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KR-102962304-B1 - method

KR102962304B1KR 102962304 B1KR102962304 B1KR 102962304B1KR-102962304-B1

Abstract

The present invention provides a method for diagnosing overactive bladder disorder (OAB), said method comprising: A step of measuring the concentration of one or more of adenosine triphosphate (ATP), acetylcholine (ACh), nitric oxide (NO), and interleukin 5 (IL-5) on a sample obtained from a subject; A step of normalizing the above concentration to the creatinine (Cr) concentration in the sample; The method includes the step of standardizing the above-mentioned normalized concentrations and the age of the subject to the following range values: age is 120 years; ATP/Cr is 0.000001; ACh/Cr is 0.1; NO is 20000; IL-5/Cr is 100; Here, the probability of having OAB ( p OAB ) = 1/1 + e - x , where X = one or more of the following values: (a) (-2.688±1.050) + 5.472±2.098 x Subject's age + 1.356±0.559 x Gender (Female=1, Male=0) + (-7.998±40.273) x [IL-5/Cr]; (b) (-2.141±0.966) + 4.506±1.902 x Subject's age + 1.034±0.519 x Gender (Female=1, Male=0) + (-5294.063±9075.456) x [ACh/Cr]; (c) (-2.825±1.072) + 5.964±2.167 x Subject's age + 1.312±0.562 x Gender (Female=1, Male=0) + 17.790±58.762 x [IL-5/Cr] + (-9180.821±12700.057) x [ACh/Cr]; (d) (-2.993±1.197) + 5.580±2.309 x Subject's Age + 1.724±0.719 x Gender (Female=1, Male=0) + 63.571±73.444 x [IL-5/Cr] + (-10908.523±13606.752) x [ACh/Cr] + (-566.991±636.589) x [ATP/Cr]; (e) (-3.090±1.200) + 5.393±2.256 x Subject's age + 1.797±0.717 x Gender (Female=1, Male=0) + 34.767±56.331 x [IL-5/Cr] + (-562.743±629.316) x [ATP/Cr]; or (f) (-2.650±1.067) + 5.516±2.120 x Subject's Age + 1.389±0.583 x Gender (Female=1, Male=0) + (-4.060±45.238) x [IL-5/Cr] + (-1.456±6.833) x [NO/Cr]; Here, a p OAB higher than the threshold indicates that the subject has OAB or is likely to develop it, and a p OAB lower than the threshold means that the subject does not have OAB.

Inventors

  • 영, 존
  • 피로우즈먼드, 세피노우드

Assignees

  • 유니버시티 오브 포츠머스 하이어 에듀케이션 코퍼레이션

Dates

Publication Date
20260508
Application Date
20200128
Priority Date
20190129

Claims (14)

