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Improving Auction Mechanisms for Online Real-Time Bidding Advertising with a Two-stage Resale Model

IFAC-PapersOnLine 2017年第1期50卷 13575-13580页

作者： Qin, Rui Yuan, Yong Wang, Fei-Yue The State Key Laboratory of Management and Control for Complex Systems Institute of Automation Chinese Academy of Sciences Beijing China Qingdao Academy of Intelligent Industries Qingdao China Research Center of Military Computational Experiments and Parallel System National University of Defense Technology Changsha China Beijing Engineering Research Center of Intelligent Systems and Technology Institute of Automation Chinese Academy of Sciences Beijing China

Real Time Bidding (RTB), widely publicized as one of the most promising big-data-driven business models for online computational advertising, has the potential of effectively monetizing user clicks and impressions via two-stage auctions with resale. Demand side platforms (DSPs) play a key role as intermediators in this auction process. Typically, the first-stage auctions will be conducted separately in each DSP to determine one winning advertiser registered on it, and in the second-stage auction, each DSP submits a bid based on its winning advertiser's bid to the ad exchange platform (AdX). The highest-bid DSP wins the ad impression from AdX and resells it to its winning advertiser in pursuit of the intermediate fee. This two-stage resale auction is a critical component in maintaining the effectiveness and efficiency of RTB ecosystems. In this paper, we strive to identify and design potential improvements for this auction mechanism with the aim of enhancing the total revenue of both advertisers and DSPs. We also validated our proposed auction mechanisms using the computational experiment approach. The experimental results indicate that our proposed mechanisms can make both advertisers and DSPs better off. Our work represents the first step towards a new research area of optimal mechanism design for RTB auctions, and is expected to provide useful managerial insights in RTB market practice. © 2017

关键词： Sales Commerce Machine design Auction mechanisms Computational advertisings Computational experiment Critical component Demand side Effectiveness and efficiencies Optimal mechanism designs Real time

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Stability and Accuracy Considerations in the Design and Implementation of Wind Turbine Power Hardware in the Loop Platform

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CSEE Journal of Power and Energy systems 2017年第2期3卷 167-175页

作者： Kui Luo Wenhui Shi Yongning Chi Qiuwei Wu Weisheng Wang State Key Laboratory of Operation and Control of Renewable Energy&Storage System China Electric Power Research Institute(CEPRI)Beijing 100192China Center for Electric Power and Energy(CEE) Department of Electrical EngineeringTechnical University of Denmark(DTU)Kgs.Lyngby 2800Denmark

There is increasing interest in the evaluation of wind turbine control capabilities for providing grid *** hardware in the loop(PHIL)simulation is an advanced method that can be used for studying the interaction of hardware with the power network,as the scaled-down actual wind turbine is connected with a simulated system through an *** consideration must be made in the design of the PHIL platform to ensure that the system is stable and yields accurate *** paper presents a method for stabilizing the PHIL interface and improving the accuracy of PHIL simulation in a real-time *** method factors in both the power and voltage scaling level,and a phase compensation *** uses the reactive power control capability of the wind turbine inverter to eliminate the phase shift imposed by the feedback current *** is accomplished with no negative impact on the dynamic behavior of the wind *** PHIL simulation results demonstrate the effectiveness of the proposed stability analysis method and phase compensation *** strength of the platform is demonstrated by extending the simulation method to wind turbine control validation.

关键词： Phase compensation power hardware in the loop stability and accuracy wind turbine

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A development and application of maintainability evaluation system using immersive VR

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IOP Conference Series: Materials Science and engineering 2019年第1期658卷

作者： Meihui Wang Yongxiang Li Chuan Lyu Xi Liu School of Reliability and Systems Engineering Beihang University China State Key Laboratory of Virtual Reality Technology System Beihang University China Technology and Engineering Center for Space Utilization Chinese Academy of Science Beijing China Xi'an Modern Control Technology Research Institute Xi'an 710065 China

