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  • Article
    Open Access
    When performance is not enough—A multidisciplinary view on clinical decision support
    (2023-06-15) Roller, Roland; Burchardt, Aljoscha; Samhammer, David; Ronicke, Simon; Duettmann, Wiebke; Schmeier, Sven; Möller, Sebastian; Dabrock, Peter; Budde, Klemens; Mayrdorfer, Manuel; Osmanodja, Bilgin
    Scientific publications about the application of machine learning models in healthcare often focus on improving performance metrics. However, beyond often short-lived improvements, many additional aspects need to be taken into consideration to make sustainable progress. What does it take to implement a clinical decision support system, what makes it usable for the domain experts, and what brings it eventually into practical usage? So far, there has been little research to answer these questions. This work presents a multidisciplinary view of machine learning in medical decision support systems and covers information technology, medical, as well as ethical aspects. The target audience is computer scientists, who plan to do research in a clinical context. The paper starts from a relatively straightforward risk prediction system in the subspecialty nephrology that was evaluated on historic patient data both intrinsically and based on a reader study with medical doctors. Although the results were quite promising, the focus of this article is not on the model itself or potential performance improvements. Instead, we want to let other researchers participate in the lessons we have learned and the insights we have gained when implementing and evaluating our system in a clinical setting within a highly interdisciplinary pilot project in the cooperation of computer scientists, medical doctors, ethicists, and legal experts.
  • Article
    Open Access
    A multiomic approach to defining the essential genome of the globally important pathogen Corynebacterium diphtheriae
    (2023-06-15) Goodall, Emily C. A.; Azevedo Antunes, Camila; Möller, Jens; Sangal, Vartul; Torres, Von Vergel L.; Gray, Jessica; Cunningham, Adam F.; Hoskisson, Paul A.; Burkovski, Andreas; Henderson, Ian R.
    Diphtheria is a respiratory disease caused by Corynebacterium diphtheriae. While the toxin-based vaccine has helped control outbreaks of the disease since the mid-20th century there has been an increase in cases in recent years, including systemic infections caused by non-toxigenic C. diphtheriae strains. Here we describe the first study of gene essentiality in C. diphtheriae, providing the most-dense Transposon Directed Insertion Sequencing (TraDIS) library in the phylum Actinobacteriota. This high-density library has allowed the identification of conserved genes across the genus and phylum with essential function and enabled the elucidation of essential domains within the resulting proteins including those involved in cell envelope biogenesis. Validation of these data through protein mass spectrometry identified hypothetical and uncharacterized proteins in the proteome which are also represented in the vaccine. These data are an important benchmark and useful resource for the Corynebacterium, Mycobacterium, Nocardia and Rhodococcus research community. It enables the identification of novel antimicrobial and vaccine targets and provides a basis for future studies of Actinobacterial biology.
  • Article
    Open Access
    Comparative analysis of retinal photoplethysmographic spatial maps and thickness of retinal nerve fiber layer
    (2023-06-15) Odstrcilik, Jan; Kolar, Radim; Horn, Folkert; Tornow, Ralf-Peter
    The paper presents a comparative study of the pulsatile attenuation amplitude (PAA) within the optic nerve head (ONH) at four different areas calculated from retinal video sequences and its relevance to the retinal nerve fiber layer thickness (RNFL) changes in normal subjects and patients with different stages of glaucoma. The proposed methodology utilizes processing of retinal video sequences acquired by a novel video ophthalmoscope. The PAA parameter measures the amplitude of heartbeat-modulated light attenuation in retinal tissue. Correlation analysis between PAA and RNFL is performed in vessel-free locations of the peripapillary region with the proposed evaluating patterns: 360° circular area, temporal semi-circle, nasal semi-circle. For comparison, the full ONH area is also included. Various positions and sizes of evaluating patterns in peripapillary region were tested which resulted in different outputs of correlation analysis. The results show significant correlation between PAA and RNFL thickness calculated in proposed areas. The highest correlation coefficient Rtemp = 0.557 (p<0.001) reflects the highest PAA-RNFL correspondence in the temporal semi-circular area, compared to the lowest value in the nasal semi-circular area (Rnasal = 0.332, p<0.001). Furthermore, the results indicate the most relevant approach to calculate PAA from the acquired video sequences is using a thin annulus near the ONH center. Finally, the paper shows the proposed photoplethysmographic principle based on innovative video ophthalmoscope can be used to analyze changes in retinal perfusion in peripapillary area and can be potentially used to assess progression of the RNFL deterioration.
  • Article
    Open Access
    Trees with anisohydric behavior as main drivers of nocturnal evapotranspiration in a tropical mountain rainforest
    (2023-06-15) Raffelsbauer, Volker; Pucha-Cofrep, Franz; Strobl, Simone; Knüsting, Johannes; Schorsch, Michael; Trachte, Katja; Scheibe, Renate; Bräuning, Achim; Windhorst, David; Bendix, Jörg; Silva, Brenner; Beck, Erwin
    This study addresses transpiration in a tropical evergreen mountain forest in the Ecuadorian Andes from the leaf to the stand level, with emphasis on nocturnal plant-water relations. The stand level: Evapotranspiration (ET) measured over 12 months with the Eddy-Covariance (ECov) technique proved as the major share (79%) of water received from precipitation. Irrespective of the humid climate, the vegetation transpired day and night. On average, 15.3% of the total daily ET were due to nocturnal transpiration. Short spells of drought increased daily ET, mainly by enhanced nighttime transpiration. Following leaf transpiration rather than air temperature and atmospheric water vapor deficit, ET showed its maximum already in the morning hours. The tree level: Due to the humid climate, the total water consumption of trees was generally low. Nevertheless, xylem sap flux measurements separated the investigated tree species into a group showing relatively high and another one with low sap flux rates. The leaf level: Transpiration rates of Tapirira guianensis, a member of the high-flux-rate group, were more than twice those of Ocotea aciphylla, a representative of the group showing low sap flux rates. Representatives of the Tapirira group operated at a relatively high leaf water potential but with a considerable diurnal amplitude, while the leaves of the Ocotea group showed low water potential and small diurnal fluctuations. Overall, the Tapirira group performed anisohydrically and the Ocotea group isohydrically. Grouping of the tree species by their water relations complied with the extents of the diurnal stem circumference fluctuations. Nighttime transpiration and hydrological type: In contrast to the isohydrically performing trees of the Ocotea group, the anisohydric trees showed considerable water vapour pressure deficit (VPD)-dependent nocturnal transpiration. Therefore, we conclude that nighttime ET at the forest level is mainly sourced by the tree species with anisohydric performance.
