If the diagnosis or prognosis of sepsis can be made early, the treatment can be made available to prevent or slow the progress of sepsis into severe sepsis or septic shock. A need, therefore, exists for methods of diagnosing systemic inflammatory conditions, including sepsis, using techniques that have satisfactory specificity and sensitivity, sufficiently early to allow effective intervention and prevention. In one aspect, the present invention is based, in part, on the discovery that the amount of total lysophosphatidylcholine in a sample from a patient can be used for rapid, sensitive and accurate diagnosis or prognosis of a systemic inflammatory condition in a subject.
In aspects of the invention, total lysophosphatidylcholine in a sample from a patient is used to assess presence of or risk for the systemic inflammatory condition. As shown in the examples below, the methods and compositions of the invention can be used for the diagnosis or prognosis of the systemic inflammatory condition.
In certain embodiments, total lysophosphatidylcholine in a sample of the subject is evaluated to assess presence or risk for a systemic inflammatory condition. As described herein, it has been discovered that the amount of total lysophosphatidylcholine in a sample from a patient can correlate with the onset of a systemic inflammatory condition and can even indicate the condition in advance of its onset.
As a result, in certain embodiments, total lysophosphatidylcholine in a sample from the patient can be used as a prognosis for a systemic inflammatory condition. The evaluation can proceed according to any technique for evaluating total lysophosphatidylcholine known to those of skill in the art. Exemplary techniques are described herein. However, the present invention provides methods based on any technique of evaluating total lysophosphatidylcholine apparent to those of skill in the art.
In another aspect, the present invention is based, in part, on the discovery of a class of lysophosphatidylcholine biomarkers that are useful for rapid, sensitive and accurate diagnosis or prognosis of a systemic inflammatory condition in a subject.
In aspects of the invention, evaluation of a biomarker of the invention in the subject is used to assess presence of or risk for the systemic inflammatory condition. In certain embodiments, the biomarker is a 1-O-acyllyso-sn-glycerophosphocholine. The acyl group can be any acyl group known to those of skill in the art. In certain embodiments, the acyl group is C 14 -C 22 acyl. In further embodiments, the acyl group is C 16 -C 18 acyl. In particular embodiments, the acyl group is C 16 acyl.
In a preferred embodiment, the acyl group is palmitoyl. In further particular embodiments, the acyl group is C 18 acyl. In a preferred embodiment, the acyl group is stearoyl. The biomarker can be any form of the biomarker from the subject, for instance any salt or solvate of the biomarker that can be identified by those of skill in the art. In certain embodiments, the biomarker is a compound according to formula I : or a salt or solvate thereof.
In formula I , R can be any acyl group known to those of skill in the art. In certain embodiments, R is C 14 -C 22 acyl. In further embodiments, R is C 16 -C 18 acyl. In particular embodiments, R is C 16 acyl.
In a preferred embodiment, R is palmitoyl. In further particular embodiments, R is C 18 acyl. In a preferred embodiment, R is stearoyl. Exemplary salts of formula I are provided by formula Ia : wherein said salt can be coordinated with any physiological organic or inorganic anion, or any physiological organic or inorganic cation, or both, known to those of skill in the art.
Exemplary physiological anions include chloride, bromide, phosphate, acetate, carbonate, bicarbonate and sulfate. Exemplary physiological cations include sodium, potassium, calcium, magnesium and ammonium. In certain aspects, the biomarker in the subject is evaluated to assess presence or risk for the systemic inflammatory condition. The evaluation can proceed according to any method of evaluating a biomarker known to those of skill in the art.
In certain embodiments, the amount of the biomarker is measured in a fluid of a subject. However, the present invention provides methods based on any technique of evaluating a biomarker of the invention apparent to those of skill in the art.
In the following description, the term lysophosphatidylcholine can refer to total lysophosphatidylcholine or to a lysophosphatidylcholine biomarker, unless specified otherwise.
Of course, the present invention provides prognosis or diagnosis based on total lysophosphatidylcholine, prognosis or diagnosis based on one or more lysophosphatidylcholine biomarkers of the invention, and prognosis or diagnosis based on total lysophosphatidylcholine along with one or more lysophosphatidylcholine biomarkers of the invention.
