| 1. |
- Ahlberg, Ernst, et al.
(författare)
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Using conformal prediction to prioritize compound synthesis in drug discovery
- 2017
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Ingår i: Proceedings of Machine Learning Research. - Stockholm : Machine Learning Research. ; , s. 174-184
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Konferensbidrag (refereegranskat)abstract
- The choice of how much money and resources to spend to understand certain problems is of high interest in many areas. This work illustrates how computational models can be more tightly coupled with experiments to generate decision data at lower cost without reducing the quality of the decision. Several different strategies are explored to illustrate the trade off between lowering costs and quality in decisions.AUC is used as a performance metric and the number of objects that can be learnt from is constrained. Some of the strategies described reach AUC values over 0.9 and outperforms strategies that are more random. The strategies that use conformal predictor p-values show varying results, although some are top performing.The application studied is taken from the drug discovery process. In the early stages of this process compounds, that potentially could become marketed drugs, are being routinely tested in experimental assays to understand the distribution and interactions in humans.
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| 2. |
- Benatar, Michael, et al.
(författare)
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Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01) : a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial
- 2024
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Ingår i: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 23:7, s. 687-699
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis.Methods: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed.Findings: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]).Interpretation: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated.Funding: Orphazyme.
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| 3. |
- Boiveau, Thomas, et al.
(författare)
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Fictitious domain method with boundary value correction using penalty-free Nitsche method
- 2018
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Ingår i: Journal of Numerical Mathematics. - : Walter de Gruyter. - 1570-2820 .- 1569-3953. ; 26:2, s. 77-95
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we consider a fictitious domain approach based on a Nitsche type method without penalty. To allow for high order approximation using piecewise affine approximation of the geometry we use a boundary value correction technique based on Taylor expansion from the approximate to the physical boundary. To ensure stability of the method a ghost penalty stabilization is considered in the boundary zone. We prove optimal error estimates in the H1-norm and estimates suboptimal by ?(h1/2) in the L2-norm. The suboptimality is due to the lack of adjoint consistency of our formulation. Numerical results are provided to corroborate the theoretical study.
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| 4. |
- Botvinik-Nezer, Rotem, et al.
(författare)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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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.
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| 5. |
- Brehony, Carina, et al.
(författare)
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Implications of Differential Age Distribution of Disease-Associated Meningococcal Lineages for Vaccine Development
- 2014
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Ingår i: Clinical and Vaccine Immunology. - : American Society for Microbiology. - 1556-6811 .- 1556-679X. ; 21:6, s. 847-853
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Tidskriftsartikel (refereegranskat)abstract
- New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects <1 year of age experienced lower risk of sequence type 11 (ST-11) cc, ST-32 cc, and ST-269 cc disease and higher risk of disease due to unassigned STs, 1- to 4-year-olds experienced lower risk of ST-11 cc and ST-32 cc disease, 5- to 14-year-olds were less likely to experience ST-11 cc and ST-269 cc disease, and >= 25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines, as different variants, or perhaps targets, may be required for different age groups.
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| 6. |
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| 7. |
- Burman, Erik, et al.
(författare)
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A Stabilized Cut Finite Element Method for the Three Field Stokes Problem
- 2015
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Ingår i: SIAM Journal on Scientific Computing. - : Society for Industrial & Applied Mathematics (SIAM). - 1064-8275 .- 1095-7197. ; 37:4, s. A1705-A1726
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Tidskriftsartikel (refereegranskat)abstract
- We propose a Nitsche-based fictitious domain method for the three field Stokes problem in which the boundary of the domain is allowed to cross through the elements of a fixed background mesh. The dependent variables of velocity, pressure, and extra-stress tensor are discretized on the background mesh using linear finite elements. This equal order approximation is stabilized using a continuous interior penalty (CIP) method. On the unfitted domain boundary, Dirichlet boundary conditions are weakly enforced using Nitsche's method. We add CIP-like ghost penalties in the boundary region and prove that our scheme is inf-sup stable and that it has optimal convergence properties independent of how the domain boundary intersects the mesh. Additionally, we demonstrate that the condition number of the system matrix is bounded independently of the boundary location. We corroborate our theoretical findings numerically.
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| 8. |
- Burman, Erik, et al.
(författare)
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CutFEM : Discretizing geometry and partial differential equations
- 2015
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Ingår i: International Journal for Numerical Methods in Engineering. - : Wiley. - 0029-5981 .- 1097-0207. ; 104:7, s. 472-501
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Tidskriftsartikel (refereegranskat)abstract
- We discuss recent advances on robust unfitted finite element methods on cut meshes. These methods are designed to facilitate computations on complex geometries obtained, for example, from computer-aided design or image data from applied sciences. Both the treatment of boundaries and interfaces and the discretization of PDEs on surfaces are discussed and illustrated numerically.
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| 9. |
- Claus, Susanne, et al.
(författare)
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A stabilized Nitsche fictitious domain formulation for the three-field Stokes problem
- 2013
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Ingår i: Proceeding of the 26th Nordic Seminar on Computational Mechanics. - : Simula Research Laboratory. - 9788292593127 ; , s. 1-6
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Konferensbidrag (refereegranskat)abstract
- We propose a Nitsche fictitious domain method for the three-field Stokes problem where the dependent variables of velocity, pressure and extra-stress tensor are discretised with linear finite elements. To stabilise the equal order approximation, we employ a continuous interior penalty (CIP) method involving the normal gradient jumps of the velocity and pressure. On the unfitted boundary, Dirichlet boundary conditions are weakly enforced using Nitsche’s method. Adding CIP-like ghostpenalties in the vicinity of the boundary allows us to prove the inf-sup stability and optimal convergence of our method and to bound the condition number independent of the location of the boundary with respect to the computational mesh. Numerical examples corroborate the theoretical findings.
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| 10. |
- Claus, Susanne, et al.
(författare)
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CutFEM : a stabilised Nitsche XFEM method for multi-physics problems
- 2015
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Ingår i: Proceedings of the 23rd Conference on Computational Mechanics. - Swansea : Swansea University. - 9780956746245 ; , s. 171-174
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Konferensbidrag (refereegranskat)abstract
- In this communication, we will give an overview over CutFEM, a new stabilised XFEM technique. Here, different PDEs are coupled across an interface, that intersects a fixed background mesh in an arbitrary manner. The boundary conditions on the interface are enforced using Nitsche-type coupling conditions [1]. Nitsche’s method offers a flexible approach to design XFEM methods that is amenable to analysis. Classically, XFEM methods suffer from ill-conditioning if the interface intersects elements close to element nodes leaving only small parts of the element covered by the physical domain. In our method, we overcome this major difficulty, by adding ghost-penalty terms to the variational formulation over the band of elements that are cut by the interface [3, 4]. In this contribution, we will illustrate the usage of CutFEM on the three field Stokes problem.
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