports overall (44-89 % in the clusters compared with 24 %). Furthermore, only a minority of reports included in these clusters included AE terms of diagnoses to explain these symptoms. Using proportional reporting ratios, the combination of headache and dizziness with either fatigue or syncope was found to be more commonly reported in HPV vaccine reports compared with non-HPV vaccine reports for females aged 9-25 years. This disproportionality remained when results were stratified by age and when those countries reporting the signals of CRPS (Japan) and POTS (Denmark) were excluded.CONCLUSIONS: Cluster analysis reveals additional reports of AEs following HPV vaccination that are serious in nature and describe symptoms that overlap those reported in cases from the recent safety signals (POTS, CRPS, and CFS), but which do not report explicit diagnoses. While the causal association between HPV vaccination and these AEs remains uncertain, more extensive analyses of spontaneous reports can better identify the relevant case series for thorough signal evaluation.
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| 10. |
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| 11. |
- Farah, Mohamed, et al.
(författare)
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Botanical Nomenclature in Pharmacovigilance and a Recommendation for Standardisation
- 2006
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Ingår i: Drug Safety. - 0114-5916. ; 29, s. 1023-1029
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclature of plants in pharmacology can be presented by pharmaceutical names or scientific names in the form of Linnaean binomials. In this paper, positive and negative aspects of both systems are discussed in the context of the scientific nomenclatural framework and the systems’ practical applicability. The Uppsala Monitoring Centre (UMC) runs the WHO Programme for International Drug Monitoring and is responsible for the WHO Adverse Drug Reaction (ADR) database that currently contains 3.6 million records WHO Adverse Drug Reaction database. In order for the UMC to monitor pharmacovigilance through ADRs to herbal medicine products the following species nomenclatural criteria are important: (i) the name should indicate only one species of plant; (ii) the source for this name must be authoritative; (iii) the name should indicate which part of the plant is used. Based on these criteria, the UMC investigated four options: (i) adopt main names used in recognised (inter-) national pharmacopoeias or authoritative publications; (ii) adopt option 1, but cite the publication for all names in abbreviated form; (iii) three-part pharmaceutical names consisting of Latinised part name plus Latinised genus name, plus Latinised specific epithet; (iv) scientific binomial names, optionally with author and plant part used. The UMC has selectedchosen for the latter option and willas its adoption utilizes the scientific botanical nomenclature as defined by the International Code of Botanical Nomenclature.
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| 12. |
- Farah, Mohamed, et al.
(författare)
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Botanical Nomenclature in Pharmacovigilance and a Recommendation for Standardisation
- 2006
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Ingår i: Drug Safety. - 0114-5916 .- 1179-1942. ; 29:11, s. 1023-1029
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclature of plants in pharmacology can be presented by pharmaceutical names or scientific names in the form of Linnaean binomials. In this paper, positive and negative aspects of both systems are discussed in the context of the scientific nomenclatural framework and the systems' practical applicability. The Uppsala Monitoring Centre (UMC) runs the WHO Programme for International Drug Monitoring and is responsible for the WHO Adverse Drug Reaction (ADR) database that currently contains 3.6 million records. In order for the UMC to monitor pharmacovigilance through ADRs to herbal medicine products the following nomenclatural criteria are important: (i) the name should indicate only one species of plant; (ii) the source for this name must be authoritative; (iii) the name should indicate which part of the plant is used. Based on these criteria, the UMC investigated four options: (i) adopt main names used in recognised (inter-) national pharmacopoeias or authoritative publications; (ii) adopt option 1, but cite the publication for all names in abbreviated form; (iii) three-part pharmaceutical names consisting of Latinised part name plus Latinised genus name, plus Latinised specific epithet; (iv) scientific binomial names, optionally with author and plant part used. The UMC has chosen the latter option and will at its adoption utilise the scientific botanical nomenclature as defined by the International Code of Botanical Nomenclature. This decision satisfies all criteria set by the UMC and renders the necessity of creating a new system or upgrading an old inconsistent system obsolete. The UMC has also issued an extensive synonymy checklist of vernacular, pharmaceutical and scientific names for the herbals in the WHO ADR database. We strongly recommend the adoption of scientific names to denote plant ingredients in medicine.
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| 13. |
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| 14. |
- Fyfe, Ralph M., et al.
(författare)
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The Holocene vegetation cover of Britain and Ireland : overcoming problems of scale and discerning patterns of openness
- 2013
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 73, s. 132-148
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Tidskriftsartikel (refereegranskat)abstract
- The vegetation of Europe has undergone substantial changes during the course of the Holocene epoch, resulting from range expansion of plants following climate amelioration, competition between taxa and disturbance through anthropogenic activities. Much of the detail of this pattern is understood from decades of pollen analytical work across Europe, and this understanding has been used to address questions relating to vegetation-climate feedback, biogeography and human impact. Recent advances in modelling the relationship between pollen and vegetation now make it possible to transform pollen proportions into estimates of vegetation cover at both regional and local spatial scales, using the Landscape Reconstruction Algorithm (LRA), i.e. the REVEALS (Regional Estimates of VEgetation Abundance from Large Sites) and the LOVE (Local VEgetation) models. This paper presents the compilation and analysis of 73 pollen stratigraphies from the British Isles, to assess the application of the LRA and describe the pattern of landscape/woodland openness (i.e. the cover of low herb and bushy vegetation) through the Holocene. The results show that multiple small sites can be used as an effective replacement for a single large site for the reconstruction of regional vegetation cover. The REVEALS vegetation estimates imply that the British Isles had a greater degree of landscape/woodland openness at the regional scale than areas on the European mainland. There is considerable spatial bias in the British Isles dataset towards wetland areas and uplands, which may explain higher estimates of landscape openness compared with Europe. Where multiple estimates of regional vegetation are available from within the same region inter-regional differences are greater than intra-regional differences, supporting the use of the REVEALS model to the estimation of regional vegetation from pollen data. (C) 2013 Elsevier Ltd. All rights reserved.
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| 15. |
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| 16. |
- Hopstadius, Johan, et al.