  • Article
    Open Access
    Th2-dependent STAT6-regulated genes in intestinal epithelial cells mediate larval trapping during secondary Heligmosomoides polygyrus bakeri infection
    (2023-06-15) Westermann, Stefanie; Schubart, Christoph; Dietschmann, Axel; Castiglione, Kirstin; Radtke, Daniel; Voehringer, David
    Gastrointestinal helminths are a major health threat worldwide. Alternatively activated macrophages (AAMs) have been shown to contribute to host protection during secondary helminth infections. AAMs express effector molecules that depend on activation of the IL-4- or IL-13-induced transcription factor signal transducer and activator of transcription 6 (STAT6). However, the specific role of STAT6-regulated genes like Arginase-1 (Arg1) from AAMs or STAT6-regulated genes in other cell types for host protection remains unclear. To address this point, we generated mice expressing STAT6 only in macrophages (Mac-STAT6 mouse). In the model of Heligmosomoides polygyrus bakeri (Hpb) infection, Mac-STAT6 mice could not trap larvae in the submucosa of the small intestine after secondary infection. Further, mice lacking Arg1 in hematopoietic and endothelial cells were still protected from secondary Hpb infection. On the other hand, specific deletion of IL-4/IL-13 in T cells blunted AAM polarization, activation of intestinal epithelial cells (IECs) and protective immunity. Deletion of IL-4Rα on IEC also caused loss of larval trapping while AAM polarization remained intact. These results show that Th2-dependent and STAT6-regulated genes in IECs are required and AAMs are not sufficient for protection against secondary Hpb infection by mechanisms that remain to be investigated.
  • Article
    Open Access
    Effects of PTH glandular and external dosing patterns on bone cell activity using a two-state receptor model—Implications for bone disease progression and treatment
    (2023-06-15) Martonová, Denisa; Lavaill, Maxence; Forwood, Mark R.; Robling, Alexander; Cooper, David M. L.; Leyendecker, Sigrid; Pivonka, Peter
    Temporal aspects of ligand specificity have been shown to play a significant role in the case of pulsatile hormone secretion, as exemplified by parathyroid hormone (PTH) binding to its receptor (PTH1R), a G-protein-coupled receptor expressed on surfaces of osteoblasts and osteocytes. The latter binding reaction regulates intracellular signalling and subsequently modulates skeletal homeostasis via bone remodelling. PTH glandular secretion patterns dictate bone cellular activity. In healthy humans, 70% of PTH is secreted in a tonic fashion, whereas 30% is secreted in low-amplitude and high-frequency bursts occurring every 10–20 min, superimposed on the tonic secretion. Changes in the PTH secretion patterns have been associated with various bone diseases. In this paper, we analyse PTH glandular secretion patterns for healthy and pathological states and their link to bone cellular responsiveness (αR). We utilise a two-state receptor ligand binding model of PTH to PTH1R together with a cellular activity function which is able to distinguish various aspects of the stimulation signal including peak dose, time of ligand exposure, and exposure period. Formulating and solving several constrained optimisation problems, we investigate the potential of pharmacological manipulation of the diseased glandular secretion and via clinical approved external PTH injections to restore healthy bone cellular responsiveness. Based on the mean experimentally reported data, our simulation results indicate cellular responsiveness in healthy subjects is sensitive to the tonic baseline stimulus and it is 28% of the computed maximum responsiveness. Simulation results for pathological cases of glucocorticoid-induced osteoporosis, hyperparathyroidism, initial and steady state hypocalcemia clamp tests indicate αR values significantly larger than the healthy baseline (1.7, 2.2, 4.9 and 1.9-times, respectively). Manipulation of the pulsatile glandular secretion pattern, while keeping the mean PTH concentration constant, allowed restoration of healthy baseline values from these catabolic bone diseases. Conversely, PTH glandular diseases that led to maximum bone cellular responsiveness below the healthy baseline value can’t be restored to baseline via glandular manipulation. However, external PTH injections allowed restoration of these latter cases.
  • Article
    Open Access
    The epidemiology of human Taenia solium infections: A systematic review of the distribution in Eastern and Southern Africa
    (2023-06-15) Zulu, Gideon; Stelzle, Dominik; Mwape, Kabemba E.; Welte, Tamara M.; Strømme, Hilde; Mubanga, Chishimba; Mutale, Wilbroad; Abraham, Annette; Hachangu, Alex; Schmidt, Veronika; Sikasunge, Chummy S.; Phiri, Isaac K.; Winkler, Andrea S.
