Biomarker for pSS-ILD poor prognosis, evaluation method and application of biomarker in related products

Abstract

The invention discloses a biomarker for pSS-ILD poor prognosis, an evaluation method and application of the biomarker in related products, and relates to the technical field of prediction of pSS-ILD poor prognosis. The biomarker of the poor prognosis of the pSS-ILD is serum CA125. The biomarker evaluation method for the poor prognosis of the pSS-ILD comprises the following steps: establishing a pSS-ILD patient queue; carrying out variable incorporation; performing chest HRCT classification and feature scoring; systematic clinical evaluation is carried out every 3-6 months, or visit is carried out more frequently according to clinical emergency situations; the prediction value of CA125 on death / lung transplantation is analyzed by adopting a subject working characteristic curve, and an optimal cutoff value is determined. The present invention reveals a potential effect of CA125 in pSS-ILD patients, especially its close association with disease severity and poor prognosis. Therefore, a theoretical basis is provided for taking CA125 as a biomarker for prognosis evaluation of pSS-ILD patients, and a new direction is also provided for application in clinical practice.

Description

Technical Field

[0001] The present invention relates to the technical field of predicting poor prognosis of pSS-ILD, and in particular to biomarkers and evaluation methods of poor prognosis of pSS-ILD and applications thereof in related products. Background Art

[0002] Primary Sjögren's syndrome (hypersensitivitypneumonitis, pSS-ILD) is a type of connective tissue disease-associated interstitial lung disease (CTD-ILD) and is an ILD with a known cause. pSS-ILD exhibits a variety of radiological and histopathological patterns. If its poor prognosis can be predicted, early treatment can improve survival. At present, the potential application value of blood circulation biomarkers in ILD patients is constantly being explored. Blood, as an important part of the body's circulatory system, includes cytokines, inflammatory mediators, protein markers, etc. Changes in these biomarkers may reflect pathophysiological processes and different states of the disease. Therefore, by analyzing biomarkers in the blood, it is expected to achieve early diagnosis of patients' conditions, monitoring of disease progression, and evaluation of treatment effects. Known biomarkers in the field of ILD include but are not limited to: sialolytic sugar chain antigen 6 (Krebs Von den Lungen-6, KL-6), surfactant protein D (surfactant protein D, SP-D), CC-chemokine ligand 18 (C-CMotif Chemokine Ligand 18, CCL18), matrix metalloproteinase 7 (Matrix Metallopeptidase 7, MMP7), etc. In recent years, serum tumor markers (such as CA125, CEA, CA153, CA19-9, etc.) are no longer limited to the screening of tumor diseases, and are gradually expanding their application in ILD.

[0003] Carbohydrate antigen 125 (CA125) is a transmembrane glycoprotein encoded by mucin 16 (MUC16) and is most commonly used to monitor patients with ovarian cancer. It is expressed in many tissues and organs of the human body and can be detected in epithelial cells of the cornea, peritoneum, pericardium, pleura, and airway epithelium, fallopian tubes, endometrium, and endocervix. CA125 expression levels can be increased in non-neoplastic diseases, including idiopathic pulmonary fibrosis (IPF) and CTD-ILD in ILD. The PROFILE multicenter study enrolled patients with IPF who were receiving treatment for the first time (ClinicalTrials.gov NCT01134822 & NCT01110694). Four serum biomarkers (SP-D, MMP7, CA19-9, and CA125) were identified. High levels of MMP7 were associated with poor survival, but the sensitivity and specificity were not high, not as good as baseline lung function or biomarkers such as SP-D, CA125, and CA19-9. SP-D, CA19-9, and CA125 are all secreted at low levels by the lung epithelium in health, of which SP-D is secreted by alveolar type 2 cells, and CA19-9 and CA125 are secreted by bronchial epithelium. However, SP-D levels remain fairly stable within three months, and rising levels are not related to the risk of death. It is more of a differential diagnosis in whether or not IPF is combined. CA19-9 is significantly higher in progressive patients than in stable patients. It is worth noting that elevated CA125 concentrations for more than 3 months are associated with an increased risk of death in IPF. Relevant studies have included patients with RA and RA-ILD and found that CA125 levels higher than normal reference values ​​(normal <35U / ml) increase the risk of RA combined with ILD.

