| 1. |
- Botvinik-Nezer, Rotem, et al.
(författare)
-
Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
-
Tidskriftsartikel (refereegranskat)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
|
|
| 2. |
- Carpenter, Stephen R., et al.
(författare)
-
Program on ecosystem change and society : an international research strategy for integrated social-ecological systems
- 2012
-
Ingår i: Current Opinion in Environmental Sustainability. - : Elsevier BV. - 1877-3435 .- 1877-3443. ; 4:1, s. 134-138
-
Tidskriftsartikel (refereegranskat)abstract
- The Program on Ecosystem Change and Society (PECS), a new initiative within the ICSU global change programs, aims to integrate research on the stewardship of social-ecological systems, the services they generate, and the relationships among natural capital, human wellbeing, livelihoods, inequality and poverty. The vision of PECS is a world where human actions have transformed to achieve sustainable stewardship of social-ecological systems. The goal of PECS is to generate the scientific and policy-relevant knowledge of social-ecological dynamics needed to enable such a shift, including mitigation of poverty. PECS is a coordinating body for diverse independently funded research projects, not a funder of research. PECS research employs a range of transdisciplinary approaches and methods, with comparative, place-based research that is international in scope at the core.
|
|
| 3. |
- Craddock, Nick, et al.
(författare)
-
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
-
Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
|
|
| 4. |
- Fischer, Joern, et al.
(författare)
-
Advancing sustainability through mainstreaming a social–ecological systems perspective
- 2015
-
Ingår i: Current Opinion in Environmental Sustainability. - : Elsevier BV. - 1877-3435 .- 1877-3443. ; 14, s. 144-149
-
Tidskriftsartikel (refereegranskat)abstract
- The concept of social-ecological systems is useful for understanding the interlinked dynamics of environmental and societal change. The concept has helped facilitate: (1) increased recognition of the dependence of humanity on ecosystems; (2) improved collaboration across disciplines, and between science and society; (3) increased methodological pluralism leading to improved systems understanding; and (4) major policy frameworks considering social-ecological interactions. Despite these advances, the potential of a social-ecological systems perspective to improve sustainability outcomes has not been fully realized. Key priorities are to: (1) better understand and govern social-ecological interactions between regions; (2) pay greater attention to long-term drivers; (3) better understand the interactions among power relations, justice, and ecosystem stewardship; and (4) develop a stronger science-society interface.
|
|
| 5. |
- Komp Lindgren, Patricia, et al.
(författare)
-
Biological cost of single and multiple norfloxacin resistance mutations in Escherichia coli implicated in urinary tract infections
- 2005
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 49:6, s. 2343-2351
-
Tidskriftsartikel (refereegranskat)abstract
- Resistance to fluoroquinolones in urinary tract infection (UTIs)caused by Escherichia coli is associated with multiple mutations,typically those that alter DNA gyrase and DNA topoisomeraseIV and those that regulate AcrAB-TolC-mediated efflux. We askedwhether a fitness cost is associated with the accumulation ofthese multiple mutations. Mutants of the susceptible E. coliUTI isolate Nu14 were selected through three to five successivesteps with norfloxacin. Each selection was performed with theMIC of the selected strain. After each selection the MIC wasmeasured; and the regions of gyrA, gyrB, parC, and parE, previouslyassociated with resistance mutations, and all of marOR and acrRwere sequenced. The first selection step yielded mutations ingyrA, gyrB, and marOR. Subsequent selection steps yielded mutationsin gyrA, parE, and marOR but not in gyrB, parC, or acrR. Resistance-associatedmutations were identified in almost all isolates after selectionsteps 1 and 2 but in less than 50% of isolates after subsequentselection steps. Selected strains were competed in vitro, inurine, and in a mouse UTI infection model against the startingstrain, Nu14. First-step mutations were not associated withsignificant fitness costs. However, the accumulation of threeor more resistance-associated mutations was usually associatedwith a large reduction in biological fitness, both in vitroand in vivo. Interestingly, in some lineages a partial restorationof fitness was associated with the accumulation of additionalmutations in late selection steps. We suggest that the relativebiological costs of multiple mutations may influence the evolutionof E. coli strains that develop resistance to fluoroquinolones.
|
|
| 6. |
- Komp Lindgren, Patricia, et al.
