Biomarker combination for screening heart failure pleural effusion, application, system, equipment and medium

Abstract

The invention discloses a biomarker combination for screening heart failure pleural effusion as well as application, a system, equipment and a medium. The biomarker combination comprises palmitoyl carnitine, stearoyl carnitine, octadecadienoyl carnitine, and the hydrothorax serum concentration ratio of at least one long-chain acyl carnitine in octadecaenoyl carnitine. The biomarker combination provided by the invention has higher clinical value in screening or auxiliary diagnosis of heart failure pleural effusion.

Description

Technical Field

[0001] This invention belongs to the field of biomarker screening technology, specifically relating to a combination of biomarkers for screening pleural effusion in heart failure, as well as their applications, systems, devices, and media. Background Technology

[0002] Pleural effusion (PE) is a common clinical sign caused by various diseases affecting the pleura. Statistically, the four most common causes of PE are malignant tumors, heart failure, pneumonia, and tuberculosis. In clinical practice, misdiagnosis of the cause of PE often leads to unnecessary treatments and examinations. Malignant pleural effusion (MPE), parapneumonic pleural effusion (PPE), and tuberculous pleural effusion (TPE) require invasive examinations, while patients with cardiogenic pleural effusion (HF) usually do not require invasive examinations and only need systemic treatment. Therefore, timely and accurate identification of the cause of PE is crucial for optimizing patient treatment, improving quality of life, and prognosis.

[0003] Traditional biochemical and immunological methods for detecting NT-proBNP have a sensitivity and specificity of approximately 90% for diagnosing heart failure (HF). However, the accuracy of NT-proBNP in diagnosing HF is affected by factors such as age and renal function. Metabolomics involves the qualitative and quantitative analysis of all small molecule metabolites in an organism, primarily studying changes in the types and quantities of metabolites after stimulation by internal and external factors. The combination of metabolomics and bioinformatics allows for in-depth exploration of disease mechanisms, diagnostic biomarkers, and the screening of drug therapeutic targets. LC-MS / MS, with its high throughput, high sensitivity, and high specificity, is particularly beneficial for the identification and screening of diagnostic biomarkers.

[0004] Acylcarnitine (AC) is a fatty acid metabolite and can serve as an important diagnostic indicator of fatty acid oxidation disorders, such as in newborn screening for inherited metabolic diseases. AC with a carbon chain length of C13-C20 is defined as long-chain acylcarnitine (LCAC), whose biological function is to transport long-chain fatty acids into mitochondria. However, whether LCAC can be used as an adjunct in the diagnosis of heart failure (HF) remains unknown.

[0005] It should be noted that the information disclosed in the background section above is only used to enhance the understanding of the background of the present invention, and therefore may include information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0006] To address the aforementioned problems in the prior art, this invention provides a combination of biomarkers for screening pleural effusion in heart failure, along with its application, system, device, and medium. The technical problem to be solved by this invention is achieved through the following technical solution: In a first aspect, the present invention provides a combination of biomarkers for screening pleural effusion in heart failure, said biomarker combination being selected from at least one of the following (a) to (d): (a) The ratio of the concentration of palmitoylcarnitine in pleural fluid samples to the concentration of palmitoylcarnitine in serum samples; (b) The ratio of the concentration of stearoylcarnitine in pleural fluid samples to the concentration of stearoylcarnitine in serum samples; (c) The ratio of the concentration of octadecadienoic carnitine in pleural fluid samples to the concentration of octadecadienoic carnitine in serum samples; (d) The ratio of the concentration of octadecenoic carnitine in pleural fluid samples to the concentration of octadecenoic carnitine in serum samples.

[0007] Secondly, the present invention provides an application of the above-mentioned detection reagent for screening combinations of biomarkers for pleural effusion in heart failure in the preparation of products for screening pleural effusion in heart failure.

