Fei Liu、Kai Wang、Hui Xu、Cheng Tang、Xian Shen、Meihao Wang、Lei Yang、Li Yang、Li Liu、Changxi Hu、Gen Li、Wei Wu、Zixing Zou、Bingzhou Li、Sian Liu、Jin Kang、Jungho Kong、Ting Li、Io Nam Wong、Xiaoying Huang、Gang Chen、Wenyang Lu、Ian Ziyar、Charlotte L Zhang、Yiwen Sun、Weihong Lin、Caiwen Ou、Manson Fok、Taiwa Hou、Winston Wang、Kanmin Xue、Yun Yin、Hao Zhu、Jonathan Gootenberg、Omar O Abudayyeh、Michael Karin、Alexandre Loupy、John E J Rasko、Trey Ideker、Huiyan Luo、Eric Oermann、Kang Zhang、International Consortium of Digital Twins in Healthcare and Medicine
作者机构
Clinical Data Science Institute, State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, and The Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Department of Urology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Artificial Intelligence Cross Disciplinary Research Institute, Faculty of Medicine, Macau University of Science and Technology, Macau, China; Guangzhou National Laboratory, Guangzhou, China.
Artificial Intelligence Cross Disciplinary Research Institute, Faculty of Medicine, Macau University of Science and Technology, Macau, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Clinical Data Science Institute, State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, and The Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
Clinical Data Science Institute, State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, and The Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Department of General Surgery, Department of Hepatobiliary Surgery, Zhejiang-Germany Interdisciplinary Joint Laboratory of Hepatobiliary-Pancreatic Tumor and Bioengineering, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Radiology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Intelligent Medical Imaging of Wenzhou, Healthcare Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Orthopedics, Key Laboratory of Hepatosplenic Surgery of Ministry of Education, the First Affiliated Hospital, Harbin Medical University, Harbin, China.
Department of Respiratory and Critical Care Medicine, Center for Big Data and Intelligent Medicine, the First Affiliated Hospital of Chongqing Medical University, Key Laboratory of Digital Health and Intelligent Medicine, Chongqing Municipal Health Commission, Chongqing Translational Medicine Center, Chongqing, China.
Department of Health Management, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Big Data and Biomedical AI, College of Future Technology, Peking University, Peking-Tsinghua Center for Life Sciences, Beijing, China.
Artificial Intelligence Cross Disciplinary Research Institute, Faculty of Medicine, Macau University of Science and Technology, Macau, China; Guangzhou National Laboratory, Guangzhou, China.
Artificial Intelligence Cross Disciplinary Research Institute, Faculty of Medicine, Macau University of Science and Technology, Macau, China.
Departments of Medicine and Bioengineering, Moores Cancer Center, School of Medicine, UC San Diego, CA, USA.
Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory of Interdisciplinary and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang, China.
Nepean Hospital, Sydney, Australia.
Key Laboratory of Intelligent Medical Imaging of Wenzhou, Healthcare Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Dongguan Hospital, Southern Medical University, Guangzhou, China.
Conde S. Januario Hospital, Macau, China.
Department of Internal Medicine, Mayo Clinic, Arizona, USA.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Clinical Data Science Institute, State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, and The Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Faculty of Health and Wellness, Faculty of Business, City University of Macau, Taipa, Macau SAR, China.
Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Gene and Cell Therapy Institute, Mass General Brigham, Cambridge, MA, USA.
Université Paris Cité, INSERM U970 PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France; Department of Kidney Transplantation, Assistance Publique - Hôpitaux de Paris, Paris, France.
Artificial Intelligence Cross Disciplinary Research Institute, Faculty of Medicine, Macau University of Science and Technology, Macau, China; Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
Departments of Medicine and Bioengineering, Moores Cancer Center, School of Medicine, UC San Diego, CA, USA; Big Data Institute, Oxford University, Oxford, UK.
Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
Departments of Neurosurgery, Radiology, and Data Science, Neuroscience Institute, NYU Langone Medical Center, New York University, New York, NY, USA.
Clinical Data Science Institute, State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, and The Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China; Artificial Intelligence Cross Disciplinary Research Institute, Faculty of Medicine, Macau University of Science and Technology, Macau, China; Guangzhou National Laboratory, Guangzhou, China; State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, China. Electronic address: kang.zhang@gmail.com.
