Apparauts and method for screening sepsis using monocyte distribution width and presepsin

Abstract

An apparatus and method for screening sepsis using monocyte distribution width and preceptin are disclosed. A method for screening sepsis using monocyte distribution width and preceptin according to one embodiment of the present invention may include: (a) acquiring first test data including a monocyte distribution width (MDW) value measured from a blood sample of a subject; (b) comparing the monocyte distribution width value with a preset first threshold value; (c) selectively acquiring second test data including a preceptin value measured from the blood sample according to the comparison result; and (d) deriving analysis information associated with sepsis of the subject using at least one of the monocyte distribution width value and the preceptin value.

Description

Technology Field

[0001] The present invention relates to a sepsis screening device and method using a mononuclear cell separation vector and preceptin. Background Technology

[0002] Sepsis is a life-threatening disease caused by severe infection, and early diagnosis and rapid treatment can significantly improve patient survival rates. Rapid identification of sepsis is essential for patient management and prognosis improvement in the emergency room, and various biomarkers are currently being utilized for the early diagnosis of sepsis.

[0003] In this regard, one of the representative biomarkers used for the early diagnosis of sepsis is Monocyte Distribution Width (MDW). Developed by Beckman Coulter, MDW is a value automatically calculated during a Complete Blood Count (CBC) and measures the size diversity of monocytes; it has been approved by the U.S. Food and Drug Administration (FDA) as an early indicator of sepsis. In particular, MDW has been recognized as a useful tool for ruling out sepsis.

[0004] Another important diagnostic marker for sepsis is preceptin, a soluble CD14 subtype derived from monocytes. It is primarily used to diagnose bacterial sepsis and can be measured by chemiluminescent immunoassay using the Sysmex HISCL system and the PATHFAST instrument manufactured by PHC Corporation.

[0005] However, conventional approaches using MDW and preceptin alone have several limitations. When MDW is measured alone, approximately 10% of sepsis patients show false negatives, and a similar proportion of sepsis patients may be missed in diagnosis when preceptin is measured alone. This can pose a significant problem in diseases where early diagnosis and treatment are crucial, such as sepsis, while performing both tests on all patients may be inefficient in terms of medical costs.

[0006] Furthermore, additional research is needed to determine whether the MDW threshold currently approved by the FDA is the optimal value for diagnosing sepsis; in particular, studies on the effectiveness of various testing strategies and optimal thresholds in emergency room settings are limited.

[0007] The technology forming the background of this invention is disclosed in Korean Registered Patent Publication No. 10-2114739. The problem to be solved

[0008] The present invention aims to solve the problems of the aforementioned conventional technology by providing a sepsis screening device and method using monocyte width (MDW) and preceptin that can enhance the efficiency of early sepsis diagnosis through the sequential measurement of monocyte width and preceptin.

[0009] The present invention aims to solve the problems of the aforementioned conventional technology by providing a sepsis screening device and method using monocyte width and preceptin that can improve cost efficiency while increasing the accuracy of sepsis diagnosis by utilizing monocyte width (MDW), which can be automatically obtained during CBC measurement without additional measurement costs, as a primary screening tool, and by subsequently measuring preceptin only when necessary based on the results of the primary screening.

[0010] The present invention aims to solve the problems of the aforementioned conventional technology by providing a sepsis screening device and method using mononuclear wave and preceptin that can provide improved diagnostic performance compared to the conventional FDA-approved threshold application method by applying an optimal threshold of mononuclear wave (MDW) for early diagnosis of sepsis.

[0011] The present invention aims to solve the problems of the aforementioned conventional technology by providing a sepsis screening device and method using mononuclear segmentation width and preceptin that minimizes the false-negative rate during sepsis diagnosis, thereby supporting the early identification and initiation of treatment for sepsis patients and ultimately contributing to the improvement of patient prognosis.

[0012] However, the technical problems that the embodiments of the present invention aim to solve are not limited to the technical problems described above, and other technical problems may exist. means of solving the problem

[0013] As a technical means for achieving the above-mentioned technical problem, a sepsis screening method using monocyte distribution width and preceptin according to one embodiment of the present invention may include: (a) a step of obtaining first test data including a monocyte distribution width (MDW) value measured from a blood sample of a subject; (b) a step of comparing the monocyte distribution width value with a preset first threshold value; (c) a step of selectively obtaining second test data including a preceptin value measured from the blood sample according to the comparison result; and (d) a step of deriving analysis information associated with sepsis of the subject using at least one of the monocyte distribution width value and the preceptin value.

[0014] Additionally, in step (c), if the value of the mononuclear separation width is less than the first threshold value, the second inspection data can be obtained.

[0015] In addition, the above step (d) can derive the analysis information based on the result of comparing the above preceptin value with a preset second threshold value.

[0016] In addition, step (a) above may obtain the mononuclear cell separation width value using a Complete Blood Count (CBC) test performed on the blood sample.

[0017] Additionally, step (d) can generate analysis information that classifies the subject as sepsis positive if the mononuclear separation width value is greater than or equal to the first threshold, or if the mononuclear separation width value is less than the first threshold but the preceptin value is greater than or equal to the second threshold.

[0018] Additionally, step (d) can generate analysis information that classifies the subject as sepsis negative if the mononuclear separation width value is less than the first threshold and the preceptin value is less than the second threshold.

[0019] In addition, the first threshold value can be set in the range of 19.45 to 21.5.

[0020] In addition, the first threshold value may be 19.45.

[0021] In addition, the second threshold value can be set within a range including 500 pg / mL.

[0022] In addition, the first threshold and the second threshold may be set so that the false negative rate of sepsis for subjects classified as sepsis negative by the analysis information is below a preset threshold level.

