title: A novel approach for selecting combination clinical markers of pathology applied to a large retrospective cohort of surgically resected pancreatic cysts.
abstract: Our objective was to develop an approach for selecting combinatorial markers of pathology from diverse clinical data types. We demonstrate this approach on the problem of pancreatic cyst classification.
  
  
  
  We analyzed 1026 patients with surgically resected pancreatic cysts, comprising 584 intraductal papillary mucinous neoplasms, 332 serous cystadenomas, 78 mucinous cystic neoplasms, and 42 solid-pseudopapillary neoplasms. To derive optimal markers for cyst classification from the preoperative clinical and radiological data, we developed a statistical approach for combining any number of categorical, dichotomous, or continuous-valued clinical parameters into individual predictors of pathology. The approach is unbiased and statistically rigorous. Millions of feature combinations were tested using 10-fold cross-validation, and the most informative features were validated in an independent cohort of 130 patients with surgically resected pancreatic cysts.
  
  
  
  We identified combinatorial clinical markers that classified serous cystadenomas with 95% sensitivity and 83% specificity; solid-pseudopapillary neoplasms with 89% sensitivity and 86% specificity; mucinous cystic neoplasms with 91% sensitivity and 83% specificity; and intraductal papillary mucinous neoplasms with 94% sensitivity and 90% specificity. No individual features were as accurate as the combination markers. We further validated these combinatorial markers on an independent cohort of 130 pancreatic cysts, and achieved high and well-balanced accuracies. Overall sensitivity and specificity for identifying patients requiring surgical resection was 84% and 81%, respectively.
  
  
  
  Our approach identified combinatorial markers for pancreatic cyst classification that had improved performance relative to the individual features they comprise. In principle, this approach can be applied to any clinical dataset comprising dichotomous, categorical, and continuous-valued parameters.
authors.affiliation: *Drs Masica and Dal Molin contributed equally as first authors.|Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: David L
authors.initials: DL
authors.lastname: Masica
authors.affiliation: *Drs Masica and Dal Molin contributed equally as first authors.|Departments of Pathology.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: Marco
authors.initials: M
authors.lastname: Dal Molin
authors.affiliation: Departments of Surgery.|Departments of Oncology.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Tyler
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Departments of Medicine.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ostovaneh
authors.affiliation: Departments of Biostatistics and Bioinformatics.
authors.forename: Amanda
authors.initials: A
authors.lastname: Blackford
authors.affiliation: Departments of Medicine.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Moran
authors.affiliation: Departments of Medicine.
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Law
authors.affiliation: Departments of Pathology.
authors.forename: Thomas
authors.initials: T
authors.lastname: Barkley
authors.affiliation: Departments of Medicine.|Departments of Oncology.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.affiliation: Departments of Medicine.
authors.forename: Marcia
authors.initials: M
authors.lastname: Irene Canto
authors.affiliation: Departments of Pathology.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: Meredith
authors.initials: M
authors.lastname: Pittman
authors.affiliation: Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.affiliation: Departments of Pathology.
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Ali
authors.affiliation: Departments of Radiology.
authors.forename: Elliot K
authors.initials: EK
authors.lastname: Fishman
authors.affiliation: Departments of Radiology.
authors.forename: Ihab R
authors.initials: IR
authors.lastname: Kamel
authors.affiliation: Departments of Radiology.
authors.forename: Siva P
authors.initials: SP
authors.lastname: Raman
authors.affiliation: Departments of Radiology.
authors.forename: Atif
authors.initials: A
authors.lastname: Zaheer
authors.affiliation: Departments of Surgery.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.affiliation: Departments of Surgery.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Makary
authors.affiliation: Departments of Surgery.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Departments of Surgery.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Departments of Surgery.
authors.forename: John L
authors.initials: JL
authors.lastname: Cameron
authors.affiliation: Departments of Surgery.
authors.forename: Neda
authors.initials: N
authors.lastname: Rezaee
authors.affiliation: Departments of Surgery.
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.affiliation: Departments of Surgery.
authors.forename: Young
authors.initials: Y
authors.lastname: Joon Ahn
authors.affiliation: Departments of Surgery.
authors.forename: Wenchuan
authors.initials: W
authors.lastname: Wu
authors.affiliation: Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Simeon
authors.initials: S
authors.lastname: Springer
authors.affiliation: Departments of Surgery.|Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Luis L
authors.initials: LL
authors.lastname: Diaz
authors.affiliation: Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.affiliation: Departments of Pathology.|Departments of Oncology.|Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.affiliation: Departments of the Sol Goldman Pancreatic Cancer Research Center.|Departments of the Ludwig Center and Howard Hughes Medical Institute at the Sidney Kimmel Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.affiliation: †Drs Lennon and Karchin contributed equally as senior authors amlennon@jhmi.edu karchin@jhu.edu.|Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland.|Departments of Oncology.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.affiliation: †Drs Lennon and Karchin contributed equally as senior authors amlennon@jhmi.edu karchin@jhu.edu.|Departments of Surgery.|Departments of Medicine.|Departments of the Sol Goldman Pancreatic Cancer Research Center.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Lennon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D014408:Biomarkers, Tumor / Q000032:analysis*; D003537:Cystadenoma / Q000175:diagnosis; D005260:Female; D006801:Humans; D008875:Middle Aged; D010181:Pancreatic Cyst / Q000175:diagnosis* / Q000601:surgery; D010190:Pancreatic Neoplasms / Q000175:diagnosis*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor
keywords: IPMN; MOCA; clinical model; combination marker; composite marker; mucinous cyst; pancreatic cyst