TY - JOUR A1 - Puget, Chloé A1 - Ganz, Jonathan A1 - Bertram, Christof A1 - Conrad, Thomas A1 - Baeblich, Malte A1 - Voss, Anne A1 - Landmann, Katharina A1 - Haake, Alexander F. H. A1 - Spree, Andreas A1 - Hartung, Svenja A1 - Aeschlimann, Leonore A1 - Soto, Sara A1 - de Brot, Simone A1 - Dettwiler, Martina A1 - Aupperle-Lellbach, Heike A1 - Bolfa, Pompei A1 - Bartel, Alexander A1 - Kiupel, Matti A1 - Breininger, Katharina A1 - Aubreville, Marc A1 - Klopfleisch, Robert T1 - Artificial intelligence predicts c-KIT exon 11 genotype by phenotype in canine cutaneous mast cell tumors: Can human observers learn it? JF - Veterinary Pathology N2 - Canine cutaneous mast cell tumors (ccMCTs) are frequent neoplasms with variable biological behaviors. Internal tandem duplication mutations in c-KIT exon 11 (c-KIT-11-ITD) are associated with poor prognosis but predict therapeutic response to tyrosine kinase inhibitors. In a previous work, deep learning algorithms managed to predict the presence of c-KIT-11-ITD on digitalized hematoxylin and eosin-stained histological slides (whole-slide images, WSIs) in up to 87% of cases, suggesting the existence of morphological features characterizing ccMCTs carrying c-KIT-11-ITD. This 3-stage blinded study aimed to identify morphological features indicative of c-KIT-11-ITD and to evaluate the ability of human observers to learn this task. 17 untrained pathologists first classified 8 WSIs and 200 image patches (highly relevant for algorithmic classification) of ccMCTs as either positive or negative for c-KIT-11-ITD. Second, they self-trained to recognize c-KIT-11-ITD by looking at the same WSIs and patches correctly sorted. Third, pathologists classified 15 new WSIs and 200 new patches according to c-KIT-11-ITD status. In addition, participants reported microscopic features they considered relevant for their decision. Without training, participants correctly classified the c-KIT-11-ITD status of 63%–88% of WSIs and 43%–55% of patches. With self-training, 25%–38% of WSIs and 55%–56% of patches were correctly classified. High cellular pleomorphism, anisokaryosis, and sparse cytoplasmic granulation were commonly suggested as features associated with c-KIT-11-ITD-positive ccMCTs, none of which showed reliable predictivity in a follow-up study. The results indicate that transfer of algorithmic skills to the human observer is difficult. A c-KIT-11-ITD-specific morphological feature remains to be extracted from the artificial intelligence model. UR - https://doi.org/10.1177/03009858251380284 Y1 - 2025 UR - https://doi.org/10.1177/03009858251380284 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-63841 SN - 1544-2217 VL - 63 IS - 2 SP - 369 EP - 379 PB - Sage CY - London ER - TY - INPR A1 - Haghofer, Andreas A1 - Parlak, Eda A1 - Bartel, Alexander A1 - Donovan, Taryn A1 - Assenmacher, Charles-Antoine A1 - Bolfa, Pompei A1 - Dark, Michael A1 - Fuchs-Baumgartinger, Andrea A1 - Klang, Andrea A1 - Jäger, Kathrin A1 - Klopfleisch, Robert A1 - Merz, Sophie A1 - Richter, Barbara A1 - Schulman, F. Yvonne A1 - Ganz, Jonathan A1 - Scharinger, Josef A1 - Aubreville, Marc A1 - Winkler, Stephan M. A1 - Kiupel, Matti A1 - Bertram, Christof T1 - Nuclear Morphometry using a Deep Learning-based Algorithm has Prognostic Relevance for Canine Cutaneous Mast Cell Tumors N2 - Variation in nuclear size and shape is an important criterion of malignancy for many tumor types; however, categorical estimates by pathologists have poor reproducibility. Measurements of nuclear characteristics (morphometry) can improve reproducibility, but manual