    Background Taenia solium is a tapeworm that causes taeniosis in humans and cysticercosis in humans and pigs. Within Eastern and Southern Africa (ESA), information on the presence of human taeniosis and cysticercosis seems scarce. This systematic review aimed to describe the current information available and gaps in the epidemiology of human T. solium infections in ESA. Methods/Principle findings Scientific literature published between 1st January 2000 and 20th June 2022 in international databases [MEDLINE (Ovid), Embase (Ovid), Global Health (Ovid), Scopus (Elsevier), African Index Medicus (via WHO Global Index Medicus), and Open Grey] was systematically reviewed for ESA. The study area included 27 countries that make up the ESA region. Information on either taeniosis, cysticercosis or NCC was available for 16 of 27 countries within the region and a total of 113 reports were retained for the review. Most case reports for cysticercosis and NCC were from South Africa, while Tanzania had the most aggregated cysticercosis reports. Eleven countries reported on NCC with seven countries reporting data on NCC and epilepsy. Unconfirmed human T. solium taeniosis cases were reported in nine countries while two countries (Madagascar and Zambia) reported confirmed T. solium cases. The cysticercosis seroprevalence ranged between 0.7–40.8% on antigen (Ag) ELISA and between 13.1–45.3% on antibody (Ab) ELISA. Based on immunoblot tests the Ab seroprevalence was between 1.7–39.3%, while the proportion of NCC-suggestive lesions on brain CT scans was between 1.0–76% depending on the study population. The human taeniosis prevalence based on microscopy ranged between 0.1–14.7%. Based on Copro Ag-ELISA studies conducted in Kenya, Rwanda, Tanzania, and Zambia, the highest prevalence of 19.7% was reported in Kenya. Conclusions Despite the public health and economic impact of T. solium in ESA, there are still large gaps in knowledge about the occurrence of the parasite, and the resulting One Health disease complex, and monitoring of T. solium taeniosis and cysticercosis is mostly not in place.
  • Article
    Open Access
    “What else to say?”–Primary health care in times of COVID-19 from the perspective of German general practitioners: An exploratory analysis of the open text field in the PRICOV-19 study
    (2023-03-22) Stark, Stefanie; Kluge, Marie; Schaubroeck, Emmily; Werner, Felix; van Poel, Esther; Willems, Sara; Roos, Marco; Kühlein, Thomas; Burggraf, Larissa
    Background The international collaboration study PRICOV-19 –Primary Health Care in times of COVID-19 aims to assess the impact of the COVID-19 pandemic on the organisation of primary health care. The German part focuses on the subjective perceptions of general practitioners on primary health care and the impact of political measures during the second wave of the COVID-19 pandemic. Within this survey, the “open text field” of the questionnaire was utilised remarkably frequently and extensively by the respondents. It became clear that the content that was named needed to be analysed in an exploratory manner. Accordingly, this paper addresses the following question: What preoccupies general practitioners in Germany during COVID-19 that we have not yet asked them enough? Methods The data collection took place throughout Germany from 01.02.2021 to 28.02.2021with a quantitative online questionnaire consisting of 53 items arranged across six topics as well as an “open text field” for further comments. The questionnaire’s open text field was analysed following the premises of the qualitative content analysis. Results The topics discussed by the respondents were: insufficient support from health policies, not being prioritised and involved in the vaccination strategy, feeling insufficient prepared, that infrastructural changes and financial concerns threatened the practice, and perceiving the own role as important, as well as that health policies affected the wellbeing of the respondents. One of the main points was the way general practitioners were not sufficiently acknowledged for their contribution to ensuring high-quality care during the pandemic. Discussion German general practitioners perceived their work and role as highly relevant during the COVID-19 pandemic. In controversy with their perception, they described political conditions in which they were the ones who contributed significantly to the fight against the pandemic but were not given enough recognition.
  • Article
    Open Access
    APSified OCT-angiography analysis: Macula vessel density in healthy eyes during office hours
    (2023-03-22) Müller, Meike; Schottenhamml, Julia; Hosari, Sami; Hohberger, Bettina; Mardin, Christian Y.
    Purpose Optical coherence tomography angiography (OCT-A) can visualize retinal capillary microcirculation non-invasively. In order to investigate potential factors influencing OCT-A diagnostics, the aim of the present study was to determine circadian changes in macular vessel density (VD) in healthy adults during office hours, considering axial length (AL) and subfoveal choroidal thickness (CT). Methods In the prospective study 30 eyes of 30 healthy subjects (mean age 28.7 ± 11.8, range 19–60 years) were recruited who underwent repeated measurements of AL, subfoveal CT and three-layer macula VD (superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP)) on a single day at three predetermined timepoints (9 AM, 3 PM, and 9 PM). For better intra- and interindividual scan comparability, the new Anatomic Positioning System function (APS, part of Glaucoma Module Premium Edition [GMPE], Heidelberg Engineering, Germany) allowing analysis of identical retinal areas, was used for quantitative OCT-A analysis. Results Overall mean macula VD was unchanged during office hours in SVP, ICP and DCP, respectively (p>0.05). In addition, AL and CT showed no statistically significant changes over time (p>0.05). Rather, a large interindividual variance of VD with different peak time was observed. Contrary to the overall data, sectorial VD changed in dependency of office hours in all layers with an increase of VD in SVP between 9 AM and 9 PM (p = 0.003), in ICP between 3 PM and 9 PM (p = 0.000), in DCP between 9 AM and 9 PM (p = 0.048), and 3 PM and 9 PM (p = 0.000), respectively. Conclusion Overall mean macula VD, subfoveal CT and AL tended not to show statistically significant changes over time in this cohort, whereas a regional analysis of VD did. Therefore, a circadian influence on capillary microcirculation should be kept in mind. Moreover, the results highlight the importance of a more detailed analysis of VD in different sectors and different vascular layers. In addition, the pattern of diurnal variation could vary inter-individually, thus a patient-specific fluctuation pattern would need to be considered when evaluating these parameters in clinical practice.