Immersing into virtual reality (VR) is a perception of being physically present in a non-physical world. Using immersive VR in maintenance brings great conveniences. For example, using virtual human operating in hazardous environment before the real person, which can prevent being hurt. In this paper, a system of immersive virtual maintenance (IVM) is presented. It is divided into three parts. The first part is Input, which contains the maintenance task and maintenance design. The second part is Method, with which making the virtual human and the users act in a unified way. The key to build IVM system is the interface between the motion capture system and virtual simulation software. The third part is Output, which presents the maintainability evaluation results. This paper focuses on how to build IVM system, the difficulties and solutions also be detailed. At last, a simple application is given

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Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

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Nature communications 2023年第1期14卷 3043页

作者： Jianxin Shi Kouya Shiraishi Jiyeon Choi Keitaro Matsuo Tzu-Yu Chen Juncheng Dai Rayjean J Hung Kexin Chen Xiao-Ou Shu Young Tae Kim Maria Teresa Landi Dongxin Lin Wei Zheng Zhihua Yin Baosen Zhou Bao Song Jiucun Wang Wei Jie Seow Lei Song I-Shou Chang Wei Hu Li-Hsin Chien Qiuyin Cai Yun-Chul Hong Hee Nam Kim Yi-Long Wu Maria Pik Wong Brian Douglas Richardson Karen M Funderburk Shilan Li Tongwu Zhang Charles Breeze Zhaoming Wang Batel Blechter Bryan A Bassig Jin Hee Kim Demetrius Albanes Jason Y Y Wong Min-Ho Shin Lap Ping Chung Yang Yang She-Juan An Hong Zheng Yasushi Yatabe Xu-Chao Zhang Young-Chul Kim Neil E Caporaso Jiang Chang James Chung Man Ho Michiaki Kubo Yataro Daigo Minsun Song Yukihide Momozawa Yoichiro Kamatani Masashi Kobayashi Kenichi Okubo Takayuki Honda Dean H Hosgood Hideo Kunitoh Harsh Patel Shun-Ichi Watanabe Yohei Miyagi Haruhiko Nakayama Shingo Matsumoto Hidehito Horinouchi Masahiro Tsuboi Ryuji Hamamoto Koichi Goto Yuichiro Ohe Atsushi Takahashi Akiteru Goto Yoshihiro Minamiya Megumi Hara Yuichiro Nishida Kenji Takeuchi Kenji Wakai Koichi Matsuda Yoshinori Murakami Kimihiro Shimizu Hiroyuki Suzuki Motonobu Saito Yoichi Ohtaki Kazumi Tanaka Tangchun Wu Fusheng Wei Hongji Dai Mitchell J Machiela Jian Su Yeul Hong Kim In-Jae Oh Victor Ho Fun Lee Gee-Chen Chang Ying-Huang Tsai Kuan-Yu Chen Ming-Shyan Huang Wu-Chou Su Yuh-Min Chen Adeline Seow Jae Yong Park Sun-Seog Kweon Kun-Chieh Chen Yu-Tang Gao Biyun Qian Chen Wu Daru Lu Jianjun Liu Ann G Schwartz Richard Houlston Margaret R Spitz Ivan P Gorlov Xifeng Wu Ping Yang Stephen Lam Adonina Tardon Chu Chen Stig E Bojesen Mattias Johansson Angela Risch Heike Bickeböller Bu-Tian Ji H-Erich Wichmann David C Christiani Gadi Rennert Susanne Arnold Paul Brennan James McKay John K Field Sanjay S Shete Loic Le Marchand Geoffrey Liu Angeline Andrew Lambertus A Kiemeney Shan Zienolddiny-Narui Kjell Grankvist Mikael Johansson Angela Cox Fiona Taylor Jian-Min Yuan Philip Lazarus Matthew B Schabath Melinda C Aldrich Hyo-Sung Jeon Shih Sheng Jiang Jae Sook Sung C Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA. jianxin.shi@nih.gov. Division of Genome Biology National Cancer Research Institute Tokyo Japan. Division of Cancer Epidemiology and Genetics National Cancer Institute Rockville MD USA. Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan. Institute of Population Health Sciences National Health Research Institutes Zhunan Taiwan. Department of Epidemiology School of Public Health Nanjing Medical University Nanjing China. Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Collaborative Innovation Center for Cancer Medicine Nanjing Medical University Nanjing China. Prosserman Centre for Population Health Research Lunenfeld-Tanenbaum Research Institute Sinai Health Toronto ON Canada. Department of Epidemiology and Biostatistics National Clinical Research Center for Cancer Key Laboratory of Molecular Cancer Epidemiology of Tianjin Tianjin Medical University Cancer Institute and Hospital Tianjin Medical University Tianjin China. Division of Epidemiology Department of Medicine Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center Nashville TN USA. Cancer Research Institute Seoul National University College of Medicine Seoul Republic of Korea. Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology Cancer Institute and Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China. Department of Epidemiology School of Public Health China Medical University Shenyang China. Department of Clinical Epidemiology and Center of Evidence Based Medicine The First Hospital of China Medical University Shenyang China. Department of Oncology Shandong Cancer Hospital and Institute Shandong Academy of Medical Sciences Jinan China. Ministry of Education Key Laboratory of Contemporary Anthropology School of Life Sciences Fudan University Shanghai China. S