[0004] The team's previous study found that the levels of serum KL-6, CEA, CA125 and CA153 in the pSS-ILD group were significantly higher than those in the non-ILD group and the healthy control group. Although the current application research of CA125 in pSS-ILD is relatively limited, its possibility as a potential biomarker for pSS-ILD deserves further exploration. Therefore, the present invention aims to evaluate whether serum CA125 can be used as a biomarker for evaluating the poor prognosis of pSS-ILD, and by analyzing its association with the severity of the disease, it is hoped that a new reference basis can be provided for the diagnosis and treatment of pSS-ILD. Summary of the invention

[0005] The technical problem to be solved by the present invention is to address the deficiencies of the above-mentioned prior art and to propose a biomarker for poor prognosis of pSS-ILD, an evaluation method and its application in related products.

[0006] To achieve its purpose, the present invention adopts the following technical solutions:

[0007] A biomarker for poor prognosis of pSS-ILD, wherein the biomarker is serum CA125.

[0008] The method for evaluating biomarkers for poor prognosis of pSS-ILD includes the following steps:

[0009] S1. Establish a cohort of pSS-ILD patients;

[0010] S2. Variable inclusion: Demographic and clinical characteristics were systematically extracted, including age, sex, disease duration, smoking history, symptoms, signs, comorbidities, tumor markers, autoantibody tests, chest HRCT, lung function tests, and oxygenation index;

[0011] S3. Chest HRCT classification and feature scoring: The patients were divided into NF-pSS-ILD group and F-pSS-ILD group according to whether there was fibrosis. The results of each HRCT scan were divided into usual interstitial pneumonia (UIP), fibrotic nonspecific interstitial pneumonia (fNSIP), cellular nonspecific interstitial pneumonia (cNSIP), lymphocytic interstitial pneumonia (LIP), organizing pneumonia (OP) and follicular bronchiolitis (FB). HRCT features including ground-glass opacities, reticular opacities, tractional bronchiectasis, honeycombing and LIP cystic lesions were recorded in detail, and manual scoring was used to quantify the degree of these imaging features.

[0012] S4. Follow-up: Systematic clinical evaluation every 3 to 6 months, or more frequently based on clinical urgency.

[0013] S5. The receiver operating characteristic curve was used to analyze the predictive value of CA125 for death / lung transplantation and determine the optimal cutoff value.

[0014] Preferably, in step S1, after excluding patients with secondary sSS-ILD, patients with the following conditions are excluded from pSS-ILD patients: (1) uncontrolled lung infection; (2) current or past malignant tumors; (3) lack of chest HRCT; (4) diseases such as chronic obstructive pulmonary disease or asthma that can seriously affect the results of pulmonary function tests.

[0015] Preferably, in step S2, a venous blood sample is collected from the patient as a baseline sample when the patient is enrolled.

[0016] Preferably, in step S4, the follow-up plan continues until an adverse outcome occurs or a predetermined endpoint is reached.

[0017] Preferably, in step S5, Cox regression analysis is performed to explore the relationship between serum CA125 level and death / lung transplantation.

[0018] Further preferably, in step S5, the survival rate is calculated using the Kaplan-Meier method, and the survival curves are compared using a log-rank test.

[0019] The present invention also provides an application of a reagent for detecting the expression amount of the biomarker in preparing a product for predicting poor prognosis of pSS-ILD.

[0020] Preferably, the product is a kit.

[0021] Beneficial effects of the present invention: The present invention reveals the potential role of CA125 in pSS-ILD patients, especially its close association with disease severity and poor prognosis. This provides a theoretical basis for CA125 as a biomarker for prognosis assessment of pSS-ILD patients, and also provides a new direction for its application in clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] For ease of explanation, the present invention is described in detail with reference to the following specific embodiments and the accompanying drawings.

[0023] Figure 1 Flowchart for screening of study population.

[0024] Figure 2 The expression diagram of serum CA125 in the death / lung transplantation group (A) and the F-pSS-ILD group (B).

[0025] Figure 3 This is a correlation analysis chart between CA125 levels and disease severity indicators.

[0026] Figure 4 Figure 2 is the ROC curve of four tumor markers.