[0008] In one embodiment of the present invention, the product is a kit for screening pleural effusion in heart failure, comprising a first detection reagent for detecting the concentration of palmitoylcarnitine in pleural fluid samples and serum samples; And / or a second detection reagent for detecting the concentration of stearoylcarnitine in pleural fluid and serum samples; And / or a third detection reagent for detecting the concentration of octadecadienoic carnitine in pleural fluid and serum samples; And / or a fourth detection reagent for detecting the concentration of octadecenoylcarnitine in pleural fluid and serum samples.

[0009] Thirdly, the present invention provides a system for screening pleural effusion in heart failure, comprising: The data acquisition module is used to obtain the concentration of long-chain acylcarnitine in serum and pleural fluid samples; including obtaining the concentration C of palmitoylcarnitine in pleural fluid samples. pC16 Compared with the concentration of palmitoylcarnitine in serum samples C sC16 And / or the concentration of stearoylcarnitine C in pleural fluid samples pC18 Compared with the concentration of stearoylcarnitine in serum samples C sC18 The concentration of octadecadienoic carnitine (C) in pleural fluid samples pC18:2 The concentration of octadecadienoic carnitine in serum samples C sC18:2 And / or the concentration of octadecenoylcarnitine C in pleural fluid samples pC18:1The concentration of octadecenoylcarnitine in serum samples C sC18:1 ; The calculation module is used to calculate the ratio of each long-chain acylcarnitine in the pleural fluid sample to that in the serum sample, K. C16 = C pC16 / C sC16 , and / or K C18 = C pC18 / C sC18 , and / or K C18:2 = C pC18:2 / C sC18:2 , and / or K C18:1 = C pC18:1 / C sC18:1 ; The judgment module compares the ratio obtained by the calculation module with a preset corresponding reference threshold. The output module outputs the risk level of heart failure pleural effusion based on the comparison results from the judgment module.

[0010] In one embodiment of the present invention, the K C16 Greater than the corresponding reference threshold α C16 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C16 The risk level of heart failure with pleural effusion is high; The K C18 Greater than the corresponding reference threshold α C18 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C18 The risk level of heart failure with pleural effusion is high; The K C18:2 Greater than the corresponding reference threshold α C18:2 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C18:2 The risk level of heart failure with pleural effusion is high; The K C18:1 Greater than the corresponding reference threshold α C18:1 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C18:1 The risk level of heart failure with pleural effusion is high.

[0011] In one embodiment of the present invention, the K C16 Reference threshold α C16 K is 0.597. C18 Reference threshold α C18 K is 0.492. C18:2 Reference threshold αC18:2 K is 0.443. C18:1 Reference threshold α C18:1 It is 0.307.

[0012] In one embodiment of the present invention, the serum sample and the pleural effusion sample are from the same subject, and the subject is a patient with pleural effusion.

[0013] Fourthly, the present invention provides an electronic device, including a memory and a processor. The memory stores a computer program, and when the processor calls the computer program in the memory, it implements the functions of each module in the system for screening pleural effusion in heart failure.

[0014] Fifthly, the present invention provides a storage medium storing a computer program for implementing the functions of each module in the system for screening pleural effusion in heart failure.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention uses the ratio of the serum concentration of at least one LCAC among palmitoylcarnitine, stearoylcarnitine, octadecadienoylcarnitine, and octadecadienoylcarnitine as a biomarker composition for screening pleural effusion in heart failure, and has high accuracy and sensitivity.

[0016] 2. The present invention also provides a system for screening pleural effusion in patients with heart failure. The system can determine the probability of a subject having pleural effusion due to heart failure by using the ratio of pleural fluid to serum concentration in the LCAC, thus providing high auxiliary value for clinical diagnosis.