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

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Attribution of PM_(2.5) exposure in Beijing-Tianjin-Hebei region to emissions:implication to control strategies

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Science Bulletin 2017年第13期62卷 957-964页

作者： Xin Li Qiang Zhang Yang Zhang Lin Zhang Yuxuan Wang Qianqian Zhang Meng Li Yixuan Zheng Guannan Geng Timothy J.Wallington Weijian Han Wei Shen Kebin He Ministry of Education Key Laboratory for Earth System Modeling Department of Earth System ScienceTsinghua University Department of Marine Earthand Atmospheric SciencesNorth Carolina State University Collaborative Innovation Center for Regional Environmental Quality Laboratory for Climate and Ocean-Atmosphere Sciences Department of Atmospheric and Oceanic SciencesSchool of PhysicsPeking University Department of Marine Sciences Texas A&M University at Galveston Department of Atmospheric Sciences Texas A&M UniversityCollege Station National Satellite Meteorological Center China Meteorological Administration Research and Advanced Engineering Ford Motor Company Asia Pacific Research Ford Motor Company State Key Joint Laboratory of Environment Simulation and Pollution Control School of EnvironmentTsinghua University

The Beijing-Tianjin-Hebei （BTH） region is one of the most heavily polluted regions in China, with both high PM2.5 concentrations and a high population density. A quantitative source-receptor relationship can provide valuable insights that can inform effective emission control strategies. Both source appor- tionment （SA） and source sensitivity （SS） can provide such information from different perspectives. In this study, both methods are applied in northern China to identify the most significant emission cate- gories and source regions for PMz5 exposure in BTH in 2013. Despite their differences, both models show similar distribution patterns for population and simulated PM2.5 concentrations, resulting in overall high PM2.5 exposure values （approximately 110 Ixg/m3） and particularly high exposure values during the win- ter （approximately 200 ktg/m3）. Both methods show that local emissions play a dominant role （70%）, with some contribution from surrounding provinces （e.g., Shandong） via regional transport. The two methods also agree on the priority of local emission controls： both identify industrial, residential, and agricultural emissions as the top three categories that should be controlled locally. In addition, the effect of control- ling agricultural ammonia emissions is approximately doubled when the co-benefits of reducing nitrate are considered. The synthesis of SA and SS for addressing specific categories of emissions provides a quantitative basis for the development of emission control strategies and policies for controlling PM2.5 in China.