(författare)
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Impact of Stratification on Adverse Drug Reaction Surveillance
- 2008
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Ingår i: Drug Safety. - 0114-5916 .- 1179-1942. ; 31:11, s. 1035-1048
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Automated screening for excessive adverse drug reaction (ADR) reporting rates has proven useful as a tool to direct clinical review in large-scale drug safety signal detection. Some measures of disproportionality can be adjusted to eliminate any undue influence on the ADR reporting rate of covariates, such as patient age or country of origin, by using a weighted average of stratum-specific measures of disproportionality. Arguments have been made in favour of routine adjustment for a set of common potential confounders using stratification. The aim of this paper is to investigate the impact of using adjusted observed-to-expected ratios, as implemented for the Empirical Bayes Geometric Mean (EBGM) and the information component (IC) measures of disproportionality, for first-pass analysis of the WHO database. METHODS: A simulation study was carried out to investigate the impact of simultaneous adjustment for several potential confounders based on stratification. Comparison between crude and adjusted observed-to-expected ratios were made based on random allocation of reports to a set of strata with a realistic distribution of stratum sizes. In a separate study, differences between the crude IC value and IC values adjusted for (combinations of) patient sex, age group, reporting quarter and country of origin, with respect to their concordance with a literature comparison were analysed. Comparison was made to the impact on signal detection performance of a triage criterion requiring reports from at least two countries before a drug-ADR pair was highlighted for clinical review. RESULTS: The simulation study demonstrated a clear tendency of the adjusted observed-to-expected ratio to spurious (and considerable) underestimation relative to the crude one, in the presence of any very small strata in a stratified database. With carefully implemented stratification that did not yield any very small strata, this tendency could be avoided. Routine adjustment for potential confounders improved signal detection performance relative to the literature comparison, but the magnitude of the improvement was modest. The improvement from the triage criterion was more considerable. DISCUSSION AND CONCLUSIONS: Our results indicate that first-pass screening based on observed-to-expected ratios adjusted with stratification may lead to missed signals in ADR surveillance, unless very small strata are avoided. In addition, the improvement in signal detection performance due to routine adjustment for a set of common confounders appears to be smaller than previously assumed. Other approaches to improving signal detection performance such as the development of refined triage criteria may be more promising areas for future research.
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| 17. |
- Janssen, Michael, et al.
(författare)
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Event Horizon Telescope observations of the jet launching and collimation in Centaurus A
- 2021
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Ingår i: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 5:10, s. 1017-1028
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Tidskriftsartikel (refereegranskat)abstract
- Very-long-baseline interferometry (VLBI) observations of active galactic nuclei at millimetre wavelengths have the power to reveal the launching and initial collimation region of extragalactic radio jets, down to 10–100 gravitational radii (rg ≡ GM/c2) scales in nearby sources1. Centaurus A is the closest radio-loud source to Earth2. It bridges the gap in mass and accretion rate between the supermassive black holes (SMBHs) in Messier 87 and our Galactic Centre. A large southern declination of −43° has, however, prevented VLBI imaging of Centaurus A below a wavelength of 1 cm thus far. Here we show the millimetre VLBI image of the source, which we obtained with the Event Horizon Telescope at 228 GHz. Compared with previous observations3, we image the jet of Centaurus A at a tenfold higher frequency and sixteen times sharper resolution and thereby probe sub-lightday structures. We reveal a highly collimated, asymmetrically edge-brightened jet as well as the fainter counterjet. We find that the source structure of Centaurus A resembles the jet in Messier 87 on ~500 rg scales remarkably well. Furthermore, we identify the location of Centaurus A’s SMBH with respect to its resolved jet core at a wavelength of 1.3 mm and conclude that the source’s event horizon shadow4 should be visible at terahertz frequencies. This location further supports the universal scale invariance of black holes over a wide range of masses5,6.
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| 18. |
- Low, Yen S., et al.
(författare)
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Cheminformatics-aided pharmacovigilance : application to Stevens-Johnson Syndrome
- 2016
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Ingår i: JAMIA Journal of the American Medical Informatics Association. - : Oxford University Press (OUP). - 1067-5027 .- 1527-974X. ; 23:5, s. 968-978
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Tidskriftsartikel (refereegranskat)abstract
- Objective Quantitative Structure-Activity Relationship (QSAR) models can predict adverse drug reactions (ADRs), and thus provide early warnings of potential hazards. Timely identification of potential safety concerns could protect patients and aid early diagnosis of ADRs among the exposed. Our objective was to determine whether global spontaneous reporting patterns might allow chemical substructures associated with Stevens-Johnson Syndrome (SJS) to be identified and utilized for ADR prediction by QSAR models. Materials and Methods Using a reference set of 364 drugs having positive or negative reporting correlations with SJS in the VigiBase global repository of individual case safety reports (Uppsala Monitoring Center, Uppsala, Sweden), chemical descriptors were computed from drug molecular structures. Random Forest and Support Vector Machines methods were used to develop QSAR models, which were validated by external 5-fold cross validation. Models were employed for virtual screening of DrugBank to predict SJS actives and inactives, which were corroborated using knowledge bases like VigiBase, ChemoText, and MicroMedex (Truven Health Analytics Inc, Ann Arbor, Michigan). Results We developed QSAR models that could accurately predict if drugs were associated with SJS (area under the curve of 75%-81%). Our 10 most active and inactive predictions were substantiated by SJS reports (or lack thereof) in the literature. Discussion Interpretation of QSAR models in terms of significant chemical descriptors suggested novel SJS structural alerts. Conclusions We have demonstrated that QSAR models can accurately identify SJS active and inactive drugs. Requiring chemical structures only, QSAR models provide effective computational means to flag potentially harmful drugs for subsequent targeted surveillance and pharmacoepidemiologic investigations.
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| 19. |
- Marquer, Laurent, et al.