[0023] Meanwhile, a sepsis screening device using monocyte distribution width and preceptin according to one embodiment of the present invention may include a test data collection unit that acquires first test data including a monocyte distribution width (MDW) value measured from a blood sample of a subject, an additional test execution unit that compares the monocyte distribution width value with a preset first threshold value and selectively acquires second test data including a preceptin value measured from the blood sample according to the comparison result, and an analysis execution unit that derives analysis information associated with sepsis of the subject using at least one of the monocyte distribution width value and the preceptin value.

[0024] In addition, the above additional inspection unit can acquire the above second inspection data if the above mononuclear separation width value is less than the above first threshold value.

[0025] In addition, the analysis performing unit can derive the analysis information based on the result of comparing the preceptin value with a preset second threshold value.

[0026] In addition, the above test data collection unit can obtain the above mononuclear cell separation width value by using a Complete Blood Count (CBC) test performed on the above blood sample.

[0027] Additionally, the analysis performing unit may generate analysis information classifying the subject as sepsis positive if the mononuclear separation width value is greater than or equal to the first threshold, or if the mononuclear separation width value is less than the first threshold but the preceptin value is greater than or equal to the second threshold.

[0028] In addition, the analysis performing unit may generate analysis information classifying the subject as sepsis negative if the mononuclear separation width value is less than the first threshold value and the preceptin value is less than the second threshold value.

[0029] The means for solving the problem described above are merely exemplary and should not be interpreted as intended to limit the present invention. In addition to the exemplary embodiments described above, additional embodiments may exist in the drawings and the detailed description of the invention. Effects of the invention

[0030] According to the means for solving the problem of the present invention described above, a sepsis screening device and method using mononuclear width and preceptin can be provided, which can enhance the efficiency of early diagnosis of sepsis through sequential measurement of mononuclear width (MDW) and preceptin.

[0031] According to the means for solving the problem of the present invention described above, a sepsis screening device and method using monocyte width and preceptin can be provided, which can improve cost efficiency while increasing the accuracy of sepsis diagnosis by utilizing the monocyte width (MDW), which can be automatically obtained during CBC measurement without additional measurement costs, as a primary screening tool, and by following up with preceptin measurement only when necessary based on the results of the primary screening.

[0032] According to the means for solving the problem of the present invention described above, by applying an optimal threshold value of the monocyte separation width (MDW) for early diagnosis of sepsis, it is possible to provide a sepsis screening device and method using monocyte separation width and preceptin that can provide improved diagnostic performance compared to the conventional FDA-approved threshold application method.

[0033] According to the means for solving the problem of the present invention described above, by minimizing the false negative rate during sepsis diagnosis, it is possible to provide a sepsis screening device and method using mononuclear segmentation width and preceptin that can support the early identification and initiation of treatment for sepsis patients and ultimately contribute to improving the patient's prognosis.

[0034] According to the aforementioned means for solving the problem of the present invention, by improving the early diagnosis and management of sepsis in emergency rooms and other medical environments, it is possible to contribute to reducing the burden of unnecessary additional tests and increasing the accuracy of diagnosis.

[0035] However, the effects obtainable from this invention are not limited to those described above, and other effects may exist. Brief explanation of the drawing

[0036] FIG. 1 is a schematic diagram of a sepsis screening system according to one embodiment of the present invention. Figure 2 is a conceptual diagram schematically illustrating the process of collecting analysis data. Figures 3a and 3b are graphs comparing MDW (monocyte width) and preceptin distribution according to the presence or absence of sepsis. Figure 4 is a scatter plot illustrating the correlation between monocyte width (MDW), preceptin values, and the occurrence of sepsis. Figure 5 is a graph showing the results of the ROC (Receiver Operating Characteristic) curve analysis of the monocyte width (MDW) in the diagnosis of sepsis. Figures 6a to 6d are conceptual diagrams for comparing the performance of multiple sepsis screening strategies, including a monocyte width (MDW)-based diagnostic method, a preceptin-based diagnostic method, and an MDW-preceptin sequential diagnostic method. Figures 7a and 7b are graphs comparing the diagnostic performance of the monocyte-divided width (MDW)-based diagnostic method, the preceptin-based diagnostic method, and the MDW-preceptin sequential diagnostic method, respectively, in terms of sensitivity, specificity, positive predictive value, negative predictive value, area under the ROC curve, and accuracy. FIG. 8 is a schematic diagram of a sepsis screening device using a mononuclear segmentation width and preceptin according to one embodiment of the present invention. FIG. 9 is a flowchart of a sepsis screening method using a mononuclear segmentation width and preceptin according to one embodiment of the present invention. Specific details for implementing the invention

[0037] Embodiments of the present invention are described below with reference to the attached drawings to enable those skilled in the art to easily implement the invention. However, the present invention may be embodied in various different forms and is not limited to the embodiments described herein. Furthermore, in order to clearly explain the present invention in the drawings, parts unrelated to the explanation have been omitted, and similar parts throughout the specification are denoted by similar reference numerals.

[0038] Throughout this specification, when a part is described as being "connected" to another part, this includes not only cases where they are "directly connected," but also cases where they are "electrically connected" or "indirectly connected" with other elements interposed between them.

[0039] Throughout the entire specification, when a component is described as being located "on," "on top," "on top," "under," "on bottom," or "on bottom" of another component, this includes not only cases where the component is in contact with the other component but also cases where another component exists between the two components.

[0040] Throughout this specification, when a part is described as "comprising" a certain component, this means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0041] The present invention relates to a sepsis screening device and method using a mononuclear cell separation vector and preceptin.

