| 1. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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| 2. |
- Baxter, Amanda L., et al.
(författare)
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Collaborative experience between scientific software projects using Agile Scrum development
- 2022
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Ingår i: Software, practice & experience. - : John Wiley & Sons. - 0038-0644 .- 1097-024X. ; 52:10, s. 2077-2096
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Tidskriftsartikel (refereegranskat)abstract
- Developing sustainable software for the scientific community requires expertise in software engineering and domain science. This can be challenging due to the unique needs of scientific software, the insufficient resources for software engineering practices in the scientific community, and the complexity of developing for evolving scientific contexts. While open-source software can partially address these concerns, it can introduce complicating dependencies and delay development. These issues can be reduced if scientists and software developers collaborate. We present a case study wherein scientists from the SuperNova Early Warning System collaborated with software developers from the Scalable Cyberinfrastructure for Multi-Messenger Astrophysics project. The collaboration addressed the difficulties of open-source software development, but presented additional risks to each team. For the scientists, there was a concern of relying on external systems and lacking control in the development process. For the developers, there was a risk in supporting a user-group while maintaining core development. These issues were mitigated by creating a second Agile Scrum framework in parallel with the developers' ongoing Agile Scrum process. This Agile collaboration promoted communication, ensured that the scientists had an active role in development, and allowed the developers to evaluate and implement the scientists' software requirements. The collaboration provided benefits for each group: the scientists actuated their development by using an existing platform, and the developers utilized the scientists' use-case to improve their systems. This case study suggests that scientists and software developers can avoid scientific computing issues by collaborating and that Agile Scrum methods can address emergent concerns.
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| 3. |
- Beelen, Rob, et al.
(författare)
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Development of NO2 and NOx land use regression models for estimating air pollution exposure in 36 study areas in Europe : the ESCAPE project
- 2013
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Ingår i: Atmospheric Environment. - : Elsevier. - 1352-2310 .- 1873-2844. ; 72, s. 10-23
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Tidskriftsartikel (refereegranskat)abstract
- Estimating within-city variability in air pollution concentrations is important. Land use regression (LUR) models are able to explain such small-scale within-city variations. Transparency in LUR model development methods is important to facilitate comparison of methods between different studies. We therefore developed LUR models in a standardized way in 36 study areas in Europe for the ESCAPE (European Study of Cohorts for Air Pollution Effects) project.Nitrogen dioxide (NO2) and nitrogen oxides (NOx) were measured with Ogawa passive samplers at 40 or 80 sites in each of the 36 study areas. The spatial variation in each area was explained by LUR modeling. Centrally and locally available Geographic Information System (GIS) variables were used as potential predictors. A leave-one out cross-validation procedure was used to evaluate the model performance.There was substantial contrast in annual average NO2 and NOx concentrations within the study areas. The model explained variances (R2) of the LUR models ranged from 55% to 92% (median 82%) for NO2 and from 49% to 91% (median 78%) for NOx. For most areas the cross-validation R2 was less than 10% lower than the model R2. Small-scale traffic and population/household density were the most common predictors. The magnitude of the explained variance depended on the contrast in measured concentrations as well as availability of GIS predictors, especially traffic intensity data were important. In an additional evaluation, models in which local traffic intensity was not offered had 10% lower R2 compared to models in the same areas in which these variables were offered.Within the ESCAPE project it was possible to develop LUR models that explained a large fraction of the spatial variance in measured annual average NO2 and NOx concentrations. These LUR models are being used to estimate outdoor concentrations at the home addresses of participants in over 30 cohort studies.
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| 4. |
- Bransford, Philip, et al.
(författare)
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ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers : An Industrial Perspective from the IQ Consortium
- 2020
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Ingår i: Molecular Pharmaceutics. - : AMER CHEMICAL SOC. - 1543-8384 .- 1543-8392. ; 17:2, s. 361-372
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Tidskriftsartikel (refereegranskat)abstract
- In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. Its members have substantial expertise in all scientific domains associated with BCS-based waivers and drug product quality, as well as considerable experience in the application of BCS-based biowaivers. The ICH process recognizes that harmonization is achieved through the development of guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side. Thus, to facilitate these efforts and to encourage open and transparent discussion of other perspectives that may exist, IQ offers their perspective on these and related topics.
