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Yannis-nicolas Francois - One of the best experts on this subject based on the ideXlab platform.
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Structural characterization of antibody drug conjugate by a combination of intact, middle-up and bottom-up techniques using sheathless capillary electrophoresis – Tandem mass spectrometry as nanoESI infusion platform and separation method
Analytica Chimica Acta, 2016Co-Authors: Nassur Said, Alain Beck, Rabah Gahoual, Lauriane Kuhn, Yannis-nicolas Francois, Emmanuelle Leize-wagnerAbstract:Antibody-drug conjugates (ADCs) represent a fast growing class of biotherapeutic products. Their production leads to a distribution of species exhibiting different number of conjugated drugs overlaying the inherent com-plexity resulting from the monoclonal antibody format, such as glycoforms. ADCs require an additional level of characterization compared to first generation of biotherapeutics obtained through multiple analytical tech-niques for complete Structure Assessment. We report the development of complementary approaches imple-menting sheathless capillary electrophoresis-mass spectrometry (sheathless CE-MS) to characterize the differ-ent aspects defining the Structure of brentuximab vedotin. Native MS using sheathless CE-MS instrument as a nanoESI infusion platform enabled accurate mass measurements and estimation of the average drug to anti-body ratio alongside to drug load distribution. Middle-up analysis performed after limited IdeS proteolysis allowed to study independently the light chain, Fab and F(ab’)2 subunits incorporating 1, 0 to 4 and 0 to 8 pay-loads respectively. Finally, a CZE-ESI-MS/MS methodology was developed in order to be compatible with hy-drophobic drug composing ADCs. From a single injection, complete sequence coverage could be achieved. Using the same dataset, glycosylation and drug-loaded peptides could be simultaneously identified revealing robust information regarding their respective localization and abundance. Drug-loaded peptide fragmentation mass spectra study demonstrated drug specific fragments reinforcing identification confidence, undescribed so far. Results reveal the method ability to characterize ADCs primary Structure in a comprehensive manner while reducing tremendously the number of experiments required. Data generated showed that sheathless CZE-ESI-MS/MS characteristics position the methodology developed as a relevant alternative for comprehensive multi-level characterization of these complex biomolecules
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glycoform separation and characterization of cetuximab variants by middle up off line capillary zone electrophoresis uv electrospray ionization ms
Analytical Chemistry, 2015Co-Authors: Michael Biacchi, Alain Beck, Nassur Said, Rabah Gahoual, Emmanuelle Leizewagner, Yannis-nicolas FrancoisAbstract:Monoclonal antibodies (mAbs) are highly complex glycoproteins that present a wide range of microheterogeneities that requires multiple analytical methods for full Structure Assessment and quality control. Capillary zone electrophoresis-mass spectrometry (CZE-MS) couplings, especially by electrospray ionization (ESI), appear to be really attractive methods for the characterization of biological samples. However, due to the presence of non- or medium volatile salts in the background electrolyte (BGE), online CZE-ESI-MS coupling is difficult to implement for mAbs isoforms separation. Here, we report an original strategy to perform off-line CZE-ESI-MS using CZE-UV/fraction collection technology to perform CZE separation, followed by ESI-MS infusion of the different fractions using the capillary electrophoresis-electrospray ionization (CESI) interface as the nanoESI infusion platform. As the aim is to conserve electrophoretic resolution and complete compatibility with ESI-MS without sample treatment, hydroxypr...