methods are time consuming. In this study, we evaluated fully automated morphometry using a deep learning-based algorithm in 96 canine cutaneous mast cell tumors with information on patient survival. Algorithmic morphometry was compared with karyomegaly estimates by 11 pathologists, manual nuclear morphometry of 12 cells by 9 pathologists, and the mitotic count as a benchmark. The prognostic value of automated morphometry was high with an area under the ROC curve regarding the tumor-specific survival of 0.943 (95% CI: 0.889 - 0.996) for the standard deviation (SD) of nuclear area, which was higher than manual morphometry of all pathologists combined (0.868, 95% CI: 0.737 - 0.991) and the mitotic count (0.885, 95% CI: 0.765 - 1.00). At the proposed thresholds, the hazard ratio for algorithmic morphometry (SD of nuclear area ≥9.0μm2) was 18.3 (95% CI: 5.0 - 67.1), for manual morphometry (SD of nuclear area ≥10.9μm2) 9.0 (95% CI: 6.0 - 13.4), for karyomegaly estimates 7.6 (95% CI: 5.7 - 10.1), and for the mitotic count 30.5 (95% CI: 7.8 - 118.0). Inter-rater reproducibility for karyomegaly estimates was fair (κ = 0.226) with highly variable sensitivity/specificity values for the individual pathologists. Reproducibility for manual morphometry (SD of nuclear area) was good (ICC = 0.654). This study supports the use of algorithmic morphometry as a prognostic test to overcome the limitations of estimates and manual measurements. UR - https://doi.org/10.48550/arXiv.2309.15031 Y1 - 2023 UR - https://doi.org/10.48550/arXiv.2309.15031 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-41401 PB - arXiv CY - Ithaca ER - TY - JOUR A1 - Bertram, Christof A1 - Aubreville, Marc A1 - Gurtner, Corinne A1 - Bartel, Alexander A1 - Corner, Sarah M. A1 - Dettwiler, Martina A1 - Kershaw, Olivia A1 - Noland, Erica L. A1 - Schmidt, Anja A1 - Sledge, Dodd G. A1 - Smedley, Rebecca C. A1 - Thaiwong, Tuddow A1 - Kiupel, Matti A1 - Maier, Andreas A1 - Klopfleisch, Robert T1 - Computerized Calculation of Mitotic Count Distribution in Canine Cutaneous Mast Cell Tumor Sections: Mitotic Count Is Area Dependent JF - Veterinary Pathology UR - https://doi.org/10.1177/0300985819890686 KW - area selection KW - high-power field KW - mitotic activity KW - mitotic figure distribution KW - tumor grading KW - tumor periphery Y1 - 2020 UR - https://doi.org/10.1177/0300985819890686 SN - 1544-2217 VL - 57 IS - 2 SP - 214 EP - 226 PB - Sage CY - London ER - TY - JOUR A1 - Bertram, Christof A1 - Aubreville, Marc A1 - Donovan, Taryn A1 - Bartel, Alexander A1 - Wilm, Frauke A1 - Marzahl, Christian A1 - Assenmacher, Charles-Antoine A1 - Becker, Kathrin A1 - Bennett, Mark A1 - Corner, Sarah M. A1 - Cossic, Brieuc A1 - Denk, Daniela A1 - Dettwiler, Martina A1 - Garcia Gonzalez, Beatriz A1 - Gurtner, Corinne A1 - Haverkamp, Ann-Kathrin A1 - Heier, Annabelle A1 - Lehmbecker, Annika A1 - Merz, Sophie A1 - Noland, Erica L. A1 - Plog, Stephanie A1 - Schmidt, Anja A1 - Sebastian, Franziska A1 - Sledge, Dodd G. A1 - Smedley, Rebecca C. A1 - Tecilla, Marco A1 - Thaiwong, Tuddow A1 - Fuchs-Baumgartinger, Andrea A1 - Meuten, Donald J. A1 - Breininger, Katharina A1 - Kiupel, Matti A1 - Maier, Andreas A1 - Klopfleisch, Robert T1 - Computer-assisted mitotic count using a deep learning–based algorithm improves interobserver reproducibility and accuracy JF - Veterinary Pathology N2 - The mitotic count (MC) is an important histological parameter for prognostication of malignant neoplasms. However, it has inter- and intraobserver discrepancies due to difficulties in selecting the region of interest (MC-ROI) and