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| 5. |
- Dasgupta, Indranil, et al.
(författare)
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Validating the use of bioimpedance spectroscopy for assessment of fluid status in children.
- 2018
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Ingår i: Pediatric nephrology. - : Springer Science and Business Media LLC. - 1432-198X .- 0931-041X. ; 33:9, s. 1601-1607
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Tidskriftsartikel (refereegranskat)abstract
- Bioimpedance spectroscopy (BIS) with a whole-body model to distinguish excess fluid from major body tissue hydration can provide objective assessment of fluid status. BIS is integrated into the Body Composition Monitor (BCM) and is validated in adults, but not children. This study aimed to (1) assess agreement between BCM-measured total body water (TBW) and a gold standard technique in healthy children, (2) compare TBW_BCM with TBW from Urea Kinetic Modelling (UKM) in haemodialysis children and (3) investigate systematic deviation from zero in measured excess fluid in healthy children across paediatric age range.TBW_BCM and excess fluid was determined from standard wrist-to-ankle BCM measurement. TBW_D2O was determined from deuterium concentration decline in serial urine samples over 5days in healthy children. UKM was used to measure body water in children receiving haemodialysis. Agreement between methods was analysed using paired t test and Bland-Altman method comparison.In 61 healthy children (6-14years, 32 male), mean TBW_BCM and TBW_D2O were 21.1±5.6and 20.5±5.8L respectively. There was good agreement between TBW_BCM and TBW_D2O (R2=0.97). In six haemodialysis children (4-13years, 4 male), 45 concomitant measurements over 8months showed good TBW_BCM and TBW_UKM agreement (mean difference -0.4L, 2SD=±3.0L). In 634 healthy children (2-17years, 300 male), BCM-measured overhydration was -0.1±0.7L (10-90th percentile -0.8 to+0.6L). There was no correlation between age and OH (p=0.28).These results suggest BCM can be used in children as young as 2years to measure normally hydrated weight and assess fluid status.
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| 6. |
- Elblaus, Ludvig, 1981-, et al.
(författare)
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Demo Hour
- 2015
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Ingår i: interactions. - : Association for Computing Machinery (ACM). - 1072-5520 .- 1558-3449. ; 22:5, s. 6-9
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Tidskriftsartikel (refereegranskat)abstract
- Interactivity is a unique forum of the ACM CHI Conference that showcases hands-on demonstrations, novel interactive technologies, and artistic installations. At CHI 2015 in Seoul we hosted more than 30 exhibits, including an invited digital interactive art exhibit. Interactivity highlights the diverse group of computer scientists, sociologists, designers, psychologists, artists, and many more who make up the CHI community.
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| 7. |
- Mair, Grant, et al.
(författare)
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Arterial Obstruction on Computed Tomographic or Magnetic Resonance Angiography and Response to Intravenous Thrombolytics in Ischemic Stroke
- 2017
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 48:2, s. 353-360
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Computed tomographic angiography and magnetic resonance angiography are used increasingly to assess arterial patency in patients with ischemic stroke. We determined which baseline angiography features predict response to intravenous thrombolytics in ischemic stroke using randomized controlled trial data.METHODS: We analyzed angiograms from the IST-3 (Third International Stroke Trial), an international, multicenter, prospective, randomized controlled trial of intravenous alteplase. Readers, masked to clinical, treatment, and outcome data, assessed prerandomization computed tomographic angiography and magnetic resonance angiography for presence, extent, location, and completeness of obstruction and collaterals. We compared angiography findings to 6-month functional outcome (Oxford Handicap Scale) and tested for interactions with alteplase, using ordinal regression in adjusted analyses. We also meta-analyzed all available angiography data from other randomized controlled trials of intravenous thrombolytics.RESULTS: In IST-3, 300 patients had prerandomization angiography (computed tomographic angiography=271 and magnetic resonance angiography=29). On multivariable analysis, more extensive angiographic obstruction and poor collaterals independently predicted poor outcome (P<0.01). We identified no significant interaction between angiography findings and alteplase effect on Oxford Handicap Scale (P≥0.075) in IST-3. In meta-analysis (5 trials of alteplase or desmoteplase, including IST-3, n=591), there was a significantly increased benefit of thrombolytics on outcome (odds ratio>1 indicates benefit) in patients with (odds ratio, 2.07; 95% confidence interval, 1.18-3.64; P=0.011) versus without (odds ratio, 0.88; 95% confidence interval, 0.58-1.35; P=0.566) arterial obstruction (P for interaction 0.017).CONCLUSIONS: Intravenous thrombolytics provide benefit to stroke patients with computed tomographic angiography or magnetic resonance angiography evidence of arterial obstruction, but the sample was underpowered to demonstrate significant treatment benefit or harm among patients with apparently patent arteries.CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN25765518.