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monoclonal antibodies biosimilarity Assessment using transient isotachophoresis capillary zone electrophoresis tandem mass spectrometry
mAbs, 2014Co-Authors: Rabah Gahoual, Alain Beck, Lauriane Kuhn, Michael Biacchi, Emmanuelle Leizewagner, Johana Chicher, Philippe Hammann, Yannis-nicolas FrancoisAbstract:Out of all categories, monoclonal antibody (mAb) therapeutics attract the most interest due to their strong therapeutic potency and specificity. Six of the 10 top-selling drugs are antibody-based therapeutics that will lose patent protection soon. The European Medicines Agency has pioneered the regulatory framework for approval of biosimilar products and approved the first biosimilar antibodies by the end of 2013. As highly complex glycoproteins with a wide range of micro-variants, mAbs require extensive characterization through multiple analytical methods for Structure Assessment rendering manufacturing control and biosimilarity studies particularly product and time-consuming. Here, capillary zone electrophoresis coupled to mass spectrometry by a sheathless interface (CESI-MS) was used to characterize marketed reference mAbs and their respective biosimilar candidate simultaneously over different facets of their primary Structure. CESI-MS/MS data were compared between approved mAbs and their biosimilar candidates to prove/disconfirm biosimilarity regarding recent regulation directives. Using only a single sample injection of 200 fmol, CESI-MS/MS data enabled 100% amino acids (AA) sequence characterization, which allows a difference of even one AA between 2 samples to be distinguished precisely. Simultaneously glycoforms were characterized regarding their Structures and position through fragmentation spectra and glycoforms semiquantitative analysis was established, showing the capacity of the developed methodology to detect up to 16 different glycans. Other posttranslational modifications hotspots were characterized while their relative occurrence levels were estimated and compared to biosimilars. These results proved the value of using CESI-MS because the separation selectivity and ionization efficiency provided by the system allowed substantial improvement in the characterization workflow robustness and accuracy. Biosimilarity Assessment could be performed routinely with a single injection of each candidate enabling improvements in the biosimilar development pipeline.
Alain Beck - One of the best experts on this subject based on the ideXlab platform.
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Structural characterization of antibody drug conjugate by a combination of intact, middle-up and bottom-up techniques using sheathless capillary electrophoresis – Tandem mass spectrometry as nanoESI infusion platform and separation method
Analytica Chimica Acta, 2016Co-Authors: Nassur Said, Alain Beck, Rabah Gahoual, Lauriane Kuhn, Yannis-nicolas Francois, Emmanuelle Leize-wagnerAbstract:Antibody-drug conjugates (ADCs) represent a fast growing class of biotherapeutic products. Their production leads to a distribution of species exhibiting different number of conjugated drugs overlaying the inherent com-plexity resulting from the monoclonal antibody format, such as glycoforms. ADCs require an additional level of characterization compared to first generation of biotherapeutics obtained through multiple analytical tech-niques for complete Structure Assessment. We report the development of complementary approaches imple-menting sheathless capillary electrophoresis-mass spectrometry (sheathless CE-MS) to characterize the differ-ent aspects defining the Structure of brentuximab vedotin. Native MS using sheathless CE-MS instrument as a nanoESI infusion platform enabled accurate mass measurements and estimation of the average drug to anti-body ratio alongside to drug load distribution. Middle-up analysis performed after limited IdeS proteolysis allowed to study independently the light chain, Fab and F(ab’)2 subunits incorporating 1, 0 to 4 and 0 to 8 pay-loads respectively. Finally, a CZE-ESI-MS/MS methodology was developed in order to be compatible with hy-drophobic drug composing ADCs. From a single injection, complete sequence coverage could be achieved. Using the same dataset, glycosylation and drug-loaded peptides could be simultaneously identified revealing robust information regarding their respective localization and abundance. Drug-loaded peptide fragmentation mass spectra study demonstrated drug specific fragments reinforcing identification confidence, undescribed so far. Results reveal the method ability to characterize ADCs primary Structure in a comprehensive manner while reducing tremendously the number of experiments required. Data generated showed that sheathless CZE-ESI-MS/MS characteristics position the methodology developed as a relevant alternative for comprehensive multi-level characterization of these complex biomolecules
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glycoform separation and characterization of cetuximab variants by middle up off line capillary zone electrophoresis uv electrospray ionization ms
Analytical Chemistry, 2015Co-Authors: Michael Biacchi, Alain Beck, Nassur Said, Rabah Gahoual, Emmanuelle Leizewagner, Yannis-nicolas FrancoisAbstract:Monoclonal antibodies (mAbs) are highly complex glycoproteins that present a wide range of microheterogeneities that requires multiple analytical methods for full Structure Assessment and quality control. Capillary zone electrophoresis-mass spectrometry (CZE-MS) couplings, especially by electrospray ionization (ESI), appear to be really attractive methods for the characterization of biological samples. However, due to the presence of non- or medium volatile salts in the background electrolyte (BGE), online CZE-ESI-MS coupling is difficult to implement for mAbs isoforms separation. Here, we report an original strategy to perform off-line CZE-ESI-MS using CZE-UV/fraction collection technology to perform CZE separation, followed by ESI-MS infusion of the different fractions using the capillary electrophoresis-electrospray ionization (CESI) interface as the nanoESI infusion platform. As the aim is to conserve electrophoretic resolution and complete compatibility with ESI-MS without sample treatment, hydroxypr...
