Transcriptional Profiling of Endobronchial Ultrasound-Guided Lymph Node Samples Aids Diagnosis of Mediastinal Lymphadenopathy.
BACKGROUND
Endobronchial ultrasound (EBUS)-guided biopsy is the mainstay for investigation of mediastinal lymphadenopathy for laboratory diagnosis of malignancy, sarcoidosis, or TB. However, improved methods for discriminating between TB and sarcoidosis and excluding malignancy are still needed. We sought to evaluate the role of genomewide transcriptional profiling to aid diagnostic processes in this setting.


METHODS
Mediastinal lymph node samples from 88 individuals were obtained by EBUS-guided aspiration for investigation of mediastinal lymphadenopathy and subjected to transcriptional profiling in addition to conventional laboratory assessments. Computational strategies were used to evaluate the potential for using the transcriptome to distinguish between diagnostic categories.


RESULTS
Molecular signatures associated with granulomas or neoplastic and metastatic processes were clearly discernible in granulomatous and malignant lymph node samples, respectively. Support vector machine (SVM) learning using differentially expressed genes showed excellent sensitivity and specificity profiles in receiver operating characteristic curve analysis with area under curve values > 0.9 for discriminating between granulomatous and nongranulomatous disease, TB and sarcoidosis, and between cancer and reactive lymphadenopathy. A two-step decision tree using SVM to distinguish granulomatous and nongranulomatous disease, then between TB and sarcoidosis in granulomatous cases, and between cancer and reactive lymphadenopathy in nongranulomatous cases, achieved > 90% specificity for each diagnosis and afforded greater sensitivity than existing tests to detect TB and cancer. In some diagnostically ambiguous cases, computational classification predicted granulomatous disease or cancer before pathologic abnormalities were evident.


CONCLUSIONS
Machine learning analysis of transcriptional profiling in mediastinal lymphadenopathy may significantly improve the clinical utility of EBUS-guided biopsies.
Department of Infection and Immunity, University College London, London, England. Electronic address: g.tomlinson@ucl.ac.uk.
Gillian S
GS
Tomlinson
Department of Infection and Immunity, University College London, London, England.
Niclas
N
Thomas
Department of Infection and Immunity, University College London, London, England.
Benjamin M
BM
Chain
Department of Infection and Immunity, University College London, London, England.
Katharine
K
Best
Department of Infection and Immunity, University College London, London, England.
Nandi
N
Simpson
Lungs for Living Research Centre, University College London, London, England.
Georgia
G
Hardavella
Lungs for Living Research Centre, University College London, London, England.
James
J
Brown
Department of Respiratory Medicine, Homerton University Hospital, London, England.
Angshu
A
Bhowmik
Lungs for Living Research Centre, University College London, London, England; Department of Thoracic Medicine, University College London Hospital, London, England.
Neal
N
Navani
Lungs for Living Research Centre, University College London, London, England.
Samuel M
SM
Janes
Research Department of Infection and Population Health, University College London, London, England.
Robert F
RF
Miller
Department of Infection and Immunity, University College London, London, England.
Mahdad
M
Noursadeghi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001999:Bronchoscopy / Q000379:methods; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration / Q000379:methods*; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008206:Lymphatic Diseases / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D008297:Male; D008477:Mediastinal Diseases / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D008482:Mediastinum; D008875:Middle Aged; D012313:RNA / Q000032:analysis*; D012372:ROC Curve; D017565:Sarcoidosis, Pulmonary / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D059467:Transcriptome; D055815:Young Adult
D012313:RNA
cancer; machine learning; sarcoidosis; transcriptome; tuberculosis