技术路线
3.67 million individuals/17.7 million clinical visits (COMPASS cohort, longitudinal EHR + chest X-ray) → Oncoformer unified multimodal transformer analysis → validation on independent external cohorts including UK Biobank, with staging independently validated against postoperative pathological endpoints and convergence on core cancer genomic pathways
Ximing Ran、Joanne Wuu、Zhaohui S Qin、Michael P McDermott、Johnathan Cooper-Knock、Yindi Li、Volkan Granit、Anne-Laure Grignon、Elizabeth Lin、Maria Catalina Fernandez、Danielle Colato、Nathan Carberry、Christina M Lill、Paolo Piazza、Andrea Malaspina、Michael Benatar
作者机构
Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA.
Department of Computer Science, Emory University, Atlanta, GA, USA.
Department of Neurology and ALS Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
NIHR Sheffield Biomedical Research Centre, Sheffield, UK.
Department of Neuromuscular Diseases, UCL Queen Square Motor Neuron Disease Center, UCL Queen Square Institute of Neurology, University College London, London, UK.
Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
Ageing and Epidemiology Unit (AGE), School of Public Health, Imperial College London, London, UK.
Nuffield Department of Medicine, Centre for Human Genetics, University of Oxford, Oxford, UK.
Department of Neurology and ALS Center, University of Miami Miller School of Medicine, Miami, FL, USA. mbenatar@med.miami.edu.
研究基于Trans-Omics for Precision Medicine项目的14,324份RNA测序样本，在包括全血（n=6,454）和肺（n=1,291）在内的六种组织和细胞类型中开展表达与剪接数量性状位点（e/sQTL）分析。研究检测到数万个次级顺式e/sQTL，表明次级顺式e/sQTL的发现仍未饱和。对UK Biobank中164种性状的全基因组关联研究信号进行精细定位，共识别出10,611个e/sQTL共定位信号，其中7,096个与次级e/sQTL共定位。结果提示，更大规模的e/sQTL分析将发现更多次级e/sQTL，从而进一步有助于GWAS解读。
为什么值得关注
编辑短评
基因表达遗传调控不是一个基因一个主信号；次级 cis-QTL 还有大量待发现，并且是解读 GWAS 风险位点的关键，很多 trans 效应本质上由 cis 中介传递。
查看扩展信息
完整作者
Peter Orchard、Thomas W Blackwell、Linda Kachuri、Peter J Castaldi、Michael H Cho、Stephanie A Christenson、Peter Durda、Stacey Gabriel、Craig P Hersh、Scott Huntsman、Seungyong Hwang、Roby Joehanes、Mari Johnson、Xingnan Li、Honghuang Lin、Ching-Ti Liu、Yongmei Liu、Angel C Y Mak、Ani W Manichaikul、David T Paik、Aabida Saferali、Joshua D Smith、Kent D Taylor、Russell P Tracy、Jiongming Wang、Mingqiang Wang、Joshua S Weinstock、Jeffrey Weiss、Heather E Wheeler、Ying Zhou、Sebastian Zöllner、Joseph C Wu、Luisa Mestroni、Sharon Graw、Matthew R G Taylor、Victor E Ortega、W Craig Johnson、Weiniu Gan、Goncalo Abecasis、Deborah A Nickerson、Namrata Gupta、Kristin Ardlie、Prescott G Woodruff、Russell P Bowler、Deborah A Meyers、Alex Reiner、Charles Kooperberg、Elad Ziv、Ramachandran S Vasan、Martin G Larson、L Adrienne Cupples、Edwin K Silverman、Stephen S Rich、Nancy Heard-Costa、Hua Tang、Jerome I Rotter、Albert V Smith、Daniel Levy、NHLBI TOPMed Consortium Multi-Omics Working Group32、NHLBI TOPMed Consortium32§、François Aguet、Laura J Scott、Laura M Raffield、Stephen C J Parker、Namiko Abe、Laura Almasy、Seth Ament、Pramod Anugu、Paul Auer、Dimitrios Avramopoulos、Adithya Balasubramanian、R Graham Barr、Lucas Barwick、Terri Beaty、Diane Becker、Lewis Becker、Amber Beitelshees、Takis Benos、Marcos Bezerra、Joshua Bis、Jennifer Brody、Ulrich Broeckel、Jai Broome、Karen Bunting、Erin Buth、Vincent Carey、Cara Carty、Richard Casaburi、Mark Chaffin、Christy Chang、Yi-Cheng Chang、Sameer Chavan、Bo-Juen Chen、Wei-Min Chen、Seung Hoan Choi、Lee-Ming Chuang、Ren-Hua Chung、Matthew Conomos、Elaine Cornell、Carolyn Crandall、James Crapo、Jeffrey Curtis、Coleen Damcott、Sean David、Lisa de Las Fuentes、Paul de Vries、Ranjan Deka、Dawn DeMeo、Scott