in identifying or classifying mitotic figures (MFs). Recent progress in the field of artificial intelligence has allowed the development of high-performance algorithms that may improve standardization of the MC. As algorithmic predictions are not flawless, computer-assisted review by pathologists may ensure reliability. In the present study, we compared partial (MC-ROI preselection) and full (additional visualization of MF candidates and display of algorithmic confidence values) computer-assisted MC analysis to the routine (unaided) MC analysis by 23 pathologists for whole-slide images of 50 canine cutaneous mast cell tumors (ccMCTs). Algorithmic predictions aimed to assist pathologists in detecting mitotic hotspot locations, reducing omission of MFs, and improving classification against imposters. The interobserver consistency for the MC significantly increased with computer assistance (interobserver correlation coefficient, ICC = 0.92) compared to the unaided approach (ICC = 0.70). Classification into prognostic stratifications had a higher accuracy with computer assistance. The algorithmically preselected hotspot MC-ROIs had a consistently higher MCs than the manually selected MC-ROIs. Compared to a ground truth (developed with immunohistochemistry for phosphohistone H3), pathologist performance in detecting individual MF was augmented when using computer assistance (F1-score of 0.68 increased to 0.79) with a reduction in false negatives by 38%. The results of this study demonstrate that computer assistance may lead to more reproducible and accurate MCs in ccMCTs. UR - https://doi.org/10.1177/03009858211067478 KW - canine cutaneous mast cell tumors KW - artificial intelligence KW - digital pathology KW - deep learning KW - mitotic figures KW - mitotic count KW - automated image analysis KW - computer assistance Y1 - 2021 UR - https://doi.org/10.1177/03009858211067478 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-13141 SN - 1544-2217 VL - 59 IS - 2 SP - 211 EP - 226 PB - Sage CY - London ER - TY - JOUR A1 - Bertram, Christof A1 - Aubreville, Marc A1 - Gurtner, Corinne A1 - Bartel, Alexander A1 - Corner, Sarah M. A1 - Dettwiler, Martina A1 - Kershaw, Olivia A1 - Noland, Erica L. A1 - Schmidt, Anja A1 - Sledge, Dodd G. A1 - Smedley, Rebecca C. A1 - Thaiwong, Tuddow A1 - Kiupel, Matti A1 - Maier, Andreas A1 - Klopfleisch, Robert T1 - Mitotic count in canine cutaneous mast cell tumours BT - not accurate but reproducible JF - Journal of Comparative Pathology UR - https://doi.org/10.1016/j.jcpa.2019.10.015 Y1 - 2020 UR - https://doi.org/10.1016/j.jcpa.2019.10.015 SN - 1532-3129 VL - 2020 IS - 174 SP - 143 PB - Elsevier CY - London ER - TY - JOUR A1 - Haghofer, Andreas A1 - Parlak, Eda A1 - Bartel, Alexander A1 - Donovan, Taryn A1 - Assenmacher, Charles-Antoine A1 - Bolfa, Pompei A1 - Dark, Michael A1 - Fuchs-Baumgartinger, Andrea A1 - Klang, Andrea A1 - Jäger, Kathrin A1 - Klopfleisch, Robert A1 - Merz, Sophie A1 - Richter, Barbara A1 - Schulman, F. Yvonne A1 - Janout, Hannah A1 - Ganz, Jonathan A1 - Scharinger, Josef A1 - Aubreville, Marc A1 - Winkler, Stephan M. A1 - Kiupel, Matti A1 - Bertram, Christof T1 - Nuclear pleomorphism in canine cutaneous mast cell tumors: Comparison of reproducibility and prognostic relevance between estimates, manual morphometry, and algorithmic morphometry JF - Veterinary Pathology N2 - Variation in nuclear size and shape is an important criterion of malignancy for many tumor types; however, categorical estimates by pathologists have poor reproducibility. Measurements of nuclear characteristics