  • Article
    Open Access
    Exploring facial expressions and action unit domains for Parkinson detection
    (2023-03-22) Gomez, Luis F.; Morales, Aythami; Fierrez, Julian; Orozco-Arroyave, Juan Rafael
    Background and objective Patients suffering from Parkinson’s disease (PD) present a reduction in facial movements called hypomimia. In this work, we propose to use machine learning facial expression analysis from face images based on action unit domains to improve PD detection. We propose different domain adaptation techniques to exploit the latest advances in automatic face analysis and face action unit detection. Methods Three different approaches are explored to model facial expressions of PD patients: (i) face analysis using single frame images and also using sequences of images, (ii) transfer learning from face analysis to action units recognition, and (iii) triplet-loss functions to improve the automatic classification between patients and healthy subjects. Results Real face images from PD patients show that it is possible to properly model elicited facial expressions using image sequences (neutral, onset-transition, apex, offset-transition, and neutral) with accuracy improvements of up to 5.5% (from 72.9% to 78.4%) with respect to single-image PD detection. We also show that our proposed action unit domain adaptation provides improvements of up to 8.9% (from 78.4% to 87.3%) with respect to face analysis. Finally, we also show that triplet-loss functions provide improvements of up to 3.6% (from 78.8% to 82.4%) with respect to action unit domain adaptation applied upon models created from scratch. The code of the experiments is available at https://github.com/luisf-gomez/Explorer-FE-AU-in-PD. Conclusions Domain adaptation via transfer learning methods seem to be a promising strategy to model hypomimia in PD patients. Considering the good results and also the fact that only up to five images per participant are considered in each sequence, we believe that this work is a step forward in the development of inexpensive computational systems suitable to model and quantify problems of PD patients in their facial expressions.
  • Article
    Open Access
    Light and electron microscopic features of preclinical pseudoexfoliation syndrome
    (2023-03-22) Suwan, Yanin; Kulnirandorn, Tuangporn; Schlötzer-Schrehardt, Ursula; Wongchaya, Sattawat; Petpiroon, Purit; Supakontanasan, Wasu; Tantraworasin, Apichat; Teekhasanee, Chaiwat
    Purpose This study sought to explore the features of the anterior lens capsule in patients with preclinical pseudoexfoliation syndrome (pPEX) via light microscopy (LM) and transmission electron microscopy (TEM). Design Cross-sectional, prospective, and observational case series. Methods We recruited consecutive patients with and without pPEX who underwent routine cataract surgery at Ramathibodi Hospital, between April 2018 and November 2020. pPEX can be characterized by pigmented spoke-wheel deposition (P) on the anterior lens capsule, midperiphery cleft/lacunae (C), faint central disc present within the photopic pupil (D), white-spoke pattern (W) noted at the midperiphery, and a combination of at least two signs (Co). LM and TEM were used to examine anterior lens capsule specimens for the presence of characteristic pseudoexfoliation material (PXM). The features of the anterior lens capsule in pPEX explored via LM and TEM were recorded. Results This study included a total of 96 patients (101 excised anterior lens capsules); among them, 34 (35 excised anterior lens capsules) exhibited pPEX signs (pPEX group) but 62 (66 excised anterior lens capsules) did not (control group). The patients had a mean age of 74 ± 7 (range, 58–89) years. LM and TEM revealed no definite PXM in any patient. In the pPEX group, LM analysis identified two capsule specimens with suspected PXM; PXM precursors were observed in 1 of the 34 excised capsule specimens analyzed via TEM. Furthermore, 39 eyes (59.09%) exhibited signs of true exfoliation syndrome (TEX) in LM analysis (12.82%, 25.64%, 10.26%, 10.26%, and 41.03% for patients exhibiting P, D, C, W, and Co, respectively). However, no TEX signs were observed in the control group. We found that the anterior lens capsules exhibiting C and D were significantly associated with TEX (odds ratio = 5.4 and 7.9; P = 0.007 and 0.004, respectively). Conclusions LM analysis revealed no definite PXMs were detected in the excised anterior lens capsules, whereas TEM analysis showed PXM precursors in one specimen (2.94%). Notably, a significant association was observed between C and D signs and TEX.
