Publications & Presentations

Publications & Presentations

Clinical Validation

Validation of a Multi-Protein Plasma Classifier to Identify Benign Lung Nodules: Journal of Thoracic Oncology.
Vachani, Anil, MD.
LWW. Journal of Thoracic Oncology, 14 Jan. 2015. Web. 26 Jan. 2015
Abstract - Indeterminate pulmonary nodules (IPNs) lack clinical or radiographic features of benign etiologies and often undergo invasive procedures unnecessarily, suggesting potential roles for diagnostic adjuncts using molecular biomarkers. The primary objective was to validate a multivariate classifier that identifies likely benign lung nodules by assaying plasma protein expression levels, yielding a range of probability estimates based on high negative predictive values (NPVs) for patients with 8 to 30 mm IPNs. ...more

Clinical Utility

Clinical Utility of a Plasma Protein Classifier for Indeterminate Lung Nodules
Anil Vachani, Zane Hammoud, Steven Springmeyer, Neri Cohen, Dao Nguyen, Christina Williamson, Sandra Starnes, Stephen Hunsucker, Scott Law, Xiao-Jun Li, Alexander Porter, Paul Kearney
LUNG First online: 16 September 2015
Abstract - Evaluation of indeterminate pulmonary nodules is a complex challenge. Most are benign but frequently undergo invasive and costly procedures to rule out malignancy. A plasma protein classifier was developed that identifies likely benign nodules that can be triaged to CT surveillance to avoid unnecessary invasive procedures. The clinical utility of this classifier was assessed in a prospective–retrospective analysis of a study enrolling 475 patients with nodules 8–30 mm in diameter who had an invasive procedure to confirm diagnosis at 12 sites. Using this classifier, 32.0 % (CI 19.5–46.7) of surgeries and 31.8 % (CI 20.9–44.4) of invasive procedures (biopsy and/or surgery) on benign nodules could have been avoided. Patients with malignancy triaged to CT surveillance by the classifier would have been 24.0 % (CI 19.2–29.4). This rate is similar to that described in clinical practices (24.5 % CI 16.2–34.4). This study demonstrates the clinical utility of a non-invasive blood test for pulmonary nodules." ...more

Management of Pulmonary Nodules by Community Pulmonologists: A Multicenter Observational Study
Nichole T. Tanner, MD, MSCR; Jyoti Aggarwal, MHS; Michael K. Gould, MD, MS; Paul Kearney, PhD; Gregory Diette, MD, MHS; Anil Vachani, MD, MS; Kenneth C. Fang, MD; Gerard A. Silvestri, MD, MS
Chest. 2015. doi:10.1378/chest.15-0630
Abstract - Pulmonary nodules (PNs) are a common reason for referral to pulmonologists. The majority of data for evaluation and management of PNs are derived from studies performed in academic medical centers. Little is known about prevalence, diagnosis, use of diagnostic testing and management of PNs by community pulmonologists. ...more

Factors That Influence Physician Decision-making for Indeterminate Pulmonary Nodules.
Vachani A, Tanner NT, Aggarwal J, Mathews C, Kearney P, Fang KC, Silvestri G, Diette GB.
Ann Am Thorac Soc. 2014 Nov 11
Abstract - Rationale: Pulmonologists frequently encounter indeterminate pulmonary nodules in practice, but it is unclear what clinical factors they rely on to guide the diagnostic evaluation and the extent to which the addition of a hypothetical diagnostic blood test would influence decision-making. Methods: Selected pulmonologists practicing in the United States were invited to participate in a conjoint exercise based on 20 randomly-generated cases varying age, smoking history and nodule size. Some cases included the result of a hypothetical blood test. Each respondent chose from among three diagnostic options for a patient: non-invasive monitoring (i.e. serial CT or PET scan), a minor procedure (i.e., biopsy or bronchoscopy), or a major procedure (i.e., VATS or thoracotomy). Multivariate logistic regression was used to assess the impact of the three risk factors and the diagnostic blood test on decision-making. Measurements and Main Results: 419 physicians participated (response rate, 10%). 153 physician surveys met predetermined criteria and were analyzed (4% of all invitees). A diagnostic procedure was recommended for 23% of 6 mm nodules, vs. 54%, 66%, 77% and 84% of nodules 10, 14, 18 and 22mm, respectively (p<.001). Older age limited recommendations for invasive testing: 54% of 80 year olds vs. 61%, 64%, 63% and 61% of patients 71, 62, 53, and 44 years old, respectively (p<.001). In multivariate analyses, nodule size, smoking history, age, and the blood test each influenced decision-making (p<.001). Conclusions: The pulmonologists who participated in this survey were more likely to proceed with invasive testing, instead of observation or additional imaging, as the size of the nodule increased. The use of a hypothetical blood test resulted in significant alterations in the decision to pursue invasive testing.