[0042] FIG. 1 is a schematic diagram of a sepsis screening system according to one embodiment of the present invention.

[0043] Referring to FIG. 1, a sepsis screening system (10) according to one embodiment of the present invention may include a sepsis screening device (100) using a mononuclear segmentation width and preceptin according to one embodiment of the present invention (hereinafter referred to as the 'screening device (100)'), a testing device (200), a user terminal (300), and a database (400).

[0044] A screening device (100), inspection equipment (200), user terminal (300), and database (400) can communicate with each other through a network (20). The network (20) refers to a connection structure that enables information exchange between each node, such as terminals and servers. Examples of such a network (20) include, but are not limited to, a 3GPP (3rd Generation Partnership Project) network, an LTE (Long Term Evolution) network, a 5G network, a WIMAX (World Interoperability for Microwave Access) network, the Internet, a LAN (Local Area Network), a Wireless LAN (Wireless Local Area Network), a WAN (Wide Area Network), a PAN (Personal Area Network), a Wi-Fi network, a Bluetooth network, a satellite broadcasting network, an analog broadcasting network, and a DMB (Digital Multimedia Broadcasting) network.

[0045] The user terminal (300) can be any type of wireless communication device, such as a smartphone, smartpad, tablet PC, PCS (Personal Communication System), GSM (Global System for Mobile communication), PDC (Personal Digital Cellular), PHS (Personal Handyphone System), PDA (Personal Digital Assistant), IMT (International Mobile Telecommunication)-2000, CDMA (Code Division Multiple Access)-2000, W-CDMA (W-Code Division Multiple Access), Wibro (Wireless Broadband Internet) terminal.

[0046] Additionally, in the description of the embodiments of the present invention, the testing equipment (200) may include various medical testing devices for measuring the monocyte separation width (MDW) value and preceptin value from a blood sample of a subject.

[0047] More specifically, the testing equipment (200) may broadly include a blood cell analyzer for performing a Complete Blood Count (CBC) test, a chemiluminescent immunoassay device for measuring preceptsin, etc. Such testing equipment (200) may communicate with the screening device (100) through a network (20) to transmit test data including measured monocyte separation width (MDW) values ​​and preceptsin values ​​to the screening device (100).

[0048] Additionally, in the description of the embodiments of the present invention, the database (400) may be a server or device for storing test result data for a subject's blood sample, analysis information associated with sepsis, clinical data for each subject, etc.

[0049] In particular, the database (400) can systematically store and manage information such as monocyte width (MDW) values, preceptin values, and sepsis positive / negative determination results derived based thereon, and the database (400) can store information regarding diagnostic performance indicators such as threshold values ​​for sepsis diagnosis, false negative rate data, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, the screening device (100) of the present invention, which is described in detail below, can operate to access the database (400) to refer to necessary information or to store new test results and analysis information.

[0050] Below, the specific functions and operations of the screening device (100) will be described in detail.

[0051] First, the screening device (100) can obtain first test data including a Monocyte Distribution Width (MDW) value measured from a blood sample of a subject.

[0052] Specifically, the screening device (100) can obtain a monocyte separation width (MDW) value using a Complete Blood Count (CBC) test performed on a blood sample of a subject.

[0053] More specifically, the screening device (100) can obtain first test data transmitted from the testing equipment (200) through the network (20). At this time, the first test data may include the monocyte width (MDW) value and related information measured by the blood analyzer of the testing equipment (200) performing a complete blood count (CBC) test on the subject's blood sample.

[0054] Meanwhile, the mononuclear cell width (MDW) has the advantage of being automatically calculated during a complete blood count (CBC) test, so it can be obtained without additional testing costs. The screening device (100) can acquire this first test data and store it in a database (400) at the same time, or determine whether additional testing is necessary based on the acquired data.

[0055] Additionally, the screening device (100) can provide the acquired first test data to medical staff through a user terminal (300), and through this, medical staff can check the subject's monocyte width (MDW) value in real time.

[0056] Additionally, the screening device (100) can compare the mononuclear particle width (MDW) value included in the first test data with a preset first threshold value, and selectively obtain second test data including a preceptin value measured from a blood sample based on the result of comparing the obtained mononuclear particle width (MDW) value with the first threshold value.

[0057] In this regard, according to one embodiment of the present invention, a first threshold value associated with the single-nuclear width (MDW) can be set in the range of 19.45 to 21.5.

[0058] More preferably, the first threshold value may be 19.45. In this regard, if the first threshold value of the monocyte width (MDW) is set to 19.45, the sensitivity of the diagnosis of sepsis can be significantly improved.

[0059] According to the experimental examples of the present invention described in detail below, through the analysis of the Receiver Operating Characteristic (ROC) curve, it was found that the highest sensitivity of 99.22% was achieved when the MDW value exceeded 19.45. This first threshold value was derived by considering the balance point of optimal sensitivity and specificity in the ROC curve analysis, and corresponds to a sepsis rule-in cut-off that is effective in minimizing the false negative rate of sepsis, particularly in the sequential measurement strategy of MDW and preceptin.

[0060] In particular, according to the experimental example of the present invention described below, when the first threshold value is set to 19.45 and the sequential measurement strategy of the screening device (100) is applied, it can be confirmed that high accuracy is achieved, as no sepsis patients are found in the group of subjects where both the monocyte separation width (MDW) and preceptin are below the threshold value.

[0061] As another example, the first threshold can be set to 21.5. In this regard, 21.5, which is applicable as the first threshold for the monocyte separation width (MDW), is the official threshold for sepsis screening approved by the U.S. Food and Drug Administration (FDA). This is a standardized value widely used for the purpose of sepsis rule-out, and its applicability in clinical settings has been verified.