[0027] Figure 5 This is a survival analysis comparison chart between the groups with serum CA125>35 (U / ml) and ≤35 (U / ml). DETAILED DESCRIPTION

[0028] The following are specific embodiments of the present invention and the accompanying drawings to further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments; in the following description, specific details such as specific configurations and components are provided only to help fully understand the embodiments of the present invention. Therefore, it should be clear to those skilled in the art that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the present invention. In addition, for the sake of clarity and brevity, the description of known functions and structures is omitted.

[0029] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features of the embodiments may be combined with each other.

[0030] A biomarker for poor prognosis of pSS-ILD, wherein the biomarker is serum CA125.

[0031] The method for evaluating biomarkers for poor prognosis of pSS-ILD includes the following steps:

[0032] S1. Establish a pSS-ILD patient cohort and exclude patients with the following conditions among pSS-ILD patients: (1) uncontrolled lung infection; (2) current or past malignancy; (3) lack of chest HRCT; (4) diseases such as chronic obstructive pulmonary disease or asthma that can seriously affect the results of pulmonary function tests.

[0033] S2. Variable inclusion: Demographic and clinical characteristics were systematically extracted, including age, sex, disease duration, smoking history, symptoms, signs, comorbidities, tumor markers, autoantibody tests, chest HRCT, lung function tests, and oxygenation index;

[0034] Autoimmune characteristics: Clinical evaluation of pSS includes evaluation of disease-characteristic symptoms, including Raynaud's phenomenon, rampant teeth, dry mouth, and dry eyes. Diagnostic methods include minor salivary gland biopsy (MSGB), autoimmune serological tests including antinuclear antibody (ANA), anti-Ro / SSA, and anti-La / SSB screening.

[0035] Tumor markers and KL-6: Venous blood samples were collected as baseline samples when patients were enrolled. Serum CA125, CEA, and squamous cell carcinoma antigen (SCC-Ag) levels were measured by immunofluorescence assay using Roche Hitachi Cobas E601 module (Tokyo, Japan). Neuron-specific enolase (NSE) was measured by Murex enzyme-linked chemiluminescence assay (Murex NSE kit, Shenzhen, China). Serum KL-6 levels were measured by ELISA (G1200, Fujirebiocorporation, Tokyo, Japan). The recommended normal ranges of each index are as follows: NSE < 16.30 ng / ml; CEA < 5.00 ng / ml; CA125 < 35.00 U / ml; SCC-Ag ≤ 1.50 ng / ml; KL-6 < 500 U / ml.

[0036] Pulmonary function tests: All included ILD patients underwent PFTs. The tests included forced vital capacity (FVC) and forced expiratory volume in one second (FEV1). In addition, the diffusion capacity for carbon monoxide per breath (DLCO-SB) was measured to assess alveolar gas exchange function and corrected for hemoglobin levels.

[0037] S3. Chest HRCT classification and feature scoring: The patients were divided into NF-pSS-ILD group and F-pSS-ILD group according to whether there was fibrosis. The results of each HRCT scan were divided into usual interstitial pneumonia (UIP), fibrotic nonspecific interstitial pneumonia (fNSIP), cellular nonspecific interstitial pneumonia (cNSIP), lymphocytic interstitial pneumonia (LIP), organizing pneumonia (OP) and follicular bronchiolitis (FB). HRCT features including ground-glass opacities, reticular opacities, tractional bronchiectasis, honeycombing and LIP cystic lesions were recorded in detail, and manual scoring was used to quantify the degree of these imaging features.

[0038] S4. Follow-up: Systematic clinical assessments are performed every 3 to 6 months, or more frequently based on clinical urgency. This follow-up regimen continues until an adverse outcome occurs or the predetermined endpoint is reached, whichever occurs first. A favorable outcome is defined as death or lung transplantation. Follow-up longer than 12 months is defined as having long-term outcomes and is included in the survival analysis.

[0039] S5. The predictive value of CA125 for death / lung transplantation was analyzed by receiver operating characteristic curve to determine the optimal cutoff value. Cox regression analysis was used to explore the relationship between serum CA125 level and death / lung transplantation. The Kaplan-Meier method was used to calculate the survival rate, and the log-rank test was used to compare the survival curves.