(författare)
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Holocene changes in vegetation composition in northern Europe: why quantitative pollen-based vegetation reconstructions matter
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 90, s. 199-216
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Tidskriftsartikel (refereegranskat)abstract
- We present pollen-based reconstructions of the spatio-temporal dynamics of northern European regional vegetation abundance through the Holocene. We apply the Regional Estimates of VEgetation Abundance from Large Sites (REVEALS) model using fossil pollen records from eighteen sites within five modern biomes in the region. The eighteen sites are classified into four time-trajectory types on the basis of principal components analysis of both the REVEALS-based vegetation estimates (RVs) and the pollen percentage (PPs). The four trajectory types are more clearly separated for RVs than PPs. Further, the timing of major Holocene shifts, rates of compositional change, and diversity indices (turnover and evenness) differ between RVs and PPs. The differences are due to the reduction by REVEALS of biases in fossil pollen assemblages caused by different basin size, and inter-taxonomic differences in pollen productivity and dispersal properties. For example, in comparison to the PPs, the RVs show an earlier increase in Corylus and Ulmus in the early-Holocene and a more pronounced increase in grassland and deforested areas since the mid-Holocene. The results suggest that the influence of deforestation and agricultural activities on plant composition and abundance from Neolithic times was stronger than previously inferred from PPs. Relative to PPs, RVs show a more rapid compositional change, a largest decrease in turnover, and less variable evenness in most of northern Europe since 5200 cal yr BP. All these changes are primarily related to the strong impact of human activities on the vegetation. This study demonstrates that RV-based estimates of diversity indices, timing of shifts, and rates of change in reconstructed vegetation provide new insights into the timing and magnitude of major human distribution on Holocene regional, vegetation, feature that are critical in the assessment of human impact on vegetation, land-cover, biodiversity, and climate in the past. (C) Elsevier Ltd.All tights reserved.
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| 20. |
- Marquer, Laurent, et al.
(författare)
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Quantifying the effects of land use and climate on Holocene vegetation in Europe
- 2017
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Ingår i: Quaternary Science Reviews. - : Pergamon Press. - 0277-3791 .- 1873-457X. ; 171, s. 20-37
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Tidskriftsartikel (refereegranskat)abstract
- Early agriculture can be detected in palaeovegetation records, but quantification of the relative importance of climate and land use in influencing regional vegetation composition since the onset of agriculture is a topic that is rarely addressed. We present a novel approach that combines pollen-based REVEALS estimates of plant cover with climate, anthropogenic land-cover and dynamic vegetation modelling results. This is used to quantify the relative impacts of land use and climate on Holocene vegetation at a sub-continental scale, i.e. northern and western Europe north of the Alps. We use redundancy analysis and variation partitioning to quantify the percentage of variation in vegetation composition explained by the climate and land-use variables, and Monte Carlo permutation tests to assess the statistical significance of each variable. We further use a similarity index to combine pollen based REVEALS estimates with climate-driven dynamic vegetation modelling results. The overall results indicate that climate is the major driver of vegetation when the Holocene is considered as a whole and at the sub-continental scale, although land use is important regionally. Four critical phases of land-use effects on vegetation are identified. The first phase (from 7000 to 6500 BP) corresponds to the early impacts on vegetation of farming and Neolithic forest clearance and to the dominance of climate as a driver of vegetation change. During the second phase (from 4500 to 4000 BP), land use becomes a major control of vegetation. Climate is still the principal driver, although its influence decreases gradually. The third phase (from 2000 to 1500 BP) is characterised by the continued role of climate on vegetation as a consequence of late-Holocene climate shifts and specific climate events that influence vegetation as well as land use. The last phase (from 500 to 350 BP) shows an acceleration of vegetation changes, in particular during the last century, caused by new farming practices and forestry in response to population growth and industrialization. This is a unique signature of anthropogenic impact within the Holocene but European vegetation remains climatically sensitive and thus may continue to respond to ongoing climate change. (C) 2017 Elsevier Ltd. All rights reserved.
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| 21. |
- Murari, A., et al.
(författare)
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A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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| 22. |
- Norén, G. Niklas, et al.
(författare)
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A statistical methodology for drug–drug interaction surveillance
- 2008
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Ingår i: Statistics in Medicine. - : Wiley. - 0277-6715 .- 1097-0258. ; 27:16, s. 3057-3070
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Tidskriftsartikel (refereegranskat)abstract
- Interaction between drug substances may yield excessive risk of adverse drug reactions (ADRs) when two drugs are taken in combination. Collections of individual case safety reports (ICSRs) related to suspected ADR incidents in clinical practice have proven to be very useful in post-marketing surveillance for pairwise drug–ADR associations, but have yet to reach their full potential for drug–drug interaction surveillance. In this paper, we implement and evaluate a shrinkage observed-to-expected ratio for exploratory analysis of suspected drug–drug interaction in ICSR data, based on comparison with an additive risk model. We argue that the limited success of previously proposed methods for drug–drug interaction detection based on ICSR data may be due to an underlying assumption that the absence of interaction is equivalent to having multiplicative risk factors. We provide empirical examples of established drug–drug interaction highlighted with our proposed approach that go undetected with logistic regression. A database wide screen for suspected drug–drug interaction in the entire WHO database is carried out to demonstrate the feasibility of the proposed approach. As always in the analysis of ICSRs, the clinical validity of hypotheses raised with the proposed method must be further reviewed and evaluated by subject matter experts.
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| 23. |
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| 24. |
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| 25. |
- Norén, G. Niklas, et al.
(författare)
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Modern methods of pharmacovigilance : detecting adverse effects of drugs
- 2009
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Ingår i: Clinical medicine (London). - 1470-2118 .- 1473-4893. ; 9:5, s. 486-489
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Tidskriftsartikel (refereegranskat)abstract
- Medicines improve health and the chances of survival in a wide variety of conditions. At the same time, no substance with pharmacological effects is without hazard. Adverse drug reactions (ADRs) can be associated with the intended pharmacological effect of the medicine (eg bleeding from warfarin), mediated by other mechanisms (eg anticholinergic effects of tricyclic antidepressants) or can be altogether unexpected (eg hypersensitivity reactions to abacavir). Some ADRs can be identified early in the development of a medicine, but knowledge of the adverse effects profile is provisional when the medicine is first marketed and usually changes over time. Premarketing clinical trials include too few patients and are too short to detect every outcome that will affect public health and individual patient safety. In addition, clinical trials are carried out in controlled settings that differ from real-world practice. This reduces their power to detect ADRs, for example those that are due to drug-drug interactions or that affect only susceptible subgroups (eg phocomelia due to thalidomide). Safety needs to be evaluated continuously throughout the life-cycle of a medicinal product.1,2 A key challenge is to identify emerging problems as early as possible, without generating false alarms.