[0062] In particular, according to the experimental example of the present invention described below, when the first threshold was set to 21.5 and the sequential measurement strategy disclosed in the present invention was applied, only 18.18% of subjects with both mononuclear particle width (MDW) and preceptin below the threshold were identified as septic patients, and this result is a result of a significant reduction in the false negative rate compared to a single measurement strategy (i.e., a mononuclear particle width-only measurement method or a preceptin-only measurement method).

[0063] In other words, the screening device (100) can improve diagnostic accuracy through a sequential measurement strategy while maintaining compatibility with existing medical systems by applying an FDA-approved threshold according to an embodiment of the present invention.

[0064] Specifically, the screening device (100) can obtain second test data including preceptin values ​​if, as a result of comparing a preset first threshold value with the subject's mononuclear width (MDW) value, the mononuclear width (MDW) value is less than the first threshold value.

[0065] In other words, the sequential measurement method introduced by this institution is designed to improve the accuracy of sepsis diagnosis while minimizing unnecessary tests for subjects; if the Monocyte Distinction Width (MDW) value is above the first threshold, the subject is judged to have a high probability of sepsis and can be classified as sepsis-positive without additional preceptin testing.

[0066] On the other hand, if the monocyte width (MDW) value is below the first threshold, the presence of sepsis can be accurately determined by additionally checking the preceptin value. This sequential approach is more cost-effective than performing both tests on all subjects, and testing time and costs can be reduced by omitting the preceptin test for subjects with an MDW value above the first threshold.

[0067] In addition, since the mononuclear cell width (MDW) test is performed automatically along with the complete blood count (CBC) test, there is an advantage in that the primary screening step can be performed without separate sample collection or additional costs.

[0068] In summary, the screening device (100) can derive analysis information associated with the subject's sepsis using at least one of the monocyte width (MDW) value and the preceptin value.

[0069] For example, if there is second inspection data obtained by the screening device (100), the screening device (100) can derive analysis information based on the result of comparing the preceptin value included in the second inspection data with a preset second threshold value.

[0070] In this regard, the second threshold can be set within a range including 500 pg / mL. This is because it is known that when the preceptin value is 500 pg / mL or higher, the likelihood of bacterial infection and sepsis increases. In this regard, according to the experimental example of the present invention described below, when this second threshold was applied, the sensitivity was 89.84% and the specificity was 39.87% when preceptin was measured alone, and the negative predictive value (NPV) when the preceptin value was less than 500 pg / mL was 82.43%, confirming that the majority of subjects with preceptin values ​​below the second threshold did not actually have sepsis.

[0071] This second threshold is particularly effective in a sequential measurement strategy with the monocyte separation width (MDW), and can improve the accuracy of sepsis diagnosis by considering both biomarkers. Additionally, the second threshold can be adjusted within the range of 450 pg / mL to 550 pg / mL according to an embodiment of the present invention, taking into account the characteristics of the target patient group or the clinical environment, and this corresponds to a parameter that can be changed through the settings of the screening device (100).

[0072] Additionally, according to one embodiment of the present invention, the screening device (100) can generate analysis information classifying a subject as positive for sepsis if the mononuclear width (MDW) value is greater than or equal to a first threshold, or if the mononuclear width (MDW) value is less than the first threshold but the preceptin value is greater than or equal to a second threshold.

[0073] Additionally, according to one embodiment of the present invention, the screening device (100) can generate analysis information classifying the subject as sepsis negative if the monocyte separation width (MDW) value is less than a first threshold and the preceptin value is less than a second threshold.

[0074] Meanwhile, in the description of the embodiments of the present invention, the first threshold and the second threshold, which serve as criteria for screening sepsis in subjects, may each be set such that the false negative rate of sepsis for subjects classified as sepsis negative by analysis information obtained through the aforementioned sequential measurement / judgment method is below a preset threshold level.

[0075] In this regard, according to one embodiment of the present invention, a screening device (100) can set a first threshold and a second threshold so that the sepsis false negative rate is less than a preset reference rate (e.g., 5%, etc.). Specifically, when the first threshold was set to 19.45 and the second threshold to 500 pg / mL, the sepsis false negative rate was found to be 0% as a result of applying a sequential measurement strategy.

[0076] This represents a significant decrease compared to the false negative rate of 9.4% (12 / 128) when measuring monocyte width (MDW) alone and 10.2% (13 / 128) when measuring preceptin alone. The reduction in the false negative rate is of great significance in sepsis management, as it prevents sepsis patients from being missed in diagnosis, thereby securing opportunities for early treatment. The threshold setting method proposed by our institution can contribute to effectively identifying patients suspected of sepsis in an emergency room setting and minimizing the burden caused by unnecessary treatments or tests.

[0077] That is, the sequential measurement strategy of mononuclear width (MDW) and preceptin disclosed herein can provide several advantages compared to existing single biomarker measurement methods. First, the screening device (100) can significantly improve the sensitivity of sepsis diagnosis, and more specifically, according to the experimental example of the present invention described below, the sensitivity was 90.63% when measuring mononuclear width (MDW) alone and 89.84% when measuring preceptin alone, but the sensitivity increased to 98.44% when the sequential measurement strategy was applied.

[0078] In addition, the sepsis false-negative rate can be minimized by the sequential measurement technique of the screening device (100). Specifically, subjects with both monocyte width (MDW) and preceptin below the threshold have a very low probability of sepsis, and in particular, when the first threshold was set to 19.45, results showed that no false-negatives occurred.

[0079] In addition, the sequential measurement strategy of the screening device (100) has the advantage of being cost-effective, as it can reduce testing costs by utilizing additional preceptin test results only when necessary, instead of performing both tests on all subjects.