[0040] The present invention also provides an application of a reagent for detecting the expression amount of the biomarker in preparing a product for predicting poor prognosis of pSS-ILD, wherein the product is a kit.

[0041] Example 1: A total of 1306 SS-ILD patients were enrolled from two centers of ILD-China, 795 sSS-ILD were excluded, 511 pSS-ILD were initially enrolled, 116 were excluded according to the exclusion criteria, and 395 pSS-ILD patients were finally enrolled, 308 survived, 87 had adverse outcomes, including 4 lung transplants, and 83 died ( Figure 1 ).

[0042] The median age of the patients included in this study was 62.00 (52.00, 69.00) years old, with a higher proportion of females (75.7%), and 17.22% of them had a history of smoking. The median time from the onset of respiratory symptoms to the diagnosis of ILD was 6.00 (2.00, 24.00) months, and the median time from pSS to ILD diagnosis was 0.00 (-6.00, 0.00) months. In terms of diagnostic sequence, pSS was diagnosed before ILD the most (53.16%), followed by simultaneous diagnosis (35.44%), and finally ILD was diagnosed before pSS (11.39%). About half of the patients had cough (53.16%) and dyspnea (50.63%), and the incidence of dry mouth was higher than that of dry eyes (42.78% vs 30.63%). Among clinical symptoms, the incidence of Velcro rales was higher than that of clubbing (41.27% vs 8.10%), and hypertension accounted for the largest proportion of complications (12.91%).

[0043] Compared with the surviving patients, the patients who died / received lung transplantation were older (66 vs 59.5 years, P < 0.001), less likely to be female (66.67% vs 78.25%, P = 0.026), more likely to have a history of smoking (25.29% vs 14.94%, P = 0.024), more likely to have cough (66.67% vs 49.35%, P = 0.004) and dyspnea (65.52% vs 46.43%, P = 0.002), more likely to have dry mouth (54.02% vs 39.61%, P = 0.016), clubbing (17.24% vs 5.52%, P < 0.001) and Velcro rales (63.22% vs 14.94%, P = 0.024). The positive rate of pulmonary hypertension was higher in the two groups (10.34% vs 2.92%, P = 0.008), and there was no significant statistical difference in pulmonary artery pressure measurement. CO -SB (expected %) was lower (all P<0.001), lymphocyte (%) was lower (6% vs 14%, P<0.001), neutrophil (%) was higher (54.50% vs 42.50%, P=0.004), tumor markers (NSE, CEA, CA125, SCC-Ag) levels were higher (all P<0.001), fibrosis type (F-pSS-ILD) accounted for the majority (79.31% vs 41.56%, P<0.001), the corresponding grid and honeycomb proportions, scores and total fibrosis scores were higher (all P<0.001), see Table 1 for details.

[0044] Table 1. Comparison of clinical characteristics of the study population

[0045]

[0046]

[0047]

[0048] Note: Data are expressed as median (interquartile range) or n (%). Nonparametric tests were used for continuous variables and X-ray diffraction analysis was used for categorical variables. 2 Or Fisher's exact test, * indicates P < 0.05, and the difference is statistically significant.

[0049] Abbreviations: NF-pSS-ILD: nonfibrotic primary Sjögren's syndrome-related interstitial lung disease; MSGB: minor salivary gland biopsy; ABG: arterial blood gas; PFTs: pulmonary function tests; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 second; DL CO -SB: single-breath carbon monoxide diffusion capacity of the lung; BALF: bronchoalveolar lavage fluid; NSE: neuron-specific enolase; CEA: carcinoembryonic antigen; CA125: carbohydrate antigen 125; SCC-Ag: squamous cell carcinoma antigen; HRCT: high-resolution CT of the chest; UIP: usual interstitial pneumonia; fNSIP: fibrotic nonspecific interstitial pneumonia; cNSIP: cellular nonspecific interstitial pneumonia; LIP: lymphocytic interstitial pneumonia; OP: organizing pneumonia; FB: follicular bronchiolitis; GGOs: ground-glass opacities.

