Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before... Show moreExisting quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. Show less
Background: Standardization of laboratory tests can be a long process, and this is the case with regards to the methods used to measure hemoglobin A(2) (HbA(2)), an important marker for beta... Show moreBackground: Standardization of laboratory tests can be a long process, and this is the case with regards to the methods used to measure hemoglobin A(2) (HbA(2)), an important marker for beta-thalassemia and other thalassemic conditions. The IFCC standardization project started in 2004, and it took at least 15 years before developing a reference measurement procedure, defining and producing calibrators and certified reference materials.Methods: A series of steps have to be undertaken in order to promote the standardization in the field, a process involving a number of stakeholders (manufacturers, scientific societies, national health bodies, laboratory professionals, clinicians). In this work we describe some possible process indicators, in order to assure that the standardization will have internal and external validity and be effective for a long time. These indicators concern the inter-method studies, elaboration of External Quality Assessment Schemes, and the evaluation of the yearly distributions of HbA(2) measurements collected in selected laboratories.Results: Preliminary results are reported concerning the yearly distributions of HbA(2), collected in two different locations, and using different analytical methods. Median yearly values were found very constant over the years, but different between methods. On the other side, results obtained on the same specimens using two different techniques, proved that results by capillary electrophoresis in 2 out of the 3 years of observation, were significantly lower than those by HPLC.Conclusion: In this document we report what has been done so far, and what has to be done to achieve the standardization of the measurement of HbA(2) worldwide. Show less
Het Europese non-foodproductveiligheidsrecht bevat productnormen die veelal als publiekrechtelijk worden bestempeld. Bij de harmonisatie gebruikt de Europese wetgever verschillende soorten... Show moreHet Europese non-foodproductveiligheidsrecht bevat productnormen die veelal als publiekrechtelijk worden bestempeld. Bij de harmonisatie gebruikt de Europese wetgever verschillende soorten productnormen, namelijk bindende eisen in richtlijnen en verordeningen en niet-bindende Europese normalisatienormen. De literatuur neemt aan dat Europese productnormen ook invloed kunnen hebben op de privaatrechtelijke normen die gelden in rechtsverhoudingen tussen bijvoorbeeld de eindgebruiker van het product en andere partijen in de handelsketen, alsmede tussen concurrenten. Dit onderzoek beantwoordt de vraag wat de exacte betekenis is van Europese productnormen voor privaatrechtelijke normstelling. Wanneer is een productnorm slechts een van de relevante omstandigheden van het geval bij de formulering van een privaatrechtelijke norm? Wanneer vult een productnorm een privaatrechtelijke norm grotendeels in, in de zin dat de productnorm het uitgangspunt vormt? Van welke omstandigheden en factoren is deze betekenis afhankelijk?Het onderzoek biedt de lezer een nadere introductie in het wat onderbelichte Europese productveiligheidsrecht en beantwoordt de hoofdvraag aan de hand van een Europeesrechtelijk, institutioneel en privaatrechtelijk perspectief. De privaatrechtelijke analyse ziet op de belangrijkste Nederlandse rechtsgronden voor doorwerking van productnormen en bevat rechtsvergelijking met het Engelse en Duitse recht. Bovendien vindt een uitvoerige analyse van Nederlandse feitenrechtspraak plaats om te zien hoe feitenrechters in de praktijk met productnormen bij de invulling van privaatrechtelijke normen omgaan. Het onderzoek besluit met een overzicht van gezichtspunten die behulpzaam kunnen zijn bij het beoordelen van de betekenis van productnormen voor privaatrechtelijke normstelling in concrete gevallen. Show less