[0017] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0018] Figure 1 These are violin plots of C16 concentration (A), C18 concentration (B), C18:2 concentration (C), C18:1 concentration (D), C18:1OH concentration (E), and C18OH concentration (F) in serum samples from patients with different types of pleural effusion, provided in embodiments of the present invention. Figure 2 These are violin diagrams of C16 concentration (A), C18 concentration (B), C18:2 concentration (C), and C18:1 concentration (D) in pleural fluid samples from patients with different types of pleural effusion, provided in embodiments of the present invention. Figure 3These are schematic diagrams (A), (B), (C), (C18:2), (D), (E), and (F) of C18:1OH concentrations in serum samples from the HF and NHF groups, provided in this embodiment of the invention. Figure 4 These are schematic diagrams (A), (B), (C), and (D) of C16, C18, C18:2, and C18:1 concentrations in pleural fluid samples from the HF and NHF groups, provided in this embodiment of the invention. Figure 5 The ROC curves (A) constructed using C16, C18, C18:2, C18:1, C18:1OH and C18OH from serum, respectively, and the ROC curves (B) constructed using C16, C18, C18:2 and C18:1 from pleural fluid samples, respectively, are provided in the embodiments of the present invention. Figure 6 The ROC curves plotted using the LCAC serum concentration ratio and NT-proBNP are provided in the embodiments of the present invention. Figure 7 This is a heatmap showing the correlation between C16, C18, C18:2, and C18:1 in pleural effusion samples, C16, C18, C18:2, and C18:1 in serum samples, and NT-proBNP, provided in an embodiment of the present invention. Figure 8 This is a schematic diagram illustrating the evaluation of the coefficients of variation of C16, C18, C18:2, C18:1, C18:1OH, and C18OH in pleural effusion samples provided in this embodiment of the invention. Figure 9 This is a decision curve plotted using the pleural effusion-serum ratio based on LCAC, provided in an embodiment of the present invention. Detailed Implementation

[0019] To further illustrate the technical means and effects adopted by the present invention to achieve the intended purpose, the following, in conjunction with the accompanying drawings and specific embodiments, provides a detailed description of a combination of biomarkers for screening pleural effusion in heart failure, its application, system, device, and medium proposed according to the present invention.

[0020] The foregoing and other technical contents, features, and effects of the present invention will be clearly presented in the following detailed description of specific embodiments in conjunction with the accompanying drawings. Through the description of the specific embodiments, a more in-depth and concrete understanding can be gained of the technical means and effects adopted by the present invention to achieve its intended purpose. However, the accompanying drawings are for reference and illustration only and are not intended to limit the technical solutions of the present invention.

[0021] It should be noted that, in this document, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, the terms "comprising," "including," or any other variations are intended to cover non-exclusive inclusion, such that an article or apparatus comprising a list of elements includes not only those elements but also other elements not expressly listed.

[0022] The term "pleural effusion" refers to an ex vivo specimen or sample. In the description of this invention, it can be understood that the pleural effusion collected from a patient with pleural effusion is a pleural effusion sample.

[0023] Example 1: Sample Acquisition and Analysis A total of 170 patients with unexplained pleural effusion were included in the study for analysis. Exclusion criteria were as follows: (i) patients with an undetermined diagnosis at discharge; (ii) pregnant women; (iii) patients under 18 years of age; (iv) patients who developed pleural effusion during hospitalization; and (v) pleural effusion caused by trauma. This study was approved by the Ethics Committee of the Affiliated Hospital of Inner Mongolia Medical University (No. 2018011). All participants signed informed consent forms. The Declaration of Helsinki was strictly followed in conducting this study.

[0024] The diagnostic criteria are as follows: Malignant pleural effusion (MPE) is diagnosed based on a positive pleural biopsy or positive pleural fluid cytology. In some patients with a high probability of MPE but negative cytology, and who are unwilling or unable to undergo pleural biopsy, the diagnosis of MPE is based on the primary tumor, after ruling out other causes of pleural effusion. Tuberculous pleural effusion (TPE) is diagnosed based on a positive pleural biopsy, positive Mycobacterium tuberculosis culture, or positive acid-fast staining. In some patients with a high probability of tuberculous pleural effusion but negative etiological evidence, and who are unwilling to undergo pleural biopsy, the diagnosis of tuberculous pleural effusion is based on a pleural fluid adenosine deaminase (ADA) activity greater than 35 U / L, good responsiveness to anti-tuberculosis treatment, and after ruling out other causes of pleural effusion. Parapneumonia pleural effusion (PPE) is diagnosed based on a clinical composite criterion, including the patient's imaging characteristics, microbial culture, physical examination, laboratory tests, medical history, and responsiveness to antibiotic treatment. The diagnostic criteria for heart failure pleural effusion (HF) include clinical manifestations, imaging features, serum NT-proBNP, and response to anti-heart failure treatment.