[0050] As shown in Table 1, the tumor markers in the death / lung transplantation group were all elevated, but only the CA125 level exceeded the normal reference range; we found that the CA125 level in the fibrosis group was significantly higher than that in the non-fibrosis group (P<0.001). Further comparison revealed that the difference in serum CA125 levels between the survival group and the death / lung transplantation group was greater than the difference between the NF-pSS-ILD and F-pSS-ILD groups (both P<0.001). Figure 2 .

[0051] The correlation analysis between CA125 and the indicators of the severity of the patient's condition was performed, such as Figure 3 As shown in the results, CA125 was negatively correlated with FVC (% pred), DLCO (% pred) and oxygenation index, with correlation coefficients r of -0.302, -0.348 and -0.217, respectively. CA125 was positively correlated with the fibrosis score of chest HRCT, with a correlation coefficient r of 0.379. It is considered that serum CA125 can be used as an indicator to assess the severity of disease in patients with pSS-ILD.

[0052] In the above results, the serum CA125 level of patients in the death / lung transplantation group was significantly higher than that of the surviving patients, and its level was related to the severity of the disease. The next step is to analyze and verify whether CA125 can be used as a biomarker to assess the risk of death / lung transplantation in pSS-ILD.

[0053] The ROC curve was used to evaluate the value of serum CA125 level in evaluating adverse prognosis, and the area under the curve (AUC) was 0.764 ( Figure 4 ), the optimal cutoff value was 34.93 (U / ml), the sensitivity and specificity were 0.788 and 0.735 respectively, and considering the clinical applicability, the integer was taken as 35 (U / ml), which was also consistent with the clinical normal reference range of CA125 (<35.00U / ml).

[0054] COX regression analysis was used to evaluate the relationship between serum CA125>35 (U / ml) and death / lung transplantation. As shown in Table 2, when the confounding factors were not adjusted, the HR (95% CI) of serum CA125>35 (U / ml) was 5.38 (3.41-8.48), P<0.001. When adjusting for age, gender, and smoking history, HR (95% CI) was 4.37 (2.73-6.98), P<0.001. When adjusting for age, gender, smoking history, FVC%pred, and DLco-SB%pred, HR (95% CI) was 3.23 (1.98-5.27), P<0.001. When adjusting for age, sex, smoking history, FVC%pred, DLco-SB%pred, traction bronchiectasis, and fibrosis score, HR (95%CI) = 2.48 (1.47-4.19), P < 0.001.

[0055] The median lung transplant-free survival time in the serum CA125>35 (U / ml) group was 51.80 months. The risk of death / lung transplantation in the CA125>35 (U / ml) group was increased compared with the CA125≤35 (U / ml) group (P<0.001)( Figure 5 ).

[0056] In summary, serum CA125>35 (U / ml) is an independent risk factor for death / lung transplantation in patients with pSS-ILD, and has a certain predictive value for death / lung transplantation. Serum CA125 can be considered as a potential biomarker for poor prognosis in patients with pSS-ILD.

[0057] Table 2. COX regression analysis of serum CA125 and death / lung transplantation

[0058]

[0059] Adjusted model 1: adjusted for age, sex, and smoking history

[0060] Adjusted model 2: adjusted for age, sex, smoking history, FVC%pred, DLco SB%pred

[0061] Adjusted model 3: adjusted for age, sex, smoking history, FVC%pred, DLco SB%pred, traction bronchiectasis, and fibrosis score

[0062] The present embodiment analyzes the serum CA125 expression level of pSS-ILD patients, and finds that the CA125 level in death / lung transplantation group obviously increases. And serum CA125 level is closely related to the severity of pSS-ILD, and the best cutoff value is consistent with the clinical normal reference value, which is 35U / ml. By controlling the mixed COX analysis, it is shown that CA125>35U / ml is an independent risk factor for poor prognosis (death or lung transplantation), and further survival analysis shows that the median survival time of CA125>35U / ml group is shorter, and prognosis is worse. These findings provide potential biomarkers for the prognostic assessment of pSS-ILD patients, which help to guide clinical decision-making.