  1. A method for providing an indicator for diagnosing overactive bladder disorder (OAB), wherein the method comprises: A step of measuring the concentration of one or more of adenosine triphosphate (ATP), acetylcholine (ACh), nitric oxide (NO), and interleukin 5 (IL-5) on a urine sample collected from a subject; A step of normalizing the above concentration to the creatinine (Cr) concentration in the urine sample; and The method includes the step of standardizing the above-mentioned normalized concentrations and the age of the subject to the following range values: age is 120 years; ATP/Cr (mol/mg x dl -1 ) is 0.000001; Ach/Cr (mol/mg x dl -1 ) is 0.1; NO/Cr (mol/mg x dl -1 ) is 20000; and IL-5/Cr (pg xml -1 /mg x dl -1 ) is 100; Here, the probability of having OAB ( p OAB ) = 1/(1+e - x ) and X = one or more of the following values: (a) (-2.688±1.050) + 5.472±2.098 x Subject's age + 1.356±0.559 x Gender (Female=1, Male=0) + (-7.998±40.273) x [IL-5/Cr]; (b) (-2.141±0.966) + 4.506±1.902 x Subject's age + 1.034±0.519 x Gender (Female=1, Male=0) + (-5294.063±9075.456) x [ACh/Cr]; (c) (-2.825±1.072) + 5.964±2.167 x Subject's age + 1.312±0.562 x Gender (Female=1, Male=0) + 17.790±58.762 x [IL-5/Cr] + (-9180.821±12700.057) x [ACh/Cr]; (d) (-2.993±1.197) + 5.580±2.309 x Subject's age + 1.724±0.719 x Gender (Female=1, Male=0) + 63.571±73.444 x [IL-5/Cr] + (-10908.523±13606.752) x [ACh/Cr] + (-566.991±636.589) x [ATP/Cr]; (e) (-3.090±1.200) + 5.393±2.256 x Subject's age + 1.797±0.717 x Gender (Female=1, Male=0) + 34.767±56.331 x [IL-5/Cr] + (-562.743±629.316) x [ATP/Cr]; or (f) (-2.650±1.067) + 5.516±2.120 x Subject's Age + 1.389±0.583 x Gender (Female=1, Male=0) + (-4.060±45.238) x [IL-5/Cr] + (-1.456±6.833) x [NO/Cr]; A method in which a p OAB higher than the threshold means that the subject has OAB or is likely to develop it, and a p OAB lower than the threshold means that the subject does not have OAB.
  2. A method according to claim 1, wherein the threshold value of p OAB is 0.5.
  3. A method according to claim 1, wherein the concentration of any one of ATP, ACh, NO, IL-5, or Cr is measured using an antibody-based platform, an RNA aptamer-based platform, or a combination thereof.
  4. The method of claim 1 further comprises the step of providing information for administering a therapeutic agent to a subject diagnosed with OAB.
  5. In paragraph 4, the method wherein the therapeutic agent is an antimuscarinic drug or a β3 adrenergic receptor agonist.
  6. In paragraph 5, The above antimuscarinic drug is a drug selected from one or more of darifenacin, oxybutinin, tolterodine, solifenacin, trospium, flavixate, propiverine, or fesoterodine, or The above β3 adrenergic receptor agonist is mirabegron, method.
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  10. A method for providing information for monitoring the progress of OAB, wherein the method comprises the step of measuring a p OAB value according to any one of claims 1 to 6, and The above p OAB value includes a first p OAB value obtained from a first urine sample and a second p OAB value obtained from a second urine sample, and A method in which the first and second p OAB values are values obtained from first and second urine samples obtained from a subject who has OAB or is suspected of having OAB.
  11. Regarding claim 10, the above first and second urine samples are samples obtained at intervals of at least two weeks, in a method.