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| 26. |
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| 27. |
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| 28. |
- Norén, G. Niklas, 1977-
(författare)
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Statistical methods for knowledge discovery in adverse drug reaction surveillance
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Collections of individual case safety reports are the main resource for early discovery of unknown adverse reactions to drugs once they have been introduced to the general public. The data sets involved are complex and based on voluntary submission of reports, but contain pieces of very important information. The aim of this thesis is to propose computationally feasible statistical methods for large-scale knowledge discovery in these data sets. The main contributions are a duplicate detection method that can reliably identify pairs of unexpectedly similar reports and a new measure for highlighting suspected drug-drug interaction. Specifically, we extend the hit-miss model for database record matching with a hit-miss mixture model for scoring numerical record fields and a new method to compensate for strong record field correlations. The extended hit-miss model is implemented for the WHO database and demonstrated to be useful in real world duplicate detection, despite the noisy and incomplete information on individual case safety reports. The Information Component measure of disproportionality has been in routine use since 1998 to screen the WHO database for excessive adverse drug reaction reporting rates. Here, it is further refined. We introduce improved credibility intervals for rare events, post-stratification adjustment for suspected confounders and an extension to higher order associations that allows for simple but robust screening for potential risk factors. A new approach to identifying reporting patterns indicative of drug-drug interaction is also proposed. Finally, we describe how imprecision estimates specific to each prediction of a Bayes classifier may be obtained with the Bayesian bootstrap. Such case-based imprecision estimates allow for better prediction when different types of errors have different associated loss, with a possible application in combining quantitative and clinical filters to highlight drug-ADR pairs for clinical review.
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| 29. |
- Norén, G. Niklas, et al.
(författare)
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Temporal pattern discovery in longitudinal electronic patient records
- 2010
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Ingår i: Data mining and knowledge discovery. - : Springer Science and Business Media LLC. - 1384-5810 .- 1573-756X. ; 20:3, s. 361-387
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Tidskriftsartikel (refereegranskat)abstract
- Large collections of electronic patient records provide a vast but still underutilised source of information on the real world use of medicines. They are maintained primarily for the purpose of patient administration, but contain a broad range of clinical information highly relevant for data analysis. While they are a standard resource for epidemiological confirmatory studies, their use in the context of exploratory data analysis is still limited. In this paper, we present a framework for open-ended pattern discovery in large patient records repositories. At the core is a graphical statistical approach to summarising and visualising the temporal association between the prescription of a drug and the occurrence of a medical event. The graphical overview contrasts the observed and expected number of occurrences of the medical event in different time periods both before and after the prescription of interest. In order to effectively screen for important temporal relationships, we introduce a new measure of temporal association, which contrasts the observed-to-expected ratio in a time period immediately after the prescription to the observed-to-expected ratio in a control period 2 years earlier. An important feature of both the observed-to-expected graph and the measure of temporal association is a statistical shrinkage towards the null hypothesis of no association, which provides protection against highlighting spurious associations. We demonstrate the usefulness of the proposed pattern discovery methodology by a set of examples from a collection of over two million patient records in the United Kingdom. The identified patterns include temporal relationships between drug prescriptions and medical events suggestive of persistent and transient risks of adverse events, possible beneficial effects of drugs, periodic co-occurrence, and systematic tendencies of patients to switch from one medication to another.
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| 30. |
- O'Bryant, Sid E, et al.
(författare)
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Guidelines for the standardization of preanalytic variables for blood-based biomarker studies in Alzheimer's disease research.
- 2015
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 11:5, s. 549-560
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Tidskriftsartikel (refereegranskat)abstract
- The lack of readily available biomarkers is a significant hindrance toward progressing to effective therapeutic and preventative strategies for Alzheimer's disease (AD). Blood-based biomarkers have potential to overcome access and cost barriers and greatly facilitate advanced neuroimaging and cerebrospinal fluid biomarker approaches. Despite the fact that preanalytical processing is the largest source of variability in laboratory testing, there are no currently available standardized preanalytical guidelines. The current international working group provides the initial starting point for such guidelines for standardized operating procedures (SOPs). It is anticipated that these guidelines will be updated as additional research findings become available. The statement provides (1) a synopsis of selected preanalytical methods utilized in many international AD cohort studies, (2) initial draft guidelines/SOPs for preanalytical methods, and (3) a list of required methodological information and protocols to be made available for publications in the field to foster cross-validation across cohorts and laboratories.
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| 31. |
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| 32. |
- Star, Kristina, et al.
(författare)
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Challenges of safe medication practice in paediatric care : A nursing perspective
- 2013
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 102:5, s. 532-538
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Tidskriftsartikel (refereegranskat)abstract
- AIMTo explore nurses' experiences of handling medications in paediatric clinical practice, with a focus on factors that hinder and facilitate safe medication practices.METHODSTwenty nurses (registered nurses) from four paediatric wards at two hospitals in Sweden were interviewed in focus groups. The interviews were analysed using content analysis.RESULTSSix themes emerged from the analysed interviews: the complexity specific for nurses working on paediatric wards are hindrances to safe medication practices; nurses concerns about medication errors causes a considerable psychological burden; the individual nurse works hard for safe medication practices and values support from other nurse colleagues; circumstances out of the ordinary are perceived as critical challenges for maintaining patient safety; nurses value clear instructions, guidelines and routines but these are often missing, variable or changeable; management, other medical professionals, the pharmacy, the pharmaceutical industry and informatics support need to respond to the requirements of the nurses working situations to improve safe medication practices.CONCLUSIONWeaknesses were apparent in the long chain of the medication delivery process. A joint effort by different professions involved in that delivery process, and a nationwide collaboration between hospitals is recommended to increase safe medication practices in paediatric care.