  • Article
    Open Access
    Common variants in breast cancer risk loci predispose to distinct tumor subtypes
    (2023-02-14) Ahearn, Thomas U.; Zhang, Haoyu; Michailidou, Kyriaki; Milne, Roger L.; Bolla, Manjeet K.; Dennis, Joe; Dunning, Alison M.; Lush, Michael; Wang, Qin; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Augustinsson, Annelie; Baten, Adinda; Becher, Heiko; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brenner, Hermann; Brooks-Wilson, Angela; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S.; Canzian, Federico; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Clarke, Christine L.; Sahlberg, Kristine K.; Ottestad, Lars; Kåresen, Rolf; Schlichting, Ellen; Holmen, Marit Muri; Sauer, Toril; Haakensen, Vilde; Engebråten, Olav; Naume, Bjørn; Fosså, Alexander; Kiserud, Cecile E.; Reinertsen, Kristin V.; Helland, Åslaug; Riis, Margit; Geisler, Jürgen; Collée, J. Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; Dwek, Miriam; Eccles, Diana M.; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Floris, Giuseppe; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Alnæs, Grethe I. Grenaker; Grip, Mervi; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Harkness, Elaine F.; Heemskerk-Gerritsen, Bernadette A. M.; Holleczek, Bernd; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Clarke, Christine; Balleine, Rosemary; Baxter, Robert; Braye, Stephen; Carpenter, Jane; Dahlstrom, Jane; Forbes, John; Lee, CSoon; Marsh, Deborah; Morey, Adrienne; Pathmanathan, Nirmala; Scott, Rodney; Simpson, Peter; Spigelman, Allan; Wilcken, Nicholas; Yip, Desmond; Zeps, Nikolajs; Fox, Stephen; Campbell, Ian; Bowtell, David; Spurdle, Amanda; Webb, Penny; de Fazio, Anna; Tassell, Margaret; Kirk, Judy; Lindeman, Geoff; Price, Melanie; Southey, Melissa; Milne, Roger; Deb, Sid; Jakimovska, Milena; Jakubowska, Anna; John, Esther M.; Jones, Michael E.; Jung, Audrey; Kaaks, Rudolf; Kauppila, Saila; Keeman, Renske; Khusnutdinova, Elza; Kitahara, Cari M.; Ko, Yon-Dschun; Koutros, Stella; Kristensen, Vessela N.; Krüger, Ute; Kubelka-Sabit, Katerina; Kurian, Allison W.; Kyriacou, Kyriacos; Lambrechts, Diether; Lee, Derrick G.; Lindblom, Annika; Linet, Martha; Lissowska, Jolanta; Llaneza, Ana; Lo, Wing-Yee; MacInnis, Robert J.; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Martinez, Maria Elena; McLean, Catriona; Meindl, Alfons; Menon, Usha; Nevanlinna, Heli; Newman, William G.; Nodora, Jesse; Offit, Kenneth; Olsson, Håkan; Orr, Nick; Park-Simon, Tjoung-Won; Patel, Alpa V.; Peto, Julian; Pita, Guillermo; Plaseska-Karanfilska, Dijana; Prentice, Ross; Punie, Kevin; Pylkäs, Katri; Radice, Paolo; Rennert, Gad; Romero, Atocha; Rüdiger, Thomas; Saloustros, Emmanouil; Sampson, Sarah; Sandler, Dale P.; Sawyer, Elinor J.; Schmutzler, Rita K.; Schoemaker, Minouk J.; Schöttker, Ben; Sherman, Mark E.; Shu, Xiao-Ou; Smichkoska, Snezhana; Southey, Melissa C.; Spinelli, John J.; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Teras, Lauren R.; Terry, Mary Beth; Torres, Diana; Troester, Melissa A.; Vachon, Celine M.; van Deurzen, Carolien H. M.; van Veen, Elke M.; Wagner, Philippe; Weinberg, Clarice R.; Wendt, Camilla; Wesseling, Jelle; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Zheng, Wei; Couch, Fergus J.; Simard, Jacques; Kraft, Peter; Easton, Douglas F.; Pharoah, Paul D. P.; Schmidt, Marjanka K.; García-Closas, Montserrat; Chatterjee, Nilanjan
    Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
  • Article
    Open Access
    Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation
    (2023-02-14) Herrmann, Johannes; Lotz, Christopher; Karagiannidis, Christian; Weber-Carstens, Steffen; Kluge, Stefan; Putensen, Christian; Wehrfritz, Andreas; Schmidt, Karsten; Ellerkmann, Richard K.; Oswald, Daniel; Lotz, Gösta; Zotzmann, Viviane; Moerer, Onnen; Kühn, Christian; Kochanek, Matthias; Muellenbach, Ralf; Gaertner, Matthias; Fichtner, Falk; Brettner, Florian; Findeisen, Michael; Heim, Markus; Lahmer, Tobias; Rosenow, Felix; Haake, Nils; Lepper, Philipp M.; Rosenberger, Peter; Braune, Stephan; Kohls, Mirjam; Heuschmann, Peter; Meybohm, Patrick; Hübsch, Martha E.; Notz, Quirin; Röder, Daniel; Kranke, Peter; Merten, Michaela L.; Jarczak, Dominik; Roedl, Kevin; Schewe, Jens-Christian; Ehrentraut, Stefan F.; Kreyer, Stefan; Castellanos, Ixchel; Brenner, Thorsten; Herbstreit, Frank; Espeter, Florian; Wiefhoff, Jan; Ellger, Björn; Raimann, Florian J.; Sonntagbauer, Michael; Wengenmayer, Tobias; Staudacher, Dawid; Natanov, Ruslan; Rolfes, Caroline; Reyher, Christian; Torje, Iuliu-Emilian; Glaser, Patricia; Rembold, Vanessa; Haseneder, Rainer; Sackarnd, Jan; Lepper, Johannes; Becker, Andre; Danziger, Guy; Metz, Carlos; Mirakaj, Valbona; Calov, Stefanie; Grau, Anna; Haas, Kirsten; Ungethüm, Katrin; Bihlmaier, Karl
    Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO2/FiO2 ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. Conclusions Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival.