关键词： PM2.5 exposureSource apportionmentSource sensitivitycontrol priorityChina

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Evaluation Model for Smart Distribution Network Planning under Energy Interconnection

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IOP Conference Series: Earth and Environmental Science 2019年第4期300卷

作者： Yan Zhang Zefu Jiang Jinsen Liu Wenxia Liu Hua Gao Yanmin Wang Power Grid Planning Research Center of Guizhou Power Grid Co. Ltd Guiyang Guizhou 550003 China State Key Laboratory of Power System and Power Generation Equipment Control and Simulation Department of Electrical Engineering Tsinghua University Haidian Beijing 100084 China

Due to the development of the energy interconnection, smart distribution networks (SDNs) should needs be transformed and upgraded to meet new demands. In order to assess the SDN planning, a new index system was conducted from the five attributes. The quantitative methods of all criteria were also defined. An evaluation model was proposed based on AHP weighting and TOPSIS methods. Empirical analysis was performed to verify the feasibility of the evaluation system.

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Lattice kinetic scheme for the Navier-Stokes equations coupled with convection-diffusion equations

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Physical Review E 2018年第3期98卷 033308-033308页

作者： Liang Wang Weifeng Zhao Xiao-Dong Wang State Key Laboratory of Alternate Electrical Power System with Renewable Energy Sources North China Electric Power University Beijing 102206 China Research Center of Engineering Thermophysics North China Electric Power University Beijing 102206 China Key Laboratory of Condition Monitoring and Control for Power Plant Equipment of Ministry of Eduction North China Electric Power University Beijing 102206 China Department of Applied Mathematics and Mechanics University of Science and Technology Beijing Beijing 100083 China

In this paper, we target two basic issues residing in some modified lattice kinetic schemes for the Navier-Stokes (NS) equations coupled with convection-diffusion equations (CDEs). First, a lattice Boltzmann (LB) model motivated by the lattice kinetic scheme (LKS) is presented for the NS equations coupled with CDEs. Due to the nonequilibrium schemes for the gradient terms contained in the equilibria as well as the discrete source term, the collision process of the present model can be implemented locally in both time and space. The Chapman-Enskog analysis shows that the macroscopic equations can be correctly recovered from the present model without additional assumptions. Second, we prove that the present modified LKS model, though written in the Bhatnagar-Gross-Krook (BGK) form, has two relaxation rates essentially. Based on this theoretical result, the modified lattice kinetic schemes in the literature should not be grouped as the BGK model, and the better numerical stability is intrinsically attributed to the adjustment of their two relaxation rates. Several benchmark thermal flow problems are simulated to validate the present model and the local nonequilibrium schemes for the shear rate and temperature gradient. The accuracy of the present model as well as its better numerical stability compared with the BGK model are verified, which supports our theoretical results. In addition, we also demonstrate that the regularized LB (RLB) model has two relaxation times as the present LKS model.

关键词： Convection Lattice-Boltzmann methods Navier-Stokes equation Rheology

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Integrated Train Ground Radio Communication system Based TD-LTE

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Chinese Journal of Electronics 2016年第4期25卷 740-745页

作者： ZHAO Hongli CAO Yuan ZHU Li XU Wei National Engineering Research Center of Rail Transportation Operation and Control System Beijing Jiaotong University State Key Laboratory of Rail Traffic Control and Safety Beijing Jiaotong University National Mobile Communications Research Lab. Southeast University

In existing metro systems,the train ground radio communication system for different applications are deployed *** and constructing the communication infrastructures repeatedly wastes substantial social resources,and it brings difficulties to maintain all these *** present the communication Quality of service(Qo S) requirement for different train ground radio *** integrated TD-LTE based train ground radio communication system for the metro system(LTE-M) is designed *** order to test the LTEM system performance,an indoor testing environment is set *** channel simulator and programmable attenuators are used to simulate the real metro *** test results show that the designed LTE-M system performance satisfies metro communication requirements.

