Precision Diagnostics in Myeloid Malignancies: Development and Validation of a National Capture-Based Gene Panel.

Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS-MGP), a capture-based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS-MGP displayed uniform coverage across all targets, including recognized difficult GC-rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit-of-detection of a 0.5% variant allele frequency (VAF), achieved by utilizing error correction and filtering against a panel-of-normals. A national interlaboratory comparison investigating 56 somatic variants demonstrated highly concordant results in both detection rate and reported VAFs. In addition, prospective analysis of 323 patients analyzed with the GMS-MGP as part of standard-of-care identified clinically significant genes as well as recurrent mutations in less well-studied genes. In conclusion, the GMS-MGP workflow supports sensitive detection of all clinically relevant genes, facilitates novel findings, and is, based on the capture-based design, easy to update once new guidelines become available. The GMS-MGP provides an important step toward nationally harmonized precision diagnostics of myeloid malignancies.

Valuation of ecotoxicological impacts from tributyltin based on a quantitative environmental assessment framework.

In the scientific literature, few valuations of biodiversity and ecosystem services following the impacts of toxicity are available, hampered by the lack of ecotoxicological documentation. Here, tributyltin is used to conduct a contingent valuation study as well as cost-benefit analysis (CBA) of measures for improving the environmental status in Swedish coastal waters of the Baltic Sea. Benefits considering different dimensions when assessing environmental status are highlighted and a quantitative environmental assessment framework based on available technology, ecological conditions, and economic valuation methodology is developed. Two scenarios are used in the valuation study: (a) achieving good environmental status by 2020 in accordance with EU legislation (USD 119 household(-1) year(-1)) and (b) achieving visible improvements by 2100 due to natural degradation (USD 108 household(-1) year(-1)) during 8 years. The later scenario was used to illustrate an application of the assessment framework. The CBA results indicate that both scenarios might generate a welfare improvement.

Baltic Sea nutrient reductions--what should we aim for?

Nutrient load reductions are needed to improve the state of the Baltic Sea, but it is still under debate how they should be implemented. In this paper, we use data from an environmental valuation study conducted in all nine Baltic Sea states to investigate public preferences of relevance to three of the involved decision-dimensions: First, the roles of nitrogen versus phosphorus reductions causing different eutrophication effects; second, the role of time - the lag between actions to reduce nutrient loads and perceived improvements; and third; the spatial dimension and the roles of actions targeting the coastal and open sea environment and different sub-basins. Our findings indicate that respondents view and value the Baltic Sea environment as a whole, and are not focussed only on their local sea area, or a particular aspect of water quality. We argue that public preferences concerning these three perspectives should be one of the factors guiding marine policy. This requires considering the entire range of eutrophication effects, in coastal and open sea areas, and including long-term and short-term measures.

Non-market valuation of the coastal environment--uniting political aims, ecological and economic knowledge.

In this paper, we examine the feasibility of using an approach for estimating Willingness-To-Pay for marine environmental improvements, based on a holistic, policy-determined scenario. Conducting valuation studies based on a policy-determined scenario is beneficial for decision-makers in terms of practical applicability but also for research in terms of e.g. data availability. Using a case study in two Swedish coastal areas, we examine whether respondents are able to understand and attach a monetary value to these types of scenarios. The tested scenarios are based on improving water quality according to the EU Water Framework Directive and reducing noise and littering according to standard-type measures in a Swedish archipelago setting. The results are promising, paving the ground for future valuation studies using this approach. However, there might be tradeoffs, since the use of scenarios like this require much preparation by researchers and much efforts by respondents. We recommend environmental managers to adopt this approach when possible, but to have these potential tradeoffs in mind. Mean monthly WTP per household for the water quality improvement scenario is estimated to 71 and 102 SEK(1) in the two study areas, respectively. The corresponding numbers for the less noise and littering scenario are 38 and 46 SEK. Valuation of noise and littering in archipelago areas has previously not been very common, making these estimates especially important for marine policy.

Methodological characteristics of academic clinical drug trials--a retrospective cohort study of applications to the Danish Medicines Agency 1993-2005.

AIM: The aim of this study was to investigate the temporal trends in characteristics of academic clinical drug trials. We here report characteristics on trial methodology. METHODS: A review of 386 approved applications of academic clinical drug trials submitted to the Danish Medicines Agency 1993-2005 was carried out. Data on 11 methodological characteristics were collected, e.g. statement of primary endpoint, use of control group, blinding, randomization, method for generation of allocation sequence, monitoring according to the principles of Good Clinical Practice (GCP monitoring) and publication. RESULTS: Statement of primary endpoint increased from 60 to 90% of trials (P < 0.0001). Comparing the period before and after implementation of the Clinical Trials Directive in 2004, intention of GCP monitoring increased from 13% to 94%. Control of medicine compliance increased from 42% to 76% (P < 0.0001) among trials with self-administration of the investigational medicinal product. Among controlled trials use of randomization increased from 78% to 94% (P= 0.0063) of trials. Remaining characteristics did not change significantly. In total 68% (264/386) were randomized controlled trials. CONCLUSIONS: Our study shows that randomization, definition of primary endpoint, GCP monitoring, and control of medicine compliance form part of a significantly increasing percentage of academic clinical drug trials. This indicates an increase in the quality of academic clinical drug research in Denmark 1993-2005. However, high numbers of unblinded randomized controlled trials and randomized controlled trials utilizing unacceptable methods for generation of allocation sequence emphasize the potential for further improvement of trial methodology.

[Effect of the GCP Directive on academic drug trials]. / Effekten af GCP-direktivet på forskerinitierede kliniske laegemiddelforsøg--sekundaerpublikation

Since 2004, adherence to Good Clinical Practice has been mandatory for all clinical drug trials. This was new to the investigator-initiated trials. Our study showed no association between the implementation of the Directive and investigator or industry-initiated trials. However, a steady decline was observed over the entire period. Presumably, the introduction of GCP did not entail a decline because of the presence of GCP units at university hospitals. Thus, researchers can conduct clinical drug trials under the same regulations as drug companies.

Effect of European Clinical Trials Directive on academic drug trials in Denmark: retrospective study of applications to the Danish Medicines Agency 1993-2006.

OBJECTIVE: To determine the impact of the European Union's Clinical Trials Directive on the number of academic drug trials carried out in Denmark. DESIGN: Retrospective review of applications for drug trials to the Danish Medicines Agency, 1993-2006. REVIEW METHODS: Applications for drug trials for alternate years were classified as academic or commercial trials. A random subset of academic trials was reviewed for number of participants in and intended monitoring of the trials. RESULTS: Academic and commercial drug trials showed an identical steady decline from 1993 to 2006 and no noticeable change after 2004 when good clinical practice became mandatory for academic trials. CONCLUSION: The Clinical Trials Directive introduced in May 2004 to ensure good clinical practice for academic drug trials was not associated with a decline in research activity in Denmark; presumably because good clinical practice units had already been in place in Danish universities since 1999. With such an infrastructure academic researchers can do drug trials under the same regulations as drug companies.