  • Article
    Open Access
    Breast cancer risks associated with missense variants in breast cancer susceptibility genes
    (2023-02-10) Dorling, Leila; Carvalho, Sara; Allen, Jamie; Parsons, Michael T.; Fortuno, Cristina; González-Neira, Anna; Heijl, Stephan M.; Adank, Muriel A.; Ahearn, Thomas U.; Andrulis, Irene L.; Auvinen, Päivi; Becher, Heiko; Beckmann, Matthias W.; Behrens, Sabine; Bermisheva, Marina; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bremer, Michael; Briceno, Ignacio; Camp, Nicola J.; Campbell, Archie; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Collée, J. Margriet; Czene, Kamila; Dennis, Joe; Dörk, Thilo; Eriksson, Mikael; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; Gabrielson, Marike; Gago-Dominguez, Manuela; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; Gündert, Melanie; Hadjisavvas, Andreas; Hahnen, Eric; Hall, Per; Hamann, Ute; Harkness, Elaine F.; Hartman, Mikael; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hoppe, Reiner; Howell, Anthony; Jakubowska, Anna; Jung, Audrey; Khusnutdinova, Elza; Kim, Sung-Won; Ko, Yon-Dschun; Kristensen, Vessela N.; Lakeman, Inge M. M.; Li, Jingmei; Lindblom, Annika; Loizidou, Maria A.; Lophatananon, Artitaya; Lubiński, Jan; Luccarini, Craig; Madsen, Michael J.; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Mavroudis, Dimitrios; Milne, Roger L.; Mohd Taib, Nur Aishah; Muir, Kenneth; Nevanlinna, Heli; Newman, William G.; Oosterwijk, Jan C.; Park, Sue K.; Peterlongo, Paolo; Radice, Paolo; Saloustros, Emmanouil; Sawyer, Elinor J.; Schmutzler, Rita K.; Shah, Mitul; Sim, Xueling; Southey, Melissa C.; Surowy, Harald; Suvanto, Maija; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van Asperen, Christi J.; Waltes, Regina; Wang, Qin; Yang, Xiaohong R.; Pharoah, Paul D. P.; Schmidt, Marjanka K.; Benitez, Javier; Vroling, Bas; Dunning, Alison M.; Teo, Soo Hwang; Kvist, Anders; de la Hoya, Miguel; Devilee, Peter; Spurdle, Amanda B.; Vreeswijk, Maaike P. G.; Easton, Douglas F.
    Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
  • Article
    Open Access
    PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~200,000 patients
    (2023-02-10) Giardiello, Daniele; Hooning, Maartje J.; Hauptmann, Michael; Keeman, Renske; Heemskerk-Gerritsen, B. A. M.; Becher, Heiko; Blomqvist, Carl; Bojesen, Stig E.; Bolla, Manjeet K.; Camp, Nicola J.; Czene, Kamila; Devilee, Peter; Eccles, Diana M.; Fasching, Peter A.; Figueroa, Jonine D.; Flyger, Henrik; García-Closas, Montserrat; Haiman, Christopher A.; Hamann, Ute; Hopper, John L.; Jakubowska, Anna; Leeuwen, Floor E.; Lindblom, Annika; Lubiński, Jan; Margolin, Sara; Martinez, Maria Elena; Nevanlinna, Heli; Nevelsteen, Ines; Pelders, Saskia; Pharoah, Paul D. P.; Siesling, Sabine; Southey, Melissa C.; van der Hout, Annemieke H.; van Hest, Liselotte P.; Chang-Claude, Jenny; Hall, Per; Easton, Douglas F.; Steyerberg, Ewout W.; Schmidt, Marjanka K.
    Background Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
  • Article
    Open Access
    A novel molecular signature identifies mixed subtypes in renal cell carcinoma with poor prognosis and independent response to immunotherapy
    (2023-02-10) Büttner, Florian A.; Winter, Stefan; Stühler, Viktoria; Rausch, Steffen; Hennenlotter, Jörg; Füssel, Susanne; Zastrow, Stefan; Meinhardt, Matthias; Toma, Marieta; Jerónimo, Carmen; Henrique, Rui; Miranda-Gonçalves, Vera; Kröger, Nils; Ribback, Silvia; Hartmann, Arndt; Agaimy, Abbas; Stöhr, Christine; Polifka, Iris; Fend, Falko; Scharpf, Marcus; Comperat, Eva; Wasinger, Gabriel; Moch, Holger; Stenzl, Arnulf; Gerlinger, Marco; Bedke, Jens; Schwab, Matthias; Schaeffeler, Elke
    Background Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes. Methods Individual RCC samples were modeled as linear combination of the main subtypes (clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC)) using computational gene expression deconvolution. The new molecular subtyping was compared with histological classification of RCC using the Cancer Genome Atlas (TCGA) cohort (n = 864; ccRCC: 512; pRCC: 287; chRCC: 65) as well as 92 independent histopathologically well-characterized RCC. Predicted continuous subtypes were correlated to cancer-specific survival (CSS) in the TCGA cohort and validated in 242 independent RCC. Association with treatment-related progression-free survival (PFS) was studied in the JAVELIN Renal 101 (n = 726) and IMmotion151 trials (n = 823). CSS and PFS were analyzed using the Kaplan–Meier and Cox regression analysis. Results One hundred seventy-four signature genes enabled reference-free molecular classification of individual RCC. We unambiguously assign tumors to either ccRCC, pRCC, or chRCC and uncover molecularly heterogeneous tumors (e.g., with ccRCC and pRCC features), which are at risk of worse outcome. Assigned proportions of molecular subtype-features significantly correlated with CSS (ccRCC (P = 4.1E − 10), pRCC (P = 6.5E − 10), chRCC (P = 8.6E − 06)) in TCGA. Translation into a numerical RCC-R(isk) score enabled prognosis in TCGA (P = 9.5E − 11). Survival modeling based on the RCC-R score compared to pathological categories was significantly improved (P = 3.6E − 11). The RCC-R score was validated in univariate (P = 3.2E − 05; HR = 3.02, 95% CI: 1.8–5.08) and multivariate analyses including clinicopathological factors (P = 0.018; HR = 2.14, 95% CI: 1.14–4.04). Heterogeneous PD-L1-positive RCC determined by molecular subtyping showed increased PFS with checkpoint inhibition versus sunitinib in the JAVELIN Renal 101 (P = 3.3E − 04; HR = 0.52, 95% CI: 0.36 − 0.75) and IMmotion151 trials (P = 0.047; HR = 0.69, 95% CI: 0.48 − 1). The prediction of PFS significantly benefits from classification into heterogeneous and unambiguous subtypes in both cohorts (P = 0.013 and P = 0.032). Conclusion Switching from categorical to continuous subtype classification across most frequent RCC subtypes enables outcome prediction and fosters personalized treatment strategies.