In some embodiments, a plurality of measurements of lysophosphatidylcholine in the subject are made over time. The time intervals can be, for instance, 3 hours, 4 hours, 6 hours, 12 hours, 24 hours or other intervals according to the judgment of the practitioner in the art.
In these embodiments, the relative amounts of lysophosphatidylcholine are evaluated for the diagnosis or prognosis of the systemic inflammatory condition by a practitioner of skill in the art. In particular embodiments, decreasing amounts of lysophosphatidylcholine indicate increasing risk for the systemic inflammatory condition, and increasing amounts of total lysophosphatidylcholine indicate decreasing risk for the systemic inflammatory condition.
In advantageous embodiments, a single sample from the subject can be sufficient for the diagnosis or prognosis of the systemic inflammatory condition.
The amount of lysophosphatidylcholine can be compared to one or more biomarkers present in the sample that are known to those of skill in the art to be maintained at a relatively constant amount in the sample in individuals similar to the subject. The amount of lysophosphatidylcholine of the invention can be assessed against this internal standard for the diagnosis or prognosis of the systemic inflammatory condition by the practitioner of skill. In particular embodiments, low amounts of lysophosphatidylcholine indicate increased risk for the systemic inflammatory condition, and high amounts of lysophosphatidylcholine indicate reduced risk for the systemic inflammatory condition.
In other embodiments, the evaluation is based on a comparison of the amount of lysophosphatidylcholine to a reference amount of lysophosphatidylcholine.
The reference amount can be, for instance, the amount of lysophosphatidylcholine in a reference individual that manifests, or will manifest within a defined period of time, one or more symptoms of the known systemic inflammatory condition. The amount can be, for instance, an absolute value or an absolute value with a margin of error or a range of values, as determined by those of skill in the art.
In certain embodiments, the reference individual exhibits, or will exhibit, symptoms of SIRS, sepsis, severe sepsis, septic shock or MOD or no symptoms of a systemic inflammatory condition. In particular embodiments, low amounts of lysophosphatidylcholine e.
Advantageously, the reference amount need not be determined by one carrying out a method of the invention. Instead, the reference amount of lysophosphatidylcholine can be identified by consulting data available to those of skill in the art. Such data can be obtained from any source available to those of skill in the art. In certain embodiments, sources can be developed with reference amounts of lysophosphatidylcholine collected by those of skill in the art according to methods described herein.
In certain embodiments, the reference amount is from a reference individual presenting symptoms of the systemic inflammatory condition. The reference individual can present symptoms of SIRS, sepsis, severe sepsis, septic shock, MOD or mortality or no symptoms of a systemic inflammatory condition. In certain embodiments, the reference amount can be evaluated at a time prior to or after presentation of symptoms.
For instance, in an advantageous embodiment, a reference amount can be the amount measured in a SIRS-positive individual 12, 24, 36 or 48 hours prior to the onset of sepsis.
Measurement of such reference amounts is within the skill of those in the art. In further embodiments, reference amounts are from a plurality of individuals presenting symptoms of one or more systemic inflammatory conditions. The reference amounts can be calculated according to any suitable statistical method known to those of skill in the art.
For instance, the reference amounts can be based on the statistical mean of reference amounts from reference individuals presenting a systemic inflammatory condition.
In advantageous embodiments, comparison is made to a value or range of values for the amount of lysophosphatidylcholine. The value or range of values can be obtained as described herein and made available to a practitioner of the methods of the invention.
The comparison can be according to any technique for comparing amounts of biomarkers known to those of skill in the art. In one embodiment, the diagnosis or prognosis of a systemic inflammatory condition is based on the difference between the amount of lysophosphatidylcholine in the subject and the reference amount.
In certain embodiments the difference between the amount of lysophosphatidylcholine in the subject and the reference amount correlates inversely with risk for the systemic inflammatory condition. In further embodiments, the reference amount is a cutoff—in other words, the subject can be assessed to have or have risk for the systemic inflammatory condition if the amount of lysophosphatidylcholine in the subject is less than a cutoff reference amount.