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| 33. |
- Star, Kristina, et al.
(författare)
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Dose Variations Associated with Formulations of NSAID Prescriptions for Children : A Descriptive Analysis of Electronic Health Records in the UK
- 2011
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Ingår i: Drug Safety. - : Springer Science and Business Media LLC. - 0114-5916 .- 1179-1942. ; 34:4, s. 307-317
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Tidskriftsartikel (refereegranskat)abstract
- Background: NSAIDs, particularly ibuprofen, are commonly prescribed for children but there is limited published research on real-life prescribed doses for this class of drugs.Objective: The aim of the study was to investigate if variations in NSAID doses prescribed to children can be explained by patient age, indication, dosage form, type of NSAID or year of prescription.Study Design: Recorded daily doses for drugs within the `Anti-rheumatics, non-steroidal plain' anatomical classification were studied. First prescriptions of a distinct NSAID substance within 13-month time periods in a patient's history were included. To enable grouping and comparison of NSAIDs, doses were analysed as prescribed daily doses (PDDs) relative to the adult defined daily dose, stated as the relative PDD (rPDD) in this study. Multiple regression analysis was performed with the rPDD as the response variable, and age, indication, dosage form, NSAID substance and year of prescription as the explanatory variables.Setting: Prescriptions from the Intercontinental Medical Statistics (IMS) Health Disease Analyzer database containing electronic health records of general practitioners in the UK issued from 1988 to December 2005.Patients: Data for children aged 2-11 years with NSAID prescriptions including daily dose information.Results: A total of 21 473 first prescriptions for 19 695 patients were studied. The vast majority of prescriptions were for ibuprofen (n = 20 855), which were therefore analysed separately. The other NSAID prescriptions were grouped (n = 618), containing diclofenac, indometacin, mefenamic acid, naproxen and piroxicam (`NSAID group'). The rPDD varied considerably with dosage form in both the ibuprofen and NSAID groups. In particular, tablets/capsules were prescribed at higher doses than liquid dosage forms. In the NSAID group, naproxen was prescribed at noticeably higher doses. The rPDD varied only slightly with age in both groups. Prescriptions indicated for rheumatic disease were associated with lower doses than other indications in the NSAID group. The rPDD was not influenced by year of prescription.Conclusions: This study shows a correlation between higher prescribed NSAID doses and tablet/capsule formulation, and highlights the need for careful choice of dose formulation when prescribing medicines for children.
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| 34. |
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| 35. |
- Star, Kristina, 1963-, et al.
(författare)
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Paediatric safety signals identified in VigiBase : Methods and results from Uppsala Monitoring Centre
- 2019
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Ingår i: Pharmacoepidemiology and Drug Safety. - : WILEY. - 1053-8569 .- 1099-1557. ; 28:5, s. 680-689
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The purpose of this study is to uncover previously unrecognised risks of medicines in paediatric pharmacovigilance reports and thereby advance a safer use of medicines in paediatrics. Methods: Individual case safety reports (ICSRs) with ages less than 18 years were retrieved from VigiBase, the World Health Organization (WHO) global database of ICSRs, in September 2014. The reports were grouped according to the following age spans: 0 to 27 days; 28 days to 23 months; 2 to 11 years; and 12 to 17 years. vigiRank, a data-driven predictive model for emerging safety signals, was used to prioritise the list of drug events by age groups. The list was manually assessed, and potential signals were identified to undergo in-depth assessment to determine whether a signal should be communicated. Results: A total of 472 drug-event pairs by paediatric age groups were the subject of an initial manual assessment. Twenty-seven drug events from the two older age groups were classified as potential signals. An in-depth assessment resulted in eight signals, of which one concerned harm in connection with off-label use of dextromethorphan and another with accidental overdose of olanzapine by young children, and the remaining signals referred to potentially new causal associations for atomoxetine (two signals), temozolamide, deferasirox, levetiracetam, and desloratadine that could be relevant also for adults. Conclusions: Clinically relevant signals were uncovered in VigiBase by using vigiRank applied to paediatric age groups. Further refinement of the methodology is needed to identify signals in reports with ages under 2 years and to capture signals specific to the paediatric population as a risk group.
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| 36. |
- Star, Kristina, et al.
(författare)
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Pharmacovigilance for Children's Sake
- 2014
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Ingår i: Drug Safety. - : Springer Science and Business Media LLC. - 0114-5916 .- 1179-1942. ; 37:2, s. 91-98
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Tidskriftsartikel (refereegranskat)abstract
- Child age-specific information on efficacy and risk of medicines can be limited for healthcare professionals and patients. It is therefore very important to make the best use of a risk planned approach to the pharmacological treatment of children. This means pharmacovigilance in the broadest sense of gaining the best data from the use of medicines in clinical practice. We consider issues that complicate safe medication use in paediatric care, as well as current progress and provide suggestions for building knowledge within paediatric pharmacovigilance to be used to minimise patient harm. The continuous development in children constitutes a challenge to prescribing and administering age-suitable doses for individual children. Children are not only different from adults but differ vastly within their own age group. Physical growth during childhood is apparent to the eye, but less obvious is the ongoing maturation of organ function important for drug disposition and action. Systematic issues such as medication errors, off-label use and the lack of age-suitable formulations are considerable obstacles for safe medication use in paediatrics. The recognition of emerging adverse drug reactions could be more challenging in developing children. Initiatives to improve the situation have been made by the WHO and regulators in the USA and EU. Age-specific changes in physiology, pharmacology and psychology, as well as systematic issues specific for children need to be considered in the work of assessing spontaneous reports in children. Pharmacovigilance needs to broaden its aims considerably beyond merely capturing new associations between drugs and events, and encompass careful collection on patient characteristics and circumstances around the reported adverse drug reaction to provide essential information that will give clues on how to prevent harm to children.
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| 37. |
- Star, Kristina, et al.
(författare)
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Pneumonia following antipsychotic prescriptions in electronic health records : a patient safety concern?