  • Article
    Open Access
    Association between exercise frequency with renal and cardiovascular outcomes in diabetic and non-diabetic individuals at high cardiovascular risk
    (2023-02-10) Böhm, Michael; Schumacher, Helmut; Werner, Christian; Keo, Koon K.; Lonn, Eva M.; Mahfoud, Felix; Speer, Thimoteus; Mancia, Giuseppe; Redon, Josep; Schmider, Roland E.; Sliwa, Karen; Marx, Nikolaus; Weber, Michael A.; Lauf, Ulrich; Williams, Bryan; Yusuf, Salim; Mann, Johannes F. E.
    Background Guidelines recommend physical activity to reduce cardiovascular (CV) events. The association between physical activity and progression of chronic kidney disease (CKD) with and without diabetes is unknown. We assessed the association of self-reported physical activity with renal and CV outcomes in high-risk patients aged ≥ 55 years over a median follow-up of 56 months in post-hoc analysis of a previously randomized trial program. Methods Analyses were done with Cox regression analysis, mixed models for repeated measures, ANOVA and χ2-test. 31,312 patients, among them 19,664 with and 11,648 without diabetes were analyzed. Results Physical activity was inversely associated with renal outcomes (doubling of creatinine, end-stage kidney disease (ESRD)) and CV outcomes (CV death, myocardial infarction, stroke, heart failure hospitalization). Moderate activity (at least 2 times/week to every day) was associated with lower risk of renal outcomes and lower incidence of new albuminuria (p < 0.0001 for both) compared to lower exercise levels. Similar results were observed for those with and without diabetes without interaction for renal outcomes (p = 0.097–0.27). Physical activity was associated with reduced eGFR decline with a moderate association between activity and diabetes status (p = 0.05). Conclusions Moderate physical activity was associated with improved kidney outcomes with a threshold at two sessions per week. The association of physical activity with renal outcomes did not meaningfully differ with or without diabetes but absolute benefit of activity was even greater in people with diabetes. Thus, risks were similar between those with diabetes undertaking high physical activity and those without diabetes but low physical activity.
  • Article
    Open Access
    RNA-seq of nine canine prostate cancer cell lines reveals diverse therapeutic target signatures
    (2023-02-10) Packeiser, Eva-Maria; Taher, Leila; Kong, Weibo; Ernst, Matthias; Beck, Julia; Hewicker-Trautwein, Marion; Brenig, Bertram; Schütz, Ekkehard; Escobar, Hugo Murua; Nolte, Ingo
    Background Canine prostate adenocarcinoma (PAC) and transitional cell carcinoma (TCC) are typically characterized by metastasis and chemoresistance. Cell lines are important model systems for developing new therapeutic strategies. However, as they adapt to culturing conditions and undergo clonal selection, they can diverge from the tissue from which they were originally derived. Therefore, a comprehensive characterization of cell lines and their original tissues is paramount. Methods This study compared the transcriptomes of nine canine cell lines derived from PAC, PAC metastasis and TCC to their respective original primary tumor or metastasis tissues. Special interests were laid on cell culture-related differences, epithelial to mesenchymal transition (EMT), the prostate and bladder cancer pathways, therapeutic targets in the PI3K-AKT signaling pathway and genes correlated with chemoresistance towards doxorubicin and carboplatin. Results Independent analyses for PAC, PAC metastasis and TCC revealed 1743, 3941 and 463 genes, respectively, differentially expressed in the cell lines relative to their original tissues (DEGs). While genes associated with tumor microenvironment were mostly downregulated in the cell lines, patient-specific EMT features were conserved. Furthermore, examination of the prostate and bladder cancer pathways revealed extensive concordance between cell lines and tissues. Interestingly, all cell lines preserved downstream PI3K-AKT signaling, but each featured a unique therapeutic target signature. Additionally, resistance towards doxorubicin was associated with G2/M cell cycle transition and cell membrane biosynthesis, while carboplatin resistance correlated with histone, m- and tRNA processing. Conclusion Comparative whole-transcriptome profiling of cell lines and their original tissues identifies models with conserved therapeutic target expression. Moreover, it is useful for selecting suitable negative controls, i.e., cell lines lacking therapeutic target expression, increasing the transfer efficiency from in vitro to primary neoplasias for new therapeutic protocols. In summary, the dataset presented here constitutes a rich resource for canine prostate and bladder cancer research.