  12. A computer system comprising a processing means/processor configured to execute the following command, wherein the command is: Receiving one or more measured concentrations of adenosine triphosphate (ATP), acetylcholine (ACh), nitric oxide (NO), interleukin 5 (IL-5), and creatinine (Cr) on a urine sample taken from a subject; Normalizing the concentrations of ATP, ACh, NO, and IL-5 to the concentration of Cr; The method includes the step of standardizing the above-mentioned normalized concentrations and the age of the subject to the following range values: age is 120 years; ATP/Cr (mol/mg x dl -1 ) is 0.000001; Ach/Cr (mol/mg x dl -1 ) is 0.1; NO/Cr (mol/mg x dl -1 ) is 20000; and IL-5/Cr (pg xml -1 /mg x dl -1 ) is 100; Calculating the value of X according to one or more of the following formulas: (a) X = (-2.688±1.050) + 5.472±2.098 x Subject's age + 1.356±0.559 x Gender (Female=1, Male=0) + (-7.998±40.273) x [IL-5/Cr]; (b) X = (-2.141±0.966) + 4.506±1.902 x Subject's age + 1.034±0.519 x Gender (Female=1, Male=0) + (-5294.063±9075.456) x [ACh/Cr]; (c) X= (-2.825±1.072) + 5.964±2.167 x Subject's Age+ 1.312±0.562 x Gender (Female=1, Male=0) + 17.790±58.762 x [IL-5/Cr] + (-9180.821±12700.057) x [ACh/Cr]; (d) X = (-2.993 ± 1.197) + 5.580 ± 2.309 x Subject's Age + 1.724 ± 0.719 x Gender (Female = 1, Male = 0) + 63.571 ± 73.444 x [IL-5/Cr] + (-10908.523 ± 13606.752) x [ACh/Cr] + (-566.991 ± 636.589) x [ATP/Cr]; (e) X = (-3.090±1.200) + 5.393±2.256 x Subject's Age + 1.797±0.717 x Gender (Female=1, Male=0) + 34.767±56.331 x [IL-5/Cr] + (-562.743±629.316) x [ATP/Cr]; or (f) X=(-2.650±1.067) + 5.516±2.120 x Subject's Age+ 1.389±0.583 x Gender (Female=1, Male=0) + (-4.060±45.238) x [IL-5/Cr] + (-1.456±6.833) x [NO/Cr]; and A computer system, which is an instruction for calculating the probability ( p OAB ) that an object has OAB using X, using the formula p OAB = 1/(1+e - x ).
  13. A computer program stored on a medium comprising instructions that, when executed by a processor/processing means, cause the processor/processing means to perform the following, wherein the instructions are: Receiving one or more measured concentrations of adenosine triphosphate (ATP), acetylcholine (ACh), nitric oxide (NO), interleukin 5 (IL-5), and creatinine (Cr) on a urine sample taken from a subject; Normalizing the concentrations of ATP, ACh, NO, and IL-5 to the concentration of creatinine; The method includes the step of standardizing the above-mentioned normalized concentrations and the age of the subject to the following range values: age is 120 years; ATP/Cr (mol/mg x dl -1 ) is 0.000001; Ach/Cr (mol/mg x dl -1 ) is 0.1; NO/Cr (mol/mg x dl -1 ) is 20000; and IL-5/Cr (pg xml -1 /mg x dl -1 ) is 100; Calculating the value of X according to one or more of the following formulas: (a) X = (-2.688±1.050) + 5.472±2.098 x Subject's age + 1.356±0.559 x Gender (Female=1, Male=0) + (-7.998±40.273) x [IL-5/Cr]; (b) X = (-2.141±0.966) + 4.506±1.902 x Subject's age + 1.034±0.519 x Gender (Female=1, Male=0) + (-5294.063±9075.456) x [ACh/Cr]; (c) X= (-2.825±1.072) + 5.964±2.167 x Subject's Age+ 1.312±0.562 x Gender (Female=1, Male=0) + 17.790±58.762 x [IL-5/Cr] + (-9180.821±12700.057) x [ACh/Cr]; (d) X = (-2.993 ± 1.197) + 5.580 ± 2.309 x Subject's Age + 1.724 ± 0.719 x Gender (Female = 1, Male = 0) + 63.571 ± 73.444 x [IL-5/Cr] + (-10908.523 ± 13606.752) x [ACh/Cr] + (-566.991 ± 636.589) x [ATP/Cr]; (e) X = (-3.090±1.200) + 5.393±2.256 x Subject's Age + 1.797±0.717 x Gender (Female=1, Male=0) + 34.767±56.331 x [IL-5/Cr] + (-562.743±629.316) x [ATP/Cr]; or (f) X=(-2.650±1.067) + 5.516±2.120 x Subject's Age+ 1.389±0.583 x Gender (Female=1, Male=0) + (-4.060±45.238) x [IL-5/Cr] + (-1.456±6.833) x [NO/Cr]; and A computer program that is an instruction to perform the calculation of the probability ( p OAB ) that an object has OAB using X, using the formula p OAB = 1/(1+e -x ).
  14. A computer-readable medium containing a computer program pursuant to Paragraph 13.