[0025] According to the above criteria, 11 patients had unclear final diagnoses, 2 patients withdrew their informed consent, and 4 patients were excluded due to a history of cancer. Ultimately, 153 patients were included in this embodiment, including 23 cases of pleural effusion due to heart failure, 66 cases of malignant pleural effusion, 32 cases of pleural effusion adjacent to pneumonia, 20 cases of tuberculous pleural effusion, and 12 cases of pleural effusion caused by other etiologies (4 cases of pulmonary embolism pleural effusion, 2 cases of mixed connective tissue disease pleural effusion, 1 case of cirrhosis pleural effusion, 1 case of pleural effusion caused by pneumothorax, 1 case of pleural effusion due to idiopathic pleural fibroelastosis, 1 case of interstitial lung disease pleural effusion, 1 case of pulmonary thromboembolism pleural effusion, and 1 case of hypoalbuminemia pleural effusion).

[0026] The 153 patients were divided into two groups: a heart failure pleural effusion group (HF group, including 23 cases of heart failure pleural effusion) and a non-heart failure pleural effusion group (NHF group, including 66 cases of malignant pleural effusion, 32 cases of parapneumonia pleural effusion, 20 cases of tuberculous pleural effusion, and 12 cases of other causes). Pleural fluid and serum samples were collected from each group. Specific sample collection and pretreatment included: 1. Sample Collection: Pleural fluid and venous blood were collected simultaneously before the patient's treatment. Venous blood samples were collected in test tubes without anticoagulants.

[0027] 2. Coagulation and centrifugation: After collection, pleural fluid and venous blood samples were left to stand at room temperature (25°C) for 4 hours to allow for full coagulation, and then centrifuged at 3000 rpm for 10 minutes.

[0028] 3. Aliquoting and storage: Carefully aspirate the supernatant (serum or pleural effusion) after centrifugation and aliquot it into pre-labeled 0.5 mL or 1.5 mL EP tubes (centrifuge tubes, Eppendorf tubes), and immediately transfer it to an ultra-low temperature freezer at -80°C for long-term storage.

[0029] Table 1 shows the baseline clinical characteristics of the subjects. The study population in this embodiment is highly representative and includes patients with various types of pleural effusion.

[0030] Table 1. Baseline characteristics of subjects from sample sources

[0031] Among them, WBC is white blood cells, LDH is lactate dehydrogenase, and NT-proBNP is the N-terminal precursor of type B natriuretic peptide.

[0032] Example 2: Sample Detection and Data Analysis The statistical methods used for data processing in this embodiment of the invention are as follows: continuous variables are represented as median and interquartile range (IQR), and categorical variables are represented as absolute numbers and percentages. The Kolmogorov-Smirnov method is used to test the normality of continuous variables. The Mann-Whitney U test or independent samples t-test is used to compare continuous variables between two groups; the Kruskal-Wallis H test or analysis of variance is used to compare continuous variables between three or more groups; and the chi-square test or Fisher's exact test is used to compare categorical data. The Spearman method is used to analyze the correlation between LCAC in serum and pleural effusion. Receiver operating characteristic (ROC) curves are used to assess the diagnostic accuracy of LCAC and NT-proBNP for HF. The Delong test is used to compare the area under the curve (AUC) of different biomarkers or models. Multiple repeated tests are performed on the same mixed pleural effusion sample, and the coefficient of variation (CV) is used to assess the stability of the data to evaluate the stability of tandem mass spectrometry for pleural effusion detection; decision curve analysis (DCA) is used to assess the net benefit of pleural effusion CP. A two-sided p < 0.05 is considered statistically significant.