Such cutoff reference amounts can be calculated according to methods described herein. The amount of total lysophosphatidylcholine in the subject can be determined according to any technique known to those of skill in the art without limitation. In certain embodiments, one of skill can measure an amount that correlates to the amount of total lysophosphatidylcholine in a sample.
For instance, in particular embodiments, one of skill can measure total free lysophosphatidylcholine, total bound lysophosphatidylcholine or total free and bound lysophosphatidylcholine in the sample to indicate the amount of total lysophosphatidylcholine in the sample.
In other words, in certain embodiments, measurement of free or bound, or both free and bound, lysophosphatidylcholine can correlate to the amount of total lysophosphatidylcholine. In certain embodiments, the technique for evaluating total lysophosphatidylcholine is not critical for the invention and need not be carried out by one practicing the methods herein. For instance, in particular embodiments, methods of the invention can comprise the single step of comparing total lysophosphatidylcholine amount in a subject to a reference total lysophosphatidylcholine amount in order to assess risk for the systemic inflammatory condition without regard to how either amount is measured.
In further embodiments, total lysophosphatidylcholine of the subject is evaluated by a technique described herein followed by comparing to a reference total lysophosphatidylcholine in order to assess risk for the systemic inflammatory condition. In certain embodiments, total lysophosphatidylcholine is evaluated by spectrometry, chromatography, immunoassay, electrophoresis or enzymatic assay as described in detail below.
In one aspect, the present invention provides fluorescent methods for assaying total lysophosphatidylcholine in a sample of a subject. In certain embodiments, the methods comprise contacting the sample of the subject with one or more reagents capable of generating a fluorescent product indicative of total lysophosphatidylcholine in the sample. The methods can be used to detect the presence of total lysophosphatidylcholine or to detect the amount of total lysophosphatidylcholine, or both, in the sample.
In particular embodiments, the sample is contacted with a fluorogenic substrate of one or more of the reagents. This fluorogenic substrate can be converted to the fluorescent product indicating total lysophosphatidylcholine. In advantageous embodiments, the reagents comprise peroxidase, choline oxidase, glycerophosphatidylcholine diesterase and lysophospholipase.
A useful fluorogenic substrate is acetyl-3,7-dihydroxyphenoxazine, a compound that can be converted to the fluorescent product 7-hydroxy-3H-phenoxazinone. Advantageously, such methods can provide the sensitivity necessary for detecting the low amounts of total lysophosphatidylcholine in subjects having, or at risk for, a systemic inflammatory condition.
The amount of the biomarker in the subject can be determined according to any technique known to those of skill in the art without limitation. In certain embodiments, the technique for evaluating the biomarker is not critical for the invention and need not be carried out by one practicing the methods herein.
For instance, in particular embodiments, methods of the invention can comprise the single step of comparing the biomarker in a subject to a reference biomarker in order to assess risk for the systemic inflammatory condition without regard to how either biomarker is measured.
In further embodiments, the biomarker of the subject is evaluated by a technique described herein followed by comparing the biomarker in a subject to a reference biomarker in order to assess risk for the systemic inflammatory condition.
In certain embodiments, the biomarker is evaluated by spectrometry, chromatography, immunoassay or electrophoresis as described in detail below.
The amount of lysophosphatidylcholine can be measured in fluids or tissues of the subject as provided herein. Processes for preparing the fluid or tissue, for example, processes for extracting or purifying lysophosphatidylcholine are described herein. Further, techniques for measuring lysophosphatidylcholine are provided herein. In another aspect, the present invention provides methods for monitoring a systemic inflammatory condition in a subject.
In such methods, evaluation of lysophosphatidylcholine is used to monitor a systemic inflammatory condition in the subject. In such methods, changes in the amount of lysophosphatidylcholine indicate changes in the systemic inflammatory condition. For instance, in certain embodiments, increasing amounts of lysophosphatidylcholine indicate decreased severity or less risk for the systemic inflammatory condition, and decreasing amounts of lysophosphatidylcholine indicate increased severity or increased risk for the systemic inflammatory condition.