Description

method The present invention relates to a method for diagnosing overactive bladder disorder (OAB), as well as a method for treating and monitoring the progression of the disease. Additionally, a computer system and a program are provided. Overactive bladder (OAB) is a symptomatic syndrome accompanied by urinary urgency, urinary frequency, nocturia, and in some cases, urge incontinence. The prevalence of OAB increases with age and affects approximately one in five adults. The nature of urinary symptoms has a significant impact on the physical, mental, social, sexual, and occupational lives of patients. While estimates of the economic burden vary, a recent meta-analysis of U.S. data reported that the annual direct cost per patient ranges from $656 to $860, and the indirect cost exceeds $11,000; the latter is attributed to falls and fractures, comorbidities, and impaired work productivity. These economic estimates are consistent with the forecast that the annual global cost would reach €3.2 trillion in 2018. Given that the urinary symptoms defining OAB are also present in LUT infections, metabolic disorders, and other urinary tract diseases, diagnosis focuses on ruling these conditions first. Therefore, diagnostic guidelines combine the patient's medical history, physical examination, and urinalysis with voiding diaries and questionnaires that score the patient's symptoms, whether essential or recommended. Questionnaire-based diagnosis of OAB faces challenges due to subjectivity and desensitization. There is no consensus regarding the score or degree of annoyance required for a positive diagnosis and the treatment of OAB. Although it is claimed that 'OAB regardless of the presence of urge incontinence is presumed to be detrusor overactivity (DO)' [Abrams et al. 2017], there is evidence to support this. In a study of 843 women with OAB symptoms (mean age 55, range: 22–73), only 54% had detrusor instability, and only 28% of 1,641 women with DO exhibited OAB symptoms [Digesu et al. 2003]. In another study [Hashim and Abrams], 10% of men and 42% of women with urge and urge incontinence did not show urodynamically proven DO, while 31% of men and 56% of women with OAB but without incontinence did not show DO. The diagnosis of OAB encompasses combinations of urgency, urinary frequency, and nocturia, regardless of the presence or absence of urinary incontinence. It lacks a differential means for confirming or even excluding OAB, which can lead to misclassification, particularly when patients are in the early stages of symptom development or when they exhibit less severe, albeit bothersome, urinary symptoms. Therefore, there is an unmet need for non-invasive, highly sensitive, and OAB-specific diagnostic tools. Although treatment for OAB has been observed to have significant effects in improving health-related quality of life, it is found that approximately 76% of those diagnosed with OAB remain untreated, while the frequency of medical treatment increases with age and the presence of comorbidities associated with OAB. Considering the clinical outcomes of polypharmacy in the elderly and the fact that polypharmacy is a significant factor in the early discontinuation of OAB treatment, identifying risk groups for OAB development would enable regular monitoring at an early stage, thereby facilitating early classification and treatment. Summary of the Invention The inventors have identified a combination of biomarkers and confounding factors (age, gender, etc.) that can be analyzed using a novel algorithm to determine the likelihood of a subject having overactive bladder disorder (OAB). In fact, the novel algorithm demonstrates particularly high accuracy in excluding OAB. That is, this algorithm can be used to exclude OAB, thereby reducing or avoiding unnecessary or inappropriate treatments. The advantage of the present invention is that the biomarkers can be obtained non-invasively, which improves the patient experience during diagnosis and can significantly reduce costs associated with diagnosis. Accordingly, in one aspect, the present invention provides a method for diagnosing overactive bladder disorder (OAB), said method comprising: A step of measuring the concentration of one or more of adenosine triphosphate (ATP), acetylcholine (ACh), nitric oxide (NO), and interleukin 5 (IL-5) on a sample obtained from a subject; A step of normalizing the above concentration to the creatinine (Cr) concentration on the sample; and The method includes the step of standardizing the above-mentioned normalized concentrations and the age of the subject to the following range values: age is 120 years; ATP/Cr is 0.000001; ACh/Cr is 0.1; NO is 20000; IL-5/Cr is 100; Here, the probability of having OAB ( pOAB ) = 1/1 + e - x , and X = one or more of the following values: (a) (-2.688±1.050) + 5.472±2.098 x Subject's age + 1.356±0.559 x Gender (Female=1, Male=0) + (-7.998±40.273) x [IL-5/Cr]; (b) (-2.141±0.966) + 4.506±1.902 x Subject's age +