- 2010
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Ingår i: British Journal of General Practice. - 0960-1643 .- 1478-5242. ; 60:579, s. 749-755
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Tidskriftsartikel (refereegranskat)abstract
- Background In screening the Intercontinental Medical Statistics (IMS) Health Disease Analyzer database of GP records from the UK, an increased registration of pneumonia subsequent to the prescription of some antipsychotic medicines was identified. Aim To investigate the temporal pattern between antipsychotic prescriptions and pneumonia with respect to age, type of pneumonia and other chest infections, and antipsychotic class. Design of study Self-controlled cohort analysis. Setting Electronic health records from the UK IMS Health Disease Analyzer database. Method Three groups of pneumonia-related International Classification of Diseases (ICD)-10 terms and prescriptions of atypical and conventional antipsychotic medicines were studied. Separate analyses were carried out for patients aged >= 65 years. The observed rate of pneumonia terms registered in different time periods in connection to antipsychotic prescriptions was contrasted to the overall rate of pneumonia terms relative to prescriptions of other drugs in the same dataset. Results In patients aged >= 65 years, an increased registration of a group of terms defined as 'acute chest infections', after atypical antipsychotic prescriptions, was identified. The corresponding increase after conventional antipsychotic prescriptions was much smaller. Bronchopneumonia had a striking increase after both atypical and conventional antipsychotic prescriptions, and was commonly recorded with fatal outcome. Few registrations of hypostatic. pneumonia were noted. Patients aged <65 years did not have a higher rate of acute chest infections after receiving antipsychotic prescriptions. Conclusion The consistent pattern of an increased rate of chest infections after atypical antipsychotic prescriptions in older people seen in this outpatient study, together with the higher risk shown in a previous study on hospitalised patients, suggests a causal relationship. This is of importance since bronchopneumonia seems highly linked to fatal outcome. In the absence of a mechanism, further investigation of the role of antipsychotics in older people is needed.
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| 38. |
- Star, Kristina, et al.
(författare)
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Rhabdomyolysis Reported for Children and Adolescents Treated with Antipsychotic Medicines : A Case Series Analysis
- 2012
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Ingår i: Journal of child and adolescent psychopharmacology. - : Mary Ann Liebert Inc. - 1044-5463 .- 1557-8992. ; 22:6, s. 440-451
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Rhabdomyolysis is a rare and potentially serious adverse drug reaction (ADR) to antipsychotic medicines. The aim of this study was to investigate the clinical circumstances surrounding the diagnosis of rhabdomyolysis in children and adolescents treated with antipsychotic medicines. We also critically reviewed individual case safety reports (ICSRs) of suspected ADRs to evaluate how clinically useful they can be in a case series analysis. Methods: This was a descriptive and an exploratory study. Published case reports and ICSRs from the World Health Organization (WHO) Global ICSR database, VigiBase, reported with rhabdomyolysis and antipsychotic medicines for patients <= 17 years years of age were described. Reporting patterns of ICSRs with rhabdomyolysis and antipsychotic medicines were explored in VigiBase for children and adolescents and for adults. The VigiBase ICSRs were also systematically evaluated regarding the report content. Results: Of the 26 evaluated reports, 6 co-reported neuroleptic malignant syndrome (NMS) and 20 reports concerned rhabdomyolysis in the absence of NMS. The reported suspected antipsychotic medicines for these 20 reports were olanzapine, risperidone, haloperidol, paliperidone, quetiapine, clozapine, cyamemazine, and aripiprazole. In VigiBase, rhabdomyolysis (in the absence of NMS) was reported more frequently with olanzapine relative to all reports for children and adolescents with antipsychotic medicines. In the range of events that preceded rhabdomyolysis, muscle pains and abdominal pain were commonly recorded to have started during the week prior to the diagnosis. Other preceding symptoms were general weakness and dark urine. Onset of rhabdomyolysis for most patients occurred at any time within 2 months of starting antipsychotic treatment, in several cases triggered by changes to the patient's drug therapy or known risk factors of rhabdomyolysis. It was found that ICSRs can contribute with additional information, but that access to free text and narratives were crucial in order to capture clinically useful features of rhabdomyolysis. Conclusion: Monitoring of children and adolescents needs to be intensified during dose increases, or when a new, added, or switched antipsychotic medicine is introduced to their drug regimen, and during exposure to known risk factors for rhabdomyolysis. The development of seemingly nonserious events, such as abdominal pain, muscle pain, weakness, and dark urine, should be followed up during antipsychotic use, as they might be precursory events to rhabdomyolysis that eventually could develop into acute renal failure.
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| 39. |
- Star, Kristina, 1963-
(författare)
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Safety of Medication in Paediatrics
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In paediatrics, the limited documentation to guide medication, the lack of suitable dosage forms, and the continuous development in childhood present a scenario where safety of medication is a particular challenge.Aim: To explore reported adverse drug reactions (ADRs) and the challenges in prescribing and administering medicines in paediatrics, in order to identify and suggest areas needing international surveillance within medication safety and improvement in the clinical setting.Methods: Four exploratory studies were conducted. Worldwide reporting of suspected ADRs (individual case safety reports, ICSR) with ages 0-17 years were examined overall. Twenty published case reports and ICSRs for adolescents, who developed a rare and incompletely documented ADR (rhabdomyolysis) during antipsychotic medicine use, were analysed in-depth. Prescribed doses of anti-inflammatory medicines were studied in a UK electronic health record database. Transcribed focus group interviews with 20 registered nurses from four paediatric wards in Sweden were analysed for factors that may promote or hinder safe medication practices. Descriptive statistics, multiple regression, and content analyses were used.Results: Although, skin reactions and anti-infective medicines were most frequently reported, and more reported in paediatric patients than in adults, medication errors and adverse reactions related to psychostimulant medicines were reported with increased frequency during 2005 to February 2010. The in-depth case analysis emphasised the need for increased vigilance following changes in patients’ medicine regimens, and indicated that ICSRs could contribute with clinically valuable information. Prescribed dose variations were associated with type of dosage form. Tablets and capsules were prescribed with a higher dose than liquid dosage forms. Six themes emerged from the interviews: preparation and administration was complex; medication errors caused considerable psychological burden; support from nurse colleagues was highly valued; unfamiliar medication was challenging; clear dose instructions were important; nurses handling medications needed to be accorded higher priority.Conclusions: Age-specific screening of ICSRs and the use of ICSRs to enhance knowledge of ADRs and medication errors need to be developed. Access to age-appropriate dosage forms is important when prescribing medicines to children. To improve medication safety practices in paediatric care, interdisciplinary collaborations across hospitals on national or even global levels are needed.