Discovery and Validation

A Blood-Based Proteomic Classifier for the Molecular Characterization of Pulmonary Nodules
Li XJ et al
Sci. Transl. Med. 5, 207ra142 (2013).
Each year, millions of pulmonary nodules are discovered by computed tomography and subsequently biopsied. Because most of these nodules are benign, many patients undergo unnecessary and costly invasive procedures. We present a 13-protein blood-based classifier that differentiates malignant and benign nodules with high confidence, thereby providing a diagnostic tool to avoid invasive biopsy on benign nodules. Using a systems biology strategy, we identified 371 protein candidates and developed a multiple reaction monitoring (MRM) assay for each. The MRM assays were applied in a three-site discovery study (n = 143) on plasma samples from patients with benign and stage IA lung cancer matched for nodule size, age, gender, and clinical site, producing a 13-protein classifier. The classifier was validated on an independent set of plasma samples (n = 104), exhibiting a negative predictive value (NPV) of 90%. Validation performance on samples from a nondiscovery clinical site showed an NPV of 94%, indicating the general effectiveness of the classifier. A pathway analysis demonstrated that the classifier proteins are likely modulated by a few transcription regulators (NF2L2, AHR, MYC, and FOS) that are associated with lung cancer, lung inflammation, and oxidative stress networks. The classifier score was independent of patient nodule size, smoking history, and age, which are risk factors used for clinical management of pulmonary nodules. Thus, this molecular test provides a potential complementary tool to help physicians in lung cancer diagnosis. ... more

Technical

An integrated quantification method to increase the precision, robustness, and resolution of protein measurement in human plasma samples.
Xiao-jun Li, Lik Wee Lee, Clive Hayward, Mi-Youn Brusniak, Pui-Yee Fong, Matthew McLean, JoAnne Mulligan, Douglas Spicer, Kenneth C Fang, Stephen W Hunsucker and Paul Kearney
Clinical Proteomics Jan 2015
Abstract - Background: Current quantification methods for mass spectrometry (MS)-based proteomics either do not provide sufficient control of variability or are difficult to implement for routine clinical testing. Results: We present here an integrated quantification (InteQuan) method that better controls pre-analytical and analytical variability than the popular quantification method using stable isotope-labeled standard peptides (SISQuan) ...more

Reference

A systems approach to prion disease
Leroy Hood et al.
Molecular Systems Biology Vol.5/March 2009

Global Proteomics: Pharmacodynamic Decision Making via Geometric Interpretations of Proteomic Analyses
Paul Kearney et al.
Journal of Proteomics & Bioinformatics Vol.1/October 2008

High Sensitivity Detection of Plasma Proteins by Multiple Reaction Monitoring of N-Glycosites
Jianru Stahl-Zeng, Vinzenz Lange, Reto Ossola, Katrin Eckhardt, Wilhelm Krek, Ruedi Aebersold, and Bruno Domon
Molecular & Cellular Proteomics 6.10 (2007)

Systems Biology and New Technologies Enable Predictive and Preventative Medicine
Leroy Hood, James R. Heath, Michael E. Phelps, Biaoyang Lin
Science 306, 640 (2004)

 
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