关键词： Communication based train control(CBTC) Train control LTE-M Performance test

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Author Correction: The power of genetic diversity in genome-wide association studies of lipids

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Nature 2023年第7965期618卷 E19-E20页

作者： Sarah E Graham Shoa L Clarke Kuan-Han H Wu Stavroula Kanoni Greg J M Zajac Shweta Ramdas Ida Surakka Ioanna Ntalla Sailaja Vedantam Thomas W Winkler Adam E Locke Eirini Marouli Mi Yeong Hwang Sohee Han Akira Narita Ananyo Choudhury Amy R Bentley Kenneth Ekoru Anurag Verma Bhavi Trivedi Hilary C Martin Karen A Hunt Qin Hui Derek Klarin Xiang Zhu Gudmar Thorleifsson Anna Helgadottir Daniel F Gudbjartsson Hilma Holm Isleifur Olafsson Masato Akiyama Saori Sakaue Chikashi Terao Masahiro Kanai Wei Zhou Ben M Brumpton Humaira Rasheed Sanni E Ruotsalainen Aki S Havulinna Yogasudha Veturi QiPing Feng Elisabeth A Rosenthal Todd Lingren Jennifer Allen Pacheco Sarah A Pendergrass Jeffrey Haessler Franco Giulianini Yuki Bradford Jason E Miller Archie Campbell Kuang Lin Iona Y Millwood George Hindy Asif Rasheed Jessica D Faul Wei Zhao David R Weir Constance Turman Hongyan Huang Mariaelisa Graff Anubha Mahajan Michael R Brown Weihua Zhang Ketian Yu Ellen M Schmidt Anita Pandit Stefan Gustafsson Xianyong Yin Jian'an Luan Jing-Hua Zhao Fumihiko Matsuda Hye-Mi Jang Kyungheon Yoon Carolina Medina-Gomez Achilleas Pitsillides Jouke Jan Hottenga Gonneke Willemsen Andrew R Wood Yingji Ji Zishan Gao Simon Haworth Ruth E Mitchell Jin Fang Chai Mette Aadahl Jie Yao Ani Manichaikul Helen R Warren Julia Ramirez Jette Bork-Jensen Line L Kårhus Anuj Goel Maria Sabater-Lleal Raymond Noordam Carlo Sidore Edoardo Fiorillo Aaron F McDaid Pedro Marques-Vidal Matthias Wielscher Stella Trompet Naveed Sattar Line T Møllehave Betina H Thuesen Matthias Munz Lingyao Zeng Jianfeng Huang Bin Yang Alaitz Poveda Azra Kurbasic Claudia Lamina Lukas Forer Markus Scholz Tessel E Galesloot Jonathan P Bradfield E Warwick Daw Joseph M Zmuda Jonathan S Mitchell Christian Fuchsberger Henry Christensen Jennifer A Brody Mary F Feitosa Mary K Wojczynski Michael Preuss Massimo Mangino Paraskevi Christofidou Niek Verweij Jan W Benjamins Jorgen Engmann Rachel L Kember Roderick C Slieker Ken Sin Lo Nuno R Zilhao Phuong Le Marcus E Kleber Graciela E Delgado Shaofeng Huo Dai Department of Internal Medicine Division of Cardiology University of Michigan Ann Arbor MI USA. VA Palo Alto Health Care System Palo Alto CA USA. Department of Medicine Division of Cardiovascular Medicine Stanford University School of Medicine Stanford CA USA. Department of Computational Medicine and Bioinformatics University of Michigan Ann Arbor MI USA. William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK. Department of Biostatistics and Center for Statistics Genetics University of Michigan Ann Arbor MI USA. Department of Genetics Perelman School of Medicine University of Pennsylvania Philadelphia PA USA. Clinical Pharmacology William Harvey Research Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London UK. Endocrinology Boston Children's Hospital Boston MA USA. Medical and Population Genetics Broad Institute Cambridge MA USA. Department of Genetic Epidemiology University of Regensburg Regensburg Germany. McDonnell Genome Institute and Department of Medicine Washington University St Louis MO USA. Department of Precision Medicine Division of Genome Science National Institute of Health Cheongju-si South Korea. Tohoku Medical Megabank Organization Tohoku University Sendai Japan. Sydney Brenner Institute for Molecular Bioscience Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa. Center for Research on Genomics and Global Health National Human Genome Research Institute National Institutes of Health Bethesda MD USA. Blizard Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK. Wellcome Sanger Institute Hinxton UK. Department of Epidemiology Emory University Rollins School of Public Health Atlanta GA USA. Atlanta VA Health Care System Decatur GA USA. Malcolm Randall VA Medical Center Gainesville FL USA. Division of Vascular Sur