Background The T-1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T-1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration ... Show moreBackground The T-1 Mapping and Extracellular volume (ECV) Standardization (T1MES) program explored T-1 mapping quality assurance using a purpose-developed phantom with Food and Drug Administration (FDA) and Conformite Europeenne (CE) regulatory clearance. We report T-1 measurement repeatability across centers describing sequence, magnet, and vendor performance. Methods Phantoms batch-manufactured in August 2015 underwent 2 years of structural imaging, B-0 and B-1, and "reference" slow T-1 testing. Temperature dependency was evaluated by the United States National Institute of Standards and Technology and by the German Physikalisch-Technische Bundesanstalt. Center-specific T-1 mapping repeatability (maximum one scan per week to minimum one per quarter year) was assessed over mean 358 (maximum 1161) days on 34 1.5 T and 22 3 T magnets using multiple T-1 mapping sequences. Image and temperature data were analyzed semi-automatically. Repeatability of serial T-1 was evaluated in terms of coefficient of variation (CoV), and linear mixed models were constructed to study the interplay of some of the known sources of T-1 variation. Results Over 2 years, phantom gel integrity remained intact (no rips/tears), B-0 and B-1 homogenous, and "reference" T-1 stable compared to baseline (% change at 1.5 T, 1.95 +/- 1.39%; 3 T, 2.22 +/- 1.44%). Per degrees Celsius, 1.5 T, T-1 (MOLLI 5s(3s)3s) increased by 11.4 ms in long native blood tubes and decreased by 1.2 ms in short post-contrast myocardium tubes. Agreement of estimated T-1 times with "reference" T-1 was similar across Siemens and Philips CMR systems at both field strengths (adjusted R-2 ranges for both field strengths, 0.99-1.00). Over 1 year, many 1.5 T and 3 T sequences/magnets were repeatable with mean CoVs < 1 and 2% respectively. Repeatability was narrower for 1.5 T over 3 T. Within T1MES repeatability for native T-1 was narrow for several sequences, for example, at 1.5 T, Siemens MOLLI 5s(3s)3s prototype number 448B (mean CoV = 0.27%) and Philips modified Look-Locker inversion recovery (MOLLI) 3s(3s)5s (CoV 0.54%), and at 3 T, Philips MOLLI 3b(3s)5b (CoV 0.33%) and Siemens shortened MOLLI (ShMOLLI) prototype 780C (CoV 0.69%). After adjusting for temperature and field strength, it was found that the T-1 mapping sequence and scanner software version (both P < 0.001 at 1.5 T and 3 T), and to a lesser extent the scanner model (P = 0.011, 1.5 T only), had the greatest influence on T-1 across multiple centers. Conclusion The T1MES CE/FDA approved phantom is a robust quality assurance device. In a multi-center setting, T-1 mapping had performance differences between field strengths, sequences, scanner software versions, and manufacturers. However, several specific combinations of field strength, sequence, and scanner are highly repeatable, and thus, have potential to provide standardized assessment of T-1 times for clinical use, although temperature correction is required for native T-1 tubes at least. Show less
Harmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based... Show moreHarmonization of acquisition and analysis protocols is an important step in the validation of BOLD MRI as a renal biomarker. This harmonization initiative provides technical recommendations based on a consensus report with the aim to move towards standardized protocols that facilitate clinical translation and comparison of data across sites. We used a recently published systematic review paper, which included a detailed summary of renal BOLD MRI technical parameters and areas of investigation in its supplementary material, as the starting point in developing the survey questionnaires for seeking consensus. Survey data were collected via the Delphi consensus process from 24 researchers on renal BOLD MRI exam preparation, data acquisition, data analysis, and interpretation. Consensus was defined as >= 75% unanimity in response. Among 31 survey questions, 14 achieved consensus resolution, 12 showed clear respondent preference (65-74% agreement), and 5 showed equal (50/50%) split in opinion among respondents. Recommendations for subject preparation, data acquisition, processing and reporting are given based on the survey results and review of the literature. These technical recommendations are aimed towards increased inter-site harmonization, a first step towards standardization of renal BOLD MRI protocols across sites. We expect this to be an iterative process updated dynamically based on progress in the field. Show less
Novakova, M.; Glier, H.; Brdickova, N.; Vlkova, M.; Santos, A.H.; Lima, M.; ... ; Kalina, T. 2019