Devine、Huyen Dinh、Harsha Doddapaneni、Qing Duan、Ravi Duggirala、Charles Eaton、Lynette Ekunwe、Adel El Boueiz、Leslie Emery、Charles Farber、Jesse Farek、Nora Franceschini、Chris Frazar、Mao Fu、Stephanie M Fullerton、Lucinda Fulton、Shanshan Gao、Yan Gao、Margery Gass、Heather Geiger、Auyon Ghosh、Chris Gignoux、David Glahn、Stephanie Gogarten、Da-Wei Gong、Harald Goring、Daniel Grine、C Charles Gu、Yue Guan、Michael Hall、Yi Han、Daniel Harris、Ben Heavner、David Herrington、Brian Hobbs、Elliott Hong、Karin Hoth、Chao Agnes Hsiung、Jianhong Hu、Yi-Jen Hung、Haley Huston、Chii Min Hwu、Rebecca Jackson、Deepti Jain、Jill Johnsen、Rich Johnston、Kimberly Jones、Michael Kessler、Alyna Khan、Ziad Khan、Wonji Kim、John Kimoff、Greg Kinney、Holly Kramer、Christoph Lange、Ethan Lange、Cathy Laurie、Cecelia Laurie、Meryl LeBoff、Sandra Lee、Wen-Jane Lee、David Levine、Joshua Lewis、Yun Li、Xihong Lin、Simin Liu、Yu Liu、Barry Make、Alisa Manning、JoAnn Manson、Lisa Martin、Melissa Marton、Susan Mathai、Susanne May、Patrick McArdle、Merry-Lynn McDonald、Sean McFarland、Daniel McGoldrick、Caitlin McHugh、Hao Mei、James Meigs、Vipin Menon、Nancy Min、Matt Moll、Zeineen Momin、May Montasser、Josyf C Mychaleckyj、Rakhi Naik、Take Naseri、Pradeep Natarajan、Sarah C Nelson、Bonnie Neltner、Caitlin Nessner、Osuji Nkechinyere、Jeff O'Connell、Tim O'Connor、Heather Ochs-Balcom、Geoffrey Okwuonu、James Pankow、Cora Parker、Gina Peloso、Juan Manuel Peralta、Marco Perez、James Perry、Ulrike Peters、Lawrence S Phillips、Toni Pollin、Julia Powers Becker、Meher Preethi Boorgula、Bruce Psaty、Dandi Qiao、Nicholas Rafaels、Mahitha Rajendran、Laura Rasmussen-Torvik、Aakrosh Ratan、Robert Reed、Elizabeth Regan、Muagututi'a Sefuiva Reupena、Rebecca Robillard、Carolina Roselli、Ingo Ruczinski、Alexi Runnels、Pamela Russell、Kathleen Ryan、Ester Cerdeira Sabino、Shabnam Salimi、Sejal Salvi、Steven Salzberg、Kevin Sandow、Jireh Santibanez、Karen Schwander、Frank Sciurba、Frédéric Sériès、Amol Shetty、Aniket Shetty、Brian Silver、Robert Skomro、Tanja Smith、Sylvia Smoller、Beverly Snively、Adrienne M Stilp、Garrett Storm、Elizabeth Streeten、Jessica Lasky Su、Yun Ju Sung、Jody Sylvia、Adam Szpiro、Margaret Taub、Simeon Taylor、Timothy A Thornton、Machiko Threlkeld、Lesley Tinker、David Tirschwell、Hemant Tiwari、Catherine Tong、Michael Tsai、Dhananjay Vaidya、Tarik Walker、Robert Wallace、Avram Walts、Fei Fei Wang、Heming Wang、Karol Watson、Jennifer Watt、Lu-Chen Weng、Jennifer Wessel、Kayleen Williams、Carla Wilson、James Wilson、Lara Winterkorn、Quenna Wong、Baojun Wu、Huichun Xu、Lisa Yanek、Ivana Yang、Seyedeh Maryam Zekavat、Snow Xueyan Zhao、Wei Zhao、Xiaofeng Zhu
作者机构
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Center for Statistical Genetics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Department of Epidemiology and Population Health, School of Medicine, Stanford University, Stanford, CA, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Department of Genetics, Stanford University, Stanford, CA, USA.
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Division of Data Driven and Digital Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
Division of Cardiology, Department of Medicine, School of Medicine, Duke University, Durham, NC, USA.
Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
Northwest Genomics Center, University of Washington, Seattle, WA, USA.
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Laboratory for Clinical Biochemistry Research, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
Program in Bioinformatics, Loyola University Chicago, Chicago, IL, USA.