In some embodiments, evaluation of lysophosphatidylcholine can indicate conversion from one systemic inflammatory condition to another such as SIRS, sepsis, severe sepsis, septic shock, MOD or mortality or no systemic inflammatory condition.
In another aspect, the present invention provides methods for monitoring treatment of a systemic inflammatory condition in a subject. In such methods, evaluation of lysophosphatidylcholine is used to monitor the systemic inflammatory condition in the subject.
For instance, in certain embodiments, increasing amounts of lysophosphatidylcholine indicate decreased severity or less risk for the systemic inflammatory condition, and decreasing amounts of total lysophosphatidylcholine indicate increased severity or increased risk for the systemic inflammatory condition.
Advantageously, treatment of the systemic inflammatory condition can be adjusted based on the monitoring. In further preferred embodiments, a subject that is SIRS-positive can be monitored for conversion to sepsis or another systemic inflammatory condition, or for conversion to SIRS-negative.
In another aspect, the present invention provides kits for the diagnosis or prognosis of a systemic inflammatory condition. In some embodiments, the kits comprise a composition suitable for evaluation of lysophosphatidylcholine. The kits can further comprise a label or labeling with instructions for using evaluation of total lysophosphatidylcholine for diagnosis or prognosis of one or more systemic inflammatory conditions.
In certain embodiments, the kit can comprise a label or labeling with reference amounts, or citations to such reference amounts, of lysophosphatidylcholine to facilitate prognosis or diagnosis of a systemic inflammatory condition with the composition of the kit.
In preferred embodiments, the subject is human. The present definition is used to clarify current clinical practice and does not represent a critical aspect of the invention see, e. Methods for determining which subjects are at risk of developing sepsis are well known to those in the art. A hallmark of SIRS is the creation of a proinflammatory state that can be marked by tachycardia, tachypnea or hyperpnea, hypotension, hypoperfusion, oliguria, leukocytosis or leukopenia, pyrexia or hypothermia and the need for volume infusion.
SIRS characteristically does not include a documented source of infection e. Thus, sepsis refers to the systemic inflammatory response to a documented infection see, e.
Because the methods of the present invention can be used to detect sepsis prior to a time that sepsis would be suspected using conventional techniques, in certain embodiments, the subject's disease status at early sepsis is confirmed retrospectively, when the manifestation of sepsis is more clinically obvious. The exact mechanism by which a subject becomes septic is not a critical aspect of the invention.
The methods of the present invention can detect the onset of sepsis independent of the origin of the infectious process. Hypoperfusion abnormalities include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.
For example, detection of a particular fragment of a compound can be indicative of the presence of the compound itself in the biological sample. A biomarker can, for example, be isolated from the biological sample, directly measured in the biological sample, or detected in or determined to be in the biological sample.
A biomarker can, for example, be functional, partially functional, or non-functional. Such a prediction is limited by the accuracy of the means used to make this determination. The present invention provides a method, e. In some embodiments, the act of predicting the development of sepsis predicting sepsis is accomplished by evaluating one or more biomarker profiles from a subject using a decision rule that is indicative of the development of sepsis and, as a result of this evaluation, receiving a result from the decision rule that indicates that the subject will become septic.
Such an evaluation of one or more biomarker profiles from a test subject using a decision rule uses some or all the amounts in the one or more biomarker profiles to obtain such a result. A peptide or polypeptide that specifically binds to an antigen may bind to other peptides or polypeptides with lower affinity, as determined by standard experimental techniques, for example, by any immunoassay well-known to those skilled in the art.
Antibodies or fragments that specifically bind to an antigen may be cross-reactive with related antigens.
Preferably, antibodies or fragments thereof that specifically bind to an antigen do not cross-react with other antigens. See, e. A reference subject is useful for establishing a reference amount of the biomarker that can be used to evaluate an amount of the biomarker in a test subject for the diagnosis or prognosis of a systemic inflammatory condition.
A biomarker profile comprises at least two such biomarkers or indications thereof, where the biomarkers can be in the same or different classes, such as, for example, a nucleic acid and a carbohydrate. A biomarker profile may also comprise at least three, four, five, 10, 20, 30 or more biomarkers or indications thereof.