[0033] Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used with an AB SCIEX API3200MD system to detect the concentrations of palmitoylcarnitine (C16), stearoylcarnitine (C18), octadecadienoylcarnitine (C18:2), octadecenoylcarnitine (C18:1), 3-hydroxy-octadecenoylcarnitine (C18:1OH), and 3-hydroxy-octadecanoylcarnitine (C18OH) in serum samples from both the HF and NHF groups. The concentrations of C16, C18, C18:2, and C18:1 in pleural effusion samples from both groups were also detected. The personnel conducting the testing were unaware of the final diagnoses of the participants corresponding to the samples. The test results were presented using the median (25th percentile – 75th percentile), as shown in Table 2.

[0034] Table 2. Results of long-chain acylcarnitine detection in serum and pleural fluid samples.

[0035] Combination Figure 1The C16 concentration in serum samples from patients with different types of pleural effusion is shown. Figure 1 (A), C18 concentration ( Figure 1 (B), C18:2 concentration ( Figure 1 C), C18:1 concentration ( Figure 1 (C18:1OH concentration) Figure 1 (E) and C18OH concentration ( Figure 1 The violin plot (F) shows the median, interquartile range, and outliers of serum samples from patients with different types of pleural effusion. Figure 2 The C16 concentration in pleural fluid samples from patients with different types of pleural effusion is shown. Figure 2 (A), C18 concentration ( Figure 2 (B), C18:2 concentration ( Figure 2 C) and C18:1 concentration ( Figure 2 The violin plot (D) shows the median, interquartile range, and outlier values ​​of pleural fluid samples from patients with different types of pleural effusion.

[0036] Following the experimental groupings in Example 1, the levels of long-chain acylcarnitine (LCAC) in serum and pleural effusion samples were compared between the HF and NHF groups. Figure 3 As shown, the concentration of C16 in serum samples from the HF group and the NHF group was compared ( Figure 3 Comparison of A and C18 concentrations ( Figure 3 Comparison of concentrations of B and C18:2 ( Figure 3 Comparison of C18:1 concentrations (C18:1) Figure 3 Comparison of C18:1OH concentrations (D) and C18:1OH Figure 3 Comparison of E and C18OH concentrations ( Figure 3 A bar chart of (F) in the middle. For example... Figure 4 As shown, the C16 concentration in pleural effusion samples from the HF group and the NHF group was compared. Figure 4 Comparison of A and C18 concentrations ( Figure 4 Comparison of concentrations of B and C18:2 ( Figure 4 Comparison of C18:1 and C18:1 concentrations Figure 4 The bar chart of D).

[0037] from Figure 3 and Figure 4As can be seen from the Mann-Whitney U test analysis, the concentrations of six long-chain acylcarnitines (C16, C18, C18:2, C18:1, C18:1OH, C18OH) in the serum samples of the HF group were significantly higher than those of the NHF group, while the concentrations of four long-chain acylcarnitines (C16, C18, C18:2, C18:1) in the pleural effusion samples of the HF group were significantly lower than those of the NHF group. This may be because acylcarnitines are ester compounds produced by the combination of fatty acids and L-carnitine. Their function is to transport the acyl group from the mitochondrial matrix for β-oxidation, thereby generating ATP to maintain cellular activity. Under normal circumstances, fatty acid oxidation is the main energy source for the myocardium, but in a failing heart, the cardiac metabolic substrate is converted from fatty acids to carbohydrates. Thus, the serum LCAC concentration in HF patients is higher than that in PE patients from other causes. Malignant pleural effusion, tuberculous pleural effusion, and parapneumonic pleural effusion are all exudates caused by increased pleural vascular permeability, while pleural effusion due to heart failure is a transudate caused by impaired cardiac pumping function and increased hydrostatic pressure in the pleural capillaries. Furthermore, although heart failure involves a weak systemic inflammatory response, its intensity is weaker than that of malignant tumors, pneumonia, and tuberculosis.

[0038] like Figure 5 As shown, (A) are ROC curves constructed using six long-chain acylcarnitines (C16, C18, C18:2, C18:1, C18:1OH, C18OH) from serum samples; (B) are ROC curves constructed using four long-chain acylcarnitines (C16, C18, C18:2, C18:1) from pleural fluid samples.