[0080] Hereinafter, an experimental example linked to the screening device (100) disclosed herein will be described with reference to FIGS. 2 to 7b.

[0081] Figure 2 is a conceptual diagram schematically illustrating the process of collecting analysis data.

[0082] Referring to Figure 2, the subject selection and test data collection process for sepsis screening in the experimental example of the present invention was examined. From June 2020 to June 2021, 483 patients suspected of having sepsis were selected. Of these, 202 patients who were under 20 years of age or had inappropriate residual plasma samples (volume less than 1 mL, hemolysis, coagulation, etc.) were excluded, and finally, 281 patients were selected as study subjects. These 281 patients had complete data for both monocyte width (MDW) and preceptin measurements, and the patients were classified into a sepsis group and a suspected sepsis group according to the Sepsis-3 criteria. Among the final study subjects, 128 (45.6%) were confirmed to have sepsis, and 14 (5.0%) were diagnosed with septic shock.

[0083] Figures 3a and 3b are graphs comparing the distribution of MDW (monocyte width) and preceptin according to the presence or absence of sepsis. Specifically, Figure 3a shows the distribution of MDW values ​​between the sepsis group and the non-sepsis group, where the red dotted line represents 21.5, which is the first threshold for MDW. Figure 3b shows the log-transformed distribution of preceptin values ​​between the sepsis group and the non-sepsis group, where the red dotted line represents 500 pg / mL, which is the second threshold for preceptin values.

[0084] Referring to Figure 3a, when the mononuclear width (MDW) values ​​were divided into quartiles, the first quartile (Q1) value was found to be 22.76. This value is similar to the threshold of 21.5 recommended by the manufacturer. The median mononuclear width (MDW) between the non-septic group and the septic group showed a statistically significant difference.

[0085] Specifically, in the non-septic group, it was 24.45 (95% confidence interval, 23.85-25.20), and in the septic group, it was 26.53 (95% confidence interval, 25.56-27.63), with P = 0.0014. These results show that the monocyte width (MDW) value can be used as a significant indicator to distinguish between septic patients and non-septic patients.

[0086] In addition, as shown in the graph of Figure 3a, the distribution of monocyte size width (MDW) values ​​in the sepsis group is skewed toward a relatively high level, which is consistent with the biological phenomenon in which the size diversity of monocytes increases when sepsis occurs.

[0087] Referring to Figure 3b, when the preceptin values ​​were divided into quartiles, the first quartile (Q1) value was found to be 493.5 pg / mL. This value is very similar to the second threshold value of 500 pg / mL, and the median preceptin between the non-septic group and the septic group showed a statistically significant difference.

[0088] Specifically, the values ​​were 590.0 pg / mL (95% confidence interval, 518.8-729.9) in the non-septic group and 1,383.5 pg / mL (95% confidence interval, 1,113.2-1,696.7) in the septic group, with P < 0.0001. These results suggest that preceptin values ​​can be used as an indicator to distinguish between septic and non-septic patients. In particular, the difference between the two groups was more pronounced with preceptin compared to monocyte width (MDW), which can be interpreted as preceptin being a biomarker that reflects a specific response to bacterial infection.

[0089] Figure 4 is a scatter plot illustrating the correlation between monocyte width (MDW), preceptin values, and the occurrence of sepsis.

[0090] Referring to Figure 4, in the scatter plot, black circles represent patients diagnosed with sepsis, white circles represent patients without sepsis, and red dotted lines represent the first threshold of the monocyte width (MDW) of 21.5 and the second threshold of the preceptin value of 500 pg / mL, respectively, and accordingly, the scatter plot is divided into four quadrants.

[0091] More specifically, referring to the scatter plot in Figure 4, only 2 out of 128 sepsis patients (1.6%) were located in the quadrant where both the monocyte width (MDW) and preceptin values ​​were below the threshold. Looking at the data for these two patients, one patient had an MDW of 20.07 and a preceptin of 397 pg / mL, while the other patient had an MDW of 19.5 and a preceptin of 333 pg / mL. These results indicate that a sequential measurement strategy using both biomarkers together is effective in minimizing the false-negative rate.

[0092] In addition, the scatter plot in Figure 4 shows that patients with sepsis are concentrated in the upper right quadrant, where the monocyte width (MDW) is high and preceptin is also high, suggesting that the combination of the two biomarkers can improve the accuracy of sepsis diagnosis.

[0093] Figure 5 is a graph showing the results of the ROC (Receiver Operating Characteristic) curve analysis of the monocyte width (MDW) in the diagnosis of sepsis.

[0094] Referring to Figure 5, the results of the Receiver Operating Characteristic (ROC) curve analysis of the Monocyte Distinction Width (MDW) in the diagnosis of sepsis can be seen. In this analysis, when the MDW value of 25.34 was set as the threshold, the Area Under the Curve (AUC) was 0.611 (95% confidence interval: 0.55-0.67), showing moderate accuracy in the diagnosis of sepsis.

[0095] In particular, when the mononuclear width (MDW) value exceeded 19.45, the highest sensitivity of 99.22% was achieved, but there is a disadvantage in that the specificity drops to 1.96% at such a low threshold. These ROC curve analysis results demonstrate that the mononuclear width (MDW) can provide high sensitivity in sepsis screening and suggest that it may be even more effective when combined with other biomarkers, such as preceptin. Furthermore, these analysis results support the first threshold for the mononuclear width (MDW) of 19.45 disclosed herein as the optimal value for minimizing the false-negative rate of sepsis.

[0096] Figures 6a to 6d are conceptual diagrams for comparing the performance of multiple sepsis screening strategies, including a monocyte width (MDW)-based diagnostic method, a preceptin-based diagnostic method, and an MDW-preceptin sequential diagnostic method.

