Methods and systems to detect and quantify the amount of LP-X and other abnormal lipoproteins in a biosample using NMR spectroscopy
Inventors
Otvos, James D. • Shalaurova, Irina • Remaley, Alan • Sampson, Maureen • Freeman, Lita
Assignees
National Institutes of Health NIH • Labcorp Holdings Inc
Publication Number
US-11467171-B2
Publication Date
2022-10-11
Expiration Date
2038-11-13
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Abstract
Described herein are methods and systems for the determination of constituents in biosamples by NMR spectroscopy and more specifically for the determination of lipoprotein constituents LP-X, LP-Y, and LP-Z in blood plasma and serum.
Core Innovation
The invention provides new methods and systems to accurately detect and quantify the amount of abnormal lipoproteins LP-X, LP-Y, and LP-Z in biosamples such as blood plasma or serum using nuclear magnetic resonance (NMR) spectroscopy. The methods involve acquiring an NMR spectrum of the biosample and applying deconvolution models, including standard and modified models that incorporate spectral references for LP-X, LP-Y, and LP-Z, to identify the presence and concentration of these abnormal lipoproteins.
The problem being solved arises from the difficulty in discerning LP-X and other abnormal lipoproteins with standard cholesterol screening techniques. LP-X is a rare abnormal lipoprotein that appears in patients with conditions like obstructive jaundice, liver disease, or lecithin-cholesterol acyltransferase (LCAT) deficiency. Its presence can be missed or misidentified, potentially leading to inappropriate treatment, such as use of statin drugs which may exacerbate the underlying condition. Traditional detection via electrophoresis is laborious and lacks accurate quantification, highlighting the need for an easily administered and accurate detection method compatible with routine testing.
Claims Coverage
The patent claims include 20 claims comprising methods for diagnosing LP-X presence, evaluating therapeutic response, systems for screening and quantifying LP-X, and computer program products for analyzing NMR spectra. The claims focus on inventive features concerning NMR-based deconvolution models and system configurations.
Method of diagnosing LP-X and LP-Z using dual deconvolution models
A method acquiring an NMR spectrum of plasma or serum and programmatically determining the presence of LP-X or LP-Z by applying a first deconvolution model excluding LP-X and LP-Z and a second, modified model including these components to detect mismatch indicative of abnormal lipoproteins.
Generating calculated lineshape based on lipoprotein component concentrations
Producing a measured lipid signal lineshape and generating a calculated lineshape based on derived concentrations of lipoprotein components including LP-X, and optionally LP-Y and LP-Z, with concentrations as functions of reference spectra and calculated coefficients.
Determining presence of LP-X or LP-Z based on correlation between calculated and measured lineshapes
Evaluating degree of correlation and identifying LP-X or LP-Z presence when mismatch or residual between calculated and measured lineshapes exceeds a predetermined threshold.
Applying linear least squares fitting for reference coefficient calculation
Using a linear least squares fit technique for calculating reference coefficients in determining lipoprotein component concentrations during deconvolution.
Specific NMR spectral regions for LP-X, LP-Y, and LP-Z methyl proton signals
Including LP-X signal at approximately 0.97±0.01 ppm, LP-Y at 0.78±0.01 ppm, and LP-Z at 0.77±0.01 ppm in the deconvolution model.
Deconvolving signals and comparing with calibration data
Deconvolving methyl proton signals corresponding to LP-X, LP-Y, and LP-Z and comparing those with a priori calibration data from standard samples to quantify concentrations in the biosample.
Including LDL, HDL, and VLDL spectra in deconvolution
Using a deconvolution model that also comprises spectra of lipoproteins LDL, HDL, and VLDL along with abnormal lipoproteins for comprehensive analysis.
Producing reports listing lipoprotein concentrations
Generating reports that list detected concentrations of lipoprotein constituents in the analyzed biosample.
Evaluating patient's response to therapy via sequential biosample analysis
Obtaining biosamples at two time points, measuring LP-X concentration in both, and determining therapy responsiveness when LP-X concentration decreases, with measurement based on NMR spectra including LP-X, LP-Y, and LP-Z.
System for screening using NMR and computational comparison
A system comprising an NMR spectrometer and computer program means to store measured lineshapes and reference spectra including LP-X, LP-Y, and LP-Z; calculate lineshapes based on derived concentrations; and determine correlation to identify presence of abnormal lipoproteins.
System including output device for reporting LP-X presence and concentration
An embodiment of the system that includes an output device configured to produce a report indicating presence or concentration of LP-X.
System configured to determine concentrations via processor analysis and calibration comparison
A system with processors configured to obtain and analyze NMR spectra detecting LP-X, LP-Y, and LP-Z methyl proton signals; deconvolve signal data; and compare to calibration data from standards to determine concentrations.
Computer program product for concentration determination
A non-transitory computer readable medium comprising program code to obtain NMR signal spectra comprising LP-X, LP-Y, and LP-Z methyl proton signals and determine LP-X concentration by deconvolution analysis.
The claims collectively cover methods and systems that utilize NMR spectroscopy and specific deconvolution models including spectral references for LP-X, LP-Y, and LP-Z to detect, quantify, and report the presence of abnormal lipoproteins in patient biosamples, along with computer program products implementing these analyses.
Stated Advantages
Provides an accurate and easily administered method to detect LP-X and other abnormal lipoproteins in biosamples using NMR spectroscopy.
Dovetails with routine patient testing, facilitating detection without additional complex procedures.
Enables quantification of LP-X, LP-Y, and LP-Z, improving diagnosis and treatment selection, particularly differentiating liver disease or LCAT deficiency from cardiovascular risk.
Allows evaluation of patient response to therapy by measuring changes in LP-X concentration over time.
Improves upon standard cholesterol screening techniques by providing specific identification and quantification of abnormal lipoproteins through spectral analysis.
Documented Applications
Detection and quantification of abnormal lipoproteins LP-X, LP-Y, and LP-Z in blood plasma or serum samples.
Screening patients for the presence of LP-X and related abnormal lipoproteins to assist in diagnosis of liver diseases, obstructive jaundice, or familial LCAT deficiency.
Evaluating patient response to therapies such as recombinant LCAT infusions by measuring LP-X levels before and after treatment.
Use in clinical disease risk assessments to avoid inappropriate therapies that may exacerbate conditions related to abnormal lipoproteins.
Integration into automated screening tests on NMR clinical analyzers for risk assessment and monitoring of clinical disease states.
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