A critical component of the EuroFlow standardization of leukemia/lymphoma immunophenotyping is instrument setup. Initially, the EuroFlow consortium developed a step-by-step standard operating... Show moreA critical component of the EuroFlow standardization of leukemia/lymphoma immunophenotyping is instrument setup. Initially, the EuroFlow consortium developed a step-by-step standard operating protocol for instrument setup of >= 8-color flow cytometers that were available in 2006, when the EuroFlow activities started. Currently, there are 14 instruments from 9 manufacturers capable of 3-laser excitation and >= 8 color measurements. The specific adaptations required in the instrument set-up to enable them to acquire the standardized 8-color EuroFlow protocols are described here. Overall, all 14 instruments can be fitted with similar violet, blue and red lasers for simultaneous measurements of >= 8 fluorescent dyes. Since individual instruments differ both on their dynamic range (scale) and emission filters, it is not accurate to simply recalculate the target values to different scale, but adjustment of PMT voltages to a given emission filter and fluorochrome, is essential. For this purpose, EuroFlow has developed an approach using Type IIB (spectrally matching) particles to set-up standardized and fully comparable fluorescence measurements, in instruments from different manufacturers, as demonstrated here for the FACSCanto II, and Navios and MACSQuant flow cytometers. Data acquired after such adjustment on any of the tested cytometry platforms could be fully superimposed and therefore analyzed together. The proposed approach can be used to derive target values for any combination of spectrally distinct fluorochromes and any distinct emission filter of any new flow cytometry platform, which enables the measurement of the 8-color EuroFlow panels in a standardized way, by creating superimposable datafiles. Show less
Kalina, T.; Brdickova, N.; Glier, H.; Fernandez, P.; Bitter, M.; Flores-Montero, J.; ... ; Orfao, A. 2019
EuroFlow Quality Assessment was designed to provide a feedback on the quality of the standardization effort in executing the EuroFlow protocols for sample preparation and instrument setup. It was... Show moreEuroFlow Quality Assessment was designed to provide a feedback on the quality of the standardization effort in executing the EuroFlow protocols for sample preparation and instrument setup. It was first beta-tested by the members of the EuroFlow consortium internally (2010 - 2013) and opened to the external participants from 2015 onwards. The goal of participation in the EuroFlow QA is to evaluate whether the technical quality of the data generated by the laboratory is comparable to the data of the EuroFlow members and thus if a non-EuroFlow member participant can use the EuroFlow reference sample database for his own patient evaluation. Also it assesses whether data are sufficiently standardized for automated population gating and alarm notification. By spring 2018, a total 87 laboratories from 32 countries on five continents have registered for the EuroFlow QA program. We evaluated 163 results of 2015-2016 QA rounds, where we noted clear improvement in the score of first-time participants (median score of 91% correct) when they participated second time or later (median score of 94% correct, p = 0,017), which was comparable to EuroFlow member scores (median score of 97% correct). Among frequent mistakes, we found non-adherence to the EuroFlow protocols (improper reagent used), improper gating and some compensation issues. In summary, we show that EuroFlow QA has a positive impact on improvement of standardized data quality of non-member laboratories adhering to the EuroFlow standard operating procedures and reagent panels. Show less
Glier, H.; Novakova, M.; Marvelde, J. te; Bijkerk, A.; Morf, D.; Thurner, D.; ... ; Kalina, T. 2019
This commentary discusses particularities of application of the EuroFlow standardization of flow cytometric analyses on three different flow cytometers. The EuroFlow consortium developed a fully... Show moreThis commentary discusses particularities of application of the EuroFlow standardization of flow cytometric analyses on three different flow cytometers. The EuroFlow consortium developed a fully standardized approach for flow cytometric immunophenotyping of hematological malignancies and primary immunodeficiencies. Standardized instrument setup is an essential part of EuroFlow standardization. Initially, the EuroFlow Consortium developed and optimized a step-by-step standard operating procedure (SOP) to setup 8-color BD FACSCanto II flow cytometer (Canto), with the later inclusion of Navios (Beckman Coulter) and BD FACSLyric (Lyric). Those SOPs were developed to enable standardized and fully comparable fluorescence measurements in the three flow cytometers. In