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| 40. |
- Star, Kristina, et al.
(författare)
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Suspected Adverse Drug Reactions Reported For Children Worldwide : An Exploratory Study Using VigiBase
- 2011
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Ingår i: Drug Safety. - : Springer Science and Business Media LLC. - 0114-5916 .- 1179-1942. ; 34:5, s. 415-428
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAs a first step towards implementing routine screening of safety issues specifically related to children at the Uppsala Monitoring Centre, this study was performed to explore reporting patterns of adverse reactions in children. ObjectiveThe first aim of this study was to characterize and contrast child reports against adult reports in an overall drug and adverse reaction review. The second aim was to highlight increases in reporting of specific adverse reactions during recent years subdivided by age group. Study DesignThis was an exploratory study of internationally compiled individual case safety reports (ICSRs). SettingReports were extracted from the WHO global ICSR database, VigiBase, up until 5 February 2010. The reports in VigiBase originate from 97 countries and the likelihood that a medicine caused the adverse effect may vary from case to case. Suspected duplicate and vaccine reports were excluded from the analysis, as were reports with age not specified. The Medical Dictionary for Regulatory Activities (MedDRA (R)) and the WHO Anatomical Therapeutic Chemical (ATC) classification were used to group adverse reactions and drugs. PatientsIn the general review, reports from 1968 to 5 February 2010 were divided into child (aged 0-17 years) and adult (>= 18 years) age groups. To highlight increases in reporting rates of specific adverse reactions during recent years, reports from 2005 to February 2010 were compared with reports from 1995 to 1999. The ten adverse reactions with the greatest difference in the proportion of reports between the two time periods were reviewed. In the latter analysis, the reports were subdivided into age groups: neonates 27 days; infants 28 days-23 months; children 2-11 years; and adolescents 12-17 years. ResultsA total of 3 472 183 reports were included in the study, of which 7.7% (268 145) were reports for children (0-17 years). Fifty-three percent of the child reports were for males, whilst 39% of reports in the adult group were for males. The proportion of reports involving children among Asian reports was 14% and was 15% among reports from Africa and Latin America, including the Caribbean. Among reports from North America, Oceania and Europe, 7% of the reports involved children. For the ATC drug classification groups, the largest difference in percentage units between the child and adult groups was seen for the anti-infective (33 vs 15%), respiratory (11 vs 5%) and dermatological (12 vs 7%) drug groups. Skin reactions were most commonly reported for the children; these were recorded in 35% of all reports for children and 23% of all reports for adults. Medication error-related terms in the younger age groups were reported with an increased frequency during recent years. This was particularly noticeable for the infants aged 28 days-23 months, recorded with accidental overdose and drug toxicity. Reactions reported in suspected connection to medicines used for attention-deficit hyperactivity disorders (ADHD) completely dominated the 2- to 11-year age group and were also common for the adolescents. This study presents variations in the reporting pattern in different age groups in VigiBase which, in some cases, could be due to susceptibilities to specific drug-related problems in certain age groups. Other likely explanations might be common drug usage and childhood diseases in these age groups. ConclusionsReports in VigiBase received internationally for more than 40 years reflect real concerns for children taking medicines. The study highlights adverse reactions with an increased reporting during recent years, particularly those connected to the introduction of ADHD medicines in the child population. To enhance patient safety, medication errors indicating administration and dosing difficulties of drugs, especially in the younger age groups, require further attention.
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| 41. |
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| 42. |
- Stephens, Lucas, et al.
(författare)
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Archaeological assessment reveals Earth’s early transformation through land use
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902
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Tidskriftsartikel (refereegranskat)abstract
- Humans began to leave lasting impacts on Earth’s surface starting 10,000 to 8000 years ago. Through a synthetic collaboration with archaeologists around the globe, Stephens et al. compiled a comprehensive picture of the trajectory of human land use worldwide during the Holocene (see the Perspective by Roberts). Hunter-gatherers, farmers, and pastoralists transformed the face of Earth earlier and to a greater extent than has been widely appreciated, a transformation that was essentially global by 3000 years before the present.Science, this issue p. 897; see also p. 865Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth’s transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
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| 43. |
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| 44. |
- Strandell, Johanna, et al.
(författare)
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Reporting Patterns Indicative of Adverse Drug Interactions : A Systematic Evaluation in VigiBase
- 2011
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Ingår i: Drug Safety. - : Springer Science and Business Media LLC. - 0114-5916 .- 1179-1942. ; 34:3, s. 253-266
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adverse drug interaction surveillance in collections of Individual Case Safety Reports (ICSRs) remains underdeveloped. Most efforts to date have focused on disproportionality analysis, but the empirical support for its value is based on isolated examples. Additionally, too little attention has been given to the potential value of the detailed content of ICSRs for improved adverse drug interaction surveillance.Objective: The aim of the study was to identify reporting patterns indicative of suspected adverse drug interactions before the drug interactions are generally established.Methods: A reference set of known adverse drug interactions and drug pairs not known to interact was constructed from information added to Stockley's Drug Interactions Alerts between the first quarter of 2007 and the third quarter of 2009. The reference set was used to systematically study differences in reporting patterns between adverse drug interactions before they are generally established and adverse drug reactions (ADRs) to drug pairs that are not known to interact, in the WHO Global ICSR Database, VigiBase. The scope of the study included pharmacological properties such as common cytochrome P450 metabolism, explicit suspicions of drug interactions as noted by the reporter, clinical details such as dose and treatment overlap, and the lower limit of the 95% credibility interval of a three-way measure of disproportionality, Omega025 (Ω025), based on the total number of reports on two drugs and one ADR together. Analyses were carried out including and excluding concomitant medicines.Results: Five reporting patterns were highlighted as particularly strong indicators of adverse drug interactions before they are known: suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair; and, finally, an excess total number of reports on the ADR together with the two drugs, as measured by Ω025. Overall, the inclusion of concomitant medicines led to a larger number of true adverse drug interactions being highlighted, but at a substantial decrease in the strength of most indicators. Notably, the inclusion of concomitant medicines completely eliminated the value of Ω025 as an indicator of adverse drug interactions, in this systematic evaluation.Conclusions: Reported suspicion of interactions as noted by the reporter in a case narrative, the assignment of the two drugs as interacting or through an ADR term; co-reporting of effect increased with the drug pair and by the Ω025 each provide unique information to highlight adverse drug interactions before they become known in the literature. To our knowledge, this is the first systematic analysis demonstrating the value of disproportionality analysis for adverse drug interactions using a comprehensive reference set, and the first study to consider a broader basis including clinical information for systematic drug interaction surveillance.