Department of Biology, Loyola University Chicago, Chicago, IL, USA.
Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Phoenix, AZ, USA.
Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA.
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Cardiovascular Research Institute, University of California, San Francisco; San Francisco, CA, USA.
Department of Genomic Sciences and Systems Biology, Cleveland Clinic, Cleveland, OH, USA.
Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA.
Department of Epidemiology, University of Washington, Seattle, WA, USA.
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
New York Genome Center, New York, NY, USA.
Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
University of Maryland, Baltimore, MD, USA.
University of Mississippi, Jackson, MS, USA.
Medical College of Wisconsin, Milwaukee, WI, USA.
Johns Hopkins University, Baltimore, MD, USA.
Baylor College of Medicine Human Genome Sequencing Center, Houston, TX, USA.
Columbia University, New York, NY, USA.
The Emmes Corporation, Rockville, MD, USA.
University of Pittsburgh, Pittsburgh, PA, USA.
Fundação de Hematologia e Hemoterapia de Pernambuco - Hemope, Recife, Brazil.
University of Washington, Seattle, WA, USA.
Brigham andWomen's Hospital, Boston, MA, USA.
Washington State University, Pullman, WA, USA.
University of California, Los Angeles, Los Angeles, CA, USA.
Broad Institute, Cambridge, MA, USA.
National Taiwan University, Taipei, Taiwan (Province of China).
University of Colorado at Denver, Denver, CO, USA.
University of Virginia, Charlottesville, VA, USA.
National Health Research Institute Taiwan, Miaoli County, Taiwan (Province of China).
University of Vermont, Burlington, VT, USA.
National Jewish Health, Denver, CO, USA.
University of Michigan, Ann Arbor, MI, USA.
University of Chicago, Chicago, IL, USA.
Washington University in St. Louis, St. Louis, MO, USA.
University of Texas Health at Houston, Houston, TX, USA.
University of Cincinnati, Cincinnati, OH, USA.
University of North Carolina, Chapel Hill, NC, USA.
University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA.
Harvard University, Cambridge, MA, USA.
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
New York Genome Center, New York City, NY, USA.
Stanford University, Stanford, CA, USA.
Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
University of Texas Rio Grande Valley School of Medicine, San Antonio, TX, USA.
University of Maryland, Philadelphia, PA, USA.
Wake Forest Baptist Health, Winston-Salem, NC, USA.
University of Iowa, Iowa City, IA.
Tri-Service General Hospital National Defense Medical Center, Taiwan (Province of China).
Blood Works Northwest, Seattle, WA, USA.
Taichung Veterans General Hospital Taiwan, Taichung City, Taiwan (Province of China).
Oklahoma State University Medical Center, Columbus, OH, USA.
Emory University, Atlanta, GA, USA.
McGill University, Montréal, QC, Canada.
University of Colorado at Denver, Aurora, CO, USA.
Loyola University, Maywood, IL, USA.
Harvard School of Public Health, Boston, MA, USA.
Brown University, Providence, RI, USA.
Broad Institute, Harvard University, Massachusetts General Hospital, Boston, MA, USA.
George Washington University, Washington, DC, USA.
University of Alabama, Birmingham, AL, USA.
Massachusetts General Hospital, Boston, MA, USA.
National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Ministry of Health, Government of Samoa, Apia, Samoa.
University at Buffalo, Buffalo, NY, USA.
University of Minnesota, Minneapolis, MN, USA.
RTI International, Research Triangle Park, NC, USA.
Boston University, Boston, MA, USA.
Northwestern University, Chicago, IL, USA.
Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa.
University of Ottawa, Ottawa, ON, Canada.
Universidade de Sao Paulo, Sao Paulo, Brazil.
University of Maryland, Seattle, WA, USA.
Lundquist Institute, Torrance, CA, USA.
Université Laval, Quebec City, Canada.
UMass Memorial Medical Center, Worcester, MA, USA.
University of Saskatchewan, Saskatoon, Canada.
Albert Einstein College of Medicine, New York, NY, USA.
Brigham and Women's Hospital, Mass General Brigham, Boston, MA, USA.
Indiana University, Indianapolis, IN, USA.
Beth Israel Deaconess Medical Center, Cambridge, MA, USA.
Henry Ford Health System, Detroit, MI, USA.
Case Western Reserve University, Cleveland, OH, USA.
为什么值得关注
编辑短评传统罕见变异检验只能得到基因水平 P 值，无法可靠估计单个变异效应；RareEffect 结合方差组分与经验贝叶斯，双层估计基因和单位点效应、校正病例对照偏倚，基于该效应构建的罕见变异 PRS 预测表现更好。