(författare)
-
Mutation Rate and Evolution of Fluoroquinolone Resistance in Escherichia coli Isolates from Patients with Urinary tract infections
- 2003
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 47:10, s. 3222-3232
-
Tidskriftsartikel (refereegranskat)abstract
- Escherichia coli strains from patients with uncomplicated urinarytract infections were examined by DNA sequencing for fluoroquinoloneresistance-associated mutations in six genes: gyrA, gyrB, parC,parE, marOR, and acrR. The 54 strains analyzed had a susceptibilityrange distributed across 15 dilutions of the fluoroquinoloneMICs. There was a correlation between the fluoroquinolone MICand the number of resistance mutations that a strain carried,with resistant strains having mutations in two to five of thesegenes. Most resistant strains carried two mutations in gyrAand one mutation in parC. In addition, many resistant strainshad mutations in parE, marOR, and/or acrR. No (resistance) mutationwas found in gyrB. Thus, the evolution of fluoroquinolone resistanceinvolves the accumulation of multiple mutations in several genes.The spontaneous mutation rate in these clinical strains variedby 2 orders of magnitude. A high mutation rate correlated stronglywith a clinical resistance phenotype. This correlation suggeststhat an increased general mutation rate may play a significantrole in the development of high-level resistance to fluoroquinolonesby increasing the rate of accumulation of rare new mutations.
|
|
| 7. |
- Komp Lindgren, Patricia, 1971-
(författare)
-
Mutations and Mutation Rate in the Development of Fluoroquinolone Resistance
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The emergence of multidrug resistant bacteria world wide is a serious problem, and very few new drugs are under development. The selection of resistant bacteria is affected by factors such as mutation rate, biological fitness cost and the rate of fitness compensation. This thesis is focused on how mutation rate affects resistance to fluoroquinolones and on exploring a dosing strategy that might slow resistance development. In a set of urinary tract Escherichia coli isolates MIC values above the breakpoint for the fluoroquinolones norfloxacin and ciprofloxacin carried at least three resistance-associated mutations. In these isolates the number of resistance mutations correlated with the mutation rate. During step-wise selection for decreased susceptibility to fluoroquinolones, the accumulation of mutations in E. coli was associated with an increasing biological cost both in vitro and in vivo. However, in some lineages an additional selection step for resistance was associated with a partial restoration of fitness. During step-wise selections we found, as expected, that reduced ciprofloxacin susceptibility frequently hitchhiked with a strong mutator phenotype. More surprisingly, we also found that reduced susceptibility was frequently associated with the emergence of rifampicin-resistant populations. We hypothesise that this correlation reflects selection for fitness-compensating mutations in RNA polymerase.Mutant prevention concentration (MPC) dosing has been proposed as a strategy to reduce the selection of resistant bacterial populations. Based on limited data it had been thought that MPC might be a simple multiple of MIC, which can easily be determined. However, we showed for a collection of susceptible urinary tract E. coli that MPC could not be predicted from MIC and must be measured directly for relevant populations. Using an in vitro kinetic model we also showed that the pharmacodynamic index that best predicted prevention of resistance development in wild type E. coli was an AUC/MPC of > 22 for ciprofloxacin.
|
|
| 8. |
|
|
| 9. |
- Lindblad-Toh, Kerstin, et al.
(författare)
-
Genome sequence, comparative analysis and haplotype structure of the domestic dog.
- 2005
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 438:7069, s. 803-19
-
Tidskriftsartikel (refereegranskat)abstract
- Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.
|
|
| 10. |
- Marcusson, Linda L, et al.
(författare)
-
Mutant prevention concentrations of ciprofloxacin for urinary tract infection isolates of Escherichia coli
- 2005
-
Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 55:6, s. 938-943
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To measure the mutant prevention concentration (MPC) of ciprofloxacin for a set of urinary tract infection (UTI) Escherichia coli isolates with different levels of susceptibility and determine whether MPC can be predicted from MIC. Methods: MPC was defined as the lowest ciprofloxacin concentration that prevented the growth of resistant colonies when 1010 bacteria were spread on solid medium and incubated for 96 h at 37°C. MIC was measured by Etest. Bacteria surviving (persisting) at MPC were isolated and quantified from agar plugs taken after 96 h. The genes hipA and hipB were amplified by PCR from persisters and sequenced. Results: Isolates with MICs above the NCCLS breakpoint for ciprofloxacin resistance (4 mg/L) typically have MPCs greater than 32 mg/L. Isolates with MICs below the breakpoint for ciprofloxacin susceptibility (1 mg/L) have MPCs up to 5 mg/L. MPC/MIC is ∼16 for most susceptible isolates but there are several notable exceptions (MPC/MIC > 100). Resistant colonies arising one dilution step below MPC often had MIC > MPC. In every case tested, a proportion of cells survived (persisted), but did not grow into colonies, at MPC, without any increase in MIC. Conclusions: MPCs were determined for all ciprofloxacin-susceptible isolates. MPC is not accurately predicted from MIC. Colonies selected below MPC frequently have MIC > MPC, suggesting multiple mutations. A small fraction of cells from all strains tested survived for 96 h at MPC, without any associated increase in MIC. These survivors/persisters are not hipAB mutants.
|
|