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| 45. |
- Strandell, Johanna, et al.
(författare)
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Rhabdomyolysis a result of azithromycin and statins : an unrecognized interaction
- 2009
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley-Blackwell. - 0306-5251 .- 1365-2125. ; 68:3, s. 427-34
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.METHODS: The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.RESULTS: The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.CONCLUSIONS: Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.
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| 46. |
- Strandell, Johanna, et al.
(författare)
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The Development and Evaluation of Triage Algorithms for Early Discovery of Adverse Drug Interactions
- 2013
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Ingår i: Drug Safety. - : Adis. - 0114-5916 .- 1179-1942. ; 36:5, s. 371-388
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Tidskriftsartikel (refereegranskat)abstract
- Background Around 20 % of all adverse drug reactions (ADRs) are due to drug interactions. Some of these will only be detected in the postmarketing setting. Effective screening in large collections of individual case safety reports (ICSRs) requires automated triages to identify signals of adverse drug interactions. Research so far has focused on statistical measures, but clinical information and pharmacological characteristics are essential in the clinical assessment and may be of great value in first-pass filtering of potential adverse drug interaction signals. less thanbrgreater than less thanbrgreater thanObjective The aim of this study was to develop triages for adverse drug interaction surveillance, and to evaluate these prospectively relative to clinical assessment. less thanbrgreater than less thanbrgreater thanMethods A broad set of variables were considered for inclusion in the triages, including cytochrome P450 (CYP) activity, explicit suspicions of drug interactions as noted by the reporter, dose and treatment overlap, and a measure of interaction disproportionality. Their unique contributions in predicting signals of adverse drug interactions were determined through logistic regression. This was based on the reporting in the WHO global ICSR database, VigiBase (TM), for a set of known adverse drug interactions and corresponding negative controls. Three triages were developed, each producing an estimated probability that a given drug-drug-ADR triplet constitutes an adverse drug interaction signal. The triages were evaluated against two separate benchmarks derived from expert clinical assessment: adverse drug interactions known in the literature and prospective adverse drug interaction signals. For reference, the triages were compared with disproportionality analysis alone using the same benchmarks. less thanbrgreater than less thanbrgreater thanResults The following were identified as valuable predictors of adverse drug interaction signals: plausible CYP metabolism; notes of suspected interaction by the reporter; and reports of unexpected therapeutic response, altered therapeutic effect with dose information and altered therapeutic effect when only two drugs had been used. The new triages identified reporting patterns corresponding to both prospective signals of adverse drug interactions and already established ones. They perform better than disproportionality analysis alone relative to both benchmarks. less thanbrgreater than less thanbrgreater thanConclusions A range of predictors for adverse drug interaction signals have been identified. They substantially improve signal detection capacity compared with disproportionality analysis alone. The value of incorporating clinical and pharmacological information in first-pass screening is clear.
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| 47. |
- Strandell, Johanna, et al.
(författare)
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Triage algorithms for early discovery of adverse drug interactions
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Most methodological research for broad surveillance of drug interactions in large collections of suspected ADR reports has focused on measures of disproportionality. However, recent results indicate that reported clinical information and pharmacological characteristics may be at least as valuable to detect adverse drug interactions early. Objective: To develop triage algorithms for adverse drug interaction surveillance, and to evaluate the algorithms prospectively relative to expert clinical assessment. Methods: A previously developed reference set based on Stockley’s Drug Interactions was used to train the algorithms. Logistic regression was used to set the relative weights of the different indicators (information potentially suggestive adverse drug interactions such as pharmacological properties including cytochrome P450 (CYP) activity; explicit suspicions of drug interactions as noted by the reporter in different forms; clinical details such as dose and treatment overlap; and a measure of disproportionality based on the total number of reports on two drugs and one ADR together) of each algorithm. Three triage algorithms were designed. All are logistic regression models producing an estimated probability that a given case series constitutes an adverse drug interaction signal. Two of them are data driven: one which used a very broad set of indicators (full data-driven) and one which used a more narrow set (lean data-driven). The third was manually derived (lean clinical) as a simplified version of the full data-driven algorithm. An independent evaluation set was constructed that consisted of 100 randomly selected case series in the WHO Global Individual Case Safety Report (ICSR) Database, VigiBase, from January 1990 to February 2011. Each algorithm’s ranking of case series was evaluated against an evaluation set. In a complementary analysis the algorithm were compared to a pure disproportionality analysis. Results: The two lean algorithms were comparable in performance. However both outperformed the full data-driven algorithm on the independent evaluation set. The areas under the curve (AUC) for the receiver operating characteristics (ROC) curves were as follows: 71% (lean clinical) and 69% (lean data-driven). For a false positive rate (FPR) of up to 0.04 the lean algorithms classifies about 14,000 case series as potential interaction signals. Thresholds corresponding to greater FPRs are unlikely to be feasible in practice. The algorithms clearly outperform disproportionality analysis alone. Conclusions: The value of incorporating clinical and pharmacological information in first-pass screening for adverse drug interactions is clear. Two triage algorithms have been proposed that each effectively identify adverse drug interaction signals and clearly outperforming pure disproportionality analysis in this respect.
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| 48. |
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| 49. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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