Compositions, methods and kits for diagnosis of lung cancer
Inventors
Kearney, Paul Edward • Fang, Kenneth Charles • Li, Xiao-Jun • Hayward, Clive
Assignees
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Publication Number
US-10338074-B2
Publication Date
2019-07-02
Expiration Date
Abstract
Methods are provided for identifying biomarker proteins that exhibit differential expression in subjects with a first lung condition versus healthy subjects or subjects with a second lung condition. Also provided are compositions comprising these biomarker proteins and methods of using these biomarker proteins or panels thereof to diagnose, classify, and monitor various lung conditions. The methods and compositions provided herein may be used to diagnose or classify a subject as having lung cancer or a non-cancerous condition, and to distinguish between different types of cancer (e.g., malignant versus benign, SCLC versus NSCLC).
Core Innovation
The invention relates to determining the likelihood that a pulmonary nodule in a subject is not lung cancer by using blood-based multiplex biomarker protein panels measured by selected reaction monitoring mass spectrometry. A blood sample obtained from the subject is contacted with a proteolytic enzyme to produce peptide fragments from a panel of proteins present in the blood sample, including LG3BP and C163A, and the produced peptide fragments are combined with labeled, synthetic peptide fragments that correspond to the produced peptide fragments from the panel.
Selected reaction monitoring mass spectrometry measures the abundance of the peptide fragments, and a probability of lung cancer score is calculated based on the peptide fragment measurements. Lung cancer is ruled out for the subject if the score is lower than a pre-determined score. The documented approach includes a quantitative performance concept in which the ruling-out decision is associated with a negative predictive value (NPV) performance target.
The score can be determined using a logistic regression model based on transition intensities, and the method includes refinements that specify the proteolytic enzyme, selected reaction monitoring mass spectrometry, labeled synthetic peptide fragments, and a pulmonary nodule having a diameter of about 0.8 cm to 2.0 cm.
Claims Coverage
The claim set includes one independent claim and dependent claims that refine the ruling-out decision with quantitative performance constraints, specify processing and measurement choices, and define mathematical formulation of the lung cancer probability score and subject criteria.
Blood protein panel producing peptide fragments for scoring
Contacting a blood sample obtained from the subject with a proteolytic enzyme to produce peptide fragments from a panel of proteins present in the blood sample, wherein the panel comprises LG3BP and C163A.
Labeled synthetic peptide corresponding to panel fragments
Combining the produced peptide fragments from the panel with labeled, synthetic peptide fragments which correspond to the produced peptide fragments from the panel.
Selected reaction monitoring mass spectrometry measurement
Performing selected reaction monitoring mass spectrometry to measure the abundance of the peptide fragments.
Probability of lung cancer score from peptide fragment measurements
Calculating a probability of lung cancer score based on the peptide fragment measurements.
Rule-out of lung cancer when score is below predetermined threshold
Ruling out lung cancer for the subject if the score is lower than a pre-determined score.
Negative predictive value requirement for the ruling-out score
The score determined in step (d) has a negative predictive value (NPV) of at least about 80%.
Logistic regression formulation of the lung cancer probability score
Computing the score using a logistic regression formula where logarithmically transformed and normalized transition intensities from a sample are combined with coefficient parameters and a panel-specific constant over a total number of transitions.
Pulmonary nodule diameter range
Including a pulmonary nodule having a diameter of about 0.8 cm to 2.0 cm.
Across the independent claim and dependent refinements, lung cancer likelihood is determined from peptide fragment abundances generated from a blood protein panel including LG3BP and C163A and measured by selected reaction monitoring mass spectrometry, followed by calculation of a probability score and a rule-out decision when the score is below a predetermined threshold, with refinements that specify NPV, logistic-regression scoring, and a pulmonary nodule diameter criterion.
Stated Advantages
Enables ruling out lung cancer for a subject when the calculated score is lower than a pre-determined score.
Provides a quantitative ruling-out performance constraint via negative predictive value (NPV) of at least about 80%.
Uses selected reaction monitoring mass spectrometry together with labeled, synthetic peptide fragments corresponding to produced peptide fragments.
Documented Applications
Diagnostic evaluation of a pulmonary nodule in a subject to determine the likelihood that the pulmonary nodule is not lung cancer, including use with intermediate-size nodules.
Ruling out lung cancer and supporting decision-making for non-small cell lung cancer (NSCLC) within the described diagnostic framework [procedural detail omitted for safety].
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