title: An active learning approach for rapid characterization of endothelial cells in human tumors.
abstract: Currently, no available pathological or molecular measures of tumor angiogenesis predict response to antiangiogenic therapies used in clinical practice. Recognizing that tumor endothelial cells (EC) and EC activation and survival signaling are the direct targets of these therapies, we sought to develop an automated platform for quantifying activity of critical signaling pathways and other biological events in EC of patient tumors by histopathology. Computer image analysis of EC in highly heterogeneous human tumors by a statistical classifier trained using examples selected by human experts performed poorly due to subjectivity and selection bias. We hypothesized that the analysis can be optimized by a more active process to aid experts in identifying informative training examples. To test this hypothesis, we incorporated a novel active learning (AL) algorithm into FARSIGHT image analysis software that aids the expert by seeking out informative examples for the operator to label. The resulting FARSIGHT-AL system identified EC with specificity and sensitivity consistently greater than 0.9 and outperformed traditional supervised classification algorithms. The system modeled individual operator preferences and generated reproducible results. Using the results of EC classification, we also quantified proliferation (Ki67) and activity in important signal transduction pathways (MAP kinase, STAT3) in immunostained human clear cell renal cell carcinoma and other tumors. FARSIGHT-AL enables characterization of EC in conventionally preserved human tumors in a more automated process suitable for testing and validating in clinical trials. The results of our study support a unique opportunity for quantifying angiogenesis in a manner that can now be tested for its ability to identify novel predictive and response biomarkers.
authors.affiliation: Department of Electrical and Computer Engineering, University of Houston, Houston, Texas, United States of America.
authors.forename: Raghav K
authors.initials: RK
authors.lastname: Padmanabhan
authors.affiliation: Department of Electrical and Computer Engineering, University of Houston, Houston, Texas, United States of America.
authors.forename: Vinay H
authors.initials: VH
authors.lastname: Somasundar
authors.affiliation: Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Griffith
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Drew
authors.initials: D
authors.lastname: Samoyedny
authors.affiliation: Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Kay See
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jiahao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina, United States of America.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Electrical and Computer Engineering, Duke University, Durham, North Carolina, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Carin
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America; Department of Medicine, Hematology/Oncology, MGH, Boston, Massachusetts, United States of America.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America; UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Dipaola
authors.affiliation: Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.affiliation: Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feldman
authors.affiliation: Department of Electrical and Computer Engineering, University of Houston, Houston, Texas, United States of America.
authors.forename: Badrinath
authors.initials: B
authors.lastname: Roysam
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: William M F
authors.initials: WM
authors.lastname: Lee
mesh_terms: D000465:Algorithms; D001185:Artificial Intelligence; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000473:pathology*; D019295:Computational Biology / Q000379:methods*; D042783:Endothelial Cells / Q000473:pathology*; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000473:pathology*; D018794:Problem-Based Learning; D015398:Signal Transduction; D013997:Time Factors