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monoclonal antibodies biosimilarity Assessment using transient isotachophoresis capillary zone electrophoresis tandem mass spectrometry
mAbs, 2014Co-Authors: Rabah Gahoual, Alain Beck, Lauriane Kuhn, Michael Biacchi, Emmanuelle Leizewagner, Johana Chicher, Philippe Hammann, Yannis-nicolas FrancoisAbstract:Out of all categories, monoclonal antibody (mAb) therapeutics attract the most interest due to their strong therapeutic potency and specificity. Six of the 10 top-selling drugs are antibody-based therapeutics that will lose patent protection soon. The European Medicines Agency has pioneered the regulatory framework for approval of biosimilar products and approved the first biosimilar antibodies by the end of 2013. As highly complex glycoproteins with a wide range of micro-variants, mAbs require extensive characterization through multiple analytical methods for Structure Assessment rendering manufacturing control and biosimilarity studies particularly product and time-consuming. Here, capillary zone electrophoresis coupled to mass spectrometry by a sheathless interface (CESI-MS) was used to characterize marketed reference mAbs and their respective biosimilar candidate simultaneously over different facets of their primary Structure. CESI-MS/MS data were compared between approved mAbs and their biosimilar candidates to prove/disconfirm biosimilarity regarding recent regulation directives. Using only a single sample injection of 200 fmol, CESI-MS/MS data enabled 100% amino acids (AA) sequence characterization, which allows a difference of even one AA between 2 samples to be distinguished precisely. Simultaneously glycoforms were characterized regarding their Structures and position through fragmentation spectra and glycoforms semiquantitative analysis was established, showing the capacity of the developed methodology to detect up to 16 different glycans. Other posttranslational modifications hotspots were characterized while their relative occurrence levels were estimated and compared to biosimilars. These results proved the value of using CESI-MS because the separation selectivity and ionization efficiency provided by the system allowed substantial improvement in the characterization workflow robustness and accuracy. Biosimilarity Assessment could be performed routinely with a single injection of each candidate enabling improvements in the biosimilar development pipeline.
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correct primary Structure Assessment and extensive glyco profiling of cetuximab by a combination of intact middle up middle down and bottom up esi and maldi mass spectrometry techniques
mAbs, 2013Co-Authors: Daniel Ayoub, Wolfgang Jabs, Anja Resemann, Waltraud Evers, Catherine Evans, Laura Main, Carsten Baessmann, Elsa Wagnerrousset, Detlev Suckau, Alain BeckAbstract:The European Medicines Agency received recently the first marketing authorization application for a biosimilar monoclonal antibody (mAb) and adopted the final guidelines on biosimilar mAbs and Fc-fusion proteins. The agency requires high similarity between biosimilar and reference products for approval. Specifically, the amino acid sequences must be identical. The glycosylation pattern of the antibody is also often considered to be a very important quality attribute due to its strong effect on quality, safety, immunogenicity, pharmacokinetics and potency. Here, we describe a case study of cetuximab, which has been marketed since 2004. Biosimilar versions of the product are now in the pipelines of numerous therapeutic antibody biosimilar developers. We applied a combination of intact, middle-down, middle-up and bottom-up electrospray ionization and matrix assisted laser desorption ionization mass spectrometry techniques to characterize the amino acid sequence and major post-translational modifications of the marketed cetuximab product, with special emphasis on glycosylation. Our results revealed a sequence error in the reported sequence of the light chain in databases and in publications, thus highlighting the potency of mass spectrometry to establish correct antibody sequences. We were also able to achieve a comprehensive identification of cetuximab’s glycoforms and glycosylation profile Assessment on both Fab and Fc domains. Taken together, the reported approaches and data form a solid framework for the comparability of antibodies and their biosimilar candidates that could be further applied to routine structural Assessments of these and other antibody-based products.