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Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification

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Nature communications 2025年第1期16卷 4852页

作者： Maria Zanti Denise G O'Mahony Michael T Parsons Leila Dorling Joe Dennis Nicholas J Boddicker Wenan Chen Chunling Hu Marc Naven Kristia Yiangou Thomas U Ahearn Christine B Ambrosone Irene L Andrulis Antonis C Antoniou Paul L Auer Caroline Baynes Clara Bodelon Natalia V Bogdanova Stig E Bojesen Manjeet K Bolla Kristen D Brantley Nicola J Camp Archie Campbell Jose E Castelao Melissa H Cessna Jenny Chang-Claude Fei Chen Georgia Chenevix-Trench Don M Conroy Kamila Czene Arcangela De Nicolo Susan M Domchek Thilo Dörk Alison M Dunning A Heather Eliassen D Gareth Evans Peter A Fasching Jonine D Figueroa Henrik Flyger Manuela Gago-Dominguez Montserrat García-Closas Gord Glendon Anna González-Neira Felix Grassmann Andreas Hadjisavvas Christopher A Haiman Ute Hamann Steven N Hart Mikael B A Hartman Weang-Kee Ho James M Hodge Reiner Hoppe Sacha J Howell Anna Jakubowska Elza K Khusnutdinova Yon-Dschun Ko Peter Kraft Vessela N Kristensen James V Lacey Jingmei Li Geok Hoon Lim Sara Lindström Artitaya Lophatananon Craig Luccarini Arto Mannermaa Maria Elena Martinez Dimitrios Mavroudis Roger L Milne Kenneth Muir Katherine L Nathanson Rocio Nuñez-Torres Nadia Obi Janet E Olson Julie R Palmer Mihalis I Panayiotidis Alpa V Patel Paul D P Pharoah Eric C Polley Muhammad U Rashid Kathryn J Ruddy Emmanouil Saloustros Elinor J Sawyer Marjanka K Schmidt Melissa C Southey Veronique Kiak-Mien Tan Soo Hwang Teo Lauren R Teras Diana Torres Amy Trentham-Dietz Thérèse Truong Celine M Vachon Qin Wang Jeffrey N Weitzel Siddhartha Yadav Song Yao Gary R Zirpoli Melissa S Cline Peter Devilee Sean V Tavtigian David E Goldgar Fergus J Couch Douglas F Easton Amanda B Spurdle Kyriaki Michailidou Biostatistics Unit The Cyprus Institute of Neurology & Genetics Nicosia Cyprus. Department of Medical Genetics Oslo University Hospital Oslo Norway. Population Health Program QIMR Berghofer Medical Research Institute Brisbane Queensland Australia. Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK. Department of Quantitative Health Sciences Division of Computational Biology Mayo Clinic Rochester MN USA. Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA. Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Department of Health and Human Services Bethesda MD USA. Department of Cancer Prevention and Control Roswell Park Comprehensive Cancer Institute Buffalo NY USA. Fred A. Litwin Center for Cancer Genetics Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada. Department of Molecular Genetics University of Toronto Toronto Ontario Canada. Division of Biostatistics Data Science Institute and Cancer Center Medical College of Wisconsin Milwaukee WI USA. Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK. Department of Population Science American Cancer Society Atlanta GA USA. Radiation Oncology Research Unit Hannover Medical School Hannover Germany. Copenhagen General Population Study Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark. Department of Clinical Biochemistry Herlev and Gentofte Hospital Copenhagen University Hospital Herlev Denmark. Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark. Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA. Department of Internal Medicine and Huntsman Cancer Institute University of Utah Salt Lake City UT USA. Centre for Genomic and Experimental Medicine Institute of Genetics & Cancer The University of Ed

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.

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