[0039] Example 3: Performance Analysis of Biomarker Combination Screening The concentration of C16 in a serum sample is defined as C. sC16 The concentration of C18 is C sC18 The concentration of C18:2 is C sC18:2 The concentration of C18:1 is C sC18:1 In the pleural effusion sample, the concentration of C16 was C pC16 The concentration of C18 is C pC18 The concentration of C18:2 is C pC18:2 The concentration of C18:1 is C pC18:1 The ratio of LCAC in the pleural effusion sample to LCAC in the serum is K. C16 = C pC16 / C sC16 K C18 = C pC18 / C sC18 K C18:2 = C pC18:2 / CsC18:2 K C18:1 = C pC18:1 / C sC18:1 Based on K respectively C16 K C18 K C18:2 or K C18:1 Construct the receiver operating characteristic (ROC) curve; see [link to ROC curve]. Figure 6 And Table 3.

[0040] Table 3. ROC curve parameters

[0041] Wherein, Serum represents serum sample, PF represents pleural fluid sample, ratio represents the ratio of LCAC in pleural fluid sample to LCAC in serum sample; PLR (95% CI) represents positive likelihood ratio (95% confidence interval), and NLR (95% CI) represents negative likelihood ratio (95% confidence interval).

[0042] according to Figure 5 (A) Table 3 and Figure 6 The results shown indicate that the AUC value of the pleural fluid serum ratio of C18:1OH and C18OH is lower than the AUC value using the serum concentrations of C18:1OH and C18OH. Therefore, the pleural fluid serum ratio of C18:1OH and C18OH is not included in the biomarker group.

[0043] According to Table 3 and Figure 6 The results shown, with ROC curves plotted using the pleural fluid serum concentration ratios of LCAC, all have an area under the curve (AUC) greater than 0.8. Specifically, the AUCs for the pleural fluid serum concentration ratios of C18 and C18:2 are both 0.85, while the AUC for the pleural fluid serum concentration ratio of C18:1 is 0.86, indicating that using the pleural fluid serum concentration ratio of LCAC can improve the accuracy of HF screening. Figure 6 The diagram also illustrates the ROC curve for diagnosing HF using serum NT-proBNP as a positive control. In this example, the areas under the curve for NT-proBNP were similar for four LCAC pleural effusion serum ratios (C16, C18, C18:2, and C18:1), indicating that these four LCAC pleural effusion serum ratios and NT-proBNP have similar diagnostic value. Figure 5 Figure (A) illustrates the ROC curve constructed using only serum C16, C18, C18:2, and C18:1. Figure 5The comparison of ROC curves constructed using only C16, C18, C18:2, and C18:1 in pleural fluid samples (Figure B) shows a significant increase in AUC. This means that using the LCAC ratio of pleural fluid to serum concentration can improve the diagnostic performance of HF in patients with pleural effusion.

[0044] like Figure 7 The image shows a heatmap of correlation analysis of C16, C18, C18:2, and C18:1 in pleural fluid samples, C16, C18, C18:2, and C18:1 in serum samples, and NT-proBNP. Figure 7 The results showed that each LCAC in serum samples had a weak positive correlation with NT-proBNP, and each LCAC in pleural effusion samples had a weak negative correlation with NT-proBNP. However, there was almost no correlation between each LCAC in pleural effusion samples and each LCAC in serum samples. This indicates that it is necessary to detect the four LCACs mentioned above in pleural effusion and serum at the same time, and suggests that the ratio of LCACs in pleural effusion to serum can improve diagnostic accuracy.

[0045] like Figure 8 The image shows 20 repeated measurements of C16, C18, C18:2, C18:1, C18:1OH, and C18OH in the same pleural effusion sample. The coefficient of variation (CV) was used to assess the stability of the data, evaluating the stability of tandem mass spectrometry (LC-MS / MS) for detecting pleural effusion samples. The results indicate that the multiple measurements of C16, C18, C18:2, and C18:1 show good stability, suggesting that LC-MS / MS technology offers higher sensitivity and specificity for targeted detection of serum and pleural effusion samples from patients.