Ahi Sema Issever - One of the best experts on this subject based on the ideXlab platform.
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trabecular bone Structure analysis in the osteoporotic spine using a clinical in vivo setup for 64 slice mdct imaging comparison to μct imaging and μfe modeling
Journal of Bone and Mineral Research, 2009Co-Authors: Thomas M Link, Markus B Huber, Patrik Rogalla, Andrew J Burghardt, Ahi Sema Issever, Marie Kentenich, Karsten Schwieger, Sharmila MajumdarAbstract:Assessment of trabecular microarchitecture may improve estimation of biomechanical strength, but visualization of trabecular bone Structure in vivo is challenging. We tested the feasibility of assessing trabecular microarchitecture in the spine using multidetector CT (MDCT) on intact human cadavers in an experimental in vivo–like setup. BMD, bone Structure (e.g., bone volume/total volume = BV/TV; trabecular thickness = Tb.Th; Structure model index = SMI) and bone texture parameters were evaluated in 45 lumbar vertebral bodies using MDCT (mean in-plane pixel size, 274 μm2; slice thickness, 500 μm). These measures were correlated with Structure measures assessed with μCT at an isotropic spatial resolution of 16 μm and to microfinite element models (μFE) of apparent modulus and stiffness. MDCT-derived BMD and Structure measures showed significant correlations to the density and Structure obtained by μCT (BMD, R2 = 0.86, p < 0.0001; BV/TV, R2 = 0.64, p < 0.0001; Tb.Th, R2 = 0.36, p < 0.01). When comparing μCT-derived measures with μFE models, the following correlations (p < 0.001) were found for apparent modulus and stiffness, respectively: BMD (R2 = 0.58 and 0.66), BV/TV (R2 = 0.44 and 0.58), and SMI (R2 = 0.44 and 0.49). However, the overall highest correlation (p < 0.001) with μFE app. modulus (R2 = 0.75) and stiffness (R2 = 0.76) was achieved by the combination of QCT-derived BMD with the bone texture measure Minkowski Dimension. In summary, although still limited by its spatial resolution, trabecular bone Structure Assessment using MDCT is overall feasible. However, when comparing with μFE-derived bone properties, BMD is superior compared with single parameters for microarchitecture, and correlations further improve when combining with texture measures.
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feasibility of measuring trabecular bone Structure of the proximal femur using 64 slice multidetector computed tomography in a clinical setting
Calcified Tissue International, 2008Co-Authors: Gerd Diederichs, Thomas M Link, Kentenich Marie, Markus B Huber, Patrik Rogalla, Andrew J Burghardt, Sharmila Majumdar, Ahi Sema IsseverAbstract:We studied the feasibility of cancellous bone Structure Assessment of the proximal femur using multidetector computed tomography (MDCT) in an simulated in vivo experimental model. The proximal femur of 15 intact human cadavers was examined using 64-row MDCT using a thin-section protocol with an in-plane spatial resolution of 273 μm. High-resolution peripheral quantitative computed tomography (HR-pQCT) of the isolated specimens with a voxel size of 82 μm served as a standard of reference. Trabecular bone Structure and optimized textural parameters were calculated in MDCT images and compared to measures obtained by HR-pQCT. Significant correlations between MDCT- and HR-pQCT-derived values for bone fraction (r = 0.87), trabecular separation (r = 0.66), and number (r = 0.53) were found. Parameters derived from textural analysis performed better in predicting trabecular separation (up to r = 0.86) and number (up to r = 0.83). Trabecular thickness could not be quantified correctly using MDCT, most likely due to its limited resolution. Individual parameters for assessement of trabecular microarchitecture can be measured using MDCT-derived imaging studies and a simulated in vivo setup. Thus, in vivo Assessment of bone architecture in addition to BMD may be feasible in clinical practice.
Rabah Gahoual - One of the best experts on this subject based on the ideXlab platform.
