title: Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.
abstract: BACKGROUND
  Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model.
  
  
  RESULTS
  We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models.
  
  
  CONCLUSIONS
  We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Collaborative Innovation Center for Genetics and Development, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.|University of Cologne, Center for Molecular Medicine (CMMC), Medical Faculty, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hertwig
authors.affiliation: NIH/NCBI, Bldg 38A/Room 8S808, 8600 Rockville Pike, Bethesda, MD, 20894, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Thierry-Mieg
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: NIH/NCBI, Bldg 38A/Room 8S808, 8600 Rockville Pike, Bethesda, MD, 20894, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Thierry-Mieg
authors.affiliation: Eli Lilly and Company Research Informatics, Lilly Corporate Center, Drop Code 0725, Indianapolis, IN, 46285, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Fondazione Bruno Kessler (FBK), Via Sommarive 18, 38123, Trento Povo, TN, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Furlanello
authors.affiliation: AbbVie Inc., Global Pharmaceutical R&D, 32 Knights Crest Court, Souderton, PA, 18964, USA.
authors.forename: Viswanath
authors.initials: V
authors.lastname: Devanarayan
authors.affiliation: GlaxoSmithKline, Discovery Analytics, Mailstop UP4335, 1250 South Collegeville Rd, Collegeville, PA, 19426, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Rush University Cancer Center, 1725 W. Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Youping
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Huixiao
authors.initials: H
authors.lastname: Hong
authors.affiliation: Collaborative Innovation Center for Genetics and Development, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Meiwen
authors.initials: M
authors.lastname: Jia
authors.affiliation: SAS Institute Inc., SAS Campus Drive, Cary, NC, 27513, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Marshfield Clinic Research Foundation, Biomedical Informatics Research Center, 1000 N Oak Avenue, Marshfield, WI, 54449, USA.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Thomson Reuters IP & Science, 5901 Priesty Drive, Carlsbad, CA, 92008, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Oberthuer
authors.affiliation: Collaborative Innovation Center for Genetics and Development, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Qing
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Su
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Volland
authors.affiliation: Center for Genomics and Division of Microbiology & Molecular Genetics, School of Medicine, Loma Linda University, Loma Linda, CA, 92350, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, GeorgiaTech and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: May D
authors.initials: MD
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Rush University Cancer Center, 1725 W. Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Junmei
authors.initials: J
authors.lastname: Ai
authors.affiliation: Fondazione Edmund Mach, CRI-CBC, San Michele all'Adige, TN, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Albanese
authors.affiliation: Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.
authors.forename: Shahab
authors.initials: S
authors.lastname: Asgharzadeh
authors.affiliation: Department of Pediatric Hematology-Oncology, Molecular Oncology, Felsenstein Medical Research Center, Schneider Children's Medical Center of Israel, Petach Tikva, 49202, Israel.
authors.forename: Smadar
authors.initials: S
authors.lastname: Avigad
authors.affiliation: SAS Institute Inc., SAS Campus Drive, Cary, NC, 27513, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Bao
authors.affiliation: Thomson Reuters IP & Science, 5901 Priesty Drive, Carlsbad, CA, 92008, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bessarabova
authors.affiliation: Marshfield Clinic Research Foundation, Center of Human Genetics, 1000 N Oak Avenue, Marshfield, WI, 54449, USA.
authors.forename: Murray H
authors.initials: MH
authors.lastname: Brilliant
authors.affiliation: Department of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Fondazione Bruno Kessler (FBK), Via Sommarive 18, 38123, Trento Povo, TN, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chierici
authors.affiliation: SAS Institute Inc., SAS Campus Drive, Cary, NC, 27513, USA.
authors.forename: Tzu-Ming
authors.initials: TM
authors.lastname: Chu
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: University of Nottingham, Children's Brain Tumour Research Centre, Queen's Medical Centre, University of Nottingham, D Floor Medical School, Nottingham, NG7 2UH, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.affiliation: Marshfield Clinic Research Foundation, Biomedical Informatics Research Center, 1000 N Oak Avenue, Marshfield, WI, 54449, USA.