[0046] See Figure 9 Decision curve analysis (DCA) was used to plot the pleural effusion-to-serum ratio of LCAC to evaluate the decision value of the LCAC ratio in screening patients with tuberculous pleural effusion. Figure 9As shown, the vertical axis represents the net benefit of the model. The red dashed line (None) is the baseline when all subjects are classified as "non-heart failure pleural effusion," and the blue diagonal dashed line (All) is the reference line when all subjects are classified as "heart failure pleural effusion." The curve corresponding to C16 represents the net benefit of using the C16 pleural effusion-to-serum ratio at different threshold probabilities; the curve corresponding to C18 represents the net benefit of using the C18 pleural effusion-to-serum ratio at different threshold probabilities; the curve corresponding to C18:2 represents the net benefit of using the C18:2 pleural effusion-to-serum ratio at different threshold probabilities; and the curve corresponding to C18:1 represents the net benefit of using the C18:1 pleural effusion-to-serum ratio at different threshold probabilities. The DCA curve plotted using the pleural effusion-to-serum ratio of LCAC provided by this invention has a larger range than the baseline strategy (full intervention or no intervention), indicating that the biomarker combination provided by this invention has high clinical net benefit and strong clinical applicability.

[0047] The present invention also provides a system for screening pleural effusion in heart failure, comprising: The data acquisition module is used to acquire the concentration of long-chain acylcarnitines in serum and pleural fluid samples; this includes acquiring the concentration C of palmitoylcarnitine in pleural fluid samples. pC16 Compared with the concentration of palmitoylcarnitine in serum samples C sC16 And / or the concentration of stearoylcarnitine C in pleural fluid samples pC18 Compared with the concentration of stearoylcarnitine in serum samples C sC18 The concentration of octadecadienoic carnitine (C) in pleural fluid samples pC18:2 The concentration of octadecadienoic carnitine in serum samples C sC18:2 And / or the concentration of octadecenoylcarnitine C in pleural fluid samples pC18:1 The concentration of octadecenoylcarnitine in serum samples C sC18:1 In this embodiment, the serum sample and the pleural effusion sample came from the same subject, and the subject was a patient with pleural effusion.

[0048] The calculation module is used to calculate the ratio of each long-chain acylcarnitine in the pleural fluid sample to that in the serum sample, K. C16 = C pC16 / C sC16 , and / or K C18 = C pC18 / C sC18 , and / or K C18:2 = C pC18:2 / C sC18:2 , and / or K C18:1 = C pC18:1 / C sC18:1The judgment module compares the ratio obtained by the calculation module with a preset reference threshold. The output module outputs the risk level of the subject's heart failure and pleural effusion based on the comparison result from the judgment module.

[0049] Another embodiment of the present invention provides a storage medium storing a computer program for executing the functions of various modules in the system for screening pleural effusion in heart failure as described in the above embodiments. A further aspect of the present invention provides an electronic device including a memory and a processor. The memory stores a computer program, and when the processor calls the computer program in the memory, it implements the functions of various modules in the system for screening pleural effusion in heart failure as described in the above embodiments. Specifically, the integrated modules implemented as software functional modules can be stored in a computer-readable storage medium. The software functional modules stored in the storage medium include several instructions to cause an electronic device (which may be a personal computer, server, or network device, etc.) or processor to execute some steps of the methods described in the various embodiments of the present invention. The aforementioned storage medium includes various media capable of storing program code, such as a USB flash drive, a portable hard drive, a read-only memory (ROM), a random access memory (RAM), a magnetic disk, or an optical disk.