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Structural characterization of antibody drug conjugate by a combination of intact, middle-up and bottom-up techniques using sheathless capillary electrophoresis – Tandem mass spectrometry as nanoESI infusion platform and separation method
Analytica Chimica Acta, 2016Co-Authors: Nassur Said, Alain Beck, Rabah Gahoual, Lauriane Kuhn, Yannis-nicolas Francois, Emmanuelle Leize-wagnerAbstract:Antibody-drug conjugates (ADCs) represent a fast growing class of biotherapeutic products. Their production leads to a distribution of species exhibiting different number of conjugated drugs overlaying the inherent com-plexity resulting from the monoclonal antibody format, such as glycoforms. ADCs require an additional level of characterization compared to first generation of biotherapeutics obtained through multiple analytical tech-niques for complete Structure Assessment. We report the development of complementary approaches imple-menting sheathless capillary electrophoresis-mass spectrometry (sheathless CE-MS) to characterize the differ-ent aspects defining the Structure of brentuximab vedotin. Native MS using sheathless CE-MS instrument as a nanoESI infusion platform enabled accurate mass measurements and estimation of the average drug to anti-body ratio alongside to drug load distribution. Middle-up analysis performed after limited IdeS proteolysis allowed to study independently the light chain, Fab and F(ab’)2 subunits incorporating 1, 0 to 4 and 0 to 8 pay-loads respectively. Finally, a CZE-ESI-MS/MS methodology was developed in order to be compatible with hy-drophobic drug composing ADCs. From a single injection, complete sequence coverage could be achieved. Using the same dataset, glycosylation and drug-loaded peptides could be simultaneously identified revealing robust information regarding their respective localization and abundance. Drug-loaded peptide fragmentation mass spectra study demonstrated drug specific fragments reinforcing identification confidence, undescribed so far. Results reveal the method ability to characterize ADCs primary Structure in a comprehensive manner while reducing tremendously the number of experiments required. Data generated showed that sheathless CZE-ESI-MS/MS characteristics position the methodology developed as a relevant alternative for comprehensive multi-level characterization of these complex biomolecules
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glycoform separation and characterization of cetuximab variants by middle up off line capillary zone electrophoresis uv electrospray ionization ms
Analytical Chemistry, 2015Co-Authors: Michael Biacchi, Alain Beck, Nassur Said, Rabah Gahoual, Emmanuelle Leizewagner, Yannis-nicolas FrancoisAbstract:Monoclonal antibodies (mAbs) are highly complex glycoproteins that present a wide range of microheterogeneities that requires multiple analytical methods for full Structure Assessment and quality control. Capillary zone electrophoresis-mass spectrometry (CZE-MS) couplings, especially by electrospray ionization (ESI), appear to be really attractive methods for the characterization of biological samples. However, due to the presence of non- or medium volatile salts in the background electrolyte (BGE), online CZE-ESI-MS coupling is difficult to implement for mAbs isoforms separation. Here, we report an original strategy to perform off-line CZE-ESI-MS using CZE-UV/fraction collection technology to perform CZE separation, followed by ESI-MS infusion of the different fractions using the capillary electrophoresis-electrospray ionization (CESI) interface as the nanoESI infusion platform. As the aim is to conserve electrophoretic resolution and complete compatibility with ESI-MS without sample treatment, hydroxypr...