[0097] Specifically, FIG. 6a is a flowchart for a mononuclear divide width (MDW)-only measurement strategy, FIG. 6b is a flowchart for a preceptin-only measurement strategy, FIG. 6c is a flowchart for a mononuclear divide width (MDW)-preceptin sequential strategy using a first threshold of 21.5, which is an FDA-approved threshold, and FIG. 6d is a flowchart for a Rule-in mononuclear divide width (MDW)-preceptin sequential strategy using a first threshold of 19.45, which is the threshold proposed herein.

[0098] Referring to Figure 6a, in the strategy of measuring only the mononuclear particle width (MDW), 250 out of a total of 281 subjects (88.9%) were classified as positive with an MDW value of 21.5 or higher, and 31 subjects (11.0%) were classified as negative. Among the 128 patients diagnosed with sepsis, 12 (9.4%) were classified as false negatives with an MDW value below the threshold. These results indicate that some sepsis patients may be missed when measuring only the MDW. Meanwhile, among the 250 subjects classified as MDW positive, 134 (53.6%) were confirmed not to actually have sepsis, indicating a significantly high false-positive rate.

[0099] Referring to Figure 6b, in the strategy of measuring preceptin alone, out of a total of 281 subjects, 207 (73.7%) were classified as positive with preceptin values ​​above the threshold of 500 pg / mL, and 74 (26.3%) were classified as negative. Among the 128 patients diagnosed with sepsis, 13 (10.2%) were classified as false negatives with preceptin values ​​below the threshold. This shows a false negative rate similar to that of measuring mononuclear cell width (MDW) alone, but the false positive rate is somewhat lower. Of the 207 subjects classified as preceptin positive, 92 (44.4%) were confirmed not to actually have sepsis, indicating a significant false positive rate that is lower than that of measuring mononuclear cell width (MDW) alone.

[0100] Referring to Figure 6c, in the sequential strategy of mononuclear width (MDW) and preceptin using an FDA-approved threshold of 21.5, 31 out of a total of 281 subjects showed MDW values ​​below the threshold. As a result of additionally testing these 31 subjects, 20 were classified as positive (preceptin values ​​above the threshold) and 11 as negative (below the threshold). Among the 11 subjects who were negative for both MDW and preceptin, only 2 (18.18%) were identified as septic patients. This demonstrates that the false-negative rate for sepsis decreased significantly to 1.6% (2 / 128) when the sequential measurement strategy was applied. This represents a significant improvement compared to the false-negative rate of 9.4% when MDW was measured alone and 10.2% when preceptin was measured alone. In addition, this sequential strategy is more cost-effective than performing both tests on all patients, and additional preceptin testing was not required for 250 subjects (88.9%) whose monocyte width (MDW) values ​​were above the threshold.

[0101] Referring to Figure 6d, in the Rule-in-Monocyte-Wide (MDW)-Preceptin sequential strategy using the proposed threshold of 19.45, only 4 out of a total of 281 subjects (1.4%) had a Monocyte-Wide (MDW) value below the threshold. As a result of additionally conducting a Preceptin test on these 4 subjects, 1 subject was classified as having a Preceptin value above the threshold (positive), and 3 subjects were classified as having a Preceptin value below the threshold (negative).

[0102] In particular, referring to Figure 6d, none of the three subjects who were negative for both mononuclear width (MDW) and preceptin were actually sepsis patients, and this result demonstrates that the sequential strategy using the proposed threshold of 19.45 can significantly reduce the false-negative rate for sepsis. However, this strategy has the disadvantage of increasing the false-positive rate because there are 277 subjects (98.6%) classified as having MDW values ​​above the threshold. Nevertheless, since minimizing false-negatives is important for diseases where early diagnosis and treatment are crucial, such as sepsis, this strategy can be clinically useful.

[0103] Figures 7a and 7b are graphs comparing the diagnostic performance of the monocyte width (MDW)-based diagnostic method, the preceptin-based diagnostic method, and the MDW-preceptin sequential diagnostic method, respectively, in terms of sensitivity, specificity, positive predictive value, negative predictive value, area under the ROC curve, and accuracy. Specifically, Figure 7a is a graph showing diagnostic indicators including the Positive Likelihood Ratio (PLR) and the Negative Likelihood Ratio (NLR), and Figure 7b is a graph showing diagnostic indicators including the Positive Predictive Value (PPV) and the Negative Predictive Value (NPV).

[0104] Referring to Figure 7a, the results of comparing the diagnostic performance of the mononuclear width (MDW), preceptin, and the sequential MDW-preceptin strategy can be seen. For the mononuclear width (MDW) alone strategy, the sensitivity was 90.63% (95% confidence interval: 84.20-95.06%) and the specificity was 12.42% (95% confidence interval: 7.65-18.71%). For the preceptin alone strategy, the sensitivity was 89.84% (95% confidence interval: 83.26-94.48%) and the specificity was 39.87% (95% confidence interval: 32.05-48.09%). When the sequential strategy of mononuclear width (MDW)-preceptin was applied, sensitivity was significantly improved to 98.44% (95% confidence interval: 94.47-99.81%), but specificity decreased to 5.88% (95% confidence interval: 2.73-10.87%).

[0105] The positive likelihood ratio (PLR) was similar for all three strategies, but the negative likelihood ratio (NLR) was lowest in the sequential strategy at 0.27 (95% confidence interval: 0.06-1.21). This indicates that the sequential strategy is most effective in minimizing sepsis false negatives. The area under the curve (AUC) was highest in the preceptin-only strategy at 0.65 (95% confidence interval: 0.59-0.70), and the accuracy was highest in the preceptin-only strategy at 62.63% (95% confidence interval: 56.69-68.31%).