[0050] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A combination of biomarkers for screening pleural effusion in heart failure, characterized in that, The combination of biomarkers is selected from at least one of the following (a) to (d): (a) The ratio of the concentration of palmitoylcarnitine in pleural fluid samples to the concentration of palmitoylcarnitine in serum samples; (b) The ratio of the concentration of stearoylcarnitine in pleural fluid samples to the concentration of stearoylcarnitine in serum samples; (c) The ratio of the concentration of octadecadienoic carnitine in pleural fluid samples to the concentration of octadecadienoic carnitine in serum samples; (d) The ratio of the concentration of octadecenoic carnitine in pleural fluid samples to the concentration of octadecenoic carnitine in serum samples.

2. The use of the detection reagent of claim 1 for screening combinations of biomarkers for pleural effusion in heart failure in the preparation of a product for screening pleural effusion in heart failure.

3. The application according to claim 2, characterized in that, The product is a kit for screening pleural effusion in heart failure, containing a first detection reagent for detecting the concentration of palmitoylcarnitine in pleural fluid and serum samples; And / or a second detection reagent for detecting the concentration of stearoylcarnitine in pleural fluid and serum samples; And / or a third detection reagent for detecting the concentration of octadecadienoic carnitine in pleural fluid and serum samples; And / or a fourth detection reagent for detecting the concentration of octadecenoylcarnitine in pleural fluid and serum samples.

4. A system for screening pleural effusion in heart failure, characterized in that, include: The data acquisition module is used to obtain the concentration of long-chain acylcarnitine in serum and pleural fluid samples; including obtaining the concentration C of palmitoylcarnitine in pleural fluid samples. pC16 Compared with the concentration of palmitoylcarnitine in serum samples C sC16 And / or the concentration of stearoylcarnitine C in pleural fluid samples pC18 Compared with the concentration of stearoylcarnitine in serum samples C sC18 The concentration of octadecadienoic carnitine (C) in pleural fluid samples pC18:2 The concentration of octadecadienoic carnitine in serum samples C sC18:2 And / or the concentration of octadecenoylcarnitine C in pleural fluid samples pC18:1 The concentration of octadecenoylcarnitine in serum samples C sC18:1 ; The calculation module is used to calculate the ratio of each long-chain acylcarnitine in the pleural fluid sample to that in the serum sample, K. C16 = C pC16 / C sC16 , and / or K C18 = C pC18 / C sC18 , and / or K C18:2 = C pC18:2 / C sC18:2 , and / or K C18:1 = C pC18:1 / C sC18:1 ; The judgment module compares the ratio obtained by the calculation module with a preset corresponding reference threshold. The output module outputs the risk level of heart failure pleural effusion based on the comparison results from the judgment module.

5. The system for screening pleural effusion in heart failure according to claim 4, characterized in that, The K C16 Greater than the corresponding reference threshold α C16 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C16 The risk level of heart failure with pleural effusion is high; The K C18 Greater than the corresponding reference threshold α C18 The risk level of heart failure with pleural effusion is low; The K C16 Less than the reference threshold α C18 The risk level of heart failure with pleural effusion is high; The K C18:2 Greater than the corresponding reference threshold α C18:2 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C18:2 The risk level of heart failure with pleural effusion is high; The K C18:1 Greater than the corresponding reference threshold α C18:1 The risk level of heart failure with pleural effusion is low; the K C16 Less than the reference threshold α C18:1 The risk level of heart failure with pleural effusion is high.

6. The system for screening pleural effusion in heart failure according to claim 5, characterized in that, The K C16 Reference threshold α C16 K is 0.

597. C18 Reference threshold α C18 K is 0.

492. C18:2 Reference threshold α C18:2 K is 0.

443. C18:1 Reference threshold α C18:1 It is 0.

307.

7. The system for screening pleural effusion in heart failure according to claim 4, characterized in that, The serum and pleural effusion samples were from the same subject, who was a patient with pleural effusion.

8. An electronic device comprising a memory and a processor, characterized in that, The memory stores a computer program, and when the processor calls the computer program in the memory, it implements the functions of each module in the system for screening pleural effusion in heart failure as described in claim 4.

9. A storage medium, characterized in that, The storage medium stores a computer program that implements the functions of each module in the system for screening pleural effusion in heart failure as described in claim 4.

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