In one embodiment, a biomarker profile comprises hundreds, or even thousands, of biomarkers or indications thereof. A biomarker profile can further comprise one or more controls or internal standards. In one embodiment, the biomarker profile comprises at least one biomarker, or indication thereof, that serves as an internal standard. In another embodiment, a biomarker profile comprises an indication of one or more types of biomarkers.
A feature can include, for example, the presence or absence of the biomarker in the biological sample, the abundance or amount of the biomarker in the sample, the ratio of amounts of molecules in the sample, etc. A feature may also be the difference between a measurable aspect of the corresponding biomarker that is taken from two samples, where the two samples are collected from a subject at two different time points.
Those of skill in the art will appreciate that other methods of computation of a feature can be devised and all such methods are within the scope of the present invention.
For example, a feature can represent the average of an abundance of a biomarker across biological samples collected from a subject at two or more time points. Furthermore, a feature can be the difference or ratio of the abundance of two or more biomarkers from a biological sample obtained from a subject in a single time point. A biomarker profile may also comprise at least three, four, five, 10, 20, 30 or more features. In one embodiment, a biomarker profile comprises hundreds, or even thousands, of features.
For instance, a phenotypic change can include an increase or decrease of a biomarker in a bodily fluid, where the change is associated with SIRS, sepsis, the onset of sepsis or with a particular stage in the progression of sepsis.
A phenotypic change can further include a change in a detectable aspect of a given state of the subject that is not a change in a measurable aspect of a biomarker. For example, a change in phenotype can include a detectable change in body temperature, respiration rate, pulse, blood pressure, or other physiological parameter. Such changes can be determined via clinical observation and measurement using conventional techniques that are well-known to the skilled artisan.
Such decision rules can take on one or more forms that are known in the art, as exemplified in Hastie et al.
A decision rule may be used to act on a data set of features to, inter alia, predict the onset of sepsis, to determine the progression of sepsis, or to diagnose sepsis. Exemplary decision rules that can be used in some embodiments of the present invention are described in further detail in Section 5. Such an evaluation of one or more biomarker profiles from a test subject using a decision rule uses some or all the features in the one or more biomarker profiles to obtain such a result.
In a preferred embodiment, a training population includes samples from subjects that are converters and subjects that are nonconverters. Representative data analysis algorithms are described in Section 5. In one specific example, a value set represents a prediction that a subject will develop sepsis. In another example, a value set represents a prediction that a subject will not develop sepsis.
The nature of this value set and the values therein is dependent upon the type of features present in the biomarker profile and the data analysis algorithm used to construct the decision rule that dictates the value set.
For example, a biomarker profile of each member of a training population can be obtained. Each such biomarker profile includes a measured feature for each biomarker. These feature values can be used by a data analysis algorithm to construct a decision rule. The data analysis algorithm can be a decision tree, described below. A decision rule defines value sets. One such value set is predictive of the onset of sepsis.
A subject whose biomarker feature values satisfy this value set is likely to become septic. For example, a value set can comprise the amount of biomarker A being less than a first value and the amount of biomarker B being less than a second value. Another such value set is predictive of a septic-free state. A subject whose biomarker feature values satisfy this value set is not likely to become septic. An exemplary value set of this could comprise biomarker A being greater than the first value and biomarker B being greater than a third value.
Where the data analysis algorithm is a neural network analysis and the final product of this neural network analysis is an appropriately weighted neural network, one value set is those ranges of biomarker profile feature values that will cause the weighted neural network to indicate that onset of sepsis is likely.
Another value set is those ranges of biomarker profile feature values that will cause the weighted neural network to indicate that onset of sepsis is not likely. Preferably, prevention refers to the use of a compound or composition in a subject not yet affected by the disease or disorder or not yet exhibiting a symptom of the disease or disorder, for instance a subject not yet infected or not yet exhibiting the symptoms of infection.
Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexyl methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds.
Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- butadienyl , 2,4-pentadienyl, 3- 1,4-pentadienyl , ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
Cocoa Beach. Cooper City. Coral Gables. Coral Springs. Crystal River. Daytona Beach. Deerfield Beach. Delray Beach. Fernandina Beach. Fort Lauderdale. Fort Myers. Fort Pierce. Fort Walton Beach. Greenacres City. Gulf Breeze. Gulf Shores. Holmes Beach. Jacksonville Beach. Jensen Beach. Task 3d pose estimation using rgb. Task gaze estimation. Task lane detection. Task semantic parsing. Task scene text recognition.
Task point cloud registration. Task time series analysis. Task music source separation. Task online multi-object tracking. Task emotion recognition in conversation. Task fine-grained image classification. Task visual place recognition. Task saliency prediction. Task transfer learning.
Task sarcasm detection. Task 3d human reconstruction. Task boundary detection. Task core set discovery. Task document layout analysis. Task classification with binary neural network. Task object counting. Task egocentric activity recognition. Task product recommendation. Task food recognition. Task action quality assessment. Task unsupervised video object segmentation. Task sound event detection. Task source code summarization.
Task 3d object recognition. Task speech separation. Task curriculum learning. Task 3d object tracking. Task audio source separation. Task abnormal event detection in video. Task object localization. Task scene flow estimation. Task video inpainting. Task multimodal unsupervised image-to-image translation.
Task language modelling. Task face sketch synthesis. Task optical flow estimation. Task monocular depth estimation. Task 3d face reconstruction. Task multiple object tracking. Task temporal action localization. Task colorectal polyps characterization. Task document classification. Task dense video captioning. Task facial landmark detection. Task abusive language. Task multimodal machine translation. Task active learning. Task lexical entailment. Task patch matching. Task bias detection.
Task activity detection. Task grasp contact prediction. Task activity recognition. Task automatic post-editing. Task dictionary learning. Task remote sensing image classification. Task video understanding. Task binarization. Task unsupervised object segmentation. Task face model. Task classification with binary weight network.
Task one-shot learning. Task speech enhancement. Task deblurring. Task video frame interpolation. Task automated theorem proving. Task chatbot. Task human action generation. Task retinal vessel segmentation. Task emotion recognition. Task scene text. Task feature selection. Task adversarial defense. Task depression detection. Task natural language inference.
Task face recognition. Task scientific results extraction. Task multi-label classification. Task fact verification. Task computed tomography ct. Task human part segmentation. Task homography estimation.
Task image denoising. Task offline rl. Task 3d pose estimation. Task video object detection. Task goal-oriented dialog. Task handwriting recognition. Task referring expression segmentation. Task gesture recognition. Task person search. Task pose estimation. Task sketch-based image retrieval.
Task semantic similarity. Task clique prediction. Task video segmentation. Task generalized zero-shot learning. Task multi-task learning. Task aesthetics quality assessment. Task human-object interaction detection. Task multivariate time series forecasting. Task sentence embedding. Task question answering. Task cross-view image-to-image translation. Task kg-to-text generation.
Task rgb salient object detection. Task crowd counting. Task latent variable models. General newreposistory for to learning - how dagshub works. Task mathematical question answering. Task autonomous driving. Task multiple instance learning. Task color constancy. Task instance segmentation. Task action unit detection. Task stochastic optimization. Task pedestrian attribute recognition. Task sentence embeddings. Task joint entity and relation extraction.
Task motion segmentation. Task emotion classification. Task fact checking. Task saliency detection. Task few-shot image classification. Task dense pixel correspondence estimation. Task scene generation. Task grammatical error correction.
Task minecraft. Task music transcription. Task hate speech detection. Task meta-learning. Task semantic segmentation. Task video retrieval. Task action segmentation. Task atari games. Task defect detection. Task conditional image generation. Task document summarization. Task coreference resolution. Task dialogue generation. Task skeleton based action recognition. Task 3d human pose estimation.
David Lee, M. Dena Moskowitz, M. Ross Moskowitz, M. Roshan Patel, M. Leon Seard, II, M. Heidi A. Stephany, M. Edward Uchio, M. Elias Wehbi, M. Ramy Youssef Yaacoub, M. Faysal A. Yafi, M. View All Specialists. Kidney Stones. Urinary Incontinence. Ureter Cancer. Enlarged Prostate. See More.
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