[0106] Referring to Figure 7b, the results of comparing the performance of each strategy in terms of positive predictive value (PPV) and negative predictive value (NPV) can be seen. For the single strategy of mononuclear width (MDW), the positive predictive value was 46.40% (95% confidence interval: 44.38-48.44%) and the negative predictive value was 61.29% (95% confidence interval: 44.42-75.82%). For the single strategy of preceptin, the positive predictive value was 55.56% (95% confidence interval: 52.04-59.02%) and the negative predictive value was 82.43% (95% confidence interval: 73.01-89.06%). When the sequential strategy of mononuclear width (MDW)-preceptin was applied, the positive predictive value was 46.67% (95% confidence interval: 45.54-47.78%), which was similar to the mononuclear width (MDW) alone strategy, but the negative predictive value was significantly improved to 81.82% (95% confidence interval: 49.75-95.34%).

[0107] These results suggest that the sequential strategy demonstrates superior performance, particularly in terms of rule-out for sepsis. Specifically, subjects with both monocyte-separated width (MDW) and preceptin scores below the threshold have a very low probability of sepsis, which can help reduce unnecessary treatments and efficiently utilize medical resources. In particular, when considering the balance between positive and negative predictive values, it can be seen that while the preceptin-only strategy is superior in terms of diagnostic accuracy, the sequential strategy is more effective in minimizing false-negative rates.

[0108] FIG. 8 is a schematic diagram of a sepsis screening device using a mononuclear segmentation width and preceptin according to one embodiment of the present invention.

[0109] Referring to FIG. 8, the screening device (100) may include an inspection data collection unit (110), an additional inspection execution unit (120), and an analysis execution unit (130).

[0110] The test data collection unit (110) can obtain first test data including the Monocyte Distribution Width (MDW) value measured from the subject's blood sample.

[0111] Specifically, the test data collection unit (110) can obtain a monocyte separation width (MDW) value using a Complete Blood Count (CBC) test performed on a blood sample of the subject.

[0112] The additional test execution unit (120) compares the mononuclear segment width (MDW) value included in the first test data with a preset first threshold value, and can selectively obtain second test data including the preceptin value measured from the blood sample according to the result of comparing the obtained mononuclear segment width (MDW) value with the first threshold value.

[0113] Specifically, the additional test execution unit (120) can obtain second test data including preceptin values ​​if, as a result of comparison execution, the monocyte separation width (MDW) value is less than the first threshold value.

[0114] The analysis execution unit (130) can derive analysis information associated with the subject's sepsis using at least one of the monocyte division width (MDW) value and the preceptin value.

[0115] For example, if there is second test data obtained by the additional test execution unit (120), the analysis execution unit (130) can derive analysis information based on the result of comparing the preceptin value included in the second test data with a preset second threshold value.

[0116] Additionally, according to one embodiment of the present invention, the analysis performing unit (130) can generate analysis information classifying the subject as sepsis positive if the monocyte separation width (MDW) value is greater than or equal to a first threshold, or if the monocyte separation width (MDW) value is less than the first threshold but the preceptin value is greater than or equal to a second threshold.

[0117] Additionally, according to one embodiment of the present invention, the analysis performing unit (130) can generate analysis information classifying the subject as sepsis negative if the monocyte separation width (MDW) value is less than a first threshold and the preceptin value is less than a second threshold.

[0118] Below, based on the details described above, we will briefly examine the operation flow of the present invention.

[0119] FIG. 9 is a flowchart of a sepsis screening method using a mononuclear segmentation width and preceptin according to one embodiment of the present invention.

[0120] The sepsis screening method using a mononuclear separation blast and preceptin illustrated in FIG. 9 can be performed by the screening device (100) described above. Therefore, even if the details are omitted below, the description of the screening device (100) can be applied in the same way to the description of the sepsis screening method using a mononuclear separation blast and preceptin.

[0121] Referring to FIG. 9, in step S11, the test data collection unit (110) can obtain (a) first test data including a Monocyte Distribution Width (MDW) value measured from a blood sample of a subject.

[0122] Specifically, in step S11, the test data collection unit (110) can obtain a monocyte separation width (MDW) value using a Complete Blood Count (CBC) test performed on a blood sample of the subject.

[0123] Next, in step S12, the additional inspection unit (120) can compare (b) the single-dose width (MDW) value included in the first inspection data with a preset first threshold value.

[0124] Next, in step S13, the additional test performing unit (120) may optionally obtain second test data including the preceptin value measured from the blood sample according to (c) the comparison result.

[0125] Specifically, in step S13, the additional test performing unit (120) can obtain second test data including preceptin values ​​if, as a result of the judgment in step S12, the acquired monocyte separation width (MDW) value is less than the first threshold value.

[0126] Next, in step S14, the analysis performing unit (130) can derive analysis information associated with the subject's sepsis using at least one of (d) the monocyte division width (MDW) value and the preceptin value.

[0127] For example, in step S14, if the analysis performing unit (130) has second inspection data obtained through step S13, it can derive analysis information based on the result of comparing the preceptin value included in the second inspection data with a preset second threshold value.

[0128] Specifically, according to one embodiment of the present invention, in step S14, the analysis performing unit (130) can generate analysis information classifying the subject as sepsis positive if the monocyte separation width (MDW) value is greater than or equal to a first threshold, or if the monocyte separation width (MDW) value is less than the first threshold but the preceptin value is greater than or equal to a second threshold.