[0063] We observed that serum CA125>35U / ml can predict the occurrence of death / lung transplantation in pSS-ILD patients. Our team conducted a comparative study on 58 ILD patients with combined tumors and 632 ILD patients without tumors in the early stage and found that serum CA125 and CEA levels of ILD patients without tumors increased, and as their levels increased, the risk of suffering from tumors increased. But in this study, about one-third of patients' serum CA125>35U / ml, it is almost impossible to have such a high cancer rate, and to avoid interference, the patients finally included in the analysis were all excluded from combined tumors, and the cause of death was also non-tumor disease. In general, the present embodiment discloses the potential role of CA125 in pSS-ILD patients, especially its close association with disease severity and poor prognosis. This provides a theoretical basis for CA125 as a biomarker for the prognosis assessment of pSS-ILD patients, and also provides a new direction for the application in clinical practice.

[0064] This embodiment is based on a prospective cohort study of the largest number of pSS-ILD patients known, with longitudinal follow-up outcomes. CA125 is a common clinical-grade test, widely used in laboratories around the world, and the normal reference range is relatively uniform. And relative to other biomarkers such as KL-6, the detection cost of CA125 is cheaper. In addition, elevated CA125 levels are associated with severe diseases, which suggests that it may have the potential to be a therapeutic biomarker.

[0065] Serum CA125 levels were elevated in pSS-ILD patients who died / lung transplanted. Serum CA125 levels and disease severity (oxygenation index, FVC, DL CO -SB, HRCT fibrosis score). Serum CA125>35 (U / ml) is an independent risk factor for death / lung transplantation in patients with pSS-ILD. Serum CA125 can be used as a biomarker to assess the poor prognosis of primary Sjögren's syndrome-related interstitial lung disease.

[0066] Those skilled in the art to which the present application belongs may make various modifications or additions to the specific embodiments described or replace them in a similar manner, but they will not deviate from the inventive concept of the present application or exceed the scope defined by the attached claims.

Claims

1. A biomarker for poor prognosis of pSS-ILD, characterized by: The biomarker is serum CA125.

2. A method for evaluating the poor prognosis of pSS-ILD by biomarkers, characterized in that: The steps include: S1. Establish a cohort of pSS-ILD patients; S2. Variable inclusion: Demographic and clinical characteristics were systematically extracted, including age, sex, disease duration, smoking history, symptoms, signs, comorbidities, tumor markers, autoantibody tests, chest HRCT, lung function tests, and oxygenation index; S3. Chest HRCT classification and feature scoring: The patients were divided into NF-pSS-ILD group and F-pSS-ILD group according to whether there was fibrosis. Each HRCT scan result was divided into usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, cellular nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, organizing pneumonia and follicular bronchiolitis. HRCT features including ground-glass opacities, reticular opacities, tractional bronchiectasis, honeycombing and LIP cystic lesions were recorded in detail, and manual scoring was used to quantify the degree of these imaging features. S4. Follow-up: Systematic clinical evaluation every 3 to 6 months, or more frequently based on clinical urgency. S5. The receiver operating characteristic curve was used to analyze the predictive value of CA125 for death / lung transplantation and determine the optimal cutoff value.

3. The biomarker evaluation method for poor prognosis of pSS-ILD according to claim 2, characterized in that: In step S1, patients with the following conditions were excluded from pSS-ILD patients: (1) uncontrolled lung infection; (2) current or previous malignancy; (3) lack of chest HRCT; (4) diseases such as chronic obstructive pulmonary disease or asthma that could seriously affect the results of pulmonary function tests.

4. The method for evaluating the poor prognosis of pSS-ILD by biomarkers according to claim 2, characterized in that: In step S2, venous blood samples are collected as baseline samples when patients are enrolled.

5. The method for evaluating the poor prognosis of pSS-ILD by biomarkers according to claim 2, characterized in that: In step S4, the follow-up plan continues until an adverse outcome occurs or a predetermined endpoint is reached.

6. The method for evaluating the poor prognosis of pSS-ILD by biomarkers according to claim 2, characterized in that: In step S5, Cox regression analysis explored the relationship between serum CA125 levels and death / lung transplantation.

7. The method for evaluating the poor prognosis of pSS-ILD by biomarkers according to claim 6, characterized in that: In step S5, the Kaplan-Meier method was used to calculate the survival rate, and the log-rank test was used to compare the survival curves.

8. Use of a reagent for detecting the expression of the biomarker according to claim 1 in preparing a product for predicting poor prognosis of pSS-ILD.

9. The use according to claim 8, characterized in that: The product is a test kit.

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