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| 8. |
- Wang, Meng, et al.
(författare)
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Performance of multi-city land use regression models for nitrogen dioxide and fine particles
- 2014
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Ingår i: Journal of Environmental Health Perspectives. - : Public Health Services, US Dept of Health and Human Services. - 0091-6765 .- 1552-9924. ; 122:8, s. 843-849
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Land use regression (LUR) models have been developed mostly to explain intraurban variations in air pollution based on often small local monitoring campaigns. Transferability of LUR models from city to city has been investigated, but little is known about the performance of models based on large numbers of monitoring sites covering a large area.OBJECTIVES: We aimed to develop European and regional LUR models and to examine their transferability to areas not used for model development.METHODS: We evaluated LUR models for nitrogen dioxide (NO2) and particulate matter (PM; PM2.5, PM2.5 absorbance) by combining standardized measurement data from 17 (PM) and 23 (NO2) ESCAPE (European Study of Cohorts for Air Pollution Effects) study areas across 14 European countries for PM and NO2. Models were evaluated with cross-validation (CV) and hold-out validation (HV). We investigated the transferability of the models by successively excluding each study area from model building.RESULTS: The European model explained 56% of the concentration variability across all sites for NO2, 86% for PM2.5, and 70% for PM2.5 absorbance. The HV R2s were only slightly lower than the model R2 (NO2, 54%; PM2.5, 80%; PM2.5 absorbance, 70%). The European NO2, PM2.5, and PM2.5 absorbance models explained a median of 59%, 48%, and 70% of within-area variability in individual areas. The transferred models predicted a modest-to-large fraction of variability in areas that were excluded from model building (median R2: NO2, 59%; PM2.5, 42%; PM2.5 absorbance, 67%).CONCLUSIONS: Using a large data set from 23 European study areas, we were able to develop LUR models for NO2 and PM metrics that predicted measurements made at independent sites and areas reasonably well. This finding is useful for assessing exposure in health studies conducted in areas where no measurements were conducted.
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| 9. |
- Wardlaw, Joanna M, et al.
(författare)
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Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3) : secondary analysis of a randomised controlled trial.
- 2015
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 14:5, s. 485-96
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Brain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase.METHODS: IST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0-2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518.FINDINGS: 3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55-0·81), large lesion (0·51, 0·38-0·68), swelling (0·59, 0·46-0·75), hyperattenuated artery (0·59, 0·47-0·75), atrophy (0·74, 0·59-0·94), and leukoaraiosis (0·72, 0·59-0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18-2·51), tissue hypoattenuation (1·54, 1·04-2·27), and hyperattenuated artery (1·54, 1·03-2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9-20·7; both signs absent, excess 3·2%, 1·4-5·1). However, no imaging findings-individually or combined-modified the effect of alteplase on independence or symptomatic intracranial haemorrhage.INTERPRETATION: Some early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke.FUNDING: UK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders.
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| 10. |
- Wardlaw, Joanna M., et al.
(författare)
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Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration
- 2013
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Ingår i: Lancet Neurology. - 1474-4465. ; 12:8, s. 822-838
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Forskningsöversikt (refereegranskat)abstract
- Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for Reporting Vascular changes on nEuroimaging (STRIVE).
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