can improve reproducibility, but current manual methods are time-consuming. The aim of this study was to explore the limitations of estimates and develop alternative morphometric solutions for canine cutaneous mast cell tumors (ccMCTs). We assessed the following nuclear evaluation methods for accuracy, reproducibility, and prognostic utility: (1) anisokaryosis estimates by 11 pathologists; (2) gold standard manual morphometry of at least 100 nuclei; (3) practicable manual morphometry with stratified sampling of 12 nuclei by 9 pathologists; and (4) automated morphometry using deep learning–based segmentation. The study included 96 ccMCTs with available outcome information. Inter-rater reproducibility of anisokaryosis estimates was low (k = 0.226), whereas it was good (intraclass correlation = 0.654) for practicable morphometry of the standard deviation (SD) of nuclear size. As compared with gold standard manual morphometry (area under the ROC curve [AUC] = 0.839, 95% confidence interval [CI] = 0.701–0.977), the prognostic value (tumor-specific survival) of SDs of nuclear area for practicable manual morphometry and automated morphometry were high with an AUC of 0.868 (95% CI = 0.737–0.991) and 0.943 (95% CI = 0.889–0.996), respectively. This study supports the use of manual morphometry with stratified sampling of 12 nuclei and algorithmic morphometry to overcome the poor reproducibility of estimates. Further studies are needed to validate our findings, determine inter-algorithmic reproducibility and algorithmic robustness, and explore tumor heterogeneity of nuclear features in entire tumor sections. UR - https://doi.org/10.1177/03009858241295399 Y1 - 2024 UR - https://doi.org/10.1177/03009858241295399 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-53661 SN - 1544-2217 SN - 0300-9858 VL - 62 IS - 2 SP - 161 EP - 177 PB - Sage CY - London ER - TY - JOUR A1 - Glahn, Imaine A1 - Haghofer, Andreas A1 - Donovan, Taryn A1 - Degasperi, Brigitte A1 - Bartel, Alexander A1 - Kreilmeier-Berger, Theresa A1 - Hyndman, Philip S. A1 - Janout, Hannah A1 - Assenmacher, Charles-Antoine A1 - Bartenschlager, Florian A1 - Bolfa, Pompei A1 - Dark, Michael A1 - Klang, Andrea A1 - Klopfleisch, Robert A1 - Merz, Sophie A1 - Richter, Barbara A1 - Schulman, F. Yvonne A1 - Ganz, Jonathan A1 - Scharinger, Josef A1 - Aubreville, Marc A1 - Winkler, Stephan M. A1 - Bertram, Christof T1 - Automated Nuclear Morphometry: A Deep Learning Approach for Prognostication in Canine Pulmonary Carcinoma to Enhance Reproducibility JF - Veterinary Sciences N2 - The integration of deep learning-based tools into diagnostic workflows is increasingly prevalent due to their efficiency and reproducibility in various settings. We investigated the utility of automated nuclear morphometry for assessing nuclear pleomorphism (NP), a criterion of malignancy in the current grading system in canine pulmonary carcinoma (cPC), and its prognostic implications. We developed a deep learning-based algorithm for evaluating NP (variation in size, i.e., anisokaryosis and/or shape) using a segmentation model. Its performance was evaluated on 46 cPC cases with comprehensive follow-up data regarding its accuracy in nuclear segmentation and its prognostic ability. Its assessment of NP was compared to manual morphometry and established prognostic tests (pathologists’ NP estimates (n = 11), mitotic count, histological grading, and TNM-stage). The standard deviation (SD) of the nuclear area, indicative of anisokaryosis, exhibited good discriminatory ability for tumor-specific survival, with an area under the