Methods for nucleic acid sequencing
Inventors
Kennedy, Giulia C. • Diggans, James • Huang, Jing • CHOI, Yoonha • KIM, Su Yeon • Pankratz, Daniel • Pagan, Moraima
Assignees
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Publication Number
US-11639527-B2
Publication Date
2023-05-02
Expiration Date
Abstract
The present invention provides methods for sequencing and analysis of nucleic acids and determining that a subject is positive for a non-usual interstitial pneumonia subtype.
Core Innovation
The invention determines that a subject is positive for usual interstitial pneumonia (UIP) when imaging is inconclusive. The method performs an imaging analysis that is inconclusive as to whether the subject has UIP, and then obtains a biological sample subsequent to the imaging analysis. From the biological sample, nucleic acid molecules are assayed to identify a level of expression of a plurality of genes associated with UIP.
A classifier is used to process the level of expression to generate a classification of the biological sample as being positive for UIP. The classifier differentiates between UIP and a plurality of non-UIP subtypes, where the plurality of non-UIP subtypes comprises hypersensitivity pneumonitis (HP), non-specific interstitial pneumonia (NSIP), sarcoidosis, respiratory bronchiolitis (RB), bronchiolitis, diffuse alveolar damage (DAD), and organizing pneumonia (OP).
The disclosed approach supports making a UIP determination despite inconclusive imaging by combining gene-expression profiling from a biological sample with a classifier that distinguishes UIP from multiple non-UIP interstitial lung disease subtypes. The invention further supports classifier training using expert pathology diagnoses as truth labels and patient-level validation, including leave-one-patient-out and 10-fold patient-level cross-validation.
Claims Coverage
The independent claim set covers a method that determines a subject is positive for usual interstitial pneumonia (UIP) when imaging is inconclusive, by assaying gene-expression levels from a biological sample and using a classifier that differentiates UIP from multiple non-UIP subtypes. Two inventive features are identified across the independent claims.
Imaging inconclusive and subsequent biological sampling
Performing an imaging analysis on the subject wherein the imaging analysis is inconclusive as to whether the subject has UIP, and obtaining a biological sample subsequent to performing the imaging analysis.
Classifier differentiating UIP from multiple non-UIP subtypes
Using a classifier to process the level of expression to generate a classification of the biological sample as being positive for UIP, where the classifier differentiates between UIP and a plurality of non-UIP subtypes comprising hypersensitivity pneumonitis (HP), non-specific interstitial pneumonia (NSIP), sarcoidosis, respiratory bronchiolitis (RB), bronchiolitis, diffuse alveolar damage (DAD), and organizing pneumonia (OP).
Overall, the claim coverage centers on using inconclusive imaging as a trigger for nucleic-acid gene-expression profiling followed by a classifier that differentiates UIP from a specified set of non-UIP interstitial lung disease subtypes.
Stated Advantages
Patient-level assessment to reduce leakage between samples from the same patient.
Documented Applications
Diagnosing interstitial lung disease by determining whether a subject is positive for usual interstitial pneumonia (UIP) when imaging is inconclusive, including differentiating UIP from non-UIP subtypes.
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