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monoclonal antibodies biosimilarity Assessment using transient isotachophoresis capillary zone electrophoresis tandem mass spectrometry
mAbs, 2014Co-Authors: Rabah Gahoual, Alain Beck, Lauriane Kuhn, Michael Biacchi, Emmanuelle Leizewagner, Johana Chicher, Philippe Hammann, Yannis-nicolas FrancoisAbstract:Out of all categories, monoclonal antibody (mAb) therapeutics attract the most interest due to their strong therapeutic potency and specificity. Six of the 10 top-selling drugs are antibody-based therapeutics that will lose patent protection soon. The European Medicines Agency has pioneered the regulatory framework for approval of biosimilar products and approved the first biosimilar antibodies by the end of 2013. As highly complex glycoproteins with a wide range of micro-variants, mAbs require extensive characterization through multiple analytical methods for Structure Assessment rendering manufacturing control and biosimilarity studies particularly product and time-consuming. Here, capillary zone electrophoresis coupled to mass spectrometry by a sheathless interface (CESI-MS) was used to characterize marketed reference mAbs and their respective biosimilar candidate simultaneously over different facets of their primary Structure. CESI-MS/MS data were compared between approved mAbs and their biosimilar candidates to prove/disconfirm biosimilarity regarding recent regulation directives. Using only a single sample injection of 200 fmol, CESI-MS/MS data enabled 100% amino acids (AA) sequence characterization, which allows a difference of even one AA between 2 samples to be distinguished precisely. Simultaneously glycoforms were characterized regarding their Structures and position through fragmentation spectra and glycoforms semiquantitative analysis was established, showing the capacity of the developed methodology to detect up to 16 different glycans. Other posttranslational modifications hotspots were characterized while their relative occurrence levels were estimated and compared to biosimilars. These results proved the value of using CESI-MS because the separation selectivity and ionization efficiency provided by the system allowed substantial improvement in the characterization workflow robustness and accuracy. Biosimilarity Assessment could be performed routinely with a single injection of each candidate enabling improvements in the biosimilar development pipeline.
Caroline C.w. Klaver - One of the best experts on this subject based on the ideXlab platform.
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The European Eye Epidemiology spectral-domain optical coherence tomography classification of macular diseases for epidemiological studies
Acta Ophthalmologica Scandinavica -Supplement-, 2019Co-Authors: Sarra Gattoussi, Gabriëlle H.s. Buitendijk, Tunde Peto, Irene Leung, Steffen Schmitz-valckenberg, Akio Oishi, Sebastian Wolf, Gabor Deak, Cécile Delcourt, Caroline C.w. KlaverAbstract:[u]Purpose:[/u] The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. [u]Methods:[/u] A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. [u]Results:[/u] Definitions and classifications are proposed for the Structure Assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, full-thickness macular hole, lamellar macular hole, macular pseudo-hole) and of the retina (retinoschisis, drusen, pigment epithelium detachment, hyper-reflective clumps, retinal pigment epithelium atrophy, intraretinal cystoid spaces, intraretinal tubular changes, subretinal fluid, subretinal material). Classifications according to size and location are defined. Illustrations of each item are provided, as well as the grading form. [u]Conclusion:[/u] The E3 SD-OCT classification has been developed to harmonize epidemiological studies. This homogenization will allow comparing and sharing data collection between European and international studies.
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The European Eye Epidemiology spectral-domain optical coherence tomography classification of macular diseases for epidemiological studies
Wiley-Blackwell, 2019Co-Authors: Gattoussi Sarra, Gabriëlle H.s. Buitendijk, Delcourt Cécile, Peto Tunde, Leung Irene, Schmitz-valckenberg Steffen, Oishi Akio, Wolf Sebastian, Deák Gábor, Caroline C.w. KlaverAbstract:\u3cp\u3ePurpose: The aim of the European Eye Epidemiology (E3) consortium was to develop a spectral-domain optical coherence tomography (SD-OCT)-based classification for macular diseases to standardize epidemiological studies. Methods: A European panel of vitreoretinal disease experts and epidemiologists belonging to the E3 consortium was assembled to define a classification for SD-OCT imaging of the macula. A series of meeting was organized, to develop, test and finalize the classification. First, grading methods used by the different research groups were presented and discussed, and a first version of classification was proposed. This first version was then tested on a set of 50 SD-OCT images in the Bordeaux and Rotterdam centres. Agreements were analysed and discussed with the panel of experts and a final version of the classification was produced. Results: Definitions and classifications are proposed for the Structure Assessment of the vitreomacular interface (visibility of vitreous interface, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, full-thickness macular hole, lamellar macular hole, macular pseudo-hole) and of the retina (retinoschisis, drusen, pigment epithelium detachment, hyper-reflective clumps, retinal pigment epithelium atrophy, intraretinal cystoid spaces, intraretinal tubular changes, subretinal fluid, subretinal material). Classifications according to size and location are defined. Illustrations of each item are provided, as well as the grading form. Conclusion: The E3 SD-OCT classification has been developed to harmonize epidemiological studies. This homogenization will allow comparing and sharing data collection between European and international studies.\u3c/p\u3