  • Article
    Open Access
    Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
    (2023-02-10) Mueller, Stefanie H.; Lai, Alvina G.; Valkovskaya, Maria; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Abu-Ful, Zomoruda; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristan J.; Augustinsson, Annelie; Baert, Thais; Freeman, Laura E. Beane; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bonanni, Bernardo; Brenner, Hermann; Brucker, Sara Y.; Buys, Saundra S.; Castelao, Jose E.; Chan, Tsun L.; Chang-Claude, Jenny; Chanock, Stephen J.; Choi, Ji-Yeob; Chung, Wendy K.; Sahlberg, Kristine K.; Børresen-Dale, Anne-Lise; Ottestad, Lars; Kåresen, Rolf; Schlichting, Ellen; Holmen, Marit Muri; Sauer, Toril; Haakensen, Vilde; Engebråten, Olav; Naume, Bjørn; Fosså, Alexander; Kiserud, Cecile E.; Reinertsen, Kristin V.; Helland, Åslaug; Riis, Margit; Geisler, Jürgen; Grenaker Alnaes, Grethe I.; Colonna, Sarah V.; Cornelissen, Sten; Couch, Fergus J.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; Dossus, Laure; Dwek, Miriam; Eccles, Diana M.; Ekici, Arif B.; Eliassen, A. Heather; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Fletcher, Olivia; Flyger, Henrik; Gago-Dominguez, Manuela; Gao, Yu-Tang; García-Closas, Montserrat; García-Sáenz, José A.; Genkinger, Jeanine; Gentry-Maharaj, Aleksandra; Grassmann, Felix; Guénel, Pascal; Gündert, Melanie; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hall, Per; Harkness, Elaine F.; Harrington, Patricia A.; Hartikainen, Jaana M.; Hartman, Mikael; Hein, Alexander; Ho, Weang-Kee; Hooning, Maartje J.; Hoppe, Reiner; Hopper, John L.; Houlston, Richard S.; Howell, Anthony; Hunter, David J.; Huo, Dezheng; Marsh, Deborah; Scott, Rodney; Baxter, Robert; Yip, Desmond; Carpenter, Jane; Davis, Alison; Pathmanathan, Nirmala; Simpson, Peter; Graham, Dinny; Sachchithananthan, Mythily; Ito, Hidemi; Iwasaki, Motoki; Jakubowska, Anna; Janni, Wolfgang; John, Esther M.; Jones, Michael E.; Jung, Audrey; Kaaks, Rudolf; Kang, Daehee; Khusnutdinova, Elza K.; Kim, Sung-Won; Kitahara, Cari M.; Koutros, Stella; Kraft, Peter; Kristensen, Vessela N.; Kubelka-Sabit, Katerina; Kurian, Allison W.; Kwong, Ava; Lacey, James V.; Lambrechts, Diether; Le Marchand, Loic; Li, Jingmei; Linet, Martha; Lo, Wing-Yee; Long, Jirong; Lophatananon, Artitaya; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Matsuo, Keitaro; Mavroudis, Dimitrios; Menon, Usha; Muir, Kenneth; Murphy, Rachel A.; Nevanlinna, Heli; Newman, William G.; Niederacher, Dieter; O’Brien, Katie M.; Obi, Nadia; Offit, Kenneth; Olopade, Olufunmilayo I.; Olshan, Andrew F.; Olsson, Håkan; Park, Sue K.; Patel, Alpa V.; Patel, Achal; Perou, Charles M.; Peto, Julian; Pharoah, Paul D. P.; Plaseska-Karanfilska, Dijana; Presneau, Nadege; Rack, Brigitte; Radice, Paolo; Ramachandran, Dhanya; Rashid, Muhammad U.; Rennert, Gad; Romero, Atocha; Ruddy, Kathryn J.; Ruebner, Matthias; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schneider, Michael O.; Scott, Christopher; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Shu, Xiao-Ou; Simard, Jacques; Surowy, Harald; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Teo, Soo Hwang; Teras, Lauren R.; Toland, Amanda E.; Tollenaar, Rob A. E. M.; Torres, Diana; Torres-Mejía, Gabriela; Troester, Melissa A.; Truong, Thérèse; Vachon, Celine M.; Vijai, Joseph; Weinberg, Clarice R.; Wendt, Camilla; Winqvist, Robert; Wolk, Alicja; Wu, Anna H.; Yamaji, Taiki; Yang, Xiaohong R.; Yu, Jyh-Cherng; Zheng, Wei; Ziogas, Argyrios; Ziv, Elad; Dunning, Alison M.; Easton, Douglas F.; Hemingway, Harry; Hamann, Ute; Kuchenbaecker, Karoline B.
    Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10−6) and AC058822.1 (P = 1.47 × 10−4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Conclusions Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts.
  • Article
    Open Access
    Correction: PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in~200,000 patients
    (2023-02-10) Giardiello, Daniele; Hooning, Maartje J.; Hauptmann, Michael; Keeman, Renske; Heemskerk-Gerritsen, B. A. M.; Becher, Heiko; Blomqvist, Carl; Bojesen, Stig E.; Bolla, Manjeet K.; Camp, Nicola J.; Czene, Kamila; Devilee, Peter; Eccles, Diana M.; Fasching, Peter A.; Figueroa, Jonine D.; Flyger, Henrik; García-Closas, Montserrat; Haiman, Christopher A.; Hamann, Ute; Hopper, John L.; Jakubowska, Anna; Leeuwen, Floor E.; Lindblom, Annika; Lubiński, Jan; Margolin, Sara; Martinez, Maria Elena; Nevanlinna, Heli; Nevelsteen, Ines; Pelders, Saskia; Pharoah, Paul D. P.; Siesling, Sabine; Southey, Melissa C.; van der Hout, Annemieke H.; van Hest, Liselotte P.; Chang-Claude, Jenny; Hall, Per; Easton, Douglas F.; Steyerberg, Ewout W.; Schmidt, Marjanka K.
    Following publication of the original article [1], the authors flagged the following error in the '3. Formula to estimate the contralateral breast cancer risk using PredictCBC-2.0A' section of additional file 1: ‘+ 0.065 × I[Radiotherapy to the breast = yes]’ had been written in place of ‘− 0.065 × I[Radiotherapy to the breast = yes]‘. The file has since been corrected. The authors thank you for reading and apologize for any inconvenience caused.