[0129] Additionally, according to one embodiment of the present invention, in step S14, the analysis performing unit (130) can generate analysis information classifying the subject as sepsis negative if the monocyte separation width (MDW) value is less than a first threshold and the preceptin value is less than a second threshold.

[0130] In the description above, steps S11 through S14 may be further divided into additional steps or combined into fewer steps according to an embodiment of the present invention. Additionally, some steps may be omitted as necessary, and the order of the steps may be changed.

[0131] A sepsis screening method using mononuclear saturation and preceptin according to one embodiment of the present invention may be implemented in the form of program instructions that can be executed through various computer means and recorded on a computer-readable medium. The computer-readable medium may include program instructions, data files, data structures, etc., either individually or in combination. The program instructions recorded on the medium may be those specifically designed and configured for the present invention, or may be those known and available to those skilled in the art of computer software. Examples of computer-readable recording media include magnetic media such as hard disks, floppy disks, and magnetic tapes; optical recording media such as CD-ROMs and DVDs; magneto-optical media such as floptical disks; and hardware devices specifically configured to store and execute program instructions, such as ROM, RAM, and flash memory. Examples of program instructions include machine code, such as that generated by a compiler, as well as high-level language code that can be executed by a computer using an interpreter, etc. The above-described hardware device may be configured to operate as one or more software modules to perform the operation of the present invention, and vice versa.

[0132] In addition, the sepsis screening method using the aforementioned mononuclear segmentation vector and preceptin can also be implemented in the form of a computer program or application executed by a computer stored on a recording medium.

[0133] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will understand that other specific forms can be easily modified without altering the technical concept or essential features of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single unit may be implemented in a distributed manner, and components described as distributed may likewise be implemented in a combined form.

[0134] The scope of the present invention is defined by the claims set forth below rather than by the detailed description above, and all modifications or variations derived from the meaning and scope of the claims and the concept of equivalents thereof should be interpreted as being included within the scope of the present invention. Explanation of the symbols

[0135] 10: Sepsis Screening System 100: Sepsis screening device using mononuclear cell separation blast and preceptin 110: Inspection Data Collection Unit 120: Additional Inspection Execution Unit 130: Analysis Execution Unit 200: Inspection equipment 300: User terminal 400: Database 20: Network

Claims

Claim 1 A screening method for sepsis using monocyte distribution width and preceptin, comprising: (a) obtaining first test data including a monocyte distribution width (MDW) value measured from a blood sample of a subject; (b) comparing the monocyte distribution width value with a preset first threshold value; (c) selectively obtaining second test data including a preceptin value measured from the blood sample according to the comparison result; and (d) deriving analysis information associated with sepsis of the subject using at least one of the monocyte distribution width value and the preceptin value. Claim 2 A screening method according to claim 1, wherein step (c) is to obtain the second test data if the mononuclear separation width value is less than the first threshold value, and step (d) is to derive the analysis information based on the result of comparing the preceptin value with a preset second threshold value. Claim 3 A screening method according to claim 1, wherein step (a) is to obtain the mononuclear cell separation width value using a Complete Blood Count (CBC) test performed on the blood sample. Claim 4 A screening method according to claim 1, wherein step (d) generates analysis information classifying the subject as sepsis positive if the mononuclear separation width value is greater than or equal to the first threshold, or if the mononuclear separation width value is less than the first threshold but the preceptin value is greater than or equal to the second threshold. Claim 5 A screening method according to claim 1, wherein step (d) generates analysis information classifying the subject as sepsis negative if the mononuclear cell separation width value is less than the first threshold value and the preceptin value is less than the second threshold value. Claim 6 A screening method according to claim 1, characterized in that the first threshold value is set in the range of 19.45 to 21.

5. Claim 7 A screening method according to claim 1, characterized in that the first threshold value is 19.

45. Claim 8 A screening method according to claim 2, characterized in that the second threshold is set within a range including 500 pg / mL. Claim 9 A screening method according to paragraph 2, wherein the first threshold and the second threshold are set such that the sepsis false negative rate for subjects classified as sepsis negative by the analysis information is below a preset threshold level. Claim 10 A screening device for sepsis using monocyte distribution width and preceptin, comprising: a test data collection unit for acquiring first test data including a monocyte distribution width (MDW) value measured from a blood sample of a subject; an additional test execution unit for comparing the monocyte distribution width value with a preset first threshold value and selectively acquiring second test data including a preceptin value measured from the blood sample according to the comparison result; and an analysis execution unit for deriving analysis information associated with sepsis of the subject using at least one of the monocyte distribution width value and the preceptin value. Claim 11 A screening device according to claim 10, wherein the additional inspection unit acquires the second inspection data if the mononuclear separation width value is less than the first threshold value, and the analysis unit derives the analysis information based on the result of comparing the preceptin value with a preset second threshold value. Claim 12 In claim 10, the screening device wherein the test data collection unit obtains the mononuclear cell separation width value using a Complete Blood Count (CBC) test performed on the blood sample. Claim 13 A screening device according to claim 11, wherein the analysis performing unit generates analysis information classifying the subject as sepsis positive if the mononuclear separation width value is greater than or equal to the first threshold value, or if the mononuclear separation width value is less than the first threshold value but the preceptin value is greater than or equal to the second threshold value, and generates analysis information classifying the subject as sepsis negative if the mononuclear separation width value is less than the first threshold value and the preceptin value is less than the second threshold value. Claim 14 A screening device according to claim 11, characterized in that the first threshold is set within a range including 19.45 and the second threshold is set within a range including 500 pg / mL. Claim 15 A screening device according to claim 11, wherein the first threshold and the second threshold are set such that the false negative rate of sepsis for subjects classified as sepsis negative by the analysis information is below a preset threshold level.

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