authors.forename: Min Max
authors.initials: MM
authors.lastname: He
authors.affiliation: Marshfield Clinic Research Foundation, Center of Human Genetics, 1000 N Oak Avenue, Marshfield, WI, 54449, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Hebbring
authors.affiliation: Department of Internal Medicine, Rush University Cancer Center, 1725 W. Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
authors.affiliation: Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, WOC1 RM400S, HFM-210, 1401 Rockville Pike, Rockville, MD, 20852, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Lababidi
authors.affiliation: Thomson Reuters IP & Science, 5901 Priesty Drive, Carlsbad, CA, 92008, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Lancashire
authors.affiliation: Department of Internal Medicine, Rush University Cancer Center, 1725 W. Harrison Street, Chicago, IL, 60612, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: AbbVie Inc., Global Pharmaceutical Research and Development, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Xin X
authors.initials: XX
authors.lastname: Lu
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.|University of Arkansas at Little Rock, UALR/UAMS Joint Bioinformatics Graduate Program, 2801 South University Avenue, Little Rock, AR, 72204, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Luo
authors.affiliation: Eli Lilly and Company, Discovery Statistics, Lilly Corporate Center, Drop Code 2036, Indianapolis, IN, 46285, USA.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Ma
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Baitang
authors.initials: B
authors.lastname: Ning
authors.affiliation: Department of Pathology, University of Valencia, Medical School, Avda. Blasco Ibáñez, 17, 46010, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Noguera
authors.affiliation: University of Cologne, Center for Molecular Medicine (CMMC), Medical Faculty, Kerpener Strasse 62, D-50924, Cologne, Germany.|Department of Translational Genomics, University of Cologne, D-50924, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Department of Biomedical Engineering, GeorgiaTech and Emory University, 313 Ferst Drive, Atlanta, GA, 30332, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Phan
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.|University of Cologne, Center for Molecular Medicine (CMMC), Medical Faculty, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Rosswog
authors.affiliation: SAS Institute Inc., SAS Campus Drive, Cary, NC, 27513, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Shao
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Theissen
authors.affiliation: Neuroblastoma Laboratory, Onco/Hematology Laboratory, SDB Department, University of Padua, Pediatric Research Institute, Padua, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Tonini
authors.affiliation: Department of Pediatrics and Genetics, Ghent University, Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: Georgia Institute of Technology, School of Electrical and Computer Engineering, 777 Atlantic Drive NW, Atlanta, GA, 30332, USA.
authors.forename: Po-Yen
authors.initials: PY
authors.lastname: Wu
authors.affiliation: Harvard Medical School, Massachusetts General Hospital, 51 Blossom Street, Boston, MA, 02114, USA.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Xiao
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Stanford University, Stanford Genome Technology Center, 855 South California Avenue, Palo Alto, CA, 94304, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Jiekun
authors.initials: J
authors.lastname: Xuan
authors.affiliation: Eli Lilly and Company Research Informatics, Lilly Corporate Center, Drop Code 0725, Indianapolis, IN, 46285, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Marshfield Clinic Research Foundation, Biomedical Informatics Research Center, 1000 N Oak Avenue, Marshfield, WI, 54449, USA.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Ye
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China.
authors.forename: Zirui
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Pathology, University of North Dakota School of Medicine, 501 N. Columbia Road RM 3573, Grand Forks, ND, 58202-9037, USA.
authors.forename: Ke K
authors.initials: KK
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Collaborative Innovation Center for Genetics and Development, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Collaborative Innovation Center for Genetics and Development, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and School of Pharmacy, Fudan University, Shanghai, 201203, China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: SAS Institute Inc., SAS Campus Drive, Cary, NC, 27513, USA.
authors.forename: Russell D
authors.initials: RD
authors.lastname: Wolfinger
authors.affiliation: East China Normal University, Center for Bioinformatics and Computational Biology, Shanghai Key Laboratory of Regulatory Biology, the Institute of Biomedical Sciences and School of Life Sciences, 500 Dongchuan Road, Shanghai, 200241, China.
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.affiliation: Department of Molecular & Cellular Biology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA, 91010, USA.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Malkas
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany.|University of Cologne, Center for Molecular Medicine (CMMC), Medical Faculty, Kerpener Strasse 62, D-50924, Cologne, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China.|Department of Biology, University of Copenhagen, Copenhagen, DK-2200, Denmark.|King Abdulaziz University, Jeddah, 21589, Saudi Arabia.|Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, DK-2200, Denmark.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA.
authors.forename: Weida
authors.initials: W
authors.lastname: Tong
authors.affiliation: Collaborative Innovation Center for Genetics and Development, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and School of Pharmacy, Fudan University, Shanghai, 201203, China. lemingshi@fudan.edu.cn.|National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR, 72079, USA. lemingshi@fudan.edu.cn.
authors.forename: Leming
authors.initials: L
authors.lastname: Shi
authors.affiliation: BGI-Shenzhen, Main Building, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083, China. pengzhiyu@genomics.org.cn.|BGI-Guangzhou, Guangzhou Higher Education Mega Center, No. 280, Waihuan East Rd., Guangzhou, 510006, China. pengzhiyu@genomics.org.cn.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Kerpener Strasse 62, D-50924, Cologne, Germany. matthias.fischer@uk-koeln.de.|University of Cologne, Center for Molecular Medicine (CMMC), Medical Faculty, Kerpener Strasse 62, D-50924, Cologne, Germany. matthias.fischer@uk-koeln.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D023381:Endpoint Determination; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008957:Models, Genetic; D009447:Neuroblastoma / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D017423:Sequence Analysis, RNA; D014407:Tumor Cells, Cultured; D055815:Young Adult