Canto and Navios, mean fluorescence intensity (MFI) of a reference peak of Rainbow beads calibration particles is used to set up photomultiplier (PMT) voltages for each detector channel in individual instruments to reach the same MFI across distinct instruments. In turn, a new feature of Lyric instruments allows to share collection of attributes that are used to place the positive population at the same position among instruments in the form of assays, as one of its components integrated in the Cytometer Setup and Tracking (CS&T) module. The EuroFlow Lyric assays thus allow for standardized acquisition of 8-color EuroFlow panels on Lyric without the need to setup the PMT voltages on the individual instruments manually.In summary, the standardized instrument setup developed by EuroFlow enables cross-platform inter- and infra-laboratory standardization of flow cytometric measurements. This commentary provides a perspective on the modifications of the standardized EuroFlow instrument setup of Canto, Navios and Lyric instruments that are described in detail in individual instrument-specfic SOPs available at the EuroFlow website. Show less
Dekkers, I.A.; Boer, A. de; Sharma, K.; Cox, E.F.; Lamb, H.J.; Buckley, D.L.; ... ; Francis, S. 2019
BackgroundWe developed a method to calculate a standard score for lung tissue mass derived from CT scan images from a control group without respiratory disease. We applied the method to images from... Show moreBackgroundWe developed a method to calculate a standard score for lung tissue mass derived from CT scan images from a control group without respiratory disease. We applied the method to images from subjects with emphysema associated with alpha-1 antitrypsin deficiency (AATD) and used it to study regional patterns of differential tissue mass.MethodsWe explored different covariates in 76 controls. Standardization was applied to facilitate comparability between different CT scanners and a standard Z-score (Standard Mass Score, SMS) was developed, representing lung tissue loss compared to normal lung mass. This normative data was defined for the entire lungs and for delineated apical, central and basal regions. The agreement with D-LCO%pred was explored in a data set of 180 patients with emphysema who participated in a trial of alpha-1-antitrypsin augmentation treatment (RAPID).ResultsLarge differences between emphysematous and normal tissue of more than 10 standard deviations were found. There was reasonable agreement between SMS and D-LCO%pred for the global densitometry (=0.252, p<0.001), varying from =0.138 to =0.219 and 0.264 (p<0.001), in the apical, central and basal region, respectively. SMS and D-LCO%pred correlated consistently across apical, central and basal regions. The SMS distribution over the different lung regions showed a distinct pattern suggesting that emphysema due to severe AATD develops from basal to central and ultimately apical regions.ConclusionsStandardization and normalization of lung densitometry is feasible and the adoption of the developed principles helps to characterize the distribution of emphysema, required for clinical decision making. Show less
This thesis deals with Dutch language education in primary schools in the eighteenth and nineteenth centuries. It focuses on the role of education in the development of Dutch as a standard... Show moreThis thesis deals with Dutch language education in primary schools in the eighteenth and nineteenth centuries. It focuses on the role of education in the development of Dutch as a standard language, with attention for educational practices, pedagogical discourse and passive exposure to language norms in school books. The transition from the eighteenth to the nineteenth century was marked by rapid societal and ideological changes. Part of these changes were reforms of the Dutch language and school system. Language was increasingly seen as a marker of national identity. Education in the national language became an important prerequisite for the development of a modern and national civil society. To facilitate national unity and language education, the norms for the Dutch language were officially codified. At the same time, new pedagogical ideals led to changes in the organization, means and methods of primary school education. Based on reports from the school inspection, pedagogical literature and school books, this thesis draws an image of theory and practice of Dutch language education in primary schools between 1750 and 1850. Show less
Bidmon, N.; Kind, S.; Welters, M.J.P.; Joseph-Pietras, D.; Laske, K.; Maurer, D.; ... ; Burg, S.H. van der 2018
BackgroundEquivalence of results among laboratories is a major mission for medical laboratories. Monitoring of test equivalence is structurally integrated in the Dutch External Quality Assessment ... Show moreBackgroundEquivalence of results among laboratories is a major mission for medical laboratories. Monitoring of test equivalence is structurally integrated in the Dutch External Quality Assessment (EQA) scheme since 2005. Commutable poolsera, single donation “spy” sera and biological variance tolerance limits have been introduced in the EQA scheme for evaluation of the degree of test equivalence and its determinants. MethodsIn the annual cycle scheme 24 samples, covering the (patho)physiological measuring range for 17 analytes, are assayed by 220 participating laboratories at biweekly intervals. Test equivalence was evaluated by calculating overall median interlaboratory coefficients of variation (CVs) and its bias and imprecision components. Data from 2005 and 2010 schemes are evaluated to investigate trends in performance and success of standardization efforts. ResultsOverall median interlaboratory CVs in 2010 were mostly better than in 2005. Median interlaboratory CVs became <5% for electrolytes and substrates, and <10% for enzymes. Improvement in median interlaboratory CVs over these five years is mainly explained by improved method standardization, especially for enzymes and creatinine. ConclusionThe Dutch EQA-program proves to be a powerful instrument to evaluate test equivalence. It allows monitoring standardization efforts in a highly effective way and gives insight into remaining standardization potential. Highlights► Equivalence of lab results worldwide is a major mission for medical laboratories. ► Commutable sera have been introduced to evaluate the degree of test equivalence. ► Median interlab CVs became <5% for electrolytes/substrates, and <10% for enzymes. ► Amelioration is mainly explained by improved method standardization. ► Commutable samples in EQAS are a powerful instrument to evaluate test equivalence. Show less
The aim of the present study is to examine the transformation of teacher training in Indonesia from 1893 to 1969. Public teacher training altered over time to keep in step with the changing... Show moreThe aim of the present study is to examine the transformation of teacher training in Indonesia from 1893 to 1969. Public teacher training altered over time to keep in step with the changing requirements in public primary school curricula which had been incurred by economic and political factors. In colonial time the government policy was to prepare Indonesian teachers in the Netherlands Indies according to a standard which would gradually be raised so that in the end, they could concur with the level of the training originally designed for their European counterparts. The introduction of the Kweekschoolplan in 1927 heralded the re-organization and transformation of the kweekschool and the Hogere Kweekschool (HKS) into Hollands Inlandse Kweekschool (HIK). Alas, the Great Depression in 1929 dispelled the colonial dream and the Japanese invasion in 1942 completely altered the next chapter in the history of Indonesian society. The post-war period witnessed three essential points: the brain-drain from schools of the Indonesians who had been educated at the HIK; the removal of Dutch from public school; and the influx of American professors to the schools of teacher training. Now the patterns of expectations of teachers in Indonesia drastically changed, but the nature of teacher training remained basically unchanged. This disjunction implies that the transition from colonial to post-colonial State revealed a paradox in which continuity and change were juxtaposed. The switch from the Dutch to the American model of teacher training in the late 1950s reflected a spirit of reform but also created confusion in the Indonesian search for the meaning of independence.The institutional re-organization of teacher training during the 1950s which continued into the 1960s reflected the bigger narrative of Indonesian State formation at the time. Here, the process of regime change displayed the politics of elimination with a startling lack of understanding of historical experience. A dichotomous way of seeing matters, a rigid option of ‘either this or that’ and a perspective which sharply differentiated between ‘we’ and ‘they’ came to the top list of priorities. Show less
Velde, E.T. van der; Foeken, H.; Witteman, T.A.; Erven, L. van; Schalij, M.J. 2012