curve (AUC) of 0.80 and a hazard ratio (HR) of 3.38. The algorithm achieved values comparable to manual morphometry. In contrast, the pathologists’ estimates of anisokaryosis resulted in HR values ranging from 0.86 to 34.8, with slight inter-observer reproducibility (k = 0.204). Other conventional tests had no significant prognostic value in our study cohort. Fully automated morphometry promises a time-efficient and reproducible assessment of NP with a high prognostic value. Further refinement of the algorithm, particularly to address undersegmentation, and application to a larger study population are required. UR - https://doi.org/10.3390/vetsci11060278 Y1 - 2024 UR - https://doi.org/10.3390/vetsci11060278 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-48612 SN - 2306-7381 VL - 11 IS - 6 PB - MDPI CY - Basel ER - TY - JOUR A1 - Fragoso-Garcia, Marco A1 - Wilm, Frauke A1 - Bertram, Christof A1 - Merz, Sophie A1 - Schmidt, Anja A1 - Donovan, Taryn A1 - Fuchs-Baumgartinger, Andrea A1 - Bartel, Alexander A1 - Marzahl, Christian A1 - Diehl, Laura A1 - Puget, Chloe A1 - Maier, Andreas A1 - Aubreville, Marc A1 - Breininger, Katharina A1 - Klopfleisch, Robert T1 - Automated diagnosis of 7 canine skin tumors using machine learning on H&E-stained whole slide images JF - Veterinary Pathology N2 - Microscopic evaluation of hematoxylin and eosin-stained slides is still the diagnostic gold standard for a variety of diseases, including neoplasms. Nevertheless, intra- and interrater variability are well documented among pathologists. So far, computer assistance via automated image analysis has shown potential to support pathologists in improving accuracy and reproducibility of quantitative tasks. In this proof of principle study, we describe a machine-learning-based algorithm for the automated diagnosis of 7 of the most common canine skin tumors: trichoblastoma, squamous cell carcinoma, peripheral nerve sheath tumor, melanoma, histiocytoma, mast cell tumor, and plasmacytoma. We selected, digitized, and annotated 350 hematoxylin and eosin-stained slides (50 per tumor type) to create a database divided into training, n = 245 whole-slide images (WSIs), validation ( n = 35 WSIs), and test sets ( n = 70 WSIs). Full annotations included the 7 tumor classes and 6 normal skin structures. The data set was used to train a convolutional neural network (CNN) for the automatic segmentation of tumor and nontumor classes. Subsequently, the detected tumor regions were classified patch-wise into 1 of the 7 tumor classes. A majority of patches-approach led to a tumor classification accuracy of the network on the slide-level of 95% (133/140 WSIs), with a patch-level precision of 85%. The same 140 WSIs were provided to 6 experienced pathologists for diagnosis, who achieved a similar slide-level accuracy of 98% (137/140 correct majority votes). Our results highlight the feasibility of artificial intelligence-based methods as a support tool in diagnostic oncologic pathology with future applications in other species and tumor types. UR - https://doi.org/10.1177/03009858231189205 KW - computer-aided diagnosis KW - computational pathology KW - digital pathology KW - dog KW - machine learning KW - skin KW - veterinary oncology Y1 - 2023 UR - https://doi.org/10.1177/03009858231189205 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-38321 SN - 0300-9858 VL - 60 IS - 6 SP - 865 EP - 875 PB - Sage CY - London ER - TY - JOUR A1 - Bertram, Christof A1 - Marzahl, Christian A1 - Bartel, Alexander A1 - Stayt, Jason A1 - Bonsembiante, Federico A1 - Beeler-Marfisi, Janet A1 - Barton, Ann K. A1 - Brocca, Ginevra A1 - Gelain, Maria Elena A1 - Gläsel, Agnes C. A1 - du Preez, Kelly A1 - Weiler, Kristina A1 - Weissenbacher-Lang, Christiane A1 - Breininger, Katharina A1 - Aubreville, Marc A1 - Maier, Andreas A1 - Klopfleisch, Robert A1 - Hill, Jenny T1 - Cytologic scoring of equine exercise-induced pulmonary hemorrhage: Performance of human experts and a deep learning-based algorithm JF - Veterinary Pathology N2 - Exercise-induced pulmonary hemorrhage (EIPH) is a relevant respiratory disease in sport horses, which can be diagnosed by examination of bronchoalveolar lavage fluid (BALF) cells using the total hemosiderin score (THS). The aim of this study was to evaluate the diagnostic accuracy and reproducibility of annotators and to validate a deep learning-based algorithm for the THS. Digitized cytological specimens stained for iron were prepared from 52 equine BALF samples. Ten annotators produced a THS for each slide according to published methods. The reference methods for comparing annotator’s and algorithmic performance included a ground truth dataset, the mean annotators’ THSs, and chemical iron measurements. Results of the study showed that annotators had marked interobserver variability of the THS, which was mostly due to a systematic error between annotators in grading the intracytoplasmatic hemosiderin content of individual macrophages. Regarding overall measurement error between the annotators, 87.7% of the variance could be reduced by using standardized grades based on the ground truth. The algorithm was highly consistent with the ground truth in assigning hemosiderin grades. Compared with the ground truth THS, annotators had an accuracy of diagnosing EIPH (THS of < or ≥ 75) of 75.7%, whereas, the algorithm had an accuracy of 92.3% with no relevant differences in correlation with chemical iron measurements. The results show that deep learning-based algorithms are useful for improving reproducibility and routine applicability of the THS. For THS by experts, a diagnostic uncertainty interval of 40 to 110 is proposed. THSs within this interval have insufficient reproducibility regarding the EIPH diagnosis. UR - https://doi.org/10.1177/03009858221137582 KW - artificial intelligence KW - automated image analysis KW - bronchoalveolar lavage fluid KW - computational pathology KW - digital pathology KW - equine KW - pulmonary hemorrhage KW - respiratory disease KW - total hemosiderin score Y1 - 2022 UR - https://doi.org/10.1177/03009858221137582 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-35196 SN - 1544-2217 VL - 60 IS - 1 SP - 75 EP - 85 PB - Sage CY - London ER - TY - CHAP A1 - Wilm, Frauke A1 - Bertram, Christof A1 - Marzahl, Christian A1 - Bartel, Alexander A1 - Donovan, Taryn A1 - Assenmacher, Charles-Antoine A1 - Becker, Kathrin A1 - Bennett, Mark A1 - Corner, Sarah M. A1 - Cossic, Brieuc A1 - Denk, Daniela A1 - Dettwiler, Martina A1 - Garcia Gonzalez, Beatriz A1 - Gurtner, Corinne A1 - Heier, Annabelle A1 - Lehmbecker, Annika A1 - Merz, Sophie A1 - Plog, Stephanie A1 - Schmidt, Anja A1 - Sebastian, Franziska A1 - Smedley, Rebecca C. A1 - Tecilla, Marco A1 - Thaiwong, Tuddow A1 - Breininger, Katharina A1 - Kiupel, Matti A1 - Maier, Andreas A1 - Klopfleisch, Robert A1 - Aubreville, Marc T1 - Influence of inter-annotator variability on automatic mitotic figure assessment T2 - Bildverarbeitung für die Medizin 2021 UR - https://doi.org/10.1007/978-3-658-33198-6_56 Y1 - 2021 UR - https://doi.org/10.1007/978-3-658-33198-6_56 SN - 978-3-658-33198-6 SP - 241 EP - 